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PRESENTS

AGINGTHE QUEST TO BEAT

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LIFE EXTENSION DIET • LONGEVITY GENES

BIONIC ORGANSWILL YOULIVE TO 120?MOLECULAR FOUNTAINS OF YOUTH

BIONIC ORGANSWILL YOULIVE TO 120?MOLECULAR FOUNTAINS OF YOUTH

LIFE EXTENSION DIET • LONGEVITY GENESCopyright 2000 Scientific American, Inc.

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PRESENTS

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When Life Knows No BoundsMark Fischetti and Gary Stix, issue editorsPostponing death changes the meaning of life.

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Summer 2000 Volume 11 Number 2

introduction

AGINGTHE QUEST TO BEAT

How Long Have You Got? Kathryn BrownTo 120 years old and beyond.Plus: World’s Oldest Creatures

Design for Living Polly ShulmanCentenarians can teach us how to age gracefully.

From Baby Boom to Geezer GlutJ. R. BrandstraderBy 2030 one in five Americans will be a senior.

Social Insecurity The EditorsDon’t count on retiring at age 65.

Living Longer: What Really Works?Robin Marantz HenigScience has yet to do much better than snake oil.Plus: Fountains of Youth

A Radical Proposal Kathryn BrownAt the molecular level, we all rust like the Tin Man of Oz.

The Famine of Youth Gary TaubesWould a starvation diet give you a few more years?Plus: Four Square Snacks a Day

Counting the Lives of a Cell Evelyn StraussThe attempt to turn back the clock for cells in decline.

the battle

against aging

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getting

ever older


Mother Nature’s Menders Mike MayStem cells might build new hearts, livers—even brains.

Spare Parts for Vital Organs David PescovitzMelding advanced materials with cell cultures maydo away with transplants. Plus: The Cryonics Gamble

Of Hyperaging and Methuselah Genes Evelyn StraussThe search is on for genes that lengthen life span—or cut it short.

Promised Land or Purgatory? Catherine JohnsonWhether old age is worth living depends on mental health.Plus: The Dangers of Overmedication and A Right to Die?

Cults of the Undying Compiled by Eugene RaikhelVisions of endless life from Gulliver to cyberpunk.

It Smells of Immortality Steve MirskySocially speaking, long life might stink.

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Preventing Good Brains from Going Bad Mia SchmiedeskampNew hope in the fight against Alzheimer’s and Parkinson’s.Plus: Coping with Alzheimer’s

Stopping Cancer Before It Starts Ken HowardFinding it early may prevent this scourge of the elderly.Plus: Reduce Your Risk of Cancer and Early Cancer Detection

Saving Hearts That Grow Old Delia K. CabeStudying everything from baldness to bacteria is helping tounlock the mysteries of atherosclerosis. Plus: Ticked Off: Anger Can Knock You Dead

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meditations on

quality of life

Scientific American Presents (ISSN 1048-0943), Volume 11, Number 2, Summer 2000, published quarterly by Sci-entific American, Inc., 415 Madison Avenue, New York, NY 10017-1111. Copyright © 2000 by Scientific American,Inc. All rights reserved. No part of this issue may be reproduced by any mechanical, photographic or electronicprocess, or in the form of a phonographic recording, nor may it be stored in a retrieval system, transmitted or oth-erwise copied for public or private use without written permission of the publisher. Periodicals Publication Rate.Postage paid at New York, N.Y., and at additional mailing offices. Canadian BN No. 127387652RT; QST No.Q1015332537. Subscription rates: one year $19.80 (outside U.S. $23.80). To purchase additional quantities: 1 to 9copies: U.S. $5.95 each plus $2.00 per copy for postage and handling (outside U.S. $5.00 P&H); 10 to 49 copies: U.S.$5.35 each, postpaid; 50 copies or more: U.S. $4.75 each, postpaid. Send payment to Scientific American, Dept.SAQ, 415 Madison Avenue, New York, NY 10017-1111. Postmaster: Send address changes to Scientific AmericanPresents, Box 5063, Harlan, IA 51593. Subscription inquiries: U.S. and Canada (800) 333-1199; other (515) 247-7631.

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THE QUEST TO BEAT AGING6 SCIENTIFIC AMERICAN PRESENTS

Once you see the pictures, you never forget. Theyelicit horror, pain and, yes, a gawking fascination.An eight-year-old boy, bald with withering limbs.A nine-year-old girl stooped like a 99-year-oldwoman. They suffer from progeria—prematureaging—and usually meet their death by the timethey reach their early teens.

What’s remarkable, however, is that many of these kids arehappy to be alive. Some have an uncanny emotional maturi-ty; they are cognizant of their genetic death sentence and em-brace the short time they have left. Their example suggeststhat knowledge of one’s own mortality, even at an age whenthe concept is normally unfathomable, can en-dow life with essential meaning.

The possibility of slowing the processes thatcause us to age, and thereby extending the hu-man life span, has been raised by recent scien-tific findings that have simultaneously provokedblistering polemics among ethicists, clergy andgerontologists. What becomes of childhood,youth, the middle years and old age if peopleroutinely live to 150? “Don’t worry, Dad, I’ll goto college when I’m 30 maybe, 40 for sure. Untilthen, I want to drink beer with my friends. Whowants to be a wage slave for 80 years?”

The philosophers maintain that if there is no end to our ex-istence, there is no motivation to fill it, to accomplish, to dogood “before we go.” They might have an argument if lifewere to become infinite, but it won’t. Research targeted to in-creasing average life span isn’t focused on immortality but onstretching it from 76 (in the U.S.) to 100 or even 120. If itsucceeds, we’ll still be inspired to live full lives.

A spate of laboratory experiments has provided clues, atthe cellular level, to the processes of aging. The implicationshave fueled hopes that medical advances will slow our de-

cline, extending longevity well beyond the century mark. Ata minimum, the findings could lead to therapies that counterthe major killers in old age, such as heart disease and cancer.

Gerontologists have a long way to go. First they have tosettle on a good definition of aging. Is senescence a geneticprogram that kicks in once we pass our childbearing yearsand evolution no longer needs us? Or is it a gradual degrad-ing of the body from daily wear and tear? We may be closingin on an answer. But even if we find the mechanisms thatcause aging, that doesn’t mean we will have figured out howto stop it. We know something about how cancer and AIDSwork, but we haven’t knocked them out. With that in mind,

a “cure” for death from old age may be nothingmore than mere fantasy.

Still, researchers have rounded up at least oneor two likely suspects in the war on decrepitude.Oxidizing agents in our bodies, created as wemetabolize food, cause our cells to degrade inthe same way that rust eats away at a car. Newdrugs, some of which may be cousins of the vi-tamins we now gobble down like jelly beans,may combat the effects of these potent chemi-cals. A harshly restrictive diet might also slowour inevitable decline.

If any of these ideas have merit, the ethicists may find long-term job security. What would happen to society if we couldall live to 100, much less 120 and up? Could it accommodatea massive population of old people? What would a “family”mean? Could we ever afford to retire? It’s possible that wecould manage the enormity of the upheavals if longevity creptup over time. After all, the average life span in the U.S. alonehas risen from 47 to 76 since 1900. That’s a 62 percent in-crease, and we’ve dealt with it.

But what if we suddenly found, say, a wonder antioxidantor some other metabolic miracle that would immediately al- W

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BY MARK FISCHETTI AND GARY STIX, ISSUE EDITORS

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THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 7

low the world to live much longer? Mil-lions in the developed world might be ableto pay for the therapy. Could the billionsof poor also do so? Society could rockettoward social and financial convulsions.

That’s why some pragmatic philosopherstake aim at the funding of longevity re-search, which they say steals money thatwould be better spent on improving thequality of life in old age, instead of the quan-tity of years. But research to extend life isexactly where cures may be found for someof the most debilitating ills the elderly face:Alzheimer’s, Parkinson’s, heart disease, liv-er and kidney disease, and cancer, not tomention depression and social isolation.

The ethical arguments are important,but they may be overridden, at least in theshort run, by our instincts for survival. Justask yourself, Do you want to die next year?Probably not. Do you want to die whenyou’re 80? “Well,” you might reason, “per-haps, if I had lived a full life and was nolonger in good health.” But ask a 79-year-old—even a very sick one—if he wants todie “next year,” and studies have shownthat his answer will almost surely be thesame as yours: “No thank you.” Whetherextra decades of life are a thrill or a bore,cheating death is a fundamental humanquest. Just as certain, though, is that if thescience fulfills its promise, the emergingcentenarian society will transform work,family and social institutions in ways wecannot even begin to imagine. ED

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THE FIRST 150-YEAR-OLD PERSON MIGHT BE ALIVE RIGHT NOW

Forget growing old gracefully. For centuries,graying adults have tried all kinds of thingsto live longer: prayers, yogurt, mystical hotsprings—even injections of goat-testicle ex-tracts. Despite it all, the maximum humanlife span hasn’t budged. At best, the statis-tics say, you can hope to reach about 120

years of age—and precious few actually do.But don’t throw out those birthday candles just

yet. Some scientists now say they’re about to trumpFather Time. Working in the lab, biologists have al-ready reared worms, fruit flies, mice and yeast thatlive twice as long as normal, thanks to mutations ina mere handful of genes. Other researchers are peer-ing into the increasing molecular disorder that char-

acterizes aging in humans,from damaged DNA to mis-behaving cells. And physiol-ogists are finding out whysome people do get to cele-brate their 100th birthdays.The oldest-known human,Jeanne Calment of France,recently died at 122, leaving

researchers to marvel at the possibilities of long life.“Who’s to say we couldn’t go 10 or 20 years long-er?” asks Caleb E. Finch, director of neurogerontol-ogy at the University of Southern California.

Given the rate at which America is aging, that’s atimely question. A century ago only 4 percent of theAmerican population was above age 65. Now 13percent is [see “From Baby Boom to Geezer Glut,”on page 22]. One crowd stands out. According tothe U.S. Census Bureau, the number of centenariansdoubled over the past decade and may increasemore than 11-fold by the year 2050. So far our se-niority is mostly attributable to improved publichealth and modern medicine. But antiaging thera-pies may soon add even more candles to the cake,says zoologist Steven N. Austad of the University ofIdaho. “The first 150-year-old person is probablyalive right now,” Austad predicts. Will it be you?

Why We Age

Ancient civilizations blamed the gods for old age. Today many scientists blame evolution, which holds that the swift hand of natural selection

weeds out genes that hinder reproduction. So genet-ic traits that cause disease early in life, before ourchildbearing years, are fairly rare. While we’re young,we’re usually healthy and strong. “Our bodies arelike rented cars,” says demographer S. Jay Olshan-sky of the University of Chicago. “We use them up,and before things start to go dramatically wrong,we pass on our genes to the next generation.”

got?how long

have you

RACONTEUR:Comedian GeorgeBurns lived to 100.When asked if hisdoctor knew he stillsmoked, Burns said,“No ... he’s dead.”

BY KATHRYN BROWN


After our baby-bearing time haspassed, however, our job is done. Evo-lution needs us no more. There are twoprevailing theories about what happensnext. According to the first, developedin the 1950s by British immunologistPeter Medawar of the University of Lon-don, harmful mutations of the humangenome kick into gear during midlife.Because natural selection is no longerlooking out for us, he reasoned, ourbodies fall prey to decline and disease.

Putting a slightly different spin on life,University of Manchester scientist Thom-as B. L. Kirkwood offered the “dispos-able soma” hypothesis in the 1970s. Itsuggests that the more energy you spendbearing babies, the less you have forother metabolic feats, such as defendingagainst mutations that cause the battlesof aging. If you live fast—having a lot ofbabies when young—you tend to dieyounger. Natural selection will gladlymake that swap, says evolutionary biol-ogist Linda Partridge of University Col-lege, London. In recent years scientistshave fleshed out this theory, proposingthat some genes act beneficially early inlife yet negatively later on.

At first glance, both evolutionary im-ages of aging seem impossible to counter.If our golden years really are determinedby mutations or subtle life trade-offs,how can scientists hope to understandaging—much less fight it? The process ofaging could be dominated by perhaps36 genes, although there may be anoth-er 200 that fine-tune it, concedesMichael R. Rose, an evolutionary biol-ogist at the University of California atIrvine. “But that doesn’t mean it’s im-possibly complicated,” he says.

In fact, Rose has already managed toassemble generations of long-lived fruitflies. In a classic experiment publishedin 1991, he collected and hatched eggslaid by middle-aged fruit flies. He thencollected the eggs of these offspring, butonly those laid late in life. On he went,repeating the process, saving only theeggs laid by older and older flies. By do-ing so, Rose was acting as an evolution-ary force: selecting for flies that repro-duced late and lived long. If a speciesconsistently delays reproduction untillater in life, over many generations, thenevolution will select for traits that allowfor longer life, so reproduction has the

best chance to succeed. After 10 gener-ations, Rose’s flies lived twice as long astheir original ancestors. “It’s possible forevolution to reshape patterns of mortal-ity,” Rose concluded.

But demographer Olshansky says weshouldn’t expect to see a similar phe-nomenon at work in humans. It wouldtake huge numbers of older motherswho delayed childbirth—and then doz-ens of generations of women who didthe same—for evolution to even corre-late the trend with longer and healthierlives, if indeed that resulted.

Altered Genes Alter Aging

Some molecular biologists contendthat these evolutionary theories arewrong altogether. They say we are

bombarded with damage from dailylife and genetic malfunctions across ourentire genome, including the reproduc-tive portion. That means that stoppingaging lies in changing our genes. Overthe past few years an increasing numberof researchers have altered animal lifespans by tweaking certain genes. “Evo-lutionary biologists would have neverthought you could change a single geneand double an organism’s life span, es-pecially without decreasing fertility,”says Cynthia J. Kenyon of the Universi-ty of California at San Francisco. “Butthat’s precisely what we’ve done.”

In Kenyon’s laboratory the longevitygene at hand is called daf-2. Wormswith a mutated daf-2 live for a month,twice the norm. Moreover, by tinkeringwith related genes—daf-12, daf-16 anddaf-23—researchers have reared wormsthat live up to four times longer thanthe normal span. Kenyon thinks the dafgenes direct hormones that ratchet upor down a worm’s rate of aging in re-sponse to environmental challenges suchas food supply or temperature. Andworms aren’t the only ones lingering onthe lab bench. Yeast, fruit flies and micehave all eked out far longer lives thannormal with the aid of a little geneticmanipulation [see “Of Hyperaging andMethuselah Genes,” on page 68].

Researchers still debate whether ag-ing is the cumulative result of life’s tinyassaults or a more programmed seriesof events determined at birth. Theydon’t know how all these genes work.

10 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING

getting

ever older

centenarians who made

Charles Greeley Abbot (1872–1973)Determined that the sun’s radiation varies.

Edward E. Kleinschmidt (1876–1977)Teletype inventor.

Madame Chiang Kai-shek (1897–present)Anti-Communist crusader.

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And even if they someday understandthe genetic mechanisms, that doesn’tmean they’ll find a “cure” for aging. Weknow how cancer works, for example,but we haven’t stopped it from com-mencing in people.

At present, we must be content withthe few pieces of the puzzle that arestarting to come together. For instance,at least four of the newfound genes af-fecting the longevity of lab creatures en-code antioxidant enzymes. These chem-icals disarm harmful oxygen molecules,called free radicals, that emerge when-ever cells turn food and oxygen into en-ergy. Like dancers looking for partners,free radicals careen within and betweencells, binding to nearby molecules anddisrupting normal activity. Over time,scientists suggest, this free-radical dam-age adds up, causing tissues and organsto deteriorate with age. This oxidizingof our bodies is often compared to the

oxidizing—rusting—of metal [see “ARadical Proposal,” on page 38].

Lab organisms endowed with certainextra longevity genes seem to fend offdamage from free radicals and similarstresses, such as UV radiation, says sci-entist Thomas E. Johnson of the Uni-versity of Colorado at Boulder. Thatmolecular trick results in longer life. Ifresearchers can reduce free radicals orboost antioxidant defenses in these ani-mals, he adds, they may be able to de-sign drugs to do the same for humans.“I’m confident we’ll find drugs thatstimulate resistance to environmentalstresses and so increase longevity,” saysJohnson, who works with GenoPlex, aDenver company he helped to found.

Not everyone is so confident. Genesthat contribute to the lengthier lives ofcertain lab animals may not explain ag-ing in people at all, argues anatomistLeonard Hayflick of the University ofCalifornia at San Francisco. “Humansare not big flies,” Hayflick says. “To ex-trapolate from flies, mice and yeast to

humans is utter nonsense. There are anincredible number of genes related toaging in humans that don’t even exist inthose organisms.”

Researchers do agree that oxidativedamage is only one possible cause ofaging. According to a recent tally, some300 theories of aging have been pro-posed—and at the very least, severalkey processes are involved. In additionto free radicals, for instance, aimlessglucose (sugar) molecules attach to pro-teins, causing those proteins to link upunnaturally and change function, possi-bly leading to hardened arteries, tough-er skin tissue, cataracts and other evilsof the silver years.

Furthermore, some cells start misbe-having all on their own. After manyyears, somatic (body) cells stop dividing,but some don’t simply die. Many ap-parently switch functions—often for theworse. Biologist Judith Campisi of Law-

rence Berkeley National Laboratory hasfound that cells that give youthful skinits smooth elasticity stop dividing andthen go awry late in life, breaking downthe very same elasticity. “As we start tounderstand how this works, we have thehope of stopping these altered func-tions,” Campisi says. This work goeshand in hand with studies of cancerouscells that won’t stop dividing, as well asstudies of multipurpose stem cells thatcould replace mature cells lost to heartdisease, Parkinson’s disease and other ills.[Studies on cell senescence are detailed in“Counting the Lives of a Cell,” on page50; “Mother Nature’s Menders,” onpage 56, describes stem cell research.]

Your Number Is Up

The biochemical bits of aging may bethe same for everyone, but they cer-tainly add up differently. Your neigh-

bor may have run a marathon at 70,while your landlord was busy havingheart surgery. Your great-aunt was a


Healthy habits now can

add years later.

a difference

Irving Berlin (1888–1989)Composer of American song standards.

Grandma Moses (1860–1961)Folk artist, began painting at 78.

Rose Kennedy (1890–1995)America’s best-known matriarch.

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how we age

BONES: Bone mineral loss begins to outstrip replacementaround age 35; loss speeds up in women at menopause.

MUSCLES: Muscle mass declines; oxygen consumptionduring exercise decreases5 to 10 percent per decade;hand grip strength falls by 45 percent by age 75.

BLOOD VESSELS: Arterialwalls thicken; systolic bloodpressure rises 20 to 25 percent between ages 20 and 75.

PANCREAS: Glucosemetabolism declines

progressively.

HEART: Heart rate duringmaximal exercise falls

by 25 percent between ages 20 and 75.

LUNGS: Maximumbreathing capacity

diminishes by 40 percentbetween ages 20 and 80.

EARS: Ability to hear high-frequency tones may decreasein 20s, low frequencies in 60s;between ages 30 and 80, menlose hearing more than twice as quickly as women.

EYES: Difficulty focusing on close objectsbegins in 40s; ability to see fine detail

decreases in 70s; from age 50,susceptibility to glare increases, and

ability to see in dim light and to detect moving targets decreases.

BRAIN: Memory and reaction timemay begin to decline around age 70.

SOURCE: Baltimore Longitudinal Study of Aging

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AGE GAUGE: Each person’s bodyages in unique ways, but ahypothetical average person canexpect these changes over time.


chess champion, but your grandfathercouldn’t remember his address. Aging isincredibly variable. “Researchers used tobelieve that the older you get, the sickeryou get,” says Harvard Medical Schoolphysician Thomas T. Perls. “That’scompletely wrong.”

To find out what “normal” aging is,researchers with the National Instituteon Aging’s Baltimore Longitudinal Studyof Aging (BLSA) examine the bodies andbrains of volunteers every two years.The longest-running scientific study ofhuman aging in the U.S., the BLSA be-gan in 1958 and now has more than1,100 active participants. The study is asnapshot of healthy aging, and yes, itdoes portray a gradual physical decline.As a senior, you probably won’t see,hear or breathe quite as easily as youonce did. But the study also suggeststhat life’s slings and arrows aren’t alloutside your control. Without exercise,for example, a 30-year-old woman willlose a quarter of her muscle mass by theage of 70. But a few jaunts around thepark or trips to the gym every week canfend off this by-product of aging.

Indeed, Perls says, starting healthyhabits now can add years later on. Doyou smoke? Keep a positive attitude?

Limit red meat? The answers to suchquestions may affect your likely expira-tion date. And if you’d like to calculatethat fateful moment yourself, try the LifeExpectancy Calculator (www.beeson.org/Livingto100/). The tool, presentedin Perls’s 1999 book, co-authored withMargery H. Silver, Living to 100: Les-sons in Living to Your Maximum Po-tential at Any Age, will put a number onyour mortality by analyzing your an-swers to 23 behavior and backgroundquestions. Perls says those of us withaverage genes and healthy habits canexpect to live until about 85.

That’s pretty good—already almosttwice as long as our recent relatives. Since1900 the average life span in the U.S.has jumped from about 47 to about 76years, according to the National Instituteon Aging. It’s not that we’re aging moreslowly. We’re living longer simply be-cause we escape many of the illnessesand events that plagued our ancestors,from death during childbirth to tubercu-losis, largely because of better sanitation,cleaner water supplies and basic medicaladvances such as immunizations. Thereis new light at the end of the tunnel,too: once you creep far enough along, it


taking it

to the limit

Vital humors Energy Heartbeats 1950s

Mammals get about one billionheartbeats. As you near that limit,your heart breaks down.

1920s–1930s

As you use energy, yourcells steadily breakdown. The fasteryou live, thefaster youburn energyand thesooner yourdemise,maintainsthis rate-of-living theory.

19th century

Vital humors control all yourbodily functions. When thesehumors run dry, your time is up.

In the good old days, aging wasn’t viewed as complex.Some scientists reasoned that, like a car with a full tank

of gas, our bodies arrive on earth topped off with some

kind of vital substance. As time passes, our tanks drainand our bodies age. Here are a few of the notorious theo-ries about life’s limits that have emerged in modern times.

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RAPID RISE: By midcentury the Census Bureau predicts the U.S.could be home tonearly 835,000 centenarians, morethan 11 times thenumber today.

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world’s

oldest creatures

Hiding inside rocky crevices 1,800 feet below the PacificOcean, rockfish stubbornly persist well past 100 years,far surpassing their peers. Giant 10-foot-long tube

worms sway in the dark depths of the Gulf of Mexico for upto 250 years. Blanding’s turtles can slosh through Midwest-ern U.S. wetlands for at least 70 years, and certain giant tortoises push 300. Defying even greater odds, somebristlecone pines high in the California and Nevada moun-tains have lived almost 5,000 years!

How do these remarkable creatures do it? Scientists aretrying to find out, hoping to learn more about how nature’sorganisms age and thus how we might lengthen humanlife. “The natural world offers hundreds of lessons in lon-gevity,” says University of Southern California gerontologistCaleb E. Finch.

One lesson: find an environment free of predators. Re-searchers have identified yelloweye and rougheye rockfishas old as 118 and 149 years, respectively, at great oceandepths. They endure partly because many of their preda-tors prefer shallower waters, says Allen H. Andrews, a re-search associate at California State University. Blanding’sturtles may outlive soft-shelled varieties because theirrough, hard exterior deflects the bite of hungry critters, ex-plains ecologist Justin D. Congdon of the Savannah RiverEcology Laboratory in Aiken, S.C.

The record-breaking bristlecone pines have also found asafe haven; they prevail at around 11,500 feet above sea lev-el, too high for the comfort of many insects or competingtrees. One pine at Nevada’s Wheeler Peak was estimated tobe 4,900 years old, based on its annual growth rings, beforeit was cut down in 1964. Amazingly, Finch says, the trees seemto reproduce just as well in their 4,000th year as in earlier days.

For a long time, scientists didn’t bother to study thelongevity of animals and plants. They assumed that mostcreatures would die before their time because of predators,competition, natural disasters, insects or disease. But thatidea is changing. To measure more precisely the effect ofenvironment on aging and longevity, University of Idahobiologist Steven N. Austad turned to an animal that nor-mally lives fast, breeds madly and dies young: the opos-sum. Austad reasoned that opossums living without theevolutionary pressure of many predators—such as owls,coyotes and wolves—would age and breed more slowly,ultimately living longer. About a decade ago he found thatvery situation on Sapelo Island, a scrap of land off the Geor-gia coast. There opossums live up to 50 percent longerthan on the mainland—and actually age more slowlyalong the way, according to Austad’s measurements oftheir tissues over time. Austad is now looking for similarlongevity in island mice, considerably easier creatures tostudy in the lab.

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seems, your chances of dying actually begin to ease. Demog-raphers have found that death rates steadily climb until about85—and then begin to slowly edge back down again. The samephenomenon holds true for some fruit flies, wasps, worms andyeast in studies led by researcher James W. Vaupel of DukeUniversity and the Max Planck Institute for Demographic Re-search in Rostock, Germany. It’s as though we all decline to acertain point, rest, get our second wind and rally back.

And some people really rally. As the number of centenari-ans in the U.S. climbs, scientists hope to learn the secrets oftheir success. Already Perls has a few hints, gathered as headof the New England Centenarian Study, which tracks morethan 450,000 older adults in Massachusetts to see whoreaches 100 and why.

So far 169 centenarians have participated in the study; thereis data on 250 others. They are a motley crew: Some exercise.Some smoke. Some brazenly defy the notion of a healthylifestyle. Nevertheless, almost all have lived free of cancer,and up to a fourth have escaped any form of dementia.

How do they do it? With luck—and a few “genetic boosterrockets,” Perls says. Studying half a dozen families that in-clude 10 or more centenarians, he is closing in on chromo-some regions with genes linked to long life. Isolating the geneswon’t be easy, but drugs to mimic their effects could one dayprevent some deadly diseases of old age. “In the future, wemay be able to look at your genetic profile, determine yourrisk for various diseases, and give you vitaminlike pills to de-lay or prevent those diseases,” Perls forecasts. Blessed withcentenarian-style health, you too may live to well over 100.[“Design for Living,” on page 18, relates more about whatscientists have learned from studying centenarians.]

Whether you will live many years beyond 100, though, re-mains to be seen. No one knows when or how scientists mightextend our life spans. It’s been more than 60 years since re-searchers first discovered that lab animals that consume fewercalories than normal—a regimen known as caloric restriction—tend to live unusually long. But scientists still don’t know howcaloric restriction works or if it can slow aging in humans [see“The Famine of Youth,” on page 44]. There are other dilem-mas as well. Could the U.S. afford legions of elderly people?Would you be alive but ridden with ailments at age 130? At150? “This research raises all kinds of ferocious social andeconomic questions,” University College’s Partridge observes.

We just might find ourselves answering these questions.“People tend to underestimate how fast the aging field ismoving,” claims biologist Leonard P. Guarente of the Mas-sachusetts Institute of Technology. “We’re uncovering themolecular basis of aging. No, we’re not at a point where wecan intervene in humans yet. But we have every reason to behopeful that day will come.”


Kathryn Brown is a writer at Science News.

Further InformationLife Expectancy Calculator can be found at www.beeson. org/Livingto100/ on the World Wide Web.

Why We Age. Steven N. Austad. John Wiley & Sons, 1997.

getting

ever older

Austad’s research underscores the flexibility—or “plas-ticity”—of aging, suggesting that the right environmentcan increase life span. The question now at hand is: Oncepredators and competition are removed, do biologicalprocesses take over and cause aging in animals, eventhose that live a squeaky-clean lifestyle?

For clues, Austad and University of Idaho ecologistDonna J. Holmes are looking skyward. Five years agothey proposed birds as the ideal animal to use in agingstudies. After all, birds are closer to humans, biologicallyspeaking, than are worms or fruit flies, the favorite sub-jects of aging-study labs. They are warm-blooded, like us,so they don’t lapse into periods of dormancy or hiberna-tion, as do fish and turtles. Moreover, some birds live fordecades against all odds.

This is even more remarkable because, to rev up forflight, birds generate extremely high levels of blood sug-ar. The 150 parakeets twittering around a basement labat the University of Idaho have blood sugar levels so highthey should be diabetic. They have elevated tempera-tures and burn energy at feverish rates. Yet they live to20, old for parakeets. These bird traits defy a primary the-ory of aging—that increased metabolism creates higherlevels of oxygen molecules, called free radicals, that oxi-dize cells, damaging tissue in ways normally associatedwith aging. Rather than rapidly growing weak and dying,birds carry on in good health, year after year.

In 1998 Holmes, Austad and their colleagues reportedthat the cells of three bird species—canaries, Europeanstarlings and budgerigars (a.k.a. parakeets)—can endure abattery of oxidative stresses with surprisingly little dam-age. The scientists exposed these bird cells, along with thecells of mice, to baths of hydrogen peroxide, bolts of radi-ation, chambers of oxygen and doses of pesticide. Underthese assaults, the DNA inside the mouse cells often un-raveled, broke or stopped replicating, typical signs of free-radical damage. The bird cells, on the other hand, dividednormally and repaired much of the induced DNA damageright away. “We don’t have any idea yet how the bird cellsare doing it,” Holmes says. “But it appears that birds havespecial enzymes that dispose of free radicals. If free radi-cals are a primary mechanism of aging, then this may ex-plain why these birds live so long.”

If the scientists find the genes responsible for birds’ re-sistance to free-radical damage, they might someday ap-ply them to humans. “Ultimately,” Holmes continues, “it’spossible that gene therapy could transfer a gene from thebird genome to the mammalian genome.” As U.S.C.’sFinch puts it, “We’re in a major discovery phase now.” If re-searchers can understand the endings of other species,we just might learn how to rewrite our own. —K.B.


THE QUEST TO BEAT AGING

de

18 SCIENTIFIC AMERICAN PRESENTS

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Jeanne Calment had the longest memory in humanmemory. As recently as 10 years ago, she recalled atrip she took to Paris where she saw an impressivenew structure going up—the Eiffel Tower. Vincentvan Gogh used to buy paint at her family’s shop inArles, and the artist made a bad impression on youngJeanne: he was ugly, bad-tempered and reeked of al-

cohol, she told reporters years later. At 85 she took up fenc-ing and at 120 gave up smoking—“It was becoming a habit,”she explained. She outlived all her descendants, including hergrandson, a doctor, who died in 1963. Asked at 115 how shesaw her future, she quipped, “Short. Very short.” But shewas wrong: she lived seven more years, dying on August 4,1997, at 122 years, five months and 14 days, the longest veri-fiable life span of any human being. She attributed her longlife variously to olive oil, wine and a sense of humor. “I haveonly one wrinkle,” she said, “and I’m sitting on it.”

Most of us, of course, can never hope for longevity (or hu-mor) to match Calment’s—she’s one in six billion, points outThomas T. Perls, acting chief of gerontology at Beth Israel

Deaconess Medical Center in Bos-ton. But the number of centenar-ians is rising every year. Accord-ing to a July 1999 census report,there are about 72,000 peopleolder than 100 in the U.S., a num-ber expected to reach 834,000within the next 50 years. Even

more important, says Richard M. Suzman, associate directorfor behavioral and social research at the National Instituteon Aging, the rate of disability in all populations, includingthe oldest old, has been dropping since 1982. Demographers,geneticists and medical researchers hope that studyinghealthy people in their 80s, 90s, 100s and beyond—“the super-stars of longevity,” as Perls refers to them—will yield vital cluesto how all of us can live longer, healthier lives.

To Leonard W. Poon, principal investigator of the GeorgiaCentenarian Study, the secret to longevity is that there is nosecret. Poon and his colleagues followed 144 cognitively in-tact, independently living centenarians, whom he calls “thecream of the crop.” Some were compared with groups ofpeople in their 60s and 80s from similar backgrounds; otherswere interviewed and tested every six months for what re-mained of their lives. He believes the most important lesson ofthe study is the qualities that stood out among the oldest old.

For example, few of the centenarians in the study smoked,were obese or drank heavily. They remained active through-out life, ate breakfast regularly, and consumed plenty of vita-min A and carotenoids by eating fruits and vegetables. “Interms of psychology and attitudes, they’ve resolved whateverissues they have, they’re sure of themselves, and they want tohave their way,” Poon says. “They would not take your wordfor anything—they want to find out for themselves. Andthey’re very protective of themselves.” Learning about the di-versity of characteristics that centenarians share, he thinks,“isn’t a bad result, because anyone can find one factor rele-

sign forWHAT CENTENARIANS CAN TEACH US ABOUT HOW TO GROW OLD

FOR THE RECORD BOOKS:Jeanne Calment, whose lifewas the longest ever docu-mented, here contemplatesthe world from the vantagepoint of 121 years, a year be-fore her death in 1997.

BY POLLY SHULMAN

living


vant to their lives, one thing that’s pos-sible to change. The diversity gives allof us hope to be able to live longer.”

Poon, a psychologist by training, con-siders motivation and attitude as impor-tant as genes. But Perls, director of theNew England Centenarian Study and aco-author of Living to 100, believes thereare genes that can guarantee their luckyrecipients a better chance to live a long,

healthy life, and he means to find them.Siblings of centenarians in his study, hepoints out, have a five times greaterchance than average of living to theirearly 90s and a 15 times greater chanceof living to 100. Of course, siblings shareenvironmental factors as well as genes.Could some of these be responsible? “Isit the chicken soup their mom makes?”Perls asks. “No, because their parentsalso live unusually long.”

Along with medical and populationstudies, the New England CentenarianStudy does genetic work with centenar-ians in collaboration with molecular geneticists. The scientists look for lon-gevity genes in families with a high pro-portion of members who live to ex-

treme old age, such as a group of sevensiblings, five of whom passed the 100-year mark. (Calment’s family is anothergood example: her father died at 93,her mother at 86.) People in the pastthought there were tens of thousands ofgenes that had a weak effect on longev-ity, but Perls and his colleagues believethere are probably just a few genes withvery strong effects: “When you see the

kind of clustering [of people] we’re see-ing, mathematically it’s got to be only afew genes—maybe just 10 or so. In onefamily, you may find one or two.” Histeam is very close to finding regions ofchromosomes, he says, that contain suchgenes. Right now they’re checking theirresults. “It’s such a big-deal finding, wewant to make sure we’re correct. Onceyou find a region, you know everyoneand his grandmother is going to be fall-ing all over themselves to find the geneson that region.”

Nir Barzilai, a gerontologist at the Al-bert Einstein College of Medicine whocollaborates with Perls’s group, is look-ing for longevity genes as well. He andhis colleagues study “founder popula-tions”—small, genetically isolated groupsthat gradually expanded to large num-bers, all the while marrying within thecommunity. One collaborator huntsthrough the genes of the Amish; Barzi-lai does the same with Ashkenazi Jews.

The fact that members of such groupsshare large amounts of genetic materialmakes it easier to find relevant genes.The geneticists compare the genes oflong-lived group members with those ofmembers with short or normal-lengthlives. Because these people have so muchgenetic material in common, any genesfound in the long-lived group but not inthe short- or normal-lived group have a

good chance of being the onesthe scientists are looking for.

But once they find them, whatgood will it do the rest of us? Ifwe’re not blessed with luckygenes, should we throw up ourhands and write our wills? Ofcourse not, Barzilai says. Thewhole point is to find out whatfunctions those genes perform,then develop medicines to mimicthem. “If they have to do withoxidation, we’ll try to manipu-late oxidation. If they increaselevels of HDL—that’s the benefi-cial kind of cholesterol—maybewe can increase HDL. Here’s an-other example: I had a 102-year-old who had a very high gradecancer, with a prognosis of twomonths, but she lived with it forfive or six years. Maybe some-thing in her genes protected herfrom this cancer,” Barzilai notes.

If so, understanding how that protec-tion worked could help doctors developcancer-fighting drugs. The genes will alsoshed light on healthy behavior. If cente-narians have genes that keep them slim,the rest of us could try to mimic that bycutting down on the excess calories, asPerls does (his work with the very oldhas inspired him to shed 15 pounds).

Although it’s too soon for genetic re-sults in their study, Barzilai and his teamhave been quizzing their centenariansfor shared characteristics. Like Poon,they’ve found a lot of diversity. “No oneof the centenarians is telling me that hedid anything special to reach that age,”Barzilai says. “Many of them ate whatthey shouldn’t have eaten, or theysmoked. But one thing they seemed tohave in common was some form offlexibility. Many of them had very hardlives. They rolled with punches, got upand continued with a good attitude.”

One tough problem is to separate


WHAT’S HIS SECRET? Artist HarryShapiro, who is 100 years old, is anAshkenazi Jew, a group being studiedin a search for longevity genes.

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cause from effect. Did Barzilai’s andPoon’s centenarians live longer becausethey rolled with the punches, or did 10decades of experience give them the wis-dom to accept experiences that wouldhave thrown them for a loop in theiryouth? Centenarian researchers wouldlike to go back in time and interviewtheir subjects at 20, 50, 80—but ofcourse, they can’t.

Butterfat for Couch Potatoes

Poon’s centenarians got plenty of vi-tamin A and ate breakfast regularly.Well and good; Mom, your doctor

and your cereal box would approve.But they also drank more whole milkand were less likely to avoid cholesterolthan the 60- and 80-year-olds in thestudy. Is butterfat good for you? Or didthey have genes that protected themfrom its deleterious effects, as Perls be-lieves? “The centenarians in our studydon’t have a history of exercise, but therest of us can’t get away with this,” hesays. And what about Calment’s ciga-rette habit? Do genes make smoking safefor some of us but deadly for others?

Such questions are important not onlyon an individual level but also demo-graphically. Understanding and predict-ing changes in the general populationand the health statistics of older peoplewill be increasingly important to poli-cymakers and health care providers aswell as to aspiring centenarians.

The demographics of the oldest pop-ulations may yield some surprises. Astudy conducted at Odense Universityin Denmark, analyzing mortality datafrom 13 European countries and Japan,showed that after age 97 a person’schance of dying at a given age slowedfrom the expected exponential growthtrend. Indeed, many diseases strike pre-ferentially at earlier ages. Rates of manycancers decline after 85, as does thechance of developing Alzheimer’s dis-ease, particularly for the 25 percent ofAmericans who have at least one copyof a gene type predisposing them to it.

On the other hand, the incidence ofother major diseases increases with age.And the very old, whose immune sys-tems have weakened with age, are moresusceptible to some common infectiousdiseases, such as pneumonia and flu. In

fact, for most of the el-derly population, Suz-man argues, mortalitygoes up, and the preva-lence of disability andchronic diseases alsoincreases with each ad-ditional year of age, al-though the rate of in-crease does seem toslow down sometimepast 90.

One factor that shedsboth light and confu-sion on the question ofwhat the oldest Ameri-cans will be like in up-coming decades is thecohort effect. Groupsborn in different de-cades have very differ-ent patterns of mor-tality and survival, Suz-man says, which canbe difficult to tease out.For example, levels of education thatAmericans attain have been rising withevery generation. Increased educationimproves their life and health expectan-cy—although why is a big mystery. Partof the explanation is that education af-fects income level, which affects health.

Education may also encourage peopleto adopt healthier lifestyles. More high-ly educated people may end up in jobsthat are less stressful, or education mayallow people to deal better with the rig-ors of stress. “It may have an impact onthe brain, and the brain may turn outto be the major arbiter of survival, rath-er than the coronary artery,” Suzmanobserves. And education is only one ofdozens of factors that vary dramaticallyfrom one decade to another, includingnutrition, smoking, sun exposure andexercise.

How much, for example, does medi-cal care affect mortality? “Oddly, that’snever been effectively measured,” Suz-man says. Medical intervention willhave an increasing impact, he believes,sometimes through information pro-duced by medical research, rather thanmedical treatments. Convincing Ameri-cans to get off the couch and shed ex-cess pounds, for instance, could have ahuge impact. So could new methods ofdisseminating information, such as the

Internet. “Life expectancy is the least ofit,” Suzman says. “More important ishealth expectancy.”

Calment notwithstanding, most of ushave genes that will take us to 85 or so,barring physical catastrophe. But ourbehavior can help reduce or eliminatechronic diseases that make the last yearspainful for many. And geneticists areplanning to search the genes of cente-narians for clues not only to killer dis-eases but also to diseases you can livewith but may not want to—things likemacular degeneration, Barzilai says, orhearing loss. “Sans teeth, sans eyes, sanstaste, sans every thing,” moaned Shake-speare, describing the last years of life.Thanks to centenarians, the future maynot need to be like that.


Polly Shulman is a freelance writer inNew York City as well as the great-grand-daughter of a centenarian.

Further Information100 over 100. Jim Heynin and PaulBoyer. Fulcrum Publishing, 1990.

Living to 100: Lessons in Living to Your Maximum Potential at AnyAge. Thomas T. Perls and Margery Hutter Silver, with John F. Lauerman.Basic Books, 1999.

AND THE WINNER IS ...114-year-old Eva Morris of Eng-land, who is currently the oldest person alive, accord-ing to the Guinness Book of Records.

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GOING GRAY:The elderly willmorph from 13percent of theU.S. populationto 20 percentby 2030.

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Want to put a face on the demographics ofaging? Meet Mary Kikukawa Fichter, who’s93. Age has largely silenced this educatedmother of seven, but she still manages asmile when her son, Joe, presides over arousing game of Trivial Pursuit for her andher friends. Mary, who was born in the U.S.

in 1906 of Japanese and Irish parents, lives in a nursinghome in northern New Jersey. Her roommate is a friend of40 years, but Mary can no longer remember her name. Joecalls the place “a bus stop for people waiting to die.” Re-membering his mother’s voice from an earlier time, he talksabout the inevitability of her passing: “I know she’d welcomeit.” Whether Mary’s age is a result of healthful habits, rela-tive wealth or just plain luck, she shares ancestry with the de-mographic group with the longest life expectancy in thecountry—Asian-American women.

Today Mary’s age is exceptional, but her present may be-come the normal future for baby boomers. The millions ofpeople born between 1946 and 1964 now create a bulge inthe U.S. population between ages 36 and 54. In another de-cade the first men and women who hoped they died beforethey got old (to quote rocker Pete Townshend) will turn 65.From that watershed forward, the number of U.S. elderlywill swell from 13 percent of the population to 20 percent by2030. The baby boom will become a geezer glut.

The sheer numbers mean many more people will live to avery old age. But American life expectancy is far from thehighest in the world, ranking 21st globally. According to the

U.S. Census Bureau’s International Programs Center, the lifeexpectancy of a U.S. citizen born in 1996 is 76, a few yearsbehind most European countries, Canada, Israel and Singa-pore. Japan is the champ at 80. “Our infant mortality ratesare somewhat higher than those in northern Europe andJapan,” says Bob Anderson, a senior statistician at the Na-tional Center for Health Statistics. “And that makes a bigdifference.”

Vagaries lie behind some of the numbers. For instance,children in Japan who are born alive but die within a fewhours are counted as fetal deaths, not infant deaths, reducingthe country’s infant mortality figures and thus raising the av-erage life expectancy. Other differences have clear causes;northern Europe’s health care system “doesn’t do quite aswell as our system at the oldest ages,” Anderson explains,“but it does much better at the youngest ages,” improvingoverall life expectancy.

Life expectancy has climbed significantly in the past centu-ry. Census Bureau analyses show that in 1900, the averagelife expectancy across the planet was less than 30 years. By1950 it had climbed to 46. By the late 1990s it was 66. By2050, projections indicate it could be 76. A large part of theincrease has been attributable to safer childbirth for babiesand mothers and declining fertility rates, lowering the inci-dence of infant deaths, which tends to drag down the averagelife expectancy in a population. Simple public health measuressuch as cleaner water, sanitation, antibiotics and basic immu-nizations account for much of the rest, eradicating widespreadkillers such as diphtheria and polio in the developed world

eezerboom to

glut

BY 2030, ONE IN FIVE AMERICANS WILL BE A SENIOR CITIZEN

BY J. R. BRANDSTRADER


ELDER EARTH: The ranks of the oldestold (age 75 and up) varywidely among nationsbut will have increasedsignificantly in manycountries by 2025.

and holding them in check elsewhere. Only in recent timeshas modern medicine significantly lengthened the years peo-ple can expect to live once they reach middle age.

Closing the Gender Gap

Living in a prosperous country is no guarantee you will reach Mary’s age, however. A study called the U.S. Bur-den of Disease and Injury, by the Harvard School of Pub-

lic Health, found a staggering 40-year gap between thelongest-lived Americans—Asian-American women—and theshortest, Native American men. Asian-American women like

Mary are outliving even Japanese women. But Native Amer-ican men in Bennett County, South Dakota, have the life ex-pectancy of a copper miner in AIDS-ravaged Botswana,which has one of the lowest life expectancies on earth.

Don’t let averages raise your hopes or fears too much,though. Plenty of people diverge from the odds. A life ex-pectancy of 76 applies to no real group, not even actual U.S.babies born in 1996. Average life expectancy is a statisticalconcept, not a predictor of how long a particular person willlive. “Life expectancy figures can speak to some general cul-tural trends,” says James Walsh, an expert in actuarial andrisk management and author of True Odds: How Risk Af-fects Your Everyday Life. “They do not speak to whetheryou, who drink half a fifth of gin a day and smoke a pack ofcigarettes, are going to live to 80.”

Nevertheless, mortality statistics tell us that in general,boomer women, unlike their great-great-grandmothers, havea better chance than their guy pals of getting that 100thbirthday party. At the beginning of this century, men outlivedwomen in many countries. As a result of better childbirthmethods, women have caught up, adding more than 30 yearsto their life expectancy during the 20th century. Men haveadded years, too, but the higher rates of smoking and occu-pational hazards among men during most of the 1900sslowed their progress as compared with women. Todaywomen in developed countries outlive men by about sixyears. Men still live longer in a few areas where women’s so-cial status is low and maternal mortality is high.

Interestingly, the gender gap is now closing in the U.S.Men’s life expectancy is rising faster than women’s becauseheart disease has been declining at a faster rate for malesthan females. At the same time, the incidence of lung cancerin females is rising faster than in males. “Women didn’t real-ly start smoking until the 1950s or 1960s,” Anderson says.“They are feeling the effects now, whereas men have already


percent of population over age 75 in 1996

leading causes of death in the U.S.

1900 1997 1. Pneumonia and flu 2. Tuberculosis3. Diarrhea and

intestinal ills 4. Heart disease5. Stroke and

brain lesions6. Kidney inflammation7. Accidents8. Cancer9. Senility

10. Diphtheria

1. Heart disease2. Cancer3. Stroke and

brain lesions4. Lung disease5. Accidents6. Pneumonia and flu7. Diabetes8. Suicide9. Kidney

inflammation10. Liver disease

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had that effect and are beginning to quit.” As women behavemore like men, they die more like men.

Improving life expectancy among U.S. males is also drivingthe nation’s overall life expectancy gains. Life expectancy of a65-year-old male in 1995 was 15.5 years, but it promises toclimb to 20 years in the first half of this century, according tomedian Census Bureau projections. The bureau’s rosiest cal-culations indicate that the life expectancy of some of the laterboomers could hit 25 years by the time they reach 65.

Poverty Hurts

Everything from income and diet to occupation and badhabits can move people off the average curve. Poor, unin-sured people have only minimal health care and succumb

to disease sooner than average. Drug overdoses, alcoholismand suicide are all factors in the early demise of many rockmusicians. Nationwide, the Bureau of Labor Statistics says,highway crashes are the leading cause of on-the-job fatalities.And left-handed people appear to be more prone to prema-ture deaths than righties are.

Although such factors may sound haphazard, they can co-alesce within certain demographic groups. “The classic caseis among black males in the United States,” Walsh says. “Theyhave a lot of really bad life expectancy stressors at the begin-ning of life,” including high child mortality, tuberculosis andhomicide, which are exacerbated by poor medical care, over-crowding and poverty. Young black men die at a rate dispro-portionate to other demographic groups. Ironically, Walshsays, “if a black man lives to 40, his life expectancy can in-crease because he has kind of made it through the early hur-dles.” Anderson notes that one of the reasons people in Swe-den live so long is because the country is economically homo-geneous and has socialized medicine. At 18 percent, Sweden’sproportion of population over 65 is the highest in the world.

All these comparisons and predictions must be taken witha grain of salt, however. The United Nations, which gathersinternational statistics, is the first to point out that globaldata collection can be pretty spotty, especially in regionswracked by disease, war and illiteracy. In the U.S., there aregaps in Census Bureau data, the fount of most national agingnumbers. But these glitches won’t stop demographers fromusing the figures. “The Census’s numbers are statisticallyvalid and well within the range of methodology used in mostdemographic surveys,” Walsh says.

Even if the count were perfect, projections derived from itmight not be. Every prediction includes an assumption thatmay or may not come to pass. What if a new bug appearsand makes short work of us? After all, the AIDS epidemicthreatens to slash life expectancy 10 to 30 years in southernAfrica in the next decade. On the other hand, maybe scien-tists will figure out a way to keep us going until age 150. Ifthey do, perhaps it would be a good move to buy shares ofHasbro; there will be a lot of boomers playing Trivial Pursuitwhile they pass the time at Mary Kikukawa Fichter’s “busstop”—providing a latter-day Joe comes to visit and orga-nizes the game.


J. R. BRANDSTRADER contributes to Barron’s magazine andthe Wall Street Journal Radio Network from New York City.

Further InformationTrue Odds: How Risk Affects Your Everyday Life. JamesWalsh. Silver Lake Publishing, 1996.

The U.S. Census Bureau (www.census.gov) is the source ofU.S. life expectancy data and collects information fromcountries worldwide. Also useful are www.overpopulation.com and the Population Reference Bureau at www.prb.orgon the World Wide Web.

over age 75 in 2025

Less than 2 percent

2–5.9 percent

6–10 percent

More than 10 percent

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PAYDAY: Ida Mae Fullerof Ludlow, Vt., receivedthe first Social Securitycheck in 1940, for$22.54. She had paidonly $22 into the infantsystem. She lived to100 and collected morethan $20,000 beforeher death in 1975.

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YOU’D BETTER SAVE LIKE CRAZY IF YOU WANT TO FUND A 30-YEAR RETIREMENT

For three generations, working Americanshave thought that Social Security wouldallow them to retire at age 65 and enjoythe good life. That dream is now a fantasy.If you want to retire with financial securi-ty, you’d better start saving and investingheavily—now. Because although our cur-

rent Social Security system has done a great job re-ducing elderly poverty and is currently running a$53-billion surplus, it faces a long-term fundingshortfall of trillions of dollars.

Unless the system is overhauled, closing that gapmeans pushing the 12.4 percent payroll tax wayup to 20 percent or more. Or cutting benefits by30 percent. So while you’re upping your savings,remember to exercise more and eat right; you mayneed to work longer than you’ve planned.

Pay as You Go

Debate over how to reform Social Security roseto fever pitch in the late 1990s and is figuringprominently in the 2000 presidential election

campaign. As the number of Americans over age65 climbs from 37 million in 1998 to 64 millionby 2025, the nation will have to grapple with animbalanced Social Security system, rising medicalcosts, health care rationing and age discrimina-tion. The very nature of retirement will change.

The debate is highly emotional because SocialSecurity is a pillar of most Americans’ retirementplanning. It has helped reduce elderly povertyfrom 35 percent of seniors in 1959 to roughly 10

percent in 1998. In that year (the latest with com-plete numbers), Social Security paid out $327 bil-lion to 38 million retirees and survivors. More than60 percent of seniors today receive most of theirretirement income from the system.

Virtually no one quarrels with Social Security’sachievements—or with the values they reflect. Thedebate is over how to sustain them as the aging ofAmerica places a wrenching strain on the system’sfinances.

Social Security was initiated by the Social Secu-rity Act of 1935 as a “pay as you go” system: cur-rent workers lay money on the table, and retireesget benefits from it. When the system is runningsurpluses, as it is today, funds not paid out are“lent” by the Social Security Administration to thegovernment to cover the cost of other programs—everything from aircraft carriers to park rangers.In exchange, the Social Security trust funds arecredited with special, nontradable debt obliga-tions from the Treasury Department. These book-keeping debts of one government unit to anotherare the only trust fund “investments” allowableby law. The funds cannot be invested, for example,in stocks or bonds. “Pay as you go” made sense in1935, because the U.S. economy was in dire straits,and the first priority of the system’s designers wasto bring immediate relief to many people who hadpaid in little or nothing. But as more people retiredover the years, the payroll taxes (or FICA, estab-lished by the Federal Insurance Contributions Act)that support Social Security’s payouts had to beraised dozens of times. FICA was originally set at

ecuritysocial

BY THE EDITORS


1 percent of all income up to $3,000.The most recent major reform, in 1983,set FICA taxes on course to this year’slevel of 12.4 percent. The maximumamount of a worker’s wages that can betaxed—“the cap”—has also risen, to$76,200 in 2000. Given an estimatedpayroll of some $3.7 trillion this year,FICA taxes should produce revenues of$479 billion, more than enough to meetthe needed payout of $409 billion.

The trouble is that Social Security’ssurpluses will evaporate. Even the $887billion in the trust fund will not beenough to meet promised future bene-fits once the huge baby-boomer genera-tion retires. The basic cause of theshortfall resides in the awesome, glacialpressures of demographics. The pay-as-you-go concept was adopted in an eraof large families, rising populations andmoderate life spans. When the retire-ment age was set at 65 in the 1930s,American life expectancy was just over61, ensuring that there would be manyactive workers paying in the funds thatwent out to retirees.

The “support ratio” of workers to re-tirees has been declining steadily as peo-ple live longer, retire earlier and havefewer children. It has fallen from 42 to1 in 1940 to 3 to 1 in 2000 and willdrop to 2.5 to 1 in 2025, when millionsof boomers will have retired and thenation’s age profile will resemble Flo-rida’s today.

By 2014, according to the system’sown trustees, Social Security will betaking in less money from FICA taxesthan it is obliged to pay out—a short-fall of $21 billion a year by 2015, risingto $252 billion by 2030, in inflation-adjusted dollars.

That doesn’t mean Social Securitywill go bankrupt. A pay-as-you-go sys-tem literally can’t do that. Even with noreform, the Social Security Administra-tion has a claim on 12.4 percent of fu-ture U.S. payroll. But from the time itgoes cash-flow negative and beginsdrawing down its trust-fund holdings,the system’s FICA income will cover adwindling part of its obligations to re-tirees. By 2037 the last trust-fund assetswill be exhausted, according to the lat-est estimates.

Without reform, this means less mon-ey for you. If, for example, you are slat-

ed to get $1,000 a month in 2037, planon getting only about $710. The short-fall is nasty, especially for the poor.

Search for a Solution

Proposals for closing Social Securi-ty’s long-term funding gap comemainly from two camps. The “tin-

kerers” want to raise payroll taxes, trimbenefits or adopt some combination ofthe two. A host of policy tweaks havebeen floated in recent years, includinglowering the inflation adjustments nowmade to benefits; requiring several mil-lion state and local workers now ex-empt from Social Security to join thesystem and begin paying FICA taxes;and delaying the age at which fullbenefits can be drawn, from 65 now to67 or even 70, and then indexing thisnumber up as longevity continues torise. Another proposal is to “pop thecap”—that is, eliminate the ceiling onwages for which the 12.4 percent FICAtax must be paid. Or just raise the tax 2percent starting right now.

All these proposals would requiresome pain. Not surprisingly, each oneprovokes furious resistance from well-funded interest groups.

The other camp, the “privatizers,”wants to raise returns by investing someof Social Security’s holdings in stocksand bonds, not just the nonmarketableTreasury Department obligations towhich Social Security’s trust fund isnow limited by law.

Most of the privatizers support thecreation of a national system of individ-ual retirement accounts—like 401(k)s—that would receive some, most or all ofa person’s incoming FICA taxes. Eachcitizen would be given some degree ofchoice over how the money is invested.Although stock markets fluctuate, pri-vatizers argue that over the long haulthey produce significantly higher returnsthan government bonds do. A variantput forward by the Clinton administra-tion would allow Social Security’s trustfund to be invested in “index funds”like the Wilshire 5000, which holdstocks in thousands of U.S. companies,so that the government, not individuals,bears the risks of market fluctuations.

Whichever way the U.S. heads, it willbe playing catch-up. Britain, Canada,


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The advancing baby-boom bulgeis dramatically altering the U.S.age profile, placing a burden onthe Social Security system.

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Sweden, Chile, Mexico, China and doz-ens of other countries have either adoptedor are debating national pension plansthat rely heavily on investments in privatecapital markets. No nation—anywhere—is establishing from scratch a public pen-sion system based on the pay-as-you-goprinciple, and every nation that has sucha structure is facing great fiscal pressure toraise taxes, cut benefits or invest in capitalmarkets to raise returns.

Although the financial considerationsin reforming Social Security are com-plex, the political challenge is even moredaunting. Social Security is ground zerofor bitter ideological and political clashesover values. Bridging these deep emo-tional divides won’t be easy but will benecessary to secure retirement for boom-ers, Gen-Xers and future generations.

Indeed, the debate over how to “fix”Social Security is a harbinger of a chang-ing attitude toward retirement. WithAmerica’s over-65 population projectedto rise to more than 20 percent of thetotal by 2025 and with birth rates de-clining, an early, lengthy retirement—it-self a relatively recent social construct—will soon become lore.

The percentage of 62-year-old menstill working in America fell from 81percent in 1950 to just 51 percent by1985, but it has since begun to tick backup, past 54 percent in 1998. Similarly,half of American men aged 70 held jobsin 1950; this fell to just 16 percent by1985 but is back up to 21 percent. WithSocial Security declining in power, se-niors may have to work longer. And giv-en the improvements in elderly health,they just may be more able—and morewilling—to work than those a genera-tion ago were.

What’s more, with younger workersin short supply, sustaining the Americaneconomy’s extended “boom” will de-pend on more seniors in the workforce.Conveniently, the shift to a service econ-omy means that there are more highlyskilled and less physically demandingjobs for seniors to compete for—or justhang on to. Longer-term, it’s not hardto envision millions of seniors planningto use their mid-60s—following their“first retirement”—to go back to schooland retool before pursuing a second orthird career, whether full- or part-time.Society may well come to see the elder-

ly as an underutilized re-source, and many boomerswill want to keep a hand inthe work of society, maybewell into their 80s.

Perhaps legislation to re-move the “earnings penal-ty” on benefits, which Pres-ident Bill Clinton signed inearly April, will help en-courage more people tostay in the workforce long-er. Under the Senior Citi-zen’s Freedom to Work Act,people between 65 and 70 will no long-er lose $1 of their Social Security bene-fits for every $3 they earn above $17,000a year.

The rising percentage of seniors andtheir high voting rate virtually assurethat politicians will be offering both theelderly and their employers new incen-tives to work longer. That’s somethingof a rosy scenario for well-heeled, well-educated seniors. But further down thefinancial food chain, millions of seniorswho lack private pension coverage orpersonal savings—roughly half the el-derly population—may have to bid forless lucrative “second careers” as check-out clerks or night guards.

What You Can Do

The best thing you can do to shieldyourself against possible futureshortfalls in Social Security is to

step up all forms of savings to cover a“worst case” gap in what the systemwill be able to pay you.

A first step is to visit the Social Secu-rity Web site. There you can request aform for getting a statement of all ofyour past Social Security payments andyour projected monthly benefits, adjust-ed for inflation (see www.ssa.gov/top10.html). Once you have returned the com-pleted form, the administration will sendyou a free report that details every pen-ny you’ve paid in FICA taxes and the

projected monthly benefit you can lookforward to (adjusted for inflation).

These data will give you a sense ofyour worst-case shortfall. As in the ear-lier example, if your inflation-adjustedmonthly payout will be $1,000 a month,you live past the year 2037, and noth-ing is done to improve Social Security’sreturn, you can expect to receive only71 percent of your benefits. So at a min-imum, you should plan now to investenough to provide you with an ad-ditional, inflation-adjusted $290 permonth—indefinitely.

Note, however, that this amount ofsavings and investment will just coveryour Social Security shortfall. Yourmonthly check will not be enough tolive on comfortably. You’ll need to cre-ate further income streams with everyform of personal and pension savingsyou can muster. Social Security benefitswere never intended to cover all thefinancial needs of all retirees. The moneywas, and is, meant to be only a base.


Further InformationOpposing views of how to manage So-cial Security can be found at The Heri-tage Foundation (pro-privatization)at www. heritage.org; and at The Eco-nomic Policy Institute (anti-privatiza-tion) at http://epinet.org on the WorldWide Web.

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3.53.02.52.01.5Workers per Retiree1.00.50.0

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SHORT SUPPORT: The ratioof workers to retirees willdrop sharply in manycountries, forcing reform inpublic pension systemsworldwide.

fewer people to bear the load

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TONIC DREAMS:We have alwayssought fountainsof youth and life-giving nostrums.

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THE ELIXIRS DU JOUR—ANTIOXIDANTS, GENE THERAPY AND AEROBIC

CONDITIONING—HAVE YET TO PROVE THAT THEY DO MUCH BETTER

THAN THE POTIONS AND PATENT MEDICINES OF YESTERYEAR

ANew Yorker cartoon shows two old geez-ers creaking in their rocking chairs on the front porch. “I don’t want to live for-ever,” says the male geezer to the female geezer. “But I damn sure don’t want tobe dead forever, either.” We may notwant to live forever, but how about for

a long, long time? How about for 200 years or 300—two or three times the age that is now consideredthe outer limit of the human life span? A longer spinon this earth is apparently something that appealsto many of us, but as the checkered history of aging“cures” makes clear, it remains an elusive goal.

Advice abounds about how to beat aging, bywhich we usually mean either living to the age of150 or more or staying youthful while living out alife span closer to the biblical threescore and 10.Some of the methods promoted over the yearshave sounded like sorcery: sleep with virgins, drinkthe blood of virile youth, get injections of a concoc-tion derived from the testes of dogs and guineapigs. These techniques have done nothing more

than line the pockets of the people hawking them.Today more temperate sages offer the same ad-

vice our mothers did: eat and drink in moderation,exercise regularly, get enough sleep. All boring, andonly marginally effective. Good health habits canmake you leaner, more aerobically fit and less liableto suffer some of the worst ravages that agingbrings—but they won’t keep you young, and theywon’t make you live much longer than you were ge-netically programmed to live.

The advice that is really getting people excitedthese days sounds much more scientific, derived asit is from what we are learning about how cells age,how that relates to organisms’ aging and how theprocess can be forestalled. But even these tech-niques—hormones, antioxidants, gene therapy, calo-rie restriction—have not been proved conclusivelyto make any difference in how long you will live orhow well you will age.

It’s true that some laboratory animals who havebeen exposed to a few of the latest rejuvenatingcompounds have indeed lived longer—on average,

works?living longer:

what really

BY ROBIN MARANTZ HENIG


from 40 to 100 percent longer whentreated with melatonin or calorie-re-stricted diets. But this does not necessar-ily translate into a human life span thatis 40 to 100 percent longer. As far as ger-ontologists are concerned, people cannotlive beyond the limit of about 120 years,with the occasional exception, such asJeanne Calment, who was 122 yearsold—and had the birth records to proveit—when she died in 1997. You andyour grandchildren, and probably yourgreat-grandchildren, will almost surelydie before you reach that limit. But you,and certainly they, are more likely thanany previous generation to achieve alife span of close to 120 years. In otherwords, scientific progress will enable agreater proportion of the populationthan ever before to live out the humanlife span to its fullest.

Centenarian Tsunami

According to the U.S. Census Bureau,more than 800,000 baby boomers will have celebrated their 100th

year by the middle of this century. Thenearly one million boomers joining theranks of the oldest old will constitute aswell of centenarians so substantial thatthe tradition of congratulating themduring the morning weather report willgo by the wayside. Millions more willreach their 80s and 90s.

But there is no guarantee that the lastdecades of those 100 or so years will be

healthy ones. Today nearly half of allAmericans over age 85 require some sortof help to get through their daily chores.Unless we make great strides in antiag-ing research, the oldest Americans ofthe new century may spend their last 30years in a state of dreadful and debili-tating dependency.

Such a spectacle struck horror in thehearts of the ancient Greeks—eventhough in their day, the average life ex-pectancy was only 18 years. They toldthe story of Tithonus, a handsome youngprince with whom Eos, the goddess ofthe dawn, had fallen in love. Unable tomarry a mortal, Eos asked Zeus to grantTithonus eternal life. He did so, andEos and Tithonus lived happily togeth-er for many years. But Eos had forgot-ten to ask Zeus to grant her lover eter-nal youth as well. So it was Tithonus’sfate to age forever. He grew weaker andsmaller; he shriveled and shrank; helost strength in his limbs and power inhis voice. As he became more and morewizened, his voice reduced to a meresqueak, Eos hid him in a basket. Titho-nus could get no relief from his cease-less aging. Eventually, he turned into agrasshopper, ignored in the basket,chirping away for all eternity.

Longevity research must go hand inhand with research on the effects of ag-ing if the result is to be of any use. Thesestudies focus on adding years to our120-year life span, whereas other anti-aging research tries to slow the progres-

sion of decline within however manyyears we have. Sometimes the same in-tervention seems to do both things; cal-orie restriction, for instance, not onlysignificantly increases the life span oflaboratory animals but also makes themmeasurably more youthful than theircontemporaries at every stage along theway. But one intervention doesn’t nec-essarily have to do with the other. Thetechniques that stave off age-related de-clines are much further along the road toreal-world usefulness than are any meth-ods of helping humans live to be 200.

These methods might not extend themaximum life span, but they do tend toincrease the average life expectancy—that is, the number of years within thatmaximum life span that the averageperson can hope to attain. When lifeexpectancy increases, it is because med-ical science has concocted a way to pre-vent some of the catastrophes responsi-ble for most premature deaths: infec-tions and accidents in the younger agegroups, heart disease and cancer aftermidlife. With the exception of infec-tions, which require medical interven-tion, most of the biggest killers of adultscan be staved off by healthy living.We’ve all heard the advice, if not fromour mothers then from our doctors, ourpartners or our television newscasters:don’t smoke; keep your weight within anormal range; eat plenty of grains, fruitsand vegetables; go easy on the red meatand animal fat; drink alcohol only in


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moderation; get some kind of exercisefor at least half an hour a day; put onsunscreen when you go outdoors; andwear your seatbelt.

By the same logic, a vigorous exerciseprogram would be good, too. But it canhave some real drawbacks for thosewho revel in their laziness. Let’s say, assome gerontologists believe, that a per-son who starts a program of vigorousaerobic exercise at the age of 40—threetimes a week for half an hour at atime—will live two years longer thanshe might have if she had remainedsedentary. Those extra two years arejust about the exact amount of time shespent exercising—not worth it, ulti-mately, for someone who hates jog-ging so much that she’d rather die alittle sooner so that she can live a lit-tle happier.

Methuselah and Beta-carotene

What if there were some easierway toward a longer life,something that did not in-

volve prolonged sacrifice? What iflongevity could be packed into apill? That is the Holy Grail that hasdriven hucksters and con men forcenturies [see box on page 36], andit is the goal of many reputable re-searchers today. We have alwayslooked for the easy way out; whenstudies showed that the healthiestpeople were those who ate the mostfruits and vegetables, American in-dustry promptly packaged the ac-tive ingredients into a more palat-able form, the beta-carotene pill.This proved to be of little health ben-efit, though; whatever it was aboutfruits and vegetables that was keep-ing people healthy was probablynot beta-carotene at all, or at leastnot beta-carotene without the othercomponents of the plant itself.

As distinct from the snake-oil sales-men of old, today’s life extensionistsbase their efforts on solid-sounding

theory. They promote “antioxidant”compounds because of the “free radicaltheory of aging,” which states that ag-ing is a matter of cellular oxidation andcan be slowed if you can prevent thatoxidation. Or they look to hormonalreplacement in anticipation that gettingcertain hormones back to youthful lev-els will lead to youthful functioning. Butit remains to be seen whether any ofthese supplements or hormones reallymake any difference, either in prolong-ing life or in delaying the disabilities ofage. So far whenever a “Methuselahfactor” pill has sounded too good to betrue, it turned out that it was.

Antioxidants, for instance, started

out full of promise for their antiagingpowers, but they still have not provedthemselves in careful clinical trials. Themost familiar antioxidants are vitaminsA,C and E—especially vitamin C, whichthe brilliant chemist Linus Pauling cele-brated in the final decades of his life.(Pauling lived to the ripe old age of 93,attributing his relatively good health tothe megadoses of vitamin C he ingestedevery day.) Their action is thought torelate to what may be a basic underly-ing mechanism of aging: the buildup inthe cell of molecules known as free rad-icals. Free radicals, the inevitable by-product of cell metabolism, are highlyreactive molecules that attach to and re-


MEGADOSE OF HYPE: Nobelist Linus Pauling linked high levels of vitamin C to prevention of cancerand heart disease, a claim that hasnever been substantiated.

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act with structures in the cell and dam-age them. As more and more of theseradicals accumulate, cell functioninggradually slows down [see “A RadicalProposal,” on page 38].

Antioxidants reduce the chances thata free radical will turn into an oxidizingmenace. The theory is provocative, butit has yet to be converted into any kindof substantive antiaging regime. In fact,studies involving beta-carotene haveshown that this powerful antioxidantnot only fails to slow aging or increase

longevity but can even be bad for yourhealth. One study designed to examinebeta-carotene’s protective effect againstlung cancer actually uncovered a higherrate of lung cancer among male smok-ers who took beta-carotene than amongcomparable smokers who took a place-bo. Another found that vitamin E pro-vided no more protection against heartattack or stroke in high-risk patientsthan did either a placebo or a popularmedication for blood pressure.

One new drug promoted for its anti-

oxidant effect—and for its role as oneof the body’s most powerful internalclocks—is melatonin. The main func-tion of this hormone, which is secretedby the pineal gland located in the centerof the brain, is to help us differentiatenight from day.

For this reason, it is not surprising thatmelatonin has proved to be useful fortreating insomnia and jet lag. But claimshave gone far beyond its effects on bio-rhythms. Melatonin is being promotedthese days to prevent diabetes, cataracts,cancer, Alzheimer’s disease, schizophre-nia and epilepsy. It has also been said toextend life span (up to 20 percent, basedon studies on laboratory rodents), treatdepression, prevent sunburn and, of


THE JOYS OF DEEP FAT: Woody Allen as Miles Monroe in the 1973 movieSleeper is revived in the 22nd century into a world that has discovered that“life-preserving foods” include steak, cream pies and deep fat, not the wheatgerm and organic honey sold in his health food store 200 years earlier.

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course, revivify an uninspired sex life.Any single compound that is sup-

posed to do all these things should raisea few eyebrows. It may turn out thatmelatonin does have some beneficialage-retarding and possibly even life-ex-tending effect, but no one has provedthis yet. We would be well advised towait for some rigorously con-ducted studies before puttingtoo much faith in this hor-mone, now sold over thecounter in grocery and healthfood stores as a “natural” di-etary supplement.

Other chemicals in the bodyare, like melatonin, present atsignificantly lower levels in

old people than in young ones. Apply-ing the logic that putting back what hasbeen lost must be rejuvenating, peoplehave been pushing supplements of “an-tiaging hormones” like DHEA, humangrowth hormone, estrogen and testos-terone as the newest and most scien-tific-sounding form of youth-restoringnostrums.

But any one of these in too large a dosecan be dangerous. DHEA, for instance,has been associated with increased risksof breast and prostate cancers, liverproblems, and masculinizing effects inwomen (acne, facial hair, voice changesand a more dangerous profile of bloodlipids). For now, the jury is still out as towhether restoring hormones to a moreyouthful level bears any relation at allto making an older body look, feel oract like a younger one.

Perils of Wheat Germ

The message here is that you shouldenter your local health food storewith extreme caution. From vita-

min E to DHEA, the fickle wisdom ofnutrition lore seems to mutate cease-lessly. In his 1973 movie Sleeper, WoodyAllen spoofed the absurdity of the eter-nal quest for dietary elixirs. A scientist

in the film, which takes place in the lat-ter part of the 22nd century, talks of thehealth foods of the day—steak andcream pies—while expressing astonish-ment that denizens of the late 20th cen-tury consumed such unwholesome fareas wheat germ and organic honey.

The only intervention ever shown to

extend maximum life span reliably, atleast in laboratory animals, is calorierestriction—a strict dietary regimen alsoknown as “undernutrition withoutmalnutrition.” Scientists have used thismethod to extend significantly the lifespans of experimental rodents, insectsand fish. In mice, for instance, limitingfood intake to one-third fewer caloriesthan normal increased a mouse’s maxi-mum expected life span of 39 monthsby more than 40 percent. This wouldtranslate in humans to a maximum lifespan of nearly 170 years [see “TheFamine of Youth,” on page 44].

Not only do calorie-restricted ani-mals tend to live longer, but they tendto look and act younger every step ofthe way. They are leaner and more ac-tive than their fully fed agemates; theirfur loses its pigment more slowly; theyare less likely to develop cancer andother diseases of old age. Even at theage of two and a half—advanced oldage for lab rodents—calorie-restrictedmice tend to look young.

The question now is whether this ap-proach will work in primates, includinghumans. Early results in monkeys ap-pear promising. In the late 1980s ger-ontologists began calorie-restriction stud-ies on 200 rhesus and squirrel monkeys;

preliminary results indicate that with a 30 percent caloric restriction—onceagain, in a diet that emphasizes under-nutrition without malnutrition—mon-keys age more slowly and possibly livelonger. The calorie-restricted monkeyshave measurements of lean body mass,fat, blood pressure, triglycerides and in-

sulin that are typically associated withtheir younger brethren. And their levelsof the hormone DHEA decrease moreslowly than expected.

But even if these monkeys live waybeyond their normal life spans—and wewill not know if they do for anotherdecade or so—it is unclear that this canbe translated into a benefit for humans.And without such assurance, whowould willingly put himself on a diet of1,500 calories a day? One of the fewwho has done so is Roy L. Walford, arespected gerontologist at the Universi-ty of California at Los Angeles, who forthe past 13 years has been limiting hisfood intake to about one third less thanthe rest of us.

In 1991 Walford signed on to thehighly publicized “experiment” knownas Biosphere 2. As the official teamdoctor, he expected that he would becalled on to take care of injuries and in-fections for the other seven “biospheri-ans” who lived together for two yearsin a self-sustaining greenhouse in theArizona desert. But he ended up doingsomething quite different. Because ofproblems in the climate and agricultur-al parts of the experiment, food wasscarce in Biosphere 2, and team mem-bers were restricted to about 1,500 cal-ories a day, made up primarily of veg-etables, beans, grains and fruit (mostlybananas). This was, in essence, the samecalorie-restricted diet Walford had beenfollowing for four years. And here hewas able to measure the effect of such a


Enter your health food store

with extreme caution.

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In the summer of 1889 the highly respected Parisianneurologist Charles-Édouard Brown-Séquard made astunning announcement to the Societé de Biologie. At

the age of 72, he had concocted an emulsion drawnfrom the testicles of dogs and guinea pigs and had in-jected himself with it. He said he felt great—and he livedon, still feeling great, for another five years.

With Brown-Séquard’s self-experiment, claims for“organotherapy” took off, and the testes of all kinds ofanimals—as well as their prostates, ovaries, pancreases,

thyroids and spleens—were cut out and ground up forthe sake of rejuvenating a gullible public.

But that 19th-century craze was only the most scientif-ic-sounding approach in the quest for long life thatdates back to ancient Greece and Rome, when the prac-tice of “gerokomy”—the injunction for old men to sleepbeside young virgins to regain their youthful vigor—waswidely and quite enthusiastically entertained. Proof ofthe value of such a remedy was said to be long-livedHermippus, headmaster of a Roman school for girls whosupposedly lived to the age of 150. The reason? A life-time spent breathing in the air around all those maidens.

Soon special potions were developed that also prom-ised a longer and more fruitful life. During the Tang dy-nasty in seventh-century China, for instance, a “goldenelixir” that took nine months to prepare was said toguarantee immortality. It was made mostly of cinnabar,combined with the red sulfate of mercury, a red salt ofarsenic, potassium and mother-of-pearl. When you drankit, the story went, you turned into a crane, took up resi-dence with the gods and lived forever.

In our own century, there have been dozens of treat-ments that were supposed to make you liveforever. Yogurt was one. Remember the vil-lage of centenarians in the Caucasus Moun-tains of Georgia, the ones who appeared onthe Dannon commercials with their ancientcraggy faces, faded babushkas and cartons ofsupermarket yogurt? It turned out that notonly was the theory of yogurt as an antiagingfood—propounded by Nobel Prize–winnerElie Metchnikoff in the early 1900s—based onthe mistaken assumption that aging wascaused by intestinal toxins, but the villagersweren’t nearly as old as they claimed. Theyjust looked it.

Then there were restorative sea algae; thedried cells of fetal pigs, sheep or rabbits; andGerovital. This last concoction was promotedin the 1970s by Romanian physician Ana As-lan. Aslan herself always looked younger thanher age, and when she died in 1988 she hadreached the respectable age of 91. Her spasand research institute had made her into oneof the richest women in Romania, all from thesales of Gerovital—which turned out to benothing more than simple Novocain, the pain-killer you get in the dentist’s office.

And how about amino guanidine? The drugattracted some attention in the mid-1990s forits ability to clear out the bulky sugar-proteinmolecules called AGEs, which were thought

to age cells in the same way that oxidized free radicalsdo—by clogging cells and preventing them from doingtheir work.

Amino guanidine seems to have fallen off the antiag-ing radar, much the way that deprenyl, bioflavinoidsand centrophenoxene have done. But never fear. Newvariations on old-fashioned snake oil—most of themdressed up in long scientific names ending in “ine” and“oid”—continue to gush through the pipeline. And, ofcourse, they will keep on coming as long as people con-tinue to look for the latest shortcut to the ever elusivefountain of youth. —R.M.H.

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RICH, RED QUACK: Ana Aslan became one of the richest women inCommunist Romania during the 1970s by selling Gerovital, a tonicthat turned out to be nothing more than ordinary Novocain.

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diet on the physiological changes of sev-en young people over the course of twoyears in their confined home.

“It happened just by a freak of chancethat I should be positioned inside, tak-ing care of these people, when the samekind of diet was forced on them,” Wal-ford has said. “So this, then, was an ex-periment of nature.” His findings werethat many of the physiological mea-surements that get worse with age—such as cholesterol, blood pressure andglucose metabolism—improved amongthe calorie-restricted biospherians.

Even if a calorie-restricted diet doesultimately add years to your life, is itworth sticking to, given the fact that itdoubtless subtracts life from your years?Is it worth it to you to spend most ofyour life being vaguely hungry to gainanother 10, 20 or 30 years?

Eating less to live longer may not bethe only strategy to deal with the perilsof aging. A significant stride toward re-newal of fading flesh and organs maycome from a small section at the end of

chromosomes that seems to resemblean internal hourglass, counting off thenumber of times a cell divides until itreaches a kind of molecular old age andthe relentless divisions halt. The telo-mere is a region at each end of the chro-mosome that acts like an aglet, the littlehard tip at the end of a shoelace. Just asthe aglet keeps the shoelace from fray-ing, the telomere keeps the chromosomeintact. But it gets progressively shorterwith each cell division, until it ultimate-ly all but disappears. When that hap-pens, the cell stops dividing—unless it isa cancer cell, which divides and growsin a way that becomes completely outof control [see “Counting the Lives of aCell,” on page 50].

Recently scientists have rejuvenatedold cells by inserting the gene for telo-merase, an enzyme that maintains thelength of telomeres, and thus prevent-ing the aglets from wearing away. Inthe laboratory, cells approaching theend of their natural lifetimes, a mile-stone called the Hayflick limit, begin di-

viding again, in some casescontinuing to multiply indefi-nitely. Scientists still have noidea whether any of these cellu-lar changes will ultimatelytranslate into a longer life spanfor humans, but some re-searchers are optimistic thatmanipulating telomeres mayserve as a treatment for reviv-ing tired tissue.

It might sound like a dreamcome true—a world where no-body ages and where peoplelive for 200 years or more—butsuch a world is still a long wayaway. This is a good thing, ba-sically, because it gives us timeto think about whether this isreally a world we want to livein or whether there’s somethinguseful, in terms of maintainingthe social balance to whichwe’ve become accustomed, inreplacing the older generationat least every 100 years or so.In the meantime, each of uscan do a tiny bit of “life exten-sion” for ourselves if we so de-sire. If you set your alarmclock half an hour earlier everymorning, you’ll be awake for

that much longer each day. At the endof 60 years, you’ll have gained a yearand a quarter of extra conscious mo-ments during which you would other-wise have been asleep—about as manymonths as would be added to the aver-age life span if we eliminated stroke asa cause of death. That is one way, onlypartly facetious, to obtain the grail ofall these other longevity quests: tomake you feel as if you’ve lived eachday allotted you, however many thatmight be, to its absolute maximum.


Robin Marantz Henig is author mostrecently of The Monk in the Garden:The Lost and Found Genius of GregorMendel, the Father of Genetics.

Further InformationHow and Why We Age.Leonard Hayflick. Ballantine Books, 1996.

A Means to an End: The BiologicalBasis of Aging and Death. William R.Clark. Oxford University Press, 1999.

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DIETARY GUINEA PIG: Gerontologist Roy L. Walford was both participant and observerin an informal experiment in calorie restriction—the most promising antiagingapproach—during the two years he spent in the self-sustaining Biosphere 2greenhouse located in the Arizona desert (seen in background).



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THERE MAY BE A WAY TO PREVENT OURSELVES

FROM RUSTING FROM THE INSIDE OUT

BY KATHRYN BROWN

You can drop cigarettes. Avoid alcohol. Butthere’s one toxin you just can’t dodge: oxy-gen. With every gulp of air, oxygen givesyou life. Some of it, however, gets convertedinside your cells into a radical molecule thatcan wreak havoc, degrading those samecells and others. A growing number of sci-

entists say this damage is what causes aging. They alsothink they may one day be able to fend off oxygen’s illeffects and help us live a lot longer.

Scientists have long known that oxygen is capri-cious. As molecules go, it gets around, reacting with allkinds of things. Mostly, that’s good. Oxygen combineswith fats and carbohydrates, in a part of cells knownas the mitochondrion, to churn out the energy thatgets you through the day. But the conversion isn’t per-fect. A small amount of oxygen is regenerated in anasty form called a free radical, or oxidant—the verycritter that causes metal to rust. The oxidants careenabout, binding to and disrupting the membranes, pro-teins, DNA and other cell structures that make yourbody work. Over time, this damage adds up, and theresult just might be an older, frailer you.

According to one estimate, oxidants bombard theDNA inside every one of our cells roughly 10,000 timesa day. Thankfully, most of the assailants are intercept-ed by a small army of antioxidant chemicals. Proteinsalso patch up the damage caused by the radicals that do

get through. “The house is always getting dirty, andwe’re always trying to clean it up,” remarks John Car-ney, chief technical officer at Centaur Pharmaceuticalsin Sunnyvale, Calif., which is developing drugs to fightvarious diseases of aging. But eventually, the theorygoes, our tired cells get less efficient at repelling free rad-icals and mopping up oxidative messes, and the dam-age accumulates. We begin to rust from the inside out.

If oxidants do send us crumbling into old age, thenramping up our biochemical defenses should extendlife. That’s what scientists are finding, at least in the flies,rats, worms and other animals they have under scruti-ny in the laboratory. Whether the techniques they arepursuing will ever lengthen life in humans remains anopen question. But some researchers think they’re get-ting close to an answer. “The key is to really understandhow oxidative damage works, and we’re learning that,”says biochemist Bruce N. Ames of the University ofCalifornia at Berkeley. “I’m convinced life expectancywill get longer a lot faster than anybody thinks.”

The Original Pollutant

Oxygen’s checkered past goes way back—about twobillion years. Around that time, scientists believe,cyanobacteria began releasing more and more

oxygen into the earth’s atmosphere, until many organ-isms were forced to either accommodate the gas or riskbeing degraded by its corrosive nature. Over time, someparticularly oxygen-adept bacteria evolved into mito-chondria, the tiny powerhouses in all human cells thatuse oxygen to help turn food into energy.

The “free radical theory of aging” was first laid out

a radicalproposal

WIZARD OF O2: Water killed the wicked witch in Oz,but oxygen may kill us, oxidizing our cells the way itrusted Dorothy’s pal the Tin Man.


about 45 years ago by Denham Har-man of the University of Nebraska. Theidea won credibility in 1969, when sci-entists identified a key antioxidant, su-peroxide dismutase (SOD), an enzymethat breaks down the harmful superox-ide, a leader among the various freeradicals that can form inside the humanbody. Soon researchers began to realizethat mitochondria created oxidants inhigh amounts. And by now dozens ofexperiments have linked oxidative dam-age and aging.

Until recently, however, that link hadbeen a matter of indirect correlation. Inthe lab, for instance, some young hu-man cells do far better than older cellsat resisting or repairing oxidative dam-age, whether the cells are being dousedwith hydrogen peroxide or stuck insidea chamber filled with pure oxygen. Also,lab flies, worms and mice carrying genet-ic mutations that proffer long life tendto withstand oxidative assaults betterthan their peers. “All these studies sug-gest oxidative damage may be an im-portant part of aging, but they lack thekind of direct experiments to nail thatlink down,” notes John Tower, a mol-ecular biologist at the University ofSouthern California. “The question is,if we actually alter oxidative stress, willit extend life?”

To find out, Tower and his U.S.C. col-league Jingtao Sun recently reared fruitflies with an engineered protein thatcould—when exposed to heat—turn upthe activity of SOD and another antiox-idant, catalase. The flies started life inthe lab normally, along with a controlgroup of flies. Then, on the fifth day, theexperimental flies got pulses of heat,ratcheting up their antioxidant defens-es. The results were striking. Most of theeveryday flies keeled over long beforesix weeks—but those with superchargedSOD, in particular, survived an averageof 48 percent longer. “That’s prettyconvincing evidence that overexpres-sion of SOD extends life,” Tower says.

That’s not the only evidence. Five yearsago William Orr and Rajindar Sohal ofSouthern Methodist University in Dal-las equipped their own flies with extracopies of genes for SOD and catalase.Those flies lingered up to a third longerthan their normal maximum life span—and seemed to age more slowly along


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CELL MEMBRANE In cell metabolism, the mitochondriaconvert glucose and oxygen into en-ergy. Oxygen radicals also form as anormal by-product.

The highly reactive oxygen radical can bind withother molecules, damaging cell proteins andmembranes. The DNA molecules in the mitochondriathemselves are especially susceptible.

CELL MEMBRANE DAMAGE

DNA DAMAGE IN MITOCHONDRION

DNA DAMAGE IN NUCLEUS


the way, exhibiting higher energy, fastermovements and less oxidative damage.Eventually, Sohal says, similar studieswill be done with mammals and then, ifdeemed safe and efficient, with humans.

Intercepting the Interloper

In the meantime, scientists hope topinpoint exactly where oxidants dotheir dirtiest work—and ways to in-

tervene. The idea, says molecular biolo-gist John Phillips of the University ofGuelph in Ontario, is to tailor therapiesto the most important injured cells,rather than trying to fight oxidativedamage throughout the body. Phillipshas one candidate cell in mind: the mo-tor neuron, which directs muscles fromthe brain and spinal cord. People with aparalyzing disease called familial amy-otrophic lateral sclerosis die early, withheavily damaged motor neurons as wellas mutations in SOD. Maybe motorneurons are a critical target of oxidants,kick-starting or dominating the processof aging.

To test that idea, Phillips and his co-workers bred fruit flies with a jolt ofone of the human superoxide dismutasecompounds, SOD1, to be expressed onlyin the flies’ motor neurons. Sure enough,the bugs lived 40 percent longer thannormal. And those extra days were live-ly ones. “We didn’t just delay dying, sothat we had geriatric flies living longer,”Phillips says. “The extended time of lifewas youth.” In contrast, boosting SOD1levels in unrelated muscle cells seems tohave had no effect on the flies’ life span,he adds. Still, questions remain. “Wedon’t really know why these animalsare living longer,” Phillips concedes. Topin down SOD’s relevance, the team isnow spiking different types of neuronswith the antioxidant to see how thevarious cells react.

Another target for protection is themitochondria inside all cells. Becausethese tiny powerhouses are the verysource of harmful oxidants, they’re thefirst cell structures to be clobbered bythe chemicals. In a 1998 study Sohal andhis co-worker Liang-Jun Yan exposedflies to high doses of pure oxygen andthen went looking for signs of oxidantsat work in the flies’ mitochondrial mem-branes. Rather than far-flung havoc, they


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The body‘s antioxidantdefenses limit damageby neutralizing most butnot all free radicals. Forexample, superoxide dismutase (SOD) helpsconvert the oxygen radi-cal superoxide into hydrogen peroxide (alsoharmful), which is thenconverted with the helpof catalase into molecularoxygen and water.

ENERGY

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OXYGEN RADICAL(SUPEROXIDE) WITHUNPAIRED ELECTRON(dark spot)

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found that oxidants targeted severalvulnerable proteins, attaching to theirstrings of DNA, forcing them out ofwork and upsetting the entire cell’s abil-ity to act normally. “Free radical dam-age during aging is not random, caus-ing decline all around our cells,” Sohalsays. “We’re talking about damage that’svery selective, and that may mean agingcomes from specific biochemical losses.”

Proof of this notion would be goodnews, Ames says. “The key thing is tounderstand how aging really works. Ifit’s the decay of mitochondrial DNA,well, we can do things to beef up theseold mitochondria.”

Ames, Tory Hagen of Oregon StateUniversity and their colleagues have donejust that. In preliminary work, theyfound that the liver cells of older rats donot fend off free radicals as well as theliver cells of younger rats do. So last year,over a two-week period, they fed a groupof older rats food laced with lipoic acid,a chemical that the mitochondria canconvert into a potent antioxidant. Afterthis high-powered diet, the older rats’liver cells deflected oxidant intruderswith greater resilience. What’s more, thesenior rats scrambled around with new

spirit and a sleeker look. “I don’t wantto say we’ve gone so far as turning oldrats back into young rats,” Ames says,“but that sure looks like what’s goingon in the mitochondria.” The team hasjust begun a study to see whether theantioxidant-endowed rats actually out-live their lab mates.

Supermarket Solutions

If antioxidants work for flies and rats,what about us? Can you down a dai-ly supplement that will extend your

years? Don’t count on it. “Everybody istalking about popping antioxidant vita-mins,” Phillips groans. “The evidence isstrong that taking moderate amountsof vitamin C and E is not harmful, butthe evidence that it’s actually useful fordelaying aging is very thin.” For onething, researchers say, your body canabsorb only so much of these vitamins;the rest goes the way of other wastes.Also, in the industrial world, most of usget enough of the basic antioxidants inour daily diets. In contrast, lab animalsthat live unusually long with extra anti-oxidants may be deficient in those chem-icals to begin with.

Even if antioxidant supplements doboost your defenses against free radi-cals, it’s tricky to know which ones—orhow much—to take. As with any ingre-dient, too much can be a bad thing. In1996, for instance, two large studiesmade news when researchers discov-ered that beta-carotene supplements—thought to help ward off some types ofcancer—actually increased rates of lungcancer among smokers who were takingthe pills. Some antioxidants hawked inhealth food stores will never do anygood; walk right past those bottles ofSOD, catalase and glutathione peroxi-dase, because these compounds mustbe created inside the body. When swal-lowed, they are simply broken down indigestion and rendered useless, research-ers state.

Still, there are some antioxidants thathold promise, Ames says, such as lipoicacid, which directly protects the mito-chondria. Perhaps, he adds, some of themore obscure antioxidants dry up in thebody as we age, leaving us more vulner-able to oxidative damage. If that’s thecase, downing extra amounts of theseconditional nutrients might slow aging’scellular effects. “We just don’t knowyet,” Ames says.

Indeed, there are a lot of unknowns.What proportion of aging changes incells are the result of oxidative damage?Is there a way to reduce the rate of oxi-dants the body churns out, rather thansimply boosting antioxidants? And whatdo all these long-lived lab mutants real-ly explain about oxidative stress in peo-ple? Sohal worries that some of the mosttouted studies are misleading. For in-stance, biologists have won lots of at-tention by reporting that in worms, sin-gle mutations in a gene called daf-2 candouble life span, partly by resisting ox-idative stress. But this is a “bogus kindof life extension,” charges Sohal, becausethe worms’ metabolism (energy level)plummets during their extra time onearth. “It’s just like going to sleep forthree years and calling those three extrayears of life,” he says. The extra time isakin to hibernation, Sohal adds, so anytherapy based on it would rob peopleof the energy they normally have.

The most basic challenge is under-standing aging itself. Growing old is aslow, subtle process that’s hard to de-


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LONGER YOUTH: Fruit flies bred with a dose of SOD1, an antioxidant en-zyme that breaks down free radicals, lived 40 percent longer than normalfruit flies did in a University of Guelph laboratory. Notably, the phase oflife extended was youth, not old age.

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fine with blood tests or cellular studies.Oxidants can muddy the picture, ob-serves Carney of Centaur Pharmaceuti-cals. After all, these omnipresent mole-cules can strike a cell’s proteins, fats orDNA, all very different beasts. “Under-standing oxidative damage and the bi-ology of aging is a massive undertak-ing,” he points out.

In the short run, Carney says, re-searchers may first unravel the role ofoxidants in specific diseases of aging.Centaur, for instance, is working ondrugs to fight Alzheimer’s and Parkin-son’s diseases. People who suffer fromthese conditions show telltale signs ofoxidative damage in the brain. Eventu-ally these studies may inch scientists clos-er to understanding basic brain changesduring aging. Carney has reason to beoptimistic. Some 10 years ago, while atthe University of Kentucky, he and hiscolleagues were the first to report thathigh levels of a synthetic antioxidant,PBN, can decrease harmful oxidativeproteins in the brains of old gerbils. “Ag-ing may indeed be a treatable process,”Carney maintains.

Self-Imposed Treatment

Some individuals are prescribingtheir own treatments. According toone idea, you can starve yourself,

cutting back on calories until yourmetabolism drops so low that fewer freeradicals are formed in the first place. Amore pleasant alternative, perhaps, ismunching on fruits and vegetables thatare high in antioxidants. Last year neu-roscientist James A. Joseph of TuftsUniversity and his colleagues reportedthat middle-aged rats fed extracts ofspinach, blueberries or strawberries foreight weeks showed marked declines inoxidative stress in their brain cells, aswell as improved memory and coordi-nation. The most successful rats noshedon blueberries—the equivalent of a cupa day for humans.

The research also highlights howmuch scientists have to learn about theprocesses that contribute to aging. Ap-parently, it’s the blend of ingredients in-side blueberries—not just isolated an-tioxidants—that benefited the racy rats.Studying the rats’ brain cells, Joseph wassurprised to find relatively few signs of

increased antioxidants. Instead he founda host of cell changes, from better anti-inflammatory activity to more pliablemembranes—all of which could act to-gether to combat aging changes.

“If you take a supplement, you neverget the benefit of a fruit or vegetablethat contains hundreds of compounds,”Joseph says. Right now researchers can’t

even identify all the compounds, muchless explain how they might work to-gether to fight free radicals. The an-swers could be years in coming. In themeantime, he asks, why not stroll downthe produce aisle? A few berries mightjust offset a little oxidation—or at leastmake the wait for answers to aging thatmuch sweeter.


Kathryn Brown is a writer at Science News in Washington, D.C.

Further InformationThe Free Radical Theory of Aging Matures. Kenneth B. Beckman and BruceN. Ames in Physiological Reviews, Vol. 78, pages 547–581; April 1998.

Extension of Drosophila Lifespan by Overexpression of Human SOD1 inMotor Neurons. Tony L. Parkes et al. in Nature Genetics, Vol. 19, No. 2, pages171–174; June 1998.

Reversals of Age-Related Declines in Neuronal Signal Transduction,Cognitive, and Motor Behavioral Deficits with Blueberry, Spinach orStrawberry Dietary Supplementation. James A. Joseph et al. in Journal ofNeuroscience, Vol. 19, No. 18, pages 8114–8121; September 15, 1999.

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Your best bet for fending off cellular damage from free radicals,scientists say, is to maintain a healthy supply of antioxidantcompounds by eating fruits and vegetables—not by taking a

pill. Here are some foods rich in antioxidants.Fruits: blueberries, cherries, kiwis, pink grapefruit, oranges,

plums, prunes, raisins, raspberries, red grapes, strawberriesVegetables: alfalfa sprouts, beets, broccoli flowers, Brussels

sprouts, corn, eggplant, kale, onions, red bell peppers, spinach



FIGHTING WEIGHT:Michael Cooperhas cut his calorieintake nearly inhalf in his bid tobeat aging.

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SEVERELY RESTRICTING DIET MAY INCREASE LIFE SPAN,

BUT FEW WILL BE ABLE TO FOLLOW SUCH A HARSH REGIMEN

Despite the national propensity for fad di-ets and miracle health cures, despite theubiquitous talk of “eating healthy”—aconcept so mercurial that every decadebrings a new definition—only a single di-etary regime has ever been conclusivelydemonstrated to extend the life span and

improve the health of laboratory animals, let alonehumans. It is known in the scientific lingo as “calo-ric restriction” or “calorie restriction” and less tech-nically as “eating considerably less than you mightnormally prefer”—perhaps 30 to even 50 percentless. In other words, an average-size human on acalorie-restricted diet might consume 1,500 caloriesa day, compared with the 2,100 calories of the typi-cal American. It’s four or five small meals a day, pre-dominantly vegetables and fruits, and a life in whichyou are perpetually cold, painfully thin and constant-ly hungry. Calorie restriction, quite simply, is a Dra-conian diet and a lifelong one at that. “It requires apsychological profile only one person in 1,000 has,”says Richard Miller, associate director for researchat the University of Michigan Geriatrics Center.

Nevertheless, the study of calorie-restricted dietshas lately become a hot-ticket item among longevityand nutrition researchers, who have taken to ex-tolling its virtues with remarkably unrestrained en-

thusiasm. Their reasons are clear—the list of thebeneficial effects of calorie restriction in laboratoryanimals reads like the packaging on a miracle cure.Calorie restriction will, for instance, increase bothaverage and maximum life spans, and the fewer cal-ories consumed, the greater the increase; it will re-duce the occurrence of virtually all age-related dis-eases, including heart disease, diabetes and cancer.It will prevent kidney disease and cataracts as wellas the development of Parkinson’s and Alzheimer’sdiseases. It will lower blood cholesterol and forestallthe age-related deterioration of the immune system.In mice, calorie restriction from an early age raisesthe maximum life span from 39 months to 56 monthsand at the same time preserves what passes for intel-lectual function: a three-year-old calorie-restrictedmouse, for example, can negotiate a maze with thequickness and ease of a normally fed mouse of sixmonths, which is the mouse version of salad days.

This harsh regime has been shown to work its life-extending magic on almost every species that’s everbeen tested—from paramecium and worms to spi-ders, insects, rodents and (although the data are stillpreliminary) primates. The two caveats are that thelater in life the animals start on caloric restriction,the less the benefit, and that the diets must includeplentiful amounts of vitamins and minerals. The an-

youthBY GARY TAUBES

thefamine of


imals must be undernourished withoutbeing malnourished, as calorie-restric-tion researchers say.

All of this, though, leaves researchersstruggling to answer three key questions:What exactly does calorie restriction dophysiologically to extend longevity andfight off disease? Will it have the sameeffect in humans? And, if so, is there away to get the benefits without the ac-tual diet? “The purpose of studying cal-orie restriction,” Miller says, “is not todevelop yet another diet that peoplewon’t follow.” Rather researchers wouldideally like to concoct a pill or potionthat will mimic the effects of calorie re-striction and produce the benefits whileallowing us to eat to our heart’s content.

In the 65 years since Clive M. McKayof Cornell University first noticed thatthe regimen doubled the life span of hislab rats, and in the decade or so sincecalorie restriction moved from the fring-es of longevity research to the main-stream, much of the laboratory workhas been aimed at discerning the funda-mental biology underlying the benefi-cial effects. What researchers generallyagree on is that the response to calorierestriction in organisms seems to be anevolutionary adaptation to periods ofscarcity. As food becomes hard to find,organisms evolve ways to “up-regulate”those defense mechanisms that increaselife span and down-regulate reproduc-tive mechanisms. That would keep the

organisms alive long enough to findfood, and at that point they could goback to reproducing and to a normalaging process, which is exactly whathappens in the laboratory.

The question of how this might workis still open. The leading hypothesis isthat calorie restriction reduces theamount of oxidative damage to thebody. Oxidative damage is the foremosttheory as to what causes the deteriora-tion that comes with age. The concept isknown in the business as the “oxygenparadox”: we require oxygen to turnthe food we eat into cellular fuel, butthe side effects of this oxygen metabo-lism are detrimental to our health. Theprocess takes place in cellular factoriescalled mitochondria, where electronsare stripped from energy-rich substanc-es—in particular, glucose—while con-verting them to the kind of fuel thatcells can use.

The electrons are then captured byoxygen atoms, which join with hydro-gen to form water. But the process isinefficient, and the electrons often goastray, resulting in the formation ofhighly reactive molecules known as freeradicals. Roy L. Walford, a gerontologistat the University of California at LosAngeles and a pioneer of calorie-restric-tion research, refers to free radicals as“great white sharks in the biochemicalsea—short-lived but voracious agents[that] oxidize and damage tissues.”

The oxidation that occurs in the hu-man body is identical to the way inwhich rust is formed in metals, so it isnot unreasonable to say that we will alleventually rust to death if given the op-portunity. The free radicals damage thetissues but also seem to damage the ge-netic material, the DNA, that codes forthe proteins required for the body’sphysiological functions. The primarycandidate for most of this damage isthe mitochondria themselves, which arenot spared by the free radicals they pro-duce. And once damaged, they produceeven more free radicals.

Calorie restriction, by this theory, re-duces the amount of fuel available forcells and the amount of oxygen neededby the mitochondria to convert the ex-isting fuel into energy, and it makes theexisting metabolic process more effic-ient. Not only do the mitochondria gen-


typical meal

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restricted meal

calories: 1,268

calories: 750

sparkling water

8 ounces

salad with lettuce1/5 head apple strudel

1 piece

peas1/2 cup

carrots1 cup

baked potato7 ouncessour cream 1 tablespoon

skim milk 1 cup

dates5 pieces

oat bran muffin1 piece

steamedspinach

1 cup

chickenbreast

3 ounces

bakedpotato7 ounces

french bread2 slicesbutter 1 1/2 tablespoons

beef sirloin6 ounces(before broiling)

From fat: 33%From protein: 22%From carbohydrates: 45%

From fat: 10%From protein: 25%From carbohydrates: 65%


erate fewer damaging free radicals, butthe lack of food also seems to up-regu-late the production of enzymes thatneutralize the free radicals.

In one of the more fascinating experi-ments in the field, Richard Weindruchand Tomas A. Prolla of the Universityof Wisconsin–Madison recently com-pared the expression of genes in youngmice, normally fed aging mice and calo-rie-restricted aging mice. Weindruch,who has been studying calorie restric-tion since he was a U.C.L.A. graduatestudent in the mid-1970s with Walford,believes that the process lowers oxida-tive stress and damage to the mitochon-dria while having its effect predomi-nantly in “critical target tissues” suchas the brain and nerve cells andheart and skeletal muscle. “Allthese tissues depend heavily onmitochondrial energy metab-olism to generate cellularenergy, and all these tissueshave fairly limited repaircapabilities,” he says.

Weindruch and Prolla ex-amined tissues from the calfmuscles of mice and foundthat normally fed aging micewere putting most of their ge-netic effort into repairing genesand proteins damaged by stress,of which a good part is oxidativedamage. The active genes of calorie-restricted mice, on the other hand,were much less involved in genetic re-pair and much more involved inbiosynthesis—building new proteinsand other cellular components—justlike the mice in the prime of their lives.

Most researchers buy the oxidative-damage theory of calorie restriction,but they disagree on two controversialaspects. One is whether calorie restric-tion actually lowers metabolism toachieve its goal, in which case the rele-vance to humans might be lessened—dowe have to go into something akin tohibernation to get the benefits of calorierestriction? The second question iswhether lowering metabolism is the pri-mary route that allows calorie restric-tion to achieve its effect on longevity.

The fact that calorie-restricted rodentshave body temperatures that are con-siderably lower than normal impliesthat the benefits of calorie restriction

come about because the less food eaten,the lower the metabolism and, hence,the lower the oxidative damage. “It’sknown that rodents can decrease theirbody temperature, their metabolic rate,and that [that] is how they survive fam-ine periods,” says Rajindar S. Sohal, abiologist at Southern Methodist Uni-versity. “But mice and rats are not hu-mans. We don’t have that mechanism.”Other researchers, however, disagreewith this interpretation of the evidence,and the argument often comes down toa dispute about how best to measuremetabolism in normally fed versuscalorie-restricted animals. “It’s a dis-tinct oversimplification to say that the

calorie-restriction phe-nomena are merely

due to a declinein metabolic

rate,” Millercomments.

“And many of the changes that occur incalorie-restricted rodents are hard toexplain by the idea that fuel and oxy-gen consumption go down.”

A Shot of Hormones

That there is more going on is sug-gested by the work of James F. Nel-son, a physiologist at the University

of Texas Health Science Center at SanAntonio. Nelson and his colleagues haveshown that calorie restriction subtlyraises the levels of hormones called glu-cocorticoids. These hormones do “prob-ably a zillion different things” in an or-ganism, Nelson says, of which research-ers have nailed down only a few. Theirprimary function is to mobilize glucosefrom the liver to provide fuel to the mus-cles during periods of stress or during aflight-or-fight response. “They also mo-bilize glucose to help you get through a


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LIGHTENING THE LOAD: A restricteddiet may reduce wear and tear onthe body and may delay the slow descent toward death from free radi-cals and other aggressors that weighdown the eater of a normal diet.

BiologicalStress

Compromised Immune System

Increase in Free Radicals

Disordered GeneExpression

Glucose (Sugar)Damage to Tissue

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fasting stage, to keep blood sugar highenough so you can keep going to yournext meal,” he says. These hormones,too, serve to fight inflammation, hint-ing that they play a direct role in thesurvival of the organism. And glucocor-ticoids are only one of a host of hor-mones in laboratory animals that seemto be affected by calorie restriction.

The Human Question

Nelson and his colleagues are cur-rently testing lab animals to findout if the hormonal changes in

calorie-restricted animals are a side ef-fect of calorie restriction or a mecha-nism that directly leads to longevity. Inone experiment, for instance, Nelson’slaboratory is spiking the drinking waterof lab mice with glucocorticoids to de-termine if the mice live longer. “Thenext thing would be to see if any ofthese effects are translatable to hu-mans,” he asserts.

The human question is the big one.The existing data on humans are verythin. Most human populations that areforced to survive on low-calorie dietsare also malnourished and are as like-ly as not to die prematurely from vita-min and mineral deficiencies. The onlyknown exception is on the Japanese is-land of Okinawa, Walford notes: “TheOkinawans have about 70 percent ofthe calorie intake of the rest of Japan.They eat mainly fish and vegetables.They have as much as 40 times the inci-dence of people over 100. They haveless diabetes, tumors and so forth thanthe rest of Japan.”

On the other hand, he adds, therecould be numerous other factors thatcontribute to the Okinawans’ longevity.Doing a controlled trial of calorie-re-stricted humans is impractical for whatDavid B. Allison, an obesity researcherat St. Luke’s-Roosevelt Hospital Centerin New York City, calls “the obviousreasons”: researchers would have to con-vince hundreds or thousands of humansto spend the better part of their lifetimeliving on an extreme diet, without be-ing able to promise them benefits. Andthe trial would, by definition, take thebetter part of a century to complete.

Instead the National Institute on Ag-ing (NIA), in collaboration with Wein-


M ichael Cooper, suffice it to say,is obsessed with the problemof aging and has been since

he was a boy. He recalls looking athis seventh-grade teacher, a bald-ing man in his 50s, and thinking, “Idon’t want to be like him,” and, hesays, “Those thoughts never left mymind.” Now Cooper is 51, a formerelectrical engineer who recentlywent back to school to study biolo-gy at Southern Methodist Universi-ty. Since the mid-1970s he has beenreading voraciously about longevi-ty, nutrition and health. And inFebruary 1986 he began practicingcalorie restriction, hoping to extendhis life well beyond the biblical

three score and 10 years. The 6’2”Cooper has reduced his daily calorieintake from 2,800 to 1,500, and hisweight has dropped over a seven-year period from 160 pounds to afeather-light 120.

Cooper would have gone lower,but he found plenty of reasons toconvince him otherwise. “For onething,” he points out, “if I was anythinner I would probably freeze todeath. I wear long thermal under-

wear year-round in Texas, and I can’tgenerate any body heat. If I sit still, Iget cold even in a warm room. Ihave a little bit of digestive trouble,probably related to consuming toofew calories. And my bones arequite vulnerable. They’re more sen-sitive to sitting. I have to sit on a pil-low. And my feet don’t have anypad on the bottom. So I have to ex-tra-pad my shoes. It’s not a big deal;I get along just fine.”

As for his daily diet, he explains,it’s basically the equivalent of ahandful of snacks a day: “Mostwouldn’t consider it very tasteful,but I like it a lot. In the morning, forinstance, I mix up wheat bran and

solid protein, and I putsome canned pumpkin init, a little bit of spices andoccasionally half a cup ofyogurt. For lunch I havevegetables. For supper Ihave two meals, one atabout 5:00, which is justvegetables, maybe threedifferent kinds. And around7:30 I have what I calldessert, which might beberries mixed up withwhey protein.”

So far Cooper sees littleevidence that his severediet has slowed the agingprocess, and it certainlyhasn’t diminished the un-aesthetic side effects, al-though he remains relent-

lessly optimistic. “My hair is thin-ner,” he notes, “and when you’rethinner you look older. Wrinklesshow up more. On the other hand, ifI weren’t doing this I might alreadybe in decrepit condition. I have noway of knowing. And even if I comedown with a disease like cancer orheart disease and I know I’m going to die, I figure I’ve probablygained a few years by doing whatI’ve done.” —G.T.

four square snacks a day

THE SKINNY ON AGING: Michael Cooperconsumes a 350-calorie lunch that includeswhey protein, brewer’s yeast and broccoli.

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druch and his colleagues, is testing thecalorie-restriction proposition on rhe-sus and squirrel monkeys, assuming thatif it works for any primates, it’s a goodbet it would work for humans. Theynow have some 200 monkeys in the trial,half on a calorie-restricted diet and halfeating normally. Even these monkeys arelikely to live 30 or 40 years, so the studyis a long-term endeavor. But the calorie-restricted monkeys are already showingsigns of unnaturally robust health.

With so little information on whethercalorie restriction will benefit humans,researchers have barely touched on howto mimic its effect without going on adiet that could take the fun out of liv-ing, and certainly out of eating, for al-

most anyone willing to try it. One possi-bility, Allison says, is to give all people,not just the excessively overweight, anti-obesity drugs. This would suppress ap-petite, but a healthy unsatisfied appetitemay be a necessary factor in convincingan organism that famine has arrivedand thus stimulate the beneficial effects.“That this might lengthen life is realspeculation, and it goes far beyond anydata,” Allison observes. “We’ve neverdemonstrated in humans that antiobesi-ty drugs even make the obese live long-er, let alone the average-weight person.”

At the NIA, George S. Roth, Donald K.Ingram and Mark P. Mattson are tryinganother tack—fooling cells into think-ing they’ve been fed when they haven’t.

They’re using a compound called 2-deoxy-D-glucose, which is virtuallyidentical to glucose but lacks two oxy-gen atoms. Once inside the body, it goeswhere glucose would normally go, butit can’t be metabolized by the cells. Thecompound is synthetic, relatively inex-pensive and has been used in researchlaboratories for years. It’s also mildlytoxic in high enough doses, however,which makes it a debatable intervention

for humans even ifit works.

The researchersgave moderate dos-es to rats for sixmonths—not longenough to establishwhether the com-pound increasedlongevity but longenough to see if itmight. With the 2-deoxy-D-glucoseadded to their diet,

the rats continued to eat the sameamount of calories, and yet they lostweight and their body temperaturedropped, as it would have had they beendieting. Their insulin levels also dropped,another hallmark of calorie restriction.This convinced the NIA researchers that2-deoxy-D-glucose was worth testing forthe lifetime of the rats, a study that’s on-going. If the rats do indeed live longer,the NIA researchers will at least haveproved that the mimetic phenomenon,as they call this calorie-restriction mim-icry, has promise. “Then we’ll look forother kinds of compounds that exert thesame effects without any toxicity,” Rothsays. That would mark a big step to-ward the ultimate goal of letting peoplehave their cake and live longer, too.


Gary Taubes is a California-based sci-ence writer.

Further InformationCaloric Restriction and Aging. Rich-ard Weindruch in Scientific American,Vol. 274, No. 1, pages 32–38; January1996.

Roy Walford, the gerontologist who isobserving a calorically restricted diet,maintains a site at www.walford.comon the World Wide Web.

UNCONTROLLEDEXPERIMENT: Oki-nawans, with 70percent of thecalorie intake ofother Japanese,count amongtheir number upto 40 times asmany centenari-ans as their coun-trymen do.

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MOLECULAR GLOWWORMS: Telomeres light up the tips of chromosomes.

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STUDIES OF CLOCKLIKE ELEMENTS IN THE NUCLEUS OF CELLS COULD

LEAD TO A RANGE OF THERAPIES THAT MIGHT BOLSTER THE

IMMUNE SYSTEM, REVERSE HEART DISEASE, EVEN COMBAT CANCER

BY EVELYN STRAUSS

acellB

iologists have always warmed to the no-tion of a cellular alarm clock that wouldmark off the moments of a cell’s life andring when its time to die had arrived. Theexistence of such a molecular timepiecemight suggest ways to slow the ticking oreven rewind the clock and thus give people

lengthened, healthier lives.

Would that biology were so manifestly simple. Mother Nature doesn’t wear aRolex, and scientists have yet to hear a ticking soundinside a cell’s walls. The closest thing that anyonehas found to a cellular clock resides at the tips ofchromosomes in the nucleus of cells. Chromosomeends, stretches of DNA called telomeres, do notcontain genes that program hereditary traits. Butthey do bear some resemblance to a kind of clock ora fuse that sets off a time bomb.

When some human cells are examined in the lab-oratory, their telomeres shorten each time a cell di-vides. As a cell divides more than a set number oftimes, its telomere fuses become too short. At thatpoint, the cell may die, or else a kind of alarm may gooff within it that causes the cell to go into a senes-

cent state, in which itceases multiplying.

Biologists have the-orized that cell senes-cence might have agood side. It could bea defense against can-cer, which is markedby uncontrolled cell

division. Cells that are unable to regrow their telo-meres should stop dividing before they can causetoo much mischief. Yet telomere shrinkage couldconceivably disrupt the repair and replenishment oftissues, making them age. “It’s absolutely clear thatthe aging of many human cells in culture is a telo-mere-dependent process,” states Titia de Lange of theRockefeller University. “The question is how sig-nificant it is for aging of the whole organism.” Doesthe behavior of cells that reside in the test tube have

CAPPING CHROMOSOMES:Telomeres—stretches ofDNA and the proteinsthat bind to them—protect the ends ofchromosomes.

countingthe lives of


anything at all to do with how we age?Scientists have now begun to explore

de Lange’s question. In animal studies,they are examining whether the wear-ing down of the telomere fuse can illu-minate the process of growing old or atleast explain why some organs start todeteriorate. “No one’s ever proved thatshort telomeres cause aging,” acknowl-edges Jerry W. Shay of the University ofTexas Southwestern Medical Center.“The only way to do that is to preventit from happening, and that’s what needsto be done—but there’s already somepretty suggestive evidence.”

Some hallmarks of aging in humans,such as hair loss or skin wrinkling, areeasy to understand as consequences ofcells’ inability to multiply, says de Lange,because the cells that replace hair andrejuvenate skin divide throughout a per-son’s lifetime. Similarly, the immune sys-tem gradually loses its ability to bounceback. Even “nonrenewing” tissue mightreplenish itself. “We know now that even

in brains, you can get new neurons,”says Calvin B. Harley of the biotechnol-ogy firm Geron Corporation. “In everytissue except possibly the heart, cells di-vide. Some divide slowly, but we live along time.”

Age-related deterioration in these andother tissue types could result from cellsrunning out of steam because of telo-mere loss, Harley asserts. At sharp turnsin blood vessels, where turbulent bloodflow wears out tissue and thus requiresrestoration, the telomeres are shorterthan in long, straight stretches.

Walking the Telomere Plank

To explore methodically what telo-meres mean to an intact animal, sci-entists genetically engineered mice

so that they have unusually short telo-meres. At first glance, you might thinkthe animals in these experiments belongin a murine nursing home. They go gray,their hair thins, their skin turns papery,

and they die young. Furthermore, they’reinfertile, presumably because the cellsdestined to become eggs or sperm can’treproduce or survive optimally. Somecells have “walked the telomere plank,”says Ronald A. DePinho of HarvardMedical School. The mice have shorttelomeres, he says, and their stem cellscan’t multiply as many times as they usu-ally do. Stem cells give rise to many celltypes, such as the various componentsof skin.

But the physiology of these micedoesn’t mimic all aspects of aging, De-Pinho cautions. “We don’t see an in-crease in cataracts or osteoporosis” orother pathology typical of old animals.“Telomere attrition does not precipitatea classical premature aging syndrome.But we do believe it influences an abso-lutely critical aspect of getting old—theability of organisms to counteract acuteand chronic stress.”

As individuals age, their organs canstill function adequately, but they re-


the long and the short

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telomerase

a

c

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chromosome

LIKE A CLOCK: Telomeres, the tipsof chromosomes, shorten everytime a cell divides, but the enzymetelomerase restores them so thattheir length stays the same in germcells, such as sperm or eggs (a). Inmature adult cells, such as the fi-broblasts of the skin, the telomereresembles a timer that marks offcell divisions. Telomerase is absentin these cells, so the telomeres con-tinue to contract (b). They do so upto the point when the cell dies orenters a senescent state (c). Whentelomerase is reactivated in the lab-oratory, some normal cells havetheir life extended indefinitely.Such reactivation occurs naturallyin most cancer cells (d ).

cell senescence cell immortality and cancer

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spond poorly when confronted by chem-ical or physical insults. “The differencebetween a young person and an old per-son is a diminished capacity to respondto major environmental stresses,” De-Pinho notes. The mice in his experimentshealed poorly after enduring variousshocks—minor surgery and chemother-apy, for example. “Wound healing re-quires robust proliferative responses,and so does replenishing the blood sup-ply after chemo wipes out white bloodcells,” he explains.

How relevant these results are to hu-mans remains to be seen, however.“Mice are not little people,” DePinhopoints out. Unlike human cells, for in-stance, mouse cells’ telomeres do notgrow shorter, so it is implausible thatmice normally age as a result of thegradual shriveling of the ends of theirchromosomes.

Although no one has directly testedthe relation between telomeres and hu-man aging or disease, nature may haveinadvertently conducted a relevant ex-

periment. Telomere defects might under-lie a rare inherited disorder called dys-keratosis congenita (DKC). Patients withthe disorder carry abnormally short telo-meres. They have discolored-lookingskin that doesn’t renew itself well.Theybecome anemic in their teens, and manydie from infections. “We can see whathappens in a telomere-deficient person,”says Kathleen Collins of the Universityof California at Berkeley, warning thatthe results need to be confirmed in morethan the two families studied so far.

The cell types that are most compro-mised in this disease, Collins says, areones that in humans produce a telo-

mere-restoring en-zyme called telomer-ase. This enzyme re-sides in the stem cells

that eventually become sperm and eggs(which need to multiply throughout alarge part of a person’s life). It is alsopresent in certain other cells—those usedto revitalize the blood and skin, for ex-ample—but not in most other types.“What the disease tells us,” Collins says,“is that there are some cell types thatneed to turn on telomerase in a normalhuman life span.”

Using telomerase to maintain the endsof chromosomes—and so heal damagedor tired organs in people of any age—has become a focus of research at Geronand a number of academic researchlaboratories. So far adding telomerase

in the laboratory has increased thehealthy life span of human cells fromthe skin, blood vessels, eyes, musclesand immune system, and Geron is cur-rently targeting these and other celltypes to develop new therapies.

Telomerase therapy might one dayhelp generate a new supply of skin andblood cells to treat lesions that don’theal or to enhance the waning immuni-ty of aging blood cells, both commonproblems of old age. Although somestem cells produce telomerase, there’snot enough to maintain telomere lengthwhen demand for reproduction is par-ticularly high, according to some re-searchers. Adding telomerase to stemcells that generate new blood and skincells could permit them to survive long-er and continue dividing to producenew cells virtually indefinitely.

Earlier this year researchers reportedthat a telomerase-based treatment al-lowed cells to stay alive in culture andthat they functioned properly whentransplanted back into a different ani-mal. Someday a similar therapy that ex-tracts cells from a patient, adds telo-merase and then reimplants them intothe donor’s body might avert the risk ofimmune rejection. The telomerase could


TELOMERE DEFECTS:A patient sufferingfrom dyskeratosiscongenita, which ischaracterized byaberrant telomeres,shows signs of pre-mature aging.

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also spur cells lining veins and arteriesto make new blood vessels when plaquebuildup blocks arteries, according toscientists at Geron.

One approach may eventually in-volve gene therapy—in which the genethat gives rise to telomerase is deliveredto the desired site in the body. Becausetelomeres are shorter in cirrhotic liversthan in healthy ones—possibly a resultof too many cycles of cell damage andsubsequent regeneration—this methodmight increase the replicative capacityof surviving liver cells and thus couldrenew livers damaged by alcohol or dis-ease. DePinho recently inserted the genefor telomerase into mice with artificial-ly induced liver damage.Production of the en-zyme reduced injury inthe animals from cirrho-sis of the liver.

Of course, gene thera-py of any type confrontsthe same safety concernsthat arose after the deathlast year of a patient re-ceiving treatment for arare metabolic diseaseunrelated to telomeres.As an alternative to genetherapy, researchers areseeking drugs that mightcontrol the gene whenit is already present incells so it can be turnedon and off at will.

Human trials of telomerase therapyhave yet to begin, and it’s not clearwhat the first treatment will be. Telo-mere shortening, Harley posits, is prob-ably “a fundamental underlying path-way that contributes to many diseas-es.” And he adds: “The technology isn’tdecades away—it’s on the horizon. Wehope to be in clinical trials within ahandful of years.”

Harley’s views have yet to achieve aconsensus among molecular biologistsand gerontologists. But even Harley de-rides the popular misconception thattelomere research will increase longevi-ty. “We’re not saying that we have amaximum life span of 120 because oftelomere loss and that if you were toactivate telomerase in a controlled way,you’d live to be 200,” Harley clarifies,adding that halting telomere loss may,

however, alleviate age-related diseases.Questions remain about whether telo-

mere shortening actually makes cells de-teriorate except in a laboratory dish.Even where scientists have established acausal link between telomere biology

and cellular life span, theyhave done it in cells re-moved from the body.The strongest proof thattelomerase reinvigoratestissues in an animalwould be to produce theenzyme in cells that nor-mally shut it off and thendetermine that it can ex-tend life in those cells.

Such experiments are under way in mice,but the results have yet to be reported.

“To connect telomere shorteningwith aging may be a brilliant stroke ofinsight, or it may represent a distrac-tion, having little to do with human ag-ing,” remarks Robert A. Weinberg ofthe Massachusetts Institute of Technol-ogy’s Whitehead Institute. “To show aconnection, you’d want to see that or-gans are giving out because they’ve losttelomeres. It would be wonderful ifthere was such a simple molecular ex-planation of the aging process, but biol-ogy doesn’t necessarily oblige.”

Even if it does help rejuvenate certaintissue, telomerase will not likely serve asan all-purpose antiaging preparation.The enzyme should not have an effecton cells that do not divide in the maturebody, many of which are involved inprocesses of aging. “A lot of what we

think of as aging takes place in nonre-producing cells,” de Lange observes.“Alzheimer’s is generally viewed as animportant aspect of human aging. Idon’t think there’s any reason to believethat those plaques [damage to the brain

produced by the disease]have anything to do withloss of the proliferativeabilities of nerve cells.”

Not all human cells arelikely to snap awake withthe addition of telomer-ase; freeing some typesfrom the chains of mor-tality (at least in the testtube) requires additional

genetic alterations. Furthermore, somecell types senesce within a small num-ber of generations—long before theirtelomeres have decayed significantly—indicating that other mechanisms canarrest growth. Even if you could makea cell immortal, you might not want to.Adding telomerase to a cell can havedire consequences. “You have to con-front the reality that you’re creating acell that is one step closer to cancer,”Weinberg says. “Cell mortality is animportant impediment to cancer.”

The Cancer Connection

Tumor cells, after all, can live forever.According to several studies, telo-merase plays a critical role in main-

taining, if not triggering, this diseasethat affects the elderly in disproportion-ate numbers. Telomerase by itself doesnot cause cancer: healthy cells err inmultiple ways in their slide toward ma-lignancy. But cancer cells do seem tohave figured out how to use telomeraseto sustain the abnormal cell division thatis the hallmark of the malady. Accord-ing to some researchers, they achievethis unchecked multiplication by acti-vating telomerase or restoring telomerelength by other mechanisms. In contrastto most normal cells, about 85 to 90


Telomerase therapy may one day

prevent liver cirrhosis.

SAFEGUARD: Damageto a mouse liver at the onset of cirrhosis(arrows in top image)was not as dire inanother mouse liverthat received the gene for telomerase(bottom).

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percent of tumor cells pro-duce telomerase. And treat-ments that inactivate telomer-ase kill cancer cells growingin the lab. “That is formalproof that the ongoing activ-ities of telomerase are essen-tial for proliferation in cancercells,” Weinberg concludes.

A drug or genetic thera-py that blocked telomerasemight quash the unbridledgrowth of malignant cells.“It’s too early to tell, butbased on the available evi-dence, we think the prospectslook good for antitelomer-ase therapy,” asserts MurrayO. Robinson of Amgen, abiotechnology firm. “It’s in-credibly exciting that telo-merase is a property thatcrosses virtually all tumor types, be-cause such drugs might be universalchemotherapeutic agents.” The idea ofdeveloping them is “not just a pie-in-the-sky hope,” he continues. “We know ifwe inhibit this enzyme we can kill tumorcells, and we know we can make inhib-itors against other enzymes of this type.”

Some scientists expect that telomere-based anticancer strategies will triggerfewer severe side effects than other che-motherapies. Most healthy cells do notcarry telomerase, and they would thusbe expected to remain unaffected if adrug were to inhibit the enzyme. Nor-mal cells that do produce telomerase—sperm, egg and stem cells—start outwith much longer telomeres than about50 percent of cancers, so cancer cellsshould stop dividing before they do.This aspect of telomere biology mightprovide a means to attack malignantcells without interfering with the nor-mal renewing activities of other cells.

Still, some researchers worry that tu-mors might develop resistance to an-titelomerase therapies. Mice that lacktelomerase can still form tumors, and

about 10 to 15 percent of human tu-mors apparently do not produce the en-zyme, suggesting that not all cancer cellsneed it. “There’s clearly some kind ofbypass pathway in mammalian cells,”warns Carol W. Greider of the JohnsHopkins University School of Medicine.Other researchers argue that resistanceof this type is unlikely to pose a seriousproblem, because none of the investiga-tions have discovered it in the types ofcells from which most cancers arise.

Telomere research has created a para-dox that must still be resolved: the en-zyme telomerase might revive an agingliver. Alternatively, it might promote

cancers. Only clinical trials will ulti-mately resolve the many lingering ques-tions about which, if any, types of telo-mere therapies might succeed for agingor cancer. The original hope that wecould trick Father Time into giving usimmortality by manipulating telomereswill probably prove naive, however. Wecannot simply rewind telomeres like anold-fashioned Swiss watch. But study-ing the tips of chromosomes as theyfritter away may still yield insights intohow the cell, the basic biological unit,grows old. That accomplishment alonewould mark a fundamental contribu-tion to the science of human aging.


Evelyn Strauss, a molecular biologist turned science writer, freelances from SantaCruz, Calif., and is a correspondent for Science magazine.

Further InformationEndgames. John Travis in Science News, Vol. 148, No. 22, page 362; November25, 1995.

Telomeres, Telomerase and Cancer. Carol W. Greider and Elizabeth H. Black-burn in Scientific American, Vol. 274, No. 2, pages 92–97; February 1996.

Descriptions of research at the biotechnology company Geron on telomerase forage-related disorders can be found at www.geron.com on the World Wide Web.

TUMOR INHIBITOR: Cancercells thrive when the enzyme telomerase is present (left). When it is inhibited, the cells changeshape and die (right).

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In the 1970s The Six Million Dollar Man television pro-gram opened each week by showing a terrible accidentthat turned astronaut Steve Austin into “a man barelyalive.” Then we heard: “Gentlemen, we can rebuild him.We have the technology.” The idea intrigued us but seemedcenturies away. It’s not. An explosion of work surround-ing stem cells, which can differentiate into many other

cell types, raises hope for medical repairs beyond our imagi-nation—mending a damaged heart, fixing a failing liver, im-proving a forgetful brain and, most exciting, significantly ex-

tending life. Instead of usingbionic parts, like the ones thatmade Steve Austin strongerand faster, this technologycould provide us with longerand healthier lives by en-abling us to control our natu-ral repair mechanisms.

This emerging field takesadvantage of a cell that may

mendersmother

nature’s

STEM CELLS MIGHT ROUTINELY REPAIR

OUR WORN-OUT TISSUE, IF SOCIETY

ACCEPTS THIS APPROACH

BY MIKE MAY

TWO FROM ONE: Neuralstem cells (inset) can give riseto differing cell types: neu-rons (yellow), which arewired to their neighbors, andglia (red), nucleated struc-tures in the background.

SCIENTIFIC AMERICAN PRESENTS 57

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emerge from the moment of concep-tion. When a sperm cell works its wayinto an egg during fertilization, somescientists consider the result to be astem cell. Other researchers considerstem cells to appear after several cell di-visions that turn a fertilized egg into ahollow sphere of cells called a blasto-cyst. That sphere includes a regioncalled the inner cell mass, consisting ofa group of stem cells. Wherever stemcells first arise, they can branch out inmany directions. A stem cell holds allthe information it needs to make bone,blood, brain—any part of a humanbody. It can also copy itself to maintaina stock of stem cells.

Many of us imagine that a humanbody builds up most of its cells and tis-sues early in life, and then everythingbegins to fall apart, cell by cell. Newfindings prove otherwise. Stem cellsbusily work away throughout our lives,acting like an army of housekeepers,cleaning up a little mess here and re-pairing some damage there. In somecases, a group of these cells work to-gether to perform gargantuan tasks.For example, the stem cells located inbone marrow must replace more thanone billion red blood cells every day.Such rebuilding might be going on con-

stantly all over the body. Stem cells alsoseem to make new cells continuouslyfor bone, liver, heart, muscle and eventhe brain, where scientists long thoughtthat we were incapable of generatingnew cells.

Bodily Tune-ups

Stem cells serve as a natural defenseagainst aging. As things wear out,these cells can repair some damage.

As we get older, though, the failures inour bodies apparently overrun the stemcells. Consequently, we decline—gettingslower, weaker, more forgetful. Never-theless, many scientists believe that theycould slow these processes with a stemcell tune-up. Moreover, a regular doseof jazzed-up stem cells might fight offdegeneration and keep us living a long-er and healthier life.

The inherent qualities of stem cellshave drawn tremendous attention tothem. To be sure, some scientists takethe Six Million Dollar Man approachand try to fabricate new parts from ex-otic metals and space-age polymers. Youcan already get an artificial hip joint, animplantable device to help with hearingloss, and replacement valves for yourheart. Some groups are even pursuing

an electronic retina. But why rely on somany different parts—essentially a newfix for every problem—when you coulduse stem cells instead? Stem cells mightbe a cure-all of sorts, basically one-stopshopping for repairing anything thatails you.

Despite the recent interest in stemcells, they are not entirely new in medi-cal therapies. Physicians have been ex-tending human lives for years by includ-ing stem cells in some treatments. Forexample, some forms of cancer, such aschildhood leukemia, require such a dev-astating dose of chemotherapy that itdestroys a patient’s bone marrow. Abone marrow transplant can restore apatient’s blood-making capability, pre-sumably because it provides a new sup-ply of blood-making stem cells. Whenphysicians started using bone marrowtransplants, though, no one had seen ahuman stem cell. They just assumed thatsuch cells existed.

In late 1998 all that changed. Two setsof researchers in the U.S.—John Gear-hart’s group at Johns Hopkins Univer-sity and James Thomson’s team at theUniversity of Wisconsin–Madison—iso-lated human stem cells. These resultsshook up science and society, raisinghope for therapeutic uses of stem cells


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SPECIALIZATION: Some scientists consider a stem cell toarise when a sperm fertilizes an egg (left). Others think itoriginates in the inner cell mass of the blastocyst, a hol-

low sphere that emerges after several cell divisions (cen-ter). Either way, stem cells can differentiate into uniquecell types, such as muscle, blood and nerve tissue (right).

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as well as a range of ethical questions.After the first reports, investigators

launched a parade of promising animalexperiments. Evan Snyder of HarvardMedical School has shown that neuralstem cells seek out damaged areas of amouse’s cortex—the highest centers ofthe brain—and make new neurons there.He has very preliminary evidence thatneural stem cells can do this in pri-mates, too. “We’re starting to move ourway up the evolutionary ladder,” Sny-der says, “suggesting that this reallymay be a kind of intervention or kindof application that we could use.” Healso mentions evidence that neural stemcells could generate new neurons inother areas of the brain and even in thespinal cord. If human neural stem cellscan go to damaged areas in the nervoussystem and create neurons there, such atechnique might fend off Parkinson’sdisease, amyotrophic lateral sclerosis(better known as Lou Gehrig’s disease)or old-age dementia.

Tissue Flipping

These findings seem to be croppingup in one organ after another. Forinstance, Bryon Petersen of the Uni-

versity of Florida says his work in ratsshowed that a cell that originated in thebone marrow could travel to the liver,incorporate into that organ and be-come a functioning liver cell. Pre-sumably, that bone marrow cellwas a blood-making stem cell. AsRonald McKay of the NationalInstitute of Neurological Disor-ders and Strokes explains, “Onereally exciting thing that’s goingon in the field at the moment is, infact, we’re sort of discovering thatthe stem cells that have been de-fined in different tissues are actually ca-pable of flipping from one tissue to an-other.” McKay notes that researchersare not absolutely sure that the flippingreally goes on in stem cells but addsthat “there are cells that are capable ofgiving rise to the cells of another tissue:brain into blood, brain into muscle,pancreas into liver, muscle into blood.”

Still, scientists must answer a crucialquestion: Do the new cells really work?In most cases, it’s hard to tell. Just be-cause a stem cell ends up in the brain

and turns into what looks exactly like aneuron doesn’t mean that it works prop-erly. Still, McKay and his colleagues didshow at least one case in which newneurons did work. First, they caused aParkinson’s-like disease in rats by killingneurons that communicate through aneurotransmitter called dopamine. Thenthey obtained neural stem cells from ratembryos and injected the cells into theParkinsonian adult rats. In less than threemonths the normal movement in mostof the treated rats improved by about75 percent.

Over this incredibly promising worklooms a controversy that threatens somestem cell research. It all revolves aroundone word: embryo. In essence, scientiststalk about two general classes of stemcells, ones that come from embryos andones from adults. Some people wouldnever condone using embryos in anyway because of ethical beliefs. If youcan get stem cells from adults, though,surely this entire problem can be re-solved by forgoing the use of embryon-ic stem cells. But, as Thomson explains,“the embryonic stem cells have the po-tential to form any-thing. It’s not clearwhat the develop-mental potential is ofsome of these otherstem cells.” In otherwords, an embryon-

ic stem cell can do itall—make any cellneeded—and adultstem cells might belimited to making afew kinds of cells.Furthermore, adult stem cells could bepartially worn out, so that they wouldnot offer the full rejuvenating benefitsof embryonic ones.

Despite all the potential benefits ofusing embryonic stem cells, workingwith them remains off-limits for re-

searchers receiving federal funding fortheir studies, as all powerful laborato-ries do. A ban put in place by the U.S.Congress on the use of federal moneymeans that research is confined to thenarrow universe of just a few privatebiotechnology companies—Geron Cor-poration and Advanced Cell Technolo-gy being the leaders. Progress in thefield is slower than it might be withoutthe prohibition. But the funding envi-ronment may change.

In November 1998 President Bill Clin-ton asked the National Bioethics Advi-sory Commission to investigate the med-ical and ethical issues behind embryonicstem cells. Its report concluded: “[T]heCommission believes that federal fund-ing for the use and derivation of [em-bryonic stem] cells should be limited totwo sources of such material: cadavericfetal tissue [from naturally aborted fe-tuses] and embryos remaining after in-fertility treatments.” The report thusencouraged federal funding for certainapproaches to stem cell research. Then,in December 1999, the National Insti-tutes of Health, the primary source of

U.S. biomedical funding, published adraft for guidelines on stem cell re-search, which went out for public com-ment. These documents suggest that theoutlook for at least limited federal sup-port has become less bleak.

But the National Bioethics Advisory

SCIENTIFIC AMERICAN PRESENTS 59

A NEW IDENTITY: Stemcells in bone marrow

transplanted from one ratto another developed into

cells that produced afunctional enzyme (red-orange areas) in the liver

of the recipient animal.


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Commission did not endorse an ap-proach called nuclear transfer, whichMichael West of Advanced Cell Tech-nology champions. In his technique, re-searchers remove the nucleus from acow’s egg, implant a human cell—say, askin cell—inside it and allow it to growembryonic stem cells. With this system,West and his colleagues might be ableto use skin cells—obtained by merelyscraping a toothpick across the insideof your cheek—to make embryonicstem cells just for you. That could beimportant because your immune sys-tem might fight off stem cells from any-one else, seeing them as foreign in-vaders, like a virus. In addition, cow’seggs come cheaply and in large num-bers. Still, combining human and cowcells started more than a little disgrun-tled mooing, because some people see itas a dangerous mixing of species. Westdefends his approach, saying, “We takethe [cow] egg and remove its DNA, sothere’s no more mixing of species than

there is when you drink cow’s milk.”In any case, you need West’s approach

only if your body really is likely to re-ject foreign stem cells. West says yourimmune system would search out for-eign cells with the efficiency of a hawkhunting a mouse. Thomson, one of thefirst to isolate human embryonic stemcells, agrees that the body would rejectstem cells as it does some organ trans-plants: “Absolutely. Once they differen-tiate, they’ll become adult cells like anyother cell in the body,” which wouldcause them to be rejected. But Thom-son’s opinion is not universal. One com-pany, Osiris Therapeutics, has foundthrough its studies that foreign stemcells are not cast out by the immune sys-tem. “It really doesn’t seem to be thecase. We don’t quite know why that is,”says Osiris scientist Mark Pittenger.

Luckily, investigators do agree onsome topics. For example, most every-one thinks they could grow these cellsin culture and keep them alive essential-

ly forever. About his human embryoniccells, for instance, Thomson says, “We’vekept them growing for well over a year.By any measure that we have, they ap-pear to be immortal.” And once re-searchers know how to culture whatev-er kind of cells they have, they canmake incredibly large numbers of them.For example, a single human skin cellcan spawn 170 trillion trillion trillioncells. Moreover, farming these cells inculture could reduce the concerns aboutusing embryonic tissue. “One of thethings I think people don’t like aboutthis is the idea of constantly going backto human embryos and doing the stuffover and over and over again,” McKaysays. “But technically, we can grow thecells, we can really grow them. I thinkthis is going to be very efficient, so youneedn’t be concerned that this is goingto be a big [embryo] harvesting indus-try. It’s not going to be like that.” Therecently created WiCell Research Insti-tute—with Thomson as its scientific di-


tissue

rejuvenationBIOENGINEERING: Companies havealready begun to contemplate med-ical techniques that would use stemcells to reverse the effects of agingon flesh, blood and numerous or-gans. A sample of bone marrowcontaining stem cells could be ex-tracted from the pelvis (a). The cellscould then be grown in a culture (b)before being removed, inserted intoa blood bag and reinjected into thebody (c). (The solution would con-tain both stem cells and progenitorcells, products of stem cells primedto make certain tissue.) In the body,this mixture would home in on loca-tions where they could help revive,say, a damaged liver or kidney. Onecompany, Aastrom Biosciences, isdeveloping a machine that will cul-ture enough stem cells over a 12-day period to make medical usespractical (photograph).

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rector—plans to grow and sell humanembryonic stem cells for research.

Although physicians already relysomewhat on stem cells—at least forbone marrow transplants—many moreclinical applications might lie just overthe horizon. Stem cells might be used torepopulate or replace cells devastatedby disease. It might even be possible totake a stem cell, nudge it chemically to-ward making the kind of tissue desiredand then control its environment in away that causes it to build an entire or-gan. The organ could then be used insomeone who needs a transplant, thepinnacle of so-called tissue engineering.

When could some of these stem celltechniques be available? “I think we’regoing to be moving into clinical trialswith human neural stem cells of sometype for some disease within two years,”Snyder says. That means that stem cell– boosting treatments could be availablein five to 10 years. Making entire or-gans from scratch, however, lies much

further in the future. In theory, physi-cians could get so good at fixing organswith stem cell treatments that such or-gan fabrication might never be needed.

Just Hit “Play”

Some companies are already count-ing on a market in stem cell med-icine. For instance, Douglas Arm-

strong of Aastrom Biosciences describesa machine developed by his companythat is primed with a sample of bonemarrow or even blood from an umbili-cal cord, both of which contain stemcells. According to Armstrong, “Theequipment operates much like a VCRwith a videocassette. The user takes thecassette, pops it into the machine andthe machine takes over. Twelve dayslater the cassette comes back out, goeson another machine and transfers thecell product to a blood bag that’s readyfor therapy.”

The resulting blood bag would con-tain stem cells as well as so-called pro-genitor cells, which are products of stemcells that are primed to make specifictissues. A physician could simply injectstem and progenitor cells into the blood-stream, and many of them would homein on locations where they were needed.

Armstrong adds, “It’s practical tothink we may be entering a future periodwhere all of us put aside a small amountof bone marrow or even our umbilicalcord blood when we are born, and thensamples of that are grown out into pop-ulations and we get infusions of thosecells later in life that might, indeed, helpus live much longer, healthier lives.”

Many hurdles lie between ongoing re-search and turning stem cell techniquesinto therapies for humans. “These ther-apies are brand-new,” Thomson says.“There are no precedents for them.”Consequently, a researcher can’t simplysee what stem cell treatments do in ratsand mice and then try the same thing inhumans. In a hypothetical example,

Thomson speculates that a newly dis-covered technique that cures diabetes inmice might not help human diabetics butinstead leave them with a worse disease—pancreatic cancer, for example. In otherwords, a treatment for a serious butsurvivable disease could give patients acertain death sentence.

“So you want to make really surewhat you’re doing isn’t worse than thedisease you’re trying to cure and thatthere’s a lot of safety involved,” Thom-son continues. “Because the therapiesare so new, going straight into humanswould be a problem.” Much more re-search on primates and then extensiveclinical testing must be completed be-fore new stem cell techniques becomeavailable as a routine form of treatment.

Scientists do know that stem cellspromise entirely new views of how thehuman body works. “For me, the abso-lute true potential of these is more inhow it’s going to give us a clue to under-stand the human body,” Thomson says.“So even if [stem cells] were never to beused for transplantation purposes, theygive you this brand-new scientific mod-el to study. If you’re interested in heartdisease, you can study populations ofhuman heart cells in tissue culture forthe first time on a regular basis.

“I think the transplantation stuff willbe important,” he goes on, “but some-day we’ll understand enough about thehuman body that these transplantationtherapies won’t be necessary, because itwill be possible to cause specific cells toregenerate themselves in ways they don’tnaturally do, because we will understandhow that development normally occurs.”

We might never see science rebuild aman with Steve Austin–like techniques.Instead researchers may rebuild us bytweaking systems that our bodies pos-sessed all along—stem cells, the ulti-mate medical weapons. Now we mustwait to see if science and society canagree on ways to use these seeminglymagical wonders of biology.


Mike May lives and works as a freelance writer in Clinton, Conn.

Further InformationStem Cells: A New Lease on Life. Elaine Fuchs and Julia A. Segre in Cell, Vol. 100,No. 1, pages 143–155; January 7, 2000.

Stem Cells: A Primer. Available at www.nih.gov/news/stemcell/primer. htm

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HOPE: A bioartificialkidney could somedayend the exhaustingregimen of dialysis.One prototype (right)has been developedby the University ofMichigan.

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ENGINEERS ARE CREATING ARTIFICIAL REPLACEMENTS

FOR FAILING HEARTS, KIDNEYS, PANCREASES AND LIVERS

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therosclerosis, diabetes, cirrhosis, hepatitis and other af-flictions kill or disable millions of people every year by ravaging their organs over time. The elderly suffer the greatest toll. Bioartificial organs—a merger of mechani-cal parts with cells grown in laboratory cultures—could reduce premature death, improve quality of life and

serve as vital bridges for seniors waiting for natural-organ transplants.

In the U.S., thousands of people die annually waiting for a trans-plant, and many thousands more never even make it onto a waitinglist, according to the United Network for Organ Sharing in Rich-

mond, Va., which manages the na-tionwide transplant network.

Engineering whole organs from scratch using pristine stem cellsthat can differentiate into any kind of body tissue would, of course,be the ultimate solution. But that is a longer-term prospect. Fornow, bioartificial organs offer the greatest hope for spare parts thatcan perform the complex tasks of a kidney, pancreas or liver. “Wecall these the smart organs,” says Bartley P. Griffith, director of theMcGowan Center for Artificial Organ Development at the Univer-sity of Pittsburgh. A heart simply pumps blood through one-wayvalves. Kidneys, pancreases and livers face the arduous task of

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chemically removing waste from incom-ing fluids and producing key compoundsfor the body. “If a heart is thought of asa first-grader,” Griffith says, “a kidney isa senior in high school, and a liver is apostdoc.”

Despite its “simplicity,” building anartificial heart has proved difficult. Theimage of Barney Clark, recipient of thefirst Jarvik-7 artificial heart in 1982,was telling; his mechanical heart, whichreplaced his failed natural heart, wasconnected by hoses to a large, thumpingpneumatic bellows outside his body thatdid the actual pumping. The unit had tobe plugged into the wall, limiting Clark’smovement. When Clark and a secondartificial heart patient, William Schroe-der, died within two years as a result ofinfections and strokes caused by bloodclots, the public’s hope in the technolo-gy died with them.

It took years for researchers to rethinktheir approach and miniaturize compo-nents. Instead of a full-blown replace-ment, recent devices have attempted toassist a failing heart until a transplantcan be found. The left ventricular assistdevice (LVAD), the foremost example,is now in clinical use. A surgeon im-plants it into the abdomen, where itpumps blood that has been divertedfrom the left ventricle, one of the heart’sfour main chambers that pump blood.The device is powered by a small consoleor portable battery pack outside thebody. The LVAD solves only some heartproblems and still requires a power ca-

ble that passes through the patient’sskin, but it buys crucial time.

LVAD progress has renewed interestin a new generation of artificial hearts.They are smaller and more efficient be-cause they move blood in a fundamen-tally different manner. Instead of pump-ing with flexing diaphragms as did theprevious generation, they have a tinyspinning impeller that propels the bloodlike a boat propeller moves water. TheMcGowan Center uses this approach inits Streamliner artificial heart, designedto be placed in the abdomen and to pushblood through the natural heart and ar-teries using a pair of tubes. Inductivecoupling could transfer energy from acoil attached to a battery worn on a beltto a secondary coil and battery implant-ed under the skin. The subcutaneousbattery would then send power to theartificial organ over a thin wire.

The Streamliner may be the Cadillacof artificial hearts. The oblong device,made of titanium, is about four incheslong, two inches across and weighs sev-eral ounces. It features an impeller sus-pended internally with magnets. “Thiseliminates the risk of failure because ofbearings wearing out,” says Griffith,who adds that the Streamliner faces atleast 18 more months of well-fundeddevelopment before it is ready for testing.

Other leading research teams are us-ing the turbine approach in experimen-tal LVADs. Thermo Cardiosystems isworking with the McGowan Center, andMicromed Technology has partneredwith the Baylor Medical Center.

Developing a “dumb” organ like theheart is a major engineering challenge,yet it pales in comparison with the com-plexity of building organs that have bio-chemical brains. To craft “smart” bio-artificial organs like the kidney, pan-

creas and liver, expertsmust combine electrical,mechanical and tissue en-gineering. The strategythus far is to take organ

cells from humans or pigs,grow them in a culture medium, thenload them into a bioreactor—a box ortube in which they are kept alive withoxygen and nutrients. The bioreactor isinserted into a larger machine outsidethe body. A patient’s blood is divertedvia tubes through the bioreactor, whereit is cleansed—similar to the setup of to-day’s kidney dialysis machines.

“Of course, the trick would be to un-derstand the cell culture science and en-gineer the bioreactor well enough toimplant one of these organs,” Griffithnotes. “I think we’re 10 years away fromthat at least.” Closer to fruition, he be-lieves, is a “get out of trouble” bioar-tificial kidney, worn like a fanny pack,that could keep a patient alive duringthe wait for a donated human organ.

Beyond the Dialysis Machine

Diabetes and hypertension—the lead-ing causes of kidney disease—plague the elderly. Today there are

more than 40,000 Americans waitingfor a kidney transplant. They must un-dergo dialysis or hemofiltration for hoursat a stretch, multiple times each week.The regimen is exhausting. Just as vex-ing is that the machines can do onlyhalf the task at hand. While the kidneyfilters urea waste products from theblood, its tubules must also reclaim 98percent of the filtrate, returning impor-tant sugars, salts and other substancesto the body. Dialysis machines just can’tpull off the second step.

By combining mechanical devices withengineered tissue, a bioartificial kidneycould perform the entire function. Neph-rologist David Humes and his colleaguesat the University of Michigan have cul-tured proximal tubule cells, whichhandle the bulk of filtrate reclamation,from pig kidneys. The cells are en-meshed along hair-thin plastic fibersthat line the inside of a polycarbonatefiltration cartridge about 10.5 incheslong and 1.4 inches in diameter. Thecartridge is housed in a larger machine.As the patient’s blood is pumped through


NEW PUSH: The McGowan Center’sprototype artificial heart propelsblood with a tiny impeller, rather thanthe power-hungry pumps used in past attempts to replace the organ.

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the bioartificial kidney, the engineeredcells filter out urea while returning theuseful compounds.

Trials of the new system conductedon dogs last year were successful, andHumes is hoping for approval from theFood and Drug Administration to be-gin human trials later this year. “At thispoint, this is a temporary device foracute kidney failure,” he explains. “Butwe’re working on devices that haveboth filtration and a tubule elementthat could be wearable. We’re in a pro-totype stage.”

According to Humes, the first-gen-eration wearable renal assist devicecould diminish a patient’s dialysis timeby 30 to 50 percent and someday possi-bly eliminate it entirely. “The first dialy-sis machine was a huge 10-by-4-footcylinder,” Humes says. “Our cartridges

do the same thing, but you can holdthem in your hand.” If fabrication ad-vances make possible even more minia-turization, he adds, he and his teammight be able to “devise one of thesefor implantation.”

An implantable bioartificial device toassist a malfunctioning pancreas wouldcreate a similar revolution in the treat-ment of insulin-dependent diabetics. Atpresent, diabetics must follow a strictdaily regimen of self-administered teststo check blood sugar levels and one ormore insulin injections to pick up theslack of a weak pancreas. But “because

there is no effective feedback mecha-nism” for the level of insulin required,injection “is done as a best guess,” saysBarry Solomon, president and chief sci-entific officer of Circe Biomedical inLexington, Mass. The resulting largeswings in glucose levels are thought tolead to the major complications of dia-betes—vascular disease, retinal diseaseand heart disease.

The goal is to automate the system.Existing implantable insulin pumpstend to leak, and electronic glucose sen-sors are notorious for failing after littlemore than a month inside the body. Butthe real shortfall is that today’s systemscannot supply the feedback informa-tion needed to administer precise andproperly timed dosages.

Circe’s PancreAssist system is designedto solve the problem. It is an insulin-on-demand system based on the body’sown chemistry. Now in preclinical de-velopment, PancreAssist is an implant-able tubular membrane surrounded byinsulin-producing islets, all contained in

a plastic housing. As the patient’s bloodflows through the center of the tube,the islets, harvested from pigs, detectchanges in the patient’s glucose levelsand respond by producing insulin whenneeded. The insulin diffuses across themembrane into the person’s blood. Themembrane prevents white blood cellsand antibodies from attacking theporcine cells, so immunosuppressantdrugs are not needed. The unit, half thesize of a hockey puck and weighingonly a few ounces, will be implantednear the kidney. “Because we’re usingcells that not only have the ability to

produce insulin but also can sense andregulate that production in response toglucose levels, we’re essentially repro-ducing what the natural pancreasdoes,” Solomon explains.

An early version of the PancreAssistproved effective in animals several yearsago, but a reengineering of the vasculargraft was required before human stud-ies could begin. Solomon hopes theslimmed-down system will be provedon animals and ready for human clini-cal trials within two years.

Letting the Liver Regenerate

The challenge is greater for a bioar-tificial liver to replace a natural onedamaged by diseases and insults

such as hepatitis C and alcoholism. Ahealthy liver metabolizes toxins, pro-duces bile, regulates the balance of manyhormones and manufactures blood-clot-ting proteins. Designing an organ to ac-complish all these complex tasks isdaunting. But a device may be neededto replace these functions only for ashort time, says Achilles Demetriou, abioartificial liver pioneer who is chair-

man of the surgery department atthe Cedars-Sinai Medical Cen-

ter in Los Angeles. “The liverhas such a remarkable capac-ity to regenerate that tem-porary support could resultin complete recovery of theinjured organ,” Demetri-

ou points out. If a dam-aged liver could be re-lieved of all its duties for

just one week, it wouldhave a good chance of repairing it-

self. There is currently no machinethat can take over the organ’s function,however.

The goal, therefore, is a bioartificialorgan that can bridge the repair time.Several companies are pursuing state-of-the-art work, including Organogene-sis in Canton, Mass., developers of FDA-approved lab-grown skin, and CirceBiomedical, whose HepatAssist systemwas developed in collaboration withDemetriou.

HepatAssist is undergoing phase IIand III clinical trials in liver transplantcenters around the U.S. It uses pig livercells in a bioreactor to remove toxins


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No “corpses” reside at the Alcor Life Extension Founda-tion. Just three dozen “patients” entombed at a rock-hard 320 degrees Fahrenheit below zero who have bet

that future physicians will have the technology to “reani-mate” them. When each one was at death’s door, a friend orfamily member had phoned Alcor’s CryoTransport team. Theoutfit rushed to the scene. Once a doctor had pronouncedthe subject clinically dead, the team put the deceased on ice,pumped the body full of medications and solutions andtransported it to Alcor headquarters in Scottsdale, Ariz.

The team then circulated glycerol, used as antifreeze, intothe major arteries to prevent damaging ice crystals fromforming among cells. The patient was then placed in a “dew-

ar”—a tall metal thermos that is filledwith liquid nitrogen. The patientsstand there today in wait. But don’tdare compare them to mummies.Cryonics, Alcor insists, has nothing todo with “bringing people back fromthe dead.”

Freeze now, revive later is certainlyone way to attempt to extend yourlongevity. The first Alcor “member”has been frozen since 1976. “If you’refeeling good and you enjoy life, it’snot a matter of figuring out why youshould do this,” says Christine Peter-son, a 42-year-old writer and Alcorsubscriber. “It’s more a question ofwhy you would want to check out.”

Nice theory—but there’s a catch.Someone someday will have to fig-ure out how to reconstruct your

body, mind and soul. And at present neither Alcor nor anyoneelse knows how to do it. Therein lies the gamble.

Peterson’s not worried. She believes a cure for aging willcome along before she needs to be frozen. “For peoplearound my age and younger, cryonics is more like backupinsurance,” she says. If a fix doesn’t materialize, then she’sbetting that nanotechnology will bring her back from thedeep freeze. Nanotechnology is one of her life’s passions. Shehas penned a book about it and is married to scientist K. EricDrexler, a maverick nanotechnology evangelist. The believ-ers say that one day thousands of nanobots—microscopicrobots one billionth of a meter long—will be able to travelthrough your body Fantastic Voyage–style, repairing cells tofix whatever ails you. The army of dutiful nanobots would re-pair widespread cellular damage caused by the freezing, re-juvenate your brain cells and rebuild your tired old body, cellby cell, into something new.

But no one has crafted a single nanobot. And althoughnanotechnology is all the rage in the popular press, manyscientists ridicule molecular robots as little more than the ru-minations of science-fiction aficionados.

Peterson has such faith in nanotechnology that she hassigned up for Alcor’s neuropreservation service—freezing justher head. It’ll simply be attached to a more youthful bodywhen it’s thawed. Nanotechnology will fix any complicationsfrom her recapitation and will subsequently keep her newbody youthful forever. Her mother, husband, friends and col-leagues such as artificial-intelligence researcher Marvin Min-sky will be glad to see it; all of them are signed up with Alcor.

Putting your frozen corpse—er, body—in Alcor’s caredoesn’t come cheap. The flat fee is $120,000. Whether that’senough for the needed half-century of minding isn’t clear.Charles Platt, a writer of science fact and fiction and director

thecryonics gamble

YOU BET YOUR LIFE:At her death, Chris-tine Peterson will befrozen in a tank by Alcor, run by LindaChamberlain (right),in hopes she can berevived and repaired.

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from the blood of patients, in a tech-nique similar to Humes’s bioartificialkidney. A cylindrical plastic cartridge14 inches long and 2.5 inches in diame-ter, lined with engineered cells, fits intoa larger machine. A patient’s bloodpasses through it for cleansing. Patientsundergo six-hour sessions for sevenconsecutive days. “By then,” Demetri-ou says, the hope is that either “theirliver recovers and takes over or they re-ceive a transplant.”

HepatAssist is intended to serve sole-ly as a bridge. An implantable liver re-placement, Demetriou believes, willprobably have to be engineered fromstem cells, a venture he asserts will be“orders of magnitude more complex”than those for other organs.

In the meantime, whichever bioartifi-cial organs emerge may face competi-tion from other organ-replacement ap-proaches that are also advancing, notesPeter Stock, associate professor of trans-plant surgery at the University of Cali-fornia at San Francisco. Most anticipat-ed, perhaps, is xenotransplantation, inwhich organs harvested from transgen-ic pigs or primates could be transplant-ed into humans. The organs would beendowed with certain human genes andengineered to not induce immune rejec-tion. Various attempts to fix faulty or-gans by altering genes directly are un-der way, too.

Whether tomorrow’s spare organs arebuilt around bioartificial cartridges, piginnards or stem cells will in the end bedetermined by lab work and by safetyand effectiveness questions that gethashed out during the FDA approvalprocess. But no matter which technolo-gy beats the organ shortage, the ultimateprize will go to the individual who getsa new lease on life after a visit to thehuman body shop of the future.


of the CryoCare Foundation, which subcontracts freezing, isn’t expecting a cryon-ics patient to be successfully resuscitated for at least 60 years.

If we all could be frozen and defrosted, the earth might become a crowdedplace. Peterson has an otherworldly solution for that, too: colonize outer space.Her vision of a space-faring society, common among her future-minded peers, isreminiscent of the late LSD guru Timothy Leary’s prescription for the human race:SMI2LE, an acronym for “space migration, intelligence increase and life extension.”

Indeed, Leary was arguably the most famous advocate of cryonics. (Contrary torumors, Walt Disney was cremated after his death in 1966, and Michael Jacksonhas never publicly announced plans to take a liquid-nitrogen bath.) But if, as En-glish scholar Samuel Johnson noted, the prospect of one’s imminent demisetends to concentrate the mind wonderfully, then eternity on ice may lose some ofits allure. During his final hours of life, Leary abruptly changed his plans for coldstorage. His stated reason, according to friends who were at his bedside: “Wakingup in the future surrounded by a bunch of men in white lab coats holding clip-boards didn’t sound like so much fun.” —D.P.

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David Pescovitz writes frequently forScientific American and is a contribut-ing editor at Wired magazine.

Further InformationAmerican Heart Association(www. americanheart.org).

McGowan Center for ArtificialOrgan Development(www.upmc.edu/mcgowan).

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OLD YOUNG PEOPLE:Hutchinson-Gilfordsyndrome patients often die by their early teens from heart disease orstroke.

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CHILDREN WITH DISEASES OF THE ELDERLY AND STUDIES OF GENES THAT

EXTEND LIFE SPAN IN ANIMALS ARE OPENING A WINDOW ON HOW WE AGE

Three-year-old Sam likes to feel starfish in his hands,and you can just forget about changing the subjectwhen he’s discussing planets. But Sam is not quiteyour average toddler. He’s almost bald, his seventeeth don’t align properly, and he is smaller thanhis peers. So far these are the only clues that he hasHutchinson-Gilford syndrome, a rare genetic disor-

der that mimics some aspects of aging.No one can predict what course Sam’s disease will take,

but children with Hutchinson-Gilford syndrome typically de-velop arthritis and grow slowly. Their skin becomes thin, andage spots and prominent veins emerge. Most acquire severeatherosclerosis that can thwart blood flow to the brain andother organs. About 50 percent of afflicted children die ofheart disease or stroke by their early teens.

When Sam’s mother isn’t talking to him about Neil Arm-strong and Buzz Aldrin, she’s in the laboratory, looking forthe biochemical basis of her son’s disease. Leslie B. Gordon’swork on Hutchinson-Gilford syndrome—and research onother related disorders—may have implications far beyondfinding a cure for a rare disease. It might also provide cluesabout the normal human aging process and yield insight intodiseases common to old age, such as atherosclerosis, whichcould lead to new avenues of research for treatments thatprolong life.

Hutchinson-Gilford syndrome is one of several humanprogerias; “progeria” means premature aging. Very little isknown about the disease, and the condition is extremelyrare—only about 100 cases have been documented since itwas first described in 1886. Although the disease appears tobe caused by a genetic defect, it doesn’t run in families, sug-gesting that the mutation occurs randomly in egg or sperm

cells or at some point after fertilization. Because researcherscan’t track the gene through relatives, this disorder doesn’tlend itself to traditional gene-hunting approaches.

So Gordon, a research associate in the department of anat-omy and cell biology at Tufts University School of Medicine,is taking a different tack. She’s focusing on the one consistentdifference between Hutchinson-Gilford patients and healthychildren: sick kids have much higher levels of a particularcompound—hyaluronic acid (HA)—in their urine. HA is nec-essary for life because it helps hold tissue together, but toomuch of it might be a bad thing, Gordon says. People withanother form of progeria, called Werner syndrome, also havehigh levels of HA, and its concentrations creep up in elderlypeople, too.

A Trickle of Evidence

Plaques that build up in the blood vessels of people who dieof heart disease are steeped in HA. “Whether it’s cause oreffect, no one really knows,” Gordon says. “These kids

have these same plaques throughout their bodies, and that’swhat plays a major role in causing heart attacks and strokes.”

The idea that HA contributes to heart disease is not new,but work in this area has been fostered recently by new ana-lytical tools. In this relatively unexplored area of research,Gordon is trying to follow the trickle of evidence to its source.She wants to find out whether the disease grows more severeas HA levels rise and to establish whether the chemical doesindeed promote plaque formation. If such a connection wereconfirmed, it could lead to therapies that fight both Hutch-inson-Gilford syndrome and cardiovascular disease by low-ering HA levels. “Any treatments that help these children will

methuselahof hyperaging and

genesBY EVELYN STRAUSS


very likely help millions of people withcardiovascular disease and potentiallyother problems associated with aging,”she says.

In another classical premature agingdisease, Werner syndrome (WS), symp-toms don’t begin until adolescence orearly adulthood. In this syndrome, hairthins and goes gray, skin wrinkles, andmuscles atrophy. Individuals with thiscondition suffer from cataracts, diabe-tes, heart disease and other afflictionsthat don’t typically strike until old age.

Although people with Hutchinson-Gilford and WS look old and sharemany ailments with geriatric patients,the physiological changes overlap onlypartially with how people usually age.

WS sufferers experience a high incidenceof cancer, for example, but “they in-clude rare, weird cancers that you don’tsee too often,” says George M. Martinof the University of Washington.

Still, these disorders can provide someintriguing insights, says W. Ted Brownof the Institute for Basic Research inDevelopmental Disabilities in Staten Is-land, N.Y. “Mutations in one gene canproduce a set of effects that dramatical-ly resemble aging. That implies that rel-atively few genes could be controllingaging.”

Several years ago scientists trackeddown the gene responsible for WS. In itshealthy form the gene encodes a proteinthat unwinds DNA, presumably so otherproteins that manipulate DNA can wrig-gle between the strands to do their work.No one yet knows exactly how a defec-tive version of this gene, which wouldgive rise to a faulty protein, could lead toWS. But many ideas are floating around.

In test-tube experiments, WS cells aremuch more susceptible than normal toharm from a compound that is toxic toDNA. These results suggest that the ab-normal WS protein might fail to repairdamaged DNA.

And that’s just one thought. Studieson a yeast protein that resembles theWS protein have suggested that it un-dermines DNA integrity in other ways.A mutation in a yeast gene that encodesthis protein shortens life span. In cellscarrying the altered gene, DNA is cutafter it loops into circles, and the endsstick together. The resulting DNA cir-cles contribute to the cell’s eventualdemise. No one has detected similarDNA rings in cells of people with WS

or from old individuals.Some researchers have con-jectured, however, that thenormal WS protein quash-es formation of aberrantDNA structures in humans,a process that might goawry when the gene suffersa mutation.

Already studies on WShave spurred investigatorsto think about new waysof looking at common dis-orders of human aging. Per-haps DNA damage fromsubtle but common varia-

tions in the WS gene may predisposepeople to vascular disease, cataractsand diabetes, even if they don’t sufferfrom a full-blown form of the disease.

The big limitation of studying hu-mans, of course, is that you can’t ma-nipulate people as you can laboratoryanimals. Enter a mutant mouse strainthat is afflicted at a young age withmany of the diseases common to olderhumans. The defect in the responsiblemouse gene—called klotho, after thegoddess in Greek mythology who spinsthe thread of life—accelerates the onsetof disorders such as atherosclerosis andosteoporosis.

Researchers have isolated the klothogene from both mice and humans. Thehuman klotho lies in a region of thechromosome with no known geneticdisorders. Because mice with defectiveklotho exhibit some aspects of prema-ture aging, the gene may be analogousto progeria genes, such as those respon-

sible for Hutchinson-Gilford and Wern-er syndromes. It’s even possible thatklotho is the yet to be revealed genethat underlies Hutchinson-Gilford. “Itwould be interesting to see if Hutchin-son-Gilford patients have a mutation inthe klotho gene,” says Makoto Kuro-oof the University of Texas SouthwesternMedical Center at Dallas.

Antiaging Hormone

Based on an analysis of klotho’sDNA and the symptoms exhibitedby the mice, Kuro-o hypothesizes

that the mutated gene encodes an aber-rant protein that circulates in the bloodand triggers age-related processes indifferent tissues—perhaps a buildup ofplaque in blood vessels. If so, the nor-mal version of the protein might do theopposite—serving as what Kuro-o callsan “antiaging hormone.” The idea ofsuch a blood-borne factor that mightkeep at least some tissues healthy is anew concept for mammalian aging,Kuro-o says. He is trying to identify themolecules with which the klotho pro-tein interacts in tissues and to figure outhow cells with defective klotho behavedifferently from normal cells.

When healthy versions of genes suchas klotho or the one underlying WS gohaywire, they expedite an organism’s de-mise. Studying these mutations and dis-orders may well yield insight into partic-ular illnesses and conditions of old age.But they will probably not shed muchlight on one of the most important ques-tions surrounding aging research—thatis, how scientists might move beyondsimply fighting diseases of old age tofinding ways of extending life span be-yond the current maximum limit ofabout 120 years.

To go further, investigators have be-gun to examine how overproducingsome proteins prolongs the lives of mi-crobes, flies and mammals. In yeast, ex-tra servings of a protein called Sir2lengthen lifetime, increasing the num-ber of times the organism can duplicate.In contrast, yeast harboring a defect inSir2 has a curtailed life span.

Yeast Sir2 keeps large stretches ofgenes turned off. Perhaps, as organismsage, they lose their ability to silence geneseffectively, suggests Leonard P. Guarente


DODDERING RODENT: A klotho mutant mouse(right) has a small, bent back, unlike a normalmouse (left), and a range of age-related disorders,such as atherosclerosis and osteoporosis.

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of the Massachusetts Institute of Tech-nology. In this scenario, activation ofparticular genes would spur changes inphysiology that lead to aging. Mam-mals, too, carry a Sir2-like protein, and itmay function in a manner similar to thatof the one in yeast. Adding to the evi-dence, results in mice suggest that loss ofsilencing may promote mouse aging, saysBruce M. Howard of the National Insti-tutes of Health. Other genes increase lifespan when overproduced as well. In flies,extra copies of enzymes that neutralizeoxidants, harmful oxygen-containingmolecules, extend the insects’ lifetimes.

If natural aging results from generaldeterioration of various bodily functions,it might seem surprising that single mu-tations could dramatically lengthen life.Last year, though, researchers reporteda strain of mouse that can live almost athird longer than normal because of amutation in one gene.

It’s now known that single gene mu-tations in other organisms can lengthenlife span. Several long-lived worms carrymutations in a gene involved in a pro-cess that appears to use chemical signalsto trigger activities inside cells. Thegene resembles one in humans that en-

codes a protein that receives messagesfrom hormones such as insulin andgrowth factors. Researchers believe ge-netic alterations in the worms that ren-der this protein insensitive to such hor-mones increase their life span. No oneknows exactly how this works, but themutant worms—known as daf-2 mu-tants—increase production of enzymesthat protect cells from oxidants [see il-lustration at left].

Studying worms suggests a generalstrategy for antiaging therapies. “If ag-ing is regulated by a hormone, it canprobably be slowed by a hormone,”says Gary B. Ruvkun of Harvard Med-ical School. A drug that regulates sucha hormone, however, may be a mixedblessing. Some but not all mutationspredicted to decrease hormone signal-ing in worms also slow metabolism. Asfor possible antiaging treatments, what’sthe point of being alive if your metab-olism is so slow that you’re essentiallyasleep? Still, it’s possible that scientistscould find a hormone that affects lon-gevity but not metabolism. Drugs thattarget such a hormone might prolong lifewithout making people sluggish. Fur-thermore, many daf-2 mutants remainhealthy and vigorous for much longerthan their normal counterparts do, sug-gesting that extending life without slow-ing anyone down might be relativelyeasy, says Cynthia J. Kenyon of the Uni-versity of California at San Francisco.

Every organism has its idiosyncrasies,but many basic truths of nature applyacross the boundaries of species. Thediscovery of hormones that apparentlycontrol life span, or some aspect of age-related diseases in worms and mice,hints at a general biological mechanismfor health and longevity that extends be-yond any single organism. In the future,we may be able to apply lessons learnedfrom our simpler cohabitants to stayyounger and healthier ourselves.


Evelyn Strauss is a science writer basedin Santa Cruz, Calif.

Further InformationBasic information about progeria can befound at the Progeria Research Foun-dation site at http://progeriaresearch.org on the World Wide Web.

CELL TWEAKING: The reproductive and sensory systems of the worm Cae-norhabditis elegans send signals affecting activity of hormones that stimu-late the daf-2 receptor on certain cells (left). Experiments suggest that thosehormones influence longevity. Manipulated worms (right) live longer thannormal when their sensory nerves are cut (a), the hormone receptor is ge-netically inactivated (b) or particular reproductive cells are injured (c).

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TWO CLUES: Studies ofidentical twins —includingSonja Buth and Wilma Bruno(right)—in which only onesibling (Buth) has Alzheimer’smay determine to what extentgenes and the environmentcontribute to the disease.

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brains from going bad

THE FIGHT AGAINST TWO LIFE-ROBBING

DISEASES, ALZHEIMER’S AND

PARKINSON’S, HAS JUST BEGUN

It’s hard to believe now, but 30 years ago the av-erage layman and the average doctor thoughtthat “senility” was the result of either normalaging or hardening of the arteries. “What doyou expect from an old person?” people wouldsay. Mercifully, science has enlightened thisrather Dickensian view. Today we may be close

to understanding what causes the major neurolog-ical diseases of old age, which ravage mental andphysical function—the very stuff of life—and intheir extreme form can kill.

But that does not mean we’ve found cures for thefour million Americans suffering from Alzheimer’sdisease and the one million with Parkinson’s. Thenumbers could swell fourfold by 2040 as babyboomers reach old age. Legions of us worship atthe temples of Physical Fitness and Cooking Light,in an attempt to ensure strong bodies at retirement.But what can we do when it’s our brains that be-tray us?

The silent siege of Alzheimer’s causes a relentlessdeterioration of memory and bodily control. Thedisease is a formidable foe. Most Alzheimer’s pa-tients are in their 70s and beyond, and those whosurvive into its final stages lose the ability to speak,walk, even lift their head as their brain slowly shuts

BY MIA SCHMIEDESKAMP

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down. Given how debilitating the phys-ical throes are, it is confounding thatthe disease first appears years earlier asmental troubles such as chronic forget-fulness and difficulty handling routinechores. Indeed, the onset is so elusivethat doctors are only now determiningwhere normal aging of the brain stopsand Alzheimer’s begins.

The borderland is a state called mildcognitive impairment (MCI). Individu-als with MCI aren’t demented, but theydo perform worse than their peers onmemory tests. They sense they are for-getful, and somebody close to them hasprobably noticed it, too. Otherwise,they do quite well, although demandingtasks such as mastering new technologymay prove challenging.

People who meet the criteria for MCIwill evolve to clinical Alzheimer’s dis-ease at a rate of 10 to 15 percent a year,according to Ronald Petersen, directorof the Mayo Alzheimer’s Disease Cen-ter. “That’s in contrast to normal elder-ly people,”—without MCI—“who doso at a rate of 1 to 2 percent a year,” hesays. Barry Reisberg, clinical director ofthe Silverstein Aging and Dementia Re-search Center at New York University,finds similar trends. When he trackedpeople with MCI in their early 70s,about two thirds progressed to Alzheim-er’s within four years.

Images of the brain can help pinpointthose most at risk. The hippocampus—

a structure closelytied to memory—at-rophies and shrinksin Alzheimer’s pa-tients. The decline isevident even duringMCI. Someday a combination of memo-ry tests and magnetic resonance imagingmay offer early warnings to those des-tined for Alzheimer’s—valuable informa-tion if drugs are developed that can pre-vent the disease or stop its progression.

Elderly people who feel forgetful butperform well in cognitive tests—Pe-tersen refers to them affectionately as“the worried well”—develop Alzheim-er’s at much lower rates, about 12 per-cent over four years in Reisberg’s study.All that’s necessary, Reisberg says, is“to reassure them.”

Older people these days do seem quickto diagnose themselves or loved ones ashaving Alzheimer’s when they are justexperiencing simple forgetfulness. Theknee-jerk response is in part the resultof stepped-up media coverage.

So what should set off alarms? Fail-ure to remember important items withincreasing frequency, Petersen says—“things that you would have remem-bered without question six monthsago”—especially if other people alsosay they see a change in you. “It’s notthat you misplaced your keys,” addsRichard Mohs of the Mount SinaiSchool of Medicine. “It’s that you

can’t figure out what you would do toget them back.”

Mohs points out that everybody getsmore forgetful with age. “The rate atwhich people can put new informationinto memory does slow down. Whenthey say, ‘I forget more,’ it’s usually thatthey just didn’t learn it quite as well.”Elderly people can boost memory bytaking extra time and care to learn newinformation.

Rays of Hope

Once Alzheimer’s is diagnosed, fami-lies can brace for the future, butthe medical profession finds itself

at something of a loss. Neurotransmit-ter-boosting drugs such as Aricept helpabout 50 to 70 percent of patients, ac-cording to Peter Rabins of the JohnsHopkins School of Medicine, but theirefforts are modest. Rabins says, “I askfamilies to think back to what the per-son was able to do seven or eight monthsago; that’s an average improvement.”Although this reprieve is precious, it’sunclear if any improvement can lastlonger than a few months. For now,managing Alzheimer’s consists mainly of


BRAIN SCAN: Reds and yellows indicate a brain’s glucosemetabolism. There is a progressive decrease from a nor-mal older person (left) to mild Alzheimer’s (below) to ad-vanced disease (right), which resembles activity in an in-fant’s brain (far right).

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emotional and practical support, plusstrategies to help patients retain skillsand live a full life [see box on next page].

An ounce of prevention may be wortha pound of cure. Various studies, includ-ing a landmark University of Kentuckystudy of elderly nuns belonging to theorder of the School Sisters of NotreDame, suggest that the brain’s ability toresist dementia is greater if it has beenmentally stimulated throughout life. “Ifyou don’t use it, you lose it,” exhortsthe University of Kentucky’s WilliamMarkesbery, part neuropathologist, partpersonal trainer.

Richard Mayeux, director of the TaubInstitute on Alzheimer’s Disease and theAging Brain at Columbia University,also finds that people with complex jobs

have reduced risk of Alzheimer’s no mat-ter their education—suggesting againthat intellectual challenge throughoutlife is important. Mohs of Mount Sinaisuggests exercising the brain by read-ing, taking classes and joining intellec-tually engaging clubs.

Caring for the body is a good idea,too. People who are aerobically fit tendto suffer less cognitive decline with nor-mal aging. Intriguingly, when Fred H.Gage of the Salk Institute for BiologicalStudies in La Jolla, Calif., allowed miceto run at will—about five kilometers aday on average—they generated manymore new neurons in their hippocampi

compared with their cage-potato coun-terparts. Others have found that pro-longed stress actually leads to hippo-campal atrophy.

The search for ways to slow or pre-vent Alzheimer’s is widening. The nuns,as well as identical twins and a groupof women in upper Manhattan, are theprimary test subjects. Many of theSchool Sisters nuns donate their brainsto the University ofKentucky’s Sanders-Brown Center on Ag-ing; Markesbery, thecenter’s director, hasexamined them andothers. One remark-able thing he sees areorgans rife with the

lesions characteristicof Alzheimer’s—fromindividuals who werenot demented.

Perhaps these brainshad something extrain reserve, or maybethey avoided stroke.

Dementia from vascular disease aloneis fairly uncommon in the U.S. Butamong nuns with the brain lesions ofAlzheimer’s, those who also had tinystrokes were more likely to be dement-ed. To lessen the risk of stroke, Markes-bery advises people to eat right, exercise,not smoke, and keep blood pressureand diabetes under control—good ad-vice in any case.

Aging women in upper Manhattanpoint the way to another possible pro-tection: estrogen. “For women who tookestrogen in the postmenopausal period,the risk of developing Alzheimer’s dis-ease subsequently was reduced by half,”explains Mayeux, who monitored about

1,100 New York City women for up tofive years for the appearance of Alz-heimer’s. The women who had takenestrogen for longer than a year showedthe greatest benefit.

Studies in Minnesota, Baltimore andItaly have yielded similar results, andresearchers hope that estrogen can alsohelp prevent dementia in those withParkinson’s disease. But estrogen is a

powerful hormone; although manywomen take it to mitigate the effects ofmenopause, it is implicated in promot-ing certain cancers of the reproductivesystem. Until clinical trials better estab-lish the ratio of risk to reward, Mayeuxdoesn’t recommend taking estrogensolely to protect against Alzheimer’s.

Scientists are eager to devise drugsthat imitate estrogen’s positive role incognition without subjecting women toan increased risk of cancer. Estrogenmay stave off Alzheimer’s disease by di-rectly influencing nerve cells in thebrain. Researchers hope to find chemi-cal substitutes that affect only these cells.Such drugs might benefit men, too: malesproduce estrogen from testosterone, andtestosterone levels wane with age. Theright estrogen might delay Alzheimer’sin men without subjecting them to thefeminizing effects of traditional hor-mone therapy.

Other promising leads come fromstudies of identical twins. In the early


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Talk of an eventual cure for Alzheimer’s generates alot of excitement, but millions of people must dealwith the devastation of the disease right now. Much

depends on creative coping.Barry Reisberg of New York University has studied the

course of Alzheimer’s for more than two decades. He ar-gues that the characteristic decline can be understoodbest as a reversal of childhood development. The suffererincrementally loses the ability to handle finances, thento dress, then to be continent, speak, walk and sit up.

This view must be handled withcaution, so that the adults are notinfantilized. But it may be useful inguiding caregivers. “A [late-stage]Alzheimer’s patient requires thesame amount of care as an infant,”Reisberg says, and he doesn’t meanjust feeding and bathing. “You wouldread to an infant; you should bereading to the [late-stage] Alzheim-er’s patient, too.” What the Alzheim-er’s sufferer needs most is attentionand activity. Simple exercise reducesagitation. Visiting them when theyget restless at night calms them.

About two thirds of Alzheimer’s patients are cared forat home by family, according to Peter Rabins of theJohns Hopkins University School of Medicine. This canbe tough. The founding of the Alzheimer’s Association in1979 focused resources to help those family members,he says. What the families need is practical assistance: anaide to help with bathing, day care so the breadwinnercan work, and emotional support.

Teaching families specific coping strategies can allevi-ate depression—among patients and caregivers alike.“Oftentimes it’s just become this stressful, difficult situa-tion,” says Linda Teri of the University of Washington.“The patients can’t do things they used to enjoy, theyget frustrated, and the caregivers may not understand

what they still like to do.”One important focus is identify-

ing appropriate pastimes. The fam-ily members of one former profes-sor with Alzheimer’s discovered apleasant, stimulating activity afterrecalling how he loved doing theNew York Times crossword puzzle.They found a variety of children’sword puzzles he could still handle.“You give caregivers strategies,ideas,” Teri says, “and they comeback and say, ‘We had a nice dayyesterday. We haven’t had that in along time.’” —M.S.

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NEW DAY: Patients with advanced dis-ease relearn basic skills at the MariaWolff Alzheimer’s center in Madrid.

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1980s John Breitner, now at the JohnsHopkins School of Public Health, helpedto show that Alzheimer’s disease aggre-gates in families: “If you could followhypothetical relatives of somebody withthe disease, let’s say siblings, out to age90 or 95, then almost half those siblingswould themselves get the disease—amuch higher rate than in the generalpopulation.” To tease out how much ofthis aggregation is a result of genetic in-heritance, rather than shared family en-vironment, several groups studied theoccurrence of Alzheimer’s in identicaland fraternal twins. The studies suggestthat one half to three fourths of a per-son’s disposition to Alzheimer’s is in-herited. But that leaves plenty of roomfor outside influences.

At Duke University, Breitner and hiscolleague Brenda Plassman focused ontwin pairs in which only one twin hadAlzheimer’s. The disease often developsin the initially unaffected twin after alag, but in some identical pairs the sec-ond twin remains free of disease for 20years after it appears in the first, in onecase almost two decades. The research-ers studied the histories, lifestyles, infirm-ities and medications of many pairs.“What surprised us,” Breitner says, “wasan unexpected association between useof anti-inflammatory drugs and the ab-sence of disease in the unaffected twin.”

Many studies have since suggested thatnonsteroidal anti-inflamma-tory drugs, such as ibupro-fen, are associated with areduced risk of Alzheimer’s,but other results have beencontradictory. The jury isalso out on other substancesproposed as neuroprotective,including very high doses ofvitamin E, until more studiesare completed. The wait fordefinitive answers shouldn’tbe long. Several trials spon-sored by the National Insti-tutes of Health or pharma-ceutical companies are al-ready under way, testinganti-inflammatories and vi-tamin E in hundreds of sub-jects with mild cognitive im-pairment. A group led byBreitner at Johns Hopkinsis seeking over 2,600 older

persons with a family history of Alz-heimer’s-like dementia for a random-ized prevention trial that could naildown the role of anti-inflammatories.

Markesbery advocates a regimen in-cluding high doses of vitamin E, C andfolic acid, plus nonsteroidal anti-inflam-matories for those at highest risk of Alz-heimer’s—people whose close relativeshave the disease, for example. But physi-

cian supervision is required; some ofthese compounds thin the blood and cancause gastrointestinal bleeding. “Rightnow we’re not recommending it forthose who don’t have the risk factors,”Markesbery notes. Eric B. Larson, alongtime Alzheimer’s researcher at theUniversity of Washington Medical Cen-ter, says, “In my own practice, I don’trecommend taking any drug for theprincipal purpose of preventing cogni-tive decline. There’s nothing out therethat’s convincing enough.”

Greater insight may come from un-derstanding the mechanisms underlyingAlzheimer’s disease. There are many

competing theories. One of the strong-est—and the one most drug companiesare pursuing—is that the primary villainis a protein fragment called Aß (A-beta)that clumps into plaques in Alzheimer’s-affected brains. Aß results when a ubiq-uitous protein called amyloid is snippedto pieces by two enzymes called proteas-es. Aß is present in everyone, althoughno one is sure what it does. But when

disposal of Aß can’t keep up with itsproduction, trouble may loom. Variousgenetic mutations that cause rare early-onset Alzheimer’s increase the produc-tion of Aß, whereas two other genes al-tered in late-onset disease may be im-portant for clearing Aß.

Protease-inhibiting drugs are in theworks at several pharmaceutical com-panies, in hopes that simply cutting backAß production will prevent Alzheim-er’s. “Drugs are about to enter clinicaltrials. They really exist, and they reverseplaque lesions in mice,” reports DennisSelkoe of Harvard Medical School, whohas been hunting down Aß for years.

Similar medicines have metwith great success in the past,including the protease inhib-itors that have recently revo-lutionized HIV treatment. Buteven if the new drugs blockAß overload and plaque for-mation, it remains to beproved whether that’s enoughto beat Alzheimer’s. And thereare always worries about sideeffects.

Another promising ap-proach is vaccination to spurthe body’s own immune sys-tem to clear Aß. Mice thatoverproduce Aß develop Alz-heimer’s-like plaques as theyage; immunization with Aßnot only prevents the appear-ance of such plaques in youngmice but reduces the extent ofexisting plaques in older ani-


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AFTEREFFECT: In a Columbia University study, womenwho had taken estrogen for postmenopausal treat-ment also postponed the onset of Alzheimer’s.

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mals. Human clinical trials are now un-der way at Elan Pharmaceuticals, a firmin South San Francisco that Selkoehelped to start in the 1980s. “Drug com-panies are working 24 hours a day, andso am I,” he explains. “My wife says,‘Why don’t you get going—you’re goingto get the disease before you cure it.’ Idon’t want that to happen.”

Calming the Parkinson’s Storm

Stronger signs of hope for fightingneurodegenerative disorders may befound in the history of treatment for

Parkinson’s disease, which strikes atage 60 on average. With no reliabletreatment decades ago, its onset oftenmeant a quick decline to yearsof crippling tremors and ri-gidity. There has since beensome success with a drugcalled levodopa. The firstwhisper of tremor or a slight-ly odd gait means that a Par-kinson’s sufferer has alreadylost 70 or 80 percent of a tinysegment of the brain thatchurns out the signaling chem-

ical dopamine. Without dopamine, neu-rons that control motor activities gohaywire, leading to shaking, slownessand rigidity. As more and more dopa-mine-producing neurons die, suffererscan develop balance problems, crip-pling distortions of the hands and feet,and episodes of freezing in midstep.Late-stage Parkinson’s often means con-finement to bed and wheelchair.

Levodopa can’t halt the progress ofthe disease, but it can replace missingdopamine, with miraculous effect. Manyof those afflicted with Parkinson’s aresymptom-free after their first dose. Doc-tors started relying on the drug in thelate 1960s, and today it is almost uni-versally prescribed. “Levodopa was re-

ally one of the great biologi-cal successes of the century,”says C. Warren Olanow ofMount Sinai.

Like most classic heroes,though, levodopa has a darkside. At first, its benefits lasthours on end, but after five or10 years many patients takelevodopa much more fre-quently and still can’t get aconsistent effect. “You couldbe in a grocery store, reach-ing into your purse to pay,and all of a sudden you go‘off’—you can’t move, andyou don’t know when you’regoing to come ‘on’ again,”says neurologist Jerrold Vi-

tek of Emory University. “One patienttold me about being bent over his couchto pick something up, and he froze likethat for two hours.” Many people alsodevelop involuntary motions in responseto the drug.

The new challenge of Parkinson’streatment is to smooth out levodopa’seffect or retire the chemical altogether.One long-standing strategy is pairinglevodopa with other drugs. Some com-pounds ensure a richer stream of lev-odopa to the brain. Others act to delaytemporarily the onset of levodopa ther-apy as long as possible. Then there isbrain surgery. It turns out that certainneurons that go awry in Parkinson’s areactually hyperactive; by burning a tinyhole in specific brain regions, surgeonscan quell tremor and alleviate rigidityto various degrees.

But the burning may not solve allproblems, and it destroys brain cells,perhaps healthy ones needed for otherfunctions. More and more, surgeonsare switching to deep brain stimulation(DBS). In this technique, an electrodeinserted deep into the brain and pow-ered by a battery implanted near thecollarbone silences neurons that wouldotherwise misfire.

DBS can turn some patients’ livesaround. Before the new surgery in 1998,Vern Setterholm’s Parkinson’s diseasehad advanced to such a degree that hehad trouble handling silverware, dress-ing himself, even shaping his face into asmile. Now the tremor in the 81-year-old retired executive’s right hand is gone,he can grin, and he enjoys exercise classa few times a week. Asked whether he’dhave this new kind of brain surgeryagain, Setterholm shoots back, “If theywanted me tomorrow, I’d be there.”

Olanow says he has patients who are“totally unable to be controlled withmedicine. They are frozen, cannot move.We turn on the stimulator, and they getup and start walking. It’s absolutelyamazing.”

The use of DBS to control Parkinson’ssymptoms was pioneered in France. Al-though still experimental, using DBS inthe thalamus and other brain structuresto ameliorate crippling rigidity is be-coming more popular. One great pay-off: DBS often reduces the side effectsof levodopa, which can then continue


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SILENT SHOCK: Electrodesinserted deep into the braindeliver current from a bat-tery implanted near the col-larbone to quiet misfiringneurons that cause severeParkinson’s disease.


to be used to manage the disease. Ste-ven Gaede of St. John Medical Centerin Tulsa, one of the first Americans toperform the procedure, figures thatabout 1,000 DBS operations were donein the U.S. last year.

Currently DBS is used for advancedParkinson’s patients, those “at the endof the rope,” Vitek says. There’s talk ofstarting much earlier, to slow Parkin-son’s before its effects become extreme.Ethical questions abound, though; therisk of major complications is 3 to 5percent, and the benefits of early useare still highly speculative.

The next dream is replacing the dopa-mine-producing neurons that die in Par-kinson’s. In one experimental approachtried at several research centers, surgeonstransplanted human fetal neurons thatproduce dopamine into the brains ofParkinson’s patients, hoping to restoresome normal dopamine manufacture.They’ve achieved modest success so far.Ideally, the transplanted cells wouldcome from the patients themselves. Thisnotion was outlandish just a few yearsago, before scientists proved that evenadult human brains generate new neu-rons from precursors known as stemcells. Gage of the Salk Institute says ofhis experimental work with animals,“We and others have shown that if youtake primitive cells from a lab culture,you can actually put them into parts ofthe brain that are damaged, and theycan turn into cells that are appropriatefor whatever is happening in that partof the brain.”

Physicians are eager to harness thisastonishing potential. Already neuro-surgeon Michel F. Lévesque of theCedars-Sinai Medical Center in Los An-geles has launched the first clinical trialusing patients’ own cells for transplant.From a snippet of brain taken duringsurgery, he says, “we are able to identi-fy about 10 to 15 neural stem cells onaverage.” Properly fed, these cells mul-tiply into the millions over four to sixmonths and are coaxed into becomingdopamine-producing neurons that canbe placed back in the patient’s ownbrain. Levesque has performed one suchtransplant so far and expects to do 12more, but it’s far too early to judge theresults.

Perhaps the only breakthrough more

exciting than giving people a shiny newset of dopamine-producing neuronswould be helping them keep the origi-nals. But no one knows what causesParkinson’s disease. The idea of a toxinis intriguing. In the 1980s drug addictswho shot up with a relative of morphineresembling a pesticide came down withthe classic symptoms of Parkinson’s.Vitek says that although some patientsseem to be genetically predisposed toacquire the disease, it’s also possible that“exposure to an environmental insultgets the ball rolling.” The details re-main a mystery.

Researchers are busy testing hundredsof drugs, hoping to toss a molecularmonkey wrench into whatever process

kills the neurons. The most promisingclinical trial began in the late 1980s andinvolved 800 early-stage Parkinson’spatients at 28 research centers. The pa-tients given a drug called selegiline de-layed levodopa therapy about ninemonths longer than those on a placebo.It’s not clear how much of the effectwas a result of preventing the disease’sspread, rather than relieving its symp-toms. (The brains weren’t dissected be-cause the patients still needed them.)“But there is no question that selegilineslowed the appearance of disability inParkinson’s patients,” says Olanow, whosat on the study’s steering committee.Whether for treatment or prevention,that’s good news.


Mia Schmiedeskamp holds a Ph.D. in biochemistry and contributes regularly toScientific American Presents.

Further InformationAlzheimer’s Disease: A Guide for Families. Lenore S. Powell and Katie Courtice.Perseus Press, 1993.

The Alzheimer’s Association outlines strategies for coping and has details of treat-ment at www.alz.org on the World Wide Web. By telephone, call 800-272-3900.

The American Parkinson’s Disease Association offers information on treatmentand helping patients at www.apdaparkinson.com on the World Wide Web. Bytelephone, call 800-223-2732.

VISIBILITY: Awareness of Parkinson’s has been raised by public figures, such asU.S. Attorney General Janet Reno, who have disclosed they are battling the disease.

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To a degree, we are all ticking time bombs. As we eat, sleep, thinkand work, our cells divide again and again. Randomly over time,occasional bad copies are created. Meanwhile external insultssuch as tobacco smoke trigger other mutations. Most of the sin-ister cells are too crippled to survive, but some do. And some-times they undergo further aberrations. When enough mutationshave occurred, the result can be cancer.

“We are all walking around with millions of premalignant cells,” ex-plains Robert A. Weinberg, professor of biology at the Massachusetts In-stitute of Technology’s Whitehead Institute. “If we live long enough, we’llall come down with one form of cancer or another.”

After decades of research, scientists are getting a more complete pictureof cancer. Most cancers do not suddenly spring up and run wild. They de-velop over many years, as a result of biochemical and genetic changes thatpush healthy cells into a precancerous state and later into cancer. Thisgreater understanding is now prompting researchers to find drugs that canintervene early in the process, rather than be resigned to battling cells thathave already become malignant.

In the short term, this “chemoprevention” strategy will probably involvechemical compounds that retard the proliferation of cancer cells in patientswho have had cancer surgery, chemotherapy or radiation, buying themmore years of life. In the longer term, it is hoped that these agents can slow,stop or even reverse precancerous cells from developing into the full-blowndisease. Ultimately, drugs would prevent normal cells from even startingdown the path to malignancy.

At the same time, researchers are trying to develop cellular imaging teststhat would indicate mutations early in the precancer stage, giving far moreadvance notice of potential trouble than do current screening tests such asPSAs, which indicate the likelihood of prostate cancer. If such early indica-tors proved reliable, they could be used throughout life, and at the firstsigns of trouble a chemoprevention strategy could be set in motion.

Because the road to cancer often takes place over 20 years or more, it isa disease skewed toward old age. Cancer is rare among children. The me-dian age of a U.S. cancer patient is 70, according to the National CancerInstitute. The odds of getting cancer after age 60 are 16 times greater thanbefore age 40, according to the National Cancer Institute.

Although we all carry around mutated cells, it fortunately takes a num-ber of mutations acting in concert to create problems. Michael B. Sporn,professor of pharmacology and medicine at Dartmouth Medical School,

ancerbefore it starts

BY KEN HOWARD


suggests we think of our body “as aknit sweater with 100 fibers goingalong the x axis and 100 fibers alongthe y axis. If you have one tear, you stillhave a functional sweater. But if you getenough tears, it’s no longer a functionalunit. The nature of carcinogenesis isone of increasing disorganization.”

The number of tears any individualsustains in a lifetime depends on anoverwhelming number of variables,from inherited genes to diet, environ-ment and lifestyle. But the time lag be-tween the early stages of the processthat leads to cancer, called carcinogene-sis, and full-blown cancer gives scien-tists a window of opportunity to stopor at least slow the process before can-cer emerges. Recent trials indicate thatcertain chemicals can indeed interruptthe steady progression from normal tocarcinogenic cells.

Don’t Wait

Cancer chemoprevention research is10 to 15 years behind cancer treat-ment research, but the field is

evolving, says David S. Alberts, directorfor cancer prevention at the ArizonaCancer Center in Tucson. “We have alot of work to do, but it makes moresense to treat precancerous lesions thanto wait for people to develop cancer.”

The idea of prevention was demon-strated in practice in 1998, when a his-toric study with a drug called tamox-ifen demonstrated that agents could beintroduced into patients to prevent can-cer from occurring. The Breast CancerPrevention Trial (BCPT) of 13,388

women at increased risk for breast can-cer showed a 49 percent reduction inbreast cancer risk for women taking ta-moxifen versus a placebo. The resultwas so dramatic that researchers identi-fied those subjects taking the placebobefore the trial ended, so they could be-gin taking the drug.

“The study proves for the first timethat you can decrease women’s chancesof getting breast cancer by taking a pill,”says Therese B. Bevers, medical directorof the M. D. Anderson Cancer Preven-tion Center in Houston. Soon after theresults were announced, the Food andDrug Administration approved tamox-ifen as the first drug that can be pre-scribed to reduce the risk of a cancer.

Tamoxifen is far from perfect, how-ever. The trial linked it with an in-creased risk for endometrial cancer andpulmonary embolisms. Over the next10 years, tamoxifen will be comparedwith another drug, raloxifene, which isused for treating osteoporosis. Duringan osteoporosis trial, it was observedthat women on raloxifene had a 76 per-cent decrease in risk for invasive breastcancer, but there was no correspondingincrease in risk for endometrial cancer.The Study of Tamoxifen and Raloxi-fene (STAR) has already begun to enroll22,000 postmenopausal women and willfollow their progress over five years.

The trial may offer clinical corrobo-ration in humans of cancer preventionseen in animal studies. Tamoxifen andraloxifene are known as selective es-trogen receptor modulators (SERMs)—chemicals that block estrogen receptionin some tissues while mimicking the hor-

mone’s effect in others. Animal studieshave shown that the use of two SERMagents with different mechanisms of ac-tion—in these cases, fenretinide and ta-moxifen—can suppress cells’ advance-ment from precancer to cancer.

Developing a Preventive Arsenal

Discovering a prevention pill for anyone cancer will nonetheless provedifficult. In breast cancer, for in-

stance, a variety of mechanisms are im-plicated, and there are various types ofbreast cancer that respond differentlyto hormones such as estrogen. “Canceris not one disease but hundreds of dis-eases,” emphasizes Steven K. Clinton,program leader for cancer preventionand control at the Ohio State Universi-ty Comprehensive Cancer Center.

Many cancers, however, harm similartissues in the body, such as the epithelialtissue that lines all internal organs.“Over half of cancer deaths in adultsare epithelial, including cancers of thelung, breast, prostate and colon,” saysDartmouth’s Sporn. “From what weknow, you have to have a lot of muta-tions—a series of multiple hits—to leadto cancer.” Because the hits accumulatewith age, intervening early could pre-vent our cellular sweater from sustainingtoo many tears as we get older and older.

The approach, then, in designing drugsto thwart carcinogenesis is to take aim atvarious points in the process where mu-tations may occur. One target is drugsthat limit the damage from substancesthat can cause cell mutations, such as to-bacco smoke, environmental pollutants


the progression towardcancerous cells

normal precancer cancer

Cells don’t “switch” from normal to cancerous. Over time,biochemical and genetic changes may cause cells to ad-vance gradually in a process of carcinogenesis from normal

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and anything toxic we may eat—from ni-trosamines in bacon to pesticide residuein fruits and vegetables. Another target isto stop random genetic miscopies fromgoing further down the road towardcancer. A third target is to intercept “freeradicals”—errant oxygen molecules re-leased during normal cellular metabo-lism that can damage cells and possiblytrigger genetic mutations. Antioxidantscurrently under study include selenium,beta-carotene and vitamin E.

Some unusual cases of cancermay provide opportunities totest the chemoprevention strate-gy. For example, people with theinherited disease familial adeno-matous polyposis (FAP)—about1 percent of colon cancer pa-tients—are at very high risk forcolon cancer. They are born witha mutation in their Apc gene, atumor-suppressant gene whosemain job is to prevent cancercells from multiplying uncontrol-lably. It leads to “lots of polypsin the colon, and 100 percent ofthe patients then develop colo-rectal cancer at a young age,”

explains Waun Ki Hong, professor ofmedicine at the M. D. Anderson CancerCenter. The current standard of care isprophylactic removal of the colon. Butrecent understanding of the carcinogene-sis of colon cancer indicates possible ad-ditional forms of treatment. Preliminarydata suggest that two anti-inflammatorydrugs, sulindac and celecoxib (Cele-brex), may reduce the number of polypsin FAP patients enrolled in clinical trials.But the long-term efficacy is uncertain.

Clinical trial data on sulindac indicatethat polyps regress while such drugs areadministered but may recur afterward,according to Robert J. Mayer, directorof the center for gastrointestinal oncolo-gy at the Dana-Farber Cancer Institutein Boston.

It is still unknown whether Celebrexwould reduce cancer in the generalpopulation, and even if it did, the drugmay have potentially adverse side ef-fects, perhaps on other organs. Investi-gators have already begun to look at abroader group of patients, those withsporadic adenoma polyps, of whom 30percent will have additional polyps af-ter three years. If the drug is deemedbeneficial and safe after a three-year tri-al, researchers might move to largerpopulations at less of a risk.

Future Prevention Trials

The design of trials for larger popula-tions will be aided by better under-standing of specific carcinogenesis

pathways. Work on the Human Gen-ome Project may contribute throughthe identification of genes that may fos-


thwarting

major killers

Most cancers stem from an accumulation of genetic faultsand exposure to environmental hazards and carcinogensover time. Preventive strategies, such as not smoking and

good diet, can reduce cancer risk, but don’t be lured by fads orpills that can purportedly “prevent” or “cure” cancer. “There are alot of people who promote substances in health food stores andsupermarkets,” says Steven K. Clinton, program leader for cancer

prevention and control at the Ohio State University Comprehen-sive Cancer Center. “These people are entrepreneurs and not sci-entists. They are selling $50 bags of garbage.”

For those of us who’d like to do something reputable to per-haps increase our odds of escaping cancer, here is the acceptedmedical wisdom, according to “7 Ways to Prevent Cancer,” bythe Harvard Center for Cancer Prevention at the Harvard Schoolof Public Health.

You can further improve your cancer defenses by knowing yourfamily’s history of cancer and getting recommended screeningtests at appropriate ages [see box on next page].

reduce your

risk of cancer

to precancerous to cancerous. Today’s treat-ments attack only the last stages. The goal is todetect this growth earlier and intervene.

Invasive carcinoma Metastasis

1. Eat a healthy diet. Make fruits and vegetables part of everymeal. Opt for chicken, fish or beans instead of red meat.Choose foods like pasta, brown rice and whole wheat bread.Lowers risk of cancers of the prostate, breast, lung, colon, rectum,stomach and pancreas.

2. Get at least 30 minutes of physical activity every day. Manyactivities count: walking, jogging, dancing. Any activity is betterthan none. Lowers risk of colon cancer and may lower risk of breastcancer.

3. Drink no more than one alcoholic drink a day. One drink isa glass of wine, a bottle of beer or a shot of liquor. Lowers risk ofcancers of the breast, colon, rectum, mouth, throat and esophagus.

4. Maintain a healthy weight. Lowers risk of cancers of thecolon, rectum, uterus and breast.

5. Don’t smoke. This includes cigarettes, pipes, cigars andchewing tobacco. Lowers risk of cancers of the lung, throat, pancreas, kidney, bladder, cervix, prostate, colon and rectum.

6. Protect yourself from sunburn. Stay out of direct sunlightbetween 10 A.M. and 4 P.M., the peak burning hours. Use hats,long-sleeved shirts, and sunscreens rated SPF 15 or higher. Donot use sunlamps or tanning booths. Lowers risk of skin cancer.

7. Follow safe sex practices. Some sexually transmitted infectionsare linked to cancers of the cervix, vagina, anus and liver. —K.H.



ter initiation of tumors. Epidemiologi-cal studies may also uncover precancer-ous associations. One example is the Al-pha-Tocopherol, Beta-Carotene CancerPrevention Study (ATBC), begun in1985 by the National Cancer Institute.The trial failed to demonstrate that beta-carotene prevented lung cancer for theFinnish smokers enrolled, but analysisdid show that the men in the vitamin E(alpha-tocopherol) arm of the study ex-perienced 34 percent fewer cases of pros-tate cancer and 16 percent fewer casesof colorectal cancer.

Discovery of biomarkers that are asso-ciated with precancerous lesions couldalso become an important tool in pre-vention studies. Myriad markers havebeen proposed, but none have yet been

validated. “We have nothing like LDL[the bad cholesterol] levels that are linkedto heart disease,” says Peter Greenwald,director of the division of cancer pre-vention at the National Cancer Institute.Finding a marker would improve re-search efficiency and save money. The

markers would also provide a basis forevaluation of the general population forrisk factors, helping doctors decide whomight be a candidate for a particularchemopreventive agent.

Other technologies to evaluate riskfactors are also being developed. Cur-rently there are only a few screening tests(such as the Pap smear for uterine can-cer) that are able to detect precancerouscells, allowing intervention before pro-gression to fully expressed cancer. Ifmore tests were developed, it wouldstill be difficult to access organs such asthe prostate, liver or breast as easily asthe cervix to get cell samples. And doc-tors can’t biopsy the entire population.Even if they could, the results wouldn’tsupport the effort: the likelihood of ac-tually hitting the specific spot in an or-gan where cancer may be developingwould be too small.

The grand solution would be theequivalent of x-rays on the gene level,so that an entire organ could be evalu-ated noninvasively. Unlike traditionalmedical imaging, which is based onmacroscopic information such as bonemass and blood flow, this “molecularimaging” could peer into cells at themicroscopic gene level, explains RalphWeissleder, director of the Center forMolecular Imaging Research at Mas-sachusetts General Hospital. Research-ers must understand more about molec-ular changes in precancerous cells, how-ever, before imaging schemes can bedevised. Weissleder estimates that prac-tical use of this tool “is decades away.”

What should people do until betterimaging technology, biomarkers andpreventive drugs arrive? Wait for moredata from the dozens of chemopreven-tion trials being supported by the Na-tional Cancer Institute. And keep eatingyour fruits and vegetables.


KEN HOWARD, a journalist based in New York City, is making sure that he eats plen-ty of grapefruit and carrots.

Further InformationPrevention of Cancer in the Next Millennium. Report of the ChemopreventionWorking Group to the American Association for Cancer Research in Cancer Re-search, Vol. 59, pages 4743–4758; October 1, 1999. (For reprints, call 215-440-9300.)

Harvard Center for Cancer Prevention (www.hsph.harvard.edu/cancer).

National Cancer Institute’s CancerNet (http://cancernet.nci.nih.gov/).

The American Cancer Society recommends the following tests to maximize early detection of cancer, thereby improving the chances for effective treatment.

GENERALA cancer-related checkup is recommended every three years for people aged 20 to 40, every year for ages 40 and older. Depending on age, the exam might checkfor cancers of the thyroid, oral cavity, skin, lymph nodes, testes and ovaries.

BREASTWomen aged 20 to 39 should have a clinical breast exam (CBE) every three years.Women aged 40 and older should have an annual mammogram and an annualCBE. All women should perform monthly breast self-examination.

COLON AND RECTUMBeginning at age 50, men and women should follow one of the schedules below:• Fecal occult blood test every year and a flexible sigmoidoscopy every five years.• Colonoscopy every 10 years.• Double-contrast barium enema every five to 10 years.A digital rectal exam should be done at the same time as sigmoidoscopy,colonoscopy or barium enema.

PROSTATEBeginning at age 50, men with a life expectancy of at least 10 years should have anannual prostate-specific antigen (PSA) blood test and a digital rectal exam. Men in high-risk groups (two or more affected first-degree relatives) and blackmen should begin at a younger age, such as 45.

UTERUSCervix: All women aged 18 and older (or younger if sexually active) should have anannual Pap test and pelvic exam. After three or more consecutive successful results,the Pap test can be performed less frequently, after discussion with a doctor.Endometrium: Women at high risk of uterine cancer should have a sample ofendometrial tissue examined when menopause begins.

early cancer detection

SOURCE: “Cancer Facts & Figures 2000,” American Cancer Society


Blood vessels are built to last. Up to about 100 years,some experts say, under normal wear and tear. Forthat to happen, you not only have to abide by aheart-healthy lifestyle—low-fat diet, weight incheck, exercise, stress management, blood pressurecontrol, good cholesterol numbers, moderate alco-hol use, no smoking—but you also should be a

woman, have the right genes and age slowly.Cut to reality: we’re not perfect. Our blood vessels endure

various assaults because of factors only some of which we

can control. We get heart disease—some 14 million Ameri-cans have it, and 500,000 die from heart attacks annually.The older we get, the more likely it is we’ll end up with it.The proof is in the numbers: heart disease affects an estimat-ed 15 percent of adults in their late 30s to early 40s, about 50percent of 55- to 64-year-olds, and 65 percent of those in thenext decade. Obviously, many of us slept through Heart Dis-ease Prevention 101.

Yet the heart cognoscenti say only half to three fourths ofheart disease cases result from the established risk factors. The


grow oldsaving hearts thatBY DELIA K. CABE

BETTER UNDERSTANDING OF ATHEROSCLEROSIS—THE INFLAMMATION AND BUILDUP

OF FATTY DEPOSITS IN BLOOD VESSELS—HAS TRIGGERED NEW APPROACHES

TO TREATING THE NATION’S LEADING CAUSE OF DEATH

BAD BUGS: Commonbacteria—Chlamydiapneumoniae (left),Helicobacter pylori(right) and othermicroorganisms—maycause infections thatlead to heart disease.

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rest come about from infection and otherfactors that may promote atherosclerosis,the buildup of fatty deposits in blood ves-sels. Indeed, current research indicatesthat all of us are in jeopardy from theleading cause of death in the U.S. “Every-one needs to maintain a healthy life-style,” says endocrinologist Joanne Man-son, chief of the division of preventivemedicine at Brigham and Women’s Hos-pital in Boston. “Everyone’s at risk.”

Efforts to find additional means ofpreventing heart disease have led to theunearthing of about 300 predictors, in-cluding bad relatives of the trouble-

maker cholesterol as well as bacteriaand baldness. Yes, baldness.

Manson and her colleagues at Har-vard Medical School, which is affiliatedwith Brigham and Women’s Hospital,published a study this year that foundthat hair loss, specifically on the crownof the head rather than at the front, islinked to a threefold greater risk ofheart disease in men. Blame it on malehormones. The connection may be ele-vated androgen levels, which are associ-ated with baldness and have beenlinked to atherosclerosis and a higherrisk of blood clotting.

Such a marker as baldness may seeman unlikely place to look for risk fac-tors. But in 1988 Manson’s group alsofound a correlation between height andheart disease. Let’s just say that tallerpeople are better off—perhaps becausethey have wider blood vessels. Such in-formation may help identify people whoare more prone to heart disease and maylead to better means for prevention andinterruption of disease progression tai-lored to an individual’s physiology. Thediscovery of many of these markersarose from a closer examination of thecycle of inflammation, plaque formation

and injury that causes atherosclero-sis, the forerunner to angina and toheart attack and stroke, the majorcauses of death and disability as wemove into later life.

The broadened understanding ofthe underlying causes of heart dis-ease has paved the way to potentialtherapies, including antibiotics andACE (angiotensin converting en-zyme) inhibitors. ACE inhibitorswere developed to control highblood pressure, but they have recent-ly been found to have therapeutic ef-fects in preventing heart disease.

Read My Lipids

Atherosclerosis, which begins inour teenage years and buildsup as we age, starts when the

smooth muscle cells underneath the endothelium, or inner lining, ofblood vessels release a signal in re-sponse to high cholesterol levels.This signal attracts monocytes—white blood cells that fight infectionand amass cholesterol, calcium andother substances. The resulting cheesymass, or plaque, bulges like a pim-ple. Over time, the endotheliumloses its elasticity and may rupture.This injury to the lining summonsclot-forming platelets, which fur-ther restrict blood flow through thealready narrowed artery. An inade-quate supply of oxygen-rich bloodto heart muscle may cause tempo-rary chest pain, or angina, and ifblood flow is completely cut off, aheart attack—in clinical terminolo-gy, a myocardial infarction. All thisfrom the best-known harbinger of


thwarting

major killersJO

HN

W. K

AR

APE

LOU

a primer on

vascular disease

OBSTRUCTIONS: The events that precipitate plaque-clogged blood vessels—the disease called atherosclerosis—begin when smooth muscle cells under-neath the inner cell lining, the endothelium, release a signal that attracts mono-cytes (a). These white blood cells migrate into and under the endothelium,where they amass cholesterol and other substances. The swollen endotheliummay rupture, drawing clot-forming platelets (b). The platelets may aggregatered blood cells and form a blood clot, or thrombus (c). The narrowed arterymay cause chest pain (angina) or, if completely obstructed, a heart attack (d).

MONOCYTE

SIGNALBLOOD

dc

b

a

PLATELET

PLAQUE (CHOLESTEROL

AND OTHER SUBSTANCES)

ENDOTHELIUM

SMOOTHMUSCLE

CELLS

TISSUE DAMAGEDIN A HEART ATTACK (MYOCARDIAL INFARCTION)

THROMBUS

RUPTURED ENDOTHELIUM

BLOCKEDARTERY


heart trouble, the lipid cholesterol. Butonly to a degree.

Cholesterol has been the cause célèbrein heart disease prevention. Fifty per-cent of Americans have elevated choles-terol levels. And the increase occurs nat-urally as we age—mostly after about age45 for men and age 55 for women.Women in their reproductive years tendto have lower levels than men of thesame age. After menopause, their chol-esterol levels rise. But we also shouldfault our lifestyles. Without a doubt,lowering dietary intake of cholesteroland saturated fats does wonders for theheart. The goal is to keep down bloodlevels of the bad cholesterol (low-densitylipoprotein, or LDL), behavior that canproduce a 25 to 35 percent reduction inwhat the pros term “cardiovascularevents”—that is, heart attacks, strokesand the like. At the same time, don’t for-get about raising your levels of goodcholesterol (high-density lipoprotein, orHDL), which mops up LDL.

But the picture’s more complex. Somepeople develop heart disease in spite ofattaining ideal lipoprotein levels. Forthem, an approach that goes beyondcontrolling cholesterol and other lipidsmay be in their future.

Six years ago researchers with theFramingham Heart Study (the decades-long study that brought us the term“risk factor”) identified a relative ofLDL called lipoprotein(a) as an inde-pendent risk factor for heart disease.Lp(a) fosters the deposition of choles-terol on artery walls and interferes withthe body’s means of dissolving clots.Lp(a) also enhances oxidation of LDL.

Oxidation is nature’s way of spoilingthings like food. But old food getsthrown out, whereas oxidized LDL staysin the bloodstream and penetrates theendothelium. Elevated levels of Lp(a),which are most likely genetic, place peo-ple in the “high risk” category, as woulda total cholesterol level greater than 240milligrams per deciliter of blood (mg/dl)or an HDL level less than 35 mg/dl.Blood tests to measure Lp(a) have be-come available, but Lp(a) is difficult tolower. Two therapies that show promiseinclude the vitamin niacin at prescrip-tion doses that are 100 times higher thanthe recommended daily allowance andthe hormone estrogen. In addition, a few

studies suggest that reduction in LDLsmay help.

But it now seems that some LDL par-ticles are worse than others. In the fewstudies done to date, people with pre-dominantly small LDL particles have arisk of heart disease between three andfour and a half times greater than thosewith large LDL particles. Why does sizematter? Small particles are more proneto oxidizing, damaging blood vesselwalls and invading them 50 percentfaster than larger particles to initiatecholesterol accumulation.

Looking for Little Stuff

Ablood test to measure LDL particles is useful in determining which drugswould be most effective in individ-

uals with heart disease or in those whohave a strong family history of it. For-tunately, current heart disease interven-tions cut down small-particle LDL levels.These include exercising, taking niacin(but only under a doctor’s supervision)or some cholesterol-lowering drugs. Dietcan also help lower triglycerides (an-other type of fat in the blood).

Even the good cholesterol, HDL, turnsinto a traitor in certain environments,much like a chameleon changes its col-ors in different surroundings, says car-diologist Alan M. Fogelman, executive

chairman of the department of medi-cine at the University of California atLos Angeles School of Medicine.

Normally, HDL prevents LDL oxida-tion. But he and other researchers haveobserved HDL in its other guise. Aftersurgery or during infections, atheroscle-rotic plaques burst more easily. Theseruptures may occur because the immunesystem has geared up to fight infection.In this environment, HDL changes intoa molecule that promotes LDL oxida-tion. If studies bear out this model, re-searchers could develop medications tothwart HDL’s metamorphosis.

The possibility that the inflammationwithin the blood vessel walls and the im-mune system’s response might be trig-gered by an infection led investigators totwo bacteria—Chlamydia pneumoniaeand Helicobacter pylori (the latter wasrecently deemed the culprit in stomachulcers)—and herpesvirus. Of these three,C. pneumoniae, which causes respirato-ry infections, has received the most at-tention. The burning question is whetherthis bacterium, which has been foundin 70 to 80 percent of plaques takenfrom heart disease patients, is an inno-cent bystander or an accomplice.

Cardiologists Jeffrey L. Anderson andJ. Brent Muhlestein of the University ofUtah are among several researchers look-ing for the answer. But these two col-


DU

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leagues were not about to take their cuefrom the scientist who gave himself anulcer by ingesting H. pylori. Instead ofhardening their arteries in the name ofmedicine, Anderson and Muhlestein opt-ed for studies on other animals. They setabout infecting rabbits, which normallydo not develop atherosclerosis, with C.pneumoniae. Plaques did indeed appear,and antibiotics reduced the number ofthese thickenings.

Having shown cause and effect, the

researchers set their sights on humanswith heart disease who had evidence ofpast infection with C. pneumoniae. Af-ter six months on the antibiotic azithro-mycin, the human subjects had a modestbut significant reduction in key markersof blood vessel inflammation: C-reac-tive protein, tumor necrosis factor, andthe interleukins IL-1 and IL-6, all ofwhich are released by the immune sys-tem. At the end of two years, Andersonand his colleagues hope to see at least a

50 percent reduction among those treat-ed with the antibiotic in the frequencyof heart attacks, angina, stroke, and pro-cedures such as angioplasty and bypasssurgery.

Anderson is among the investigatorstaking part in long-term trials now un-der way at several medical institutionswith large numbers of human subjects.If antibiotics do significantly reduce theincidence, physicians say this would bea major advance in heart disease treat-


ABarnes and Noble or Borders bookstore carries many of the 1,000 or so stress management guides, primers and tomes all intent on revitalizing, detoxing and stream-

lining the lives of road ragers and drivers in the fast lane, id-iots and dummies, managers and underlings, and a host ofothers based on the principles of Zen or the habits of zebras.The promise is inner peace and healing, emotional wellnessand self-renewal in six seconds, one minute, 16 minutes or aday. Or you could avoid sweat-ing the small stuff altogether.

Why the fervor to calm down?The most important reason canbe found in the title of a book,Anger Kills, written by psychia-trist Redford B. Williams, one ofthe pioneers in the researchlinking heart disease to Type Abehavior. Type A people arethose who are driven, tense,competitive and hostile, and hiswork showed that these folksare on the road to cardiac ruin.Stress may age their hearts fast-er than a New York minute—and it only gets worse as theyget older. A study conducted bypsychologist James A. Blumen-thal of Duke University MedicalCenter, where Williams is direc-tor of behavioral research, foundthat a group of physicians fromthe University of North Carolinaat Chapel Hill who scored in theupper half of a hostility ques-tionnaire administered at age 25had a four to five times greaterchance than those with lower

scores of developing heart disease by the time they were 50.Williams and others have since sifted through Type A char-

acteristics and found that some of the traits are worse foryour health. Overt anger has dire consequences, as Williamswrites. One study found that an episode of anger doublesheart attack risk up to two hours later. But no increased risk oc-curred in people who took aspirin, which prevents the bloodclots that could cause a heart attack. Such research hinted at aconnection between clotting tendencies and anger.

Now stress researchers are focusing on blood flow to theheart to try to uncover a direct relation between stress andheart disease. Ischemia, a lack of blood flow to the heart

caused by narrowed or blockedarteries, may produce transientchest pain called angina andmay lead to a heart attack. In the1990s several studies showedthat ischemia can be induced bymental stress in the laboratoryand by negative emotions indaily life. Hostility and anger wereusually the culprits.

Results of the largest study todate to measure the heart’s physi-ological response to stress—whichcombined blood tests and pres-sure measurements along withradionuclide angiography to viewblood flow through the heart—reached publication in the Jour-nal of Health Psychology earlythis year. Headed by psycholo-gist Mark Ketterer of Henry FordHospital in Detroit, the studyshowed that laboratory-inducedstress—especially anger and irri-tability—in heart disease pa-tients caused ischemia more thanhalf the time. Women, whomore readily acknowledge theiranger, fared better. Williams’s

HOT UNDER THE BREAST POCKET: James A. Blumen-thal of Duke University Medical Center uses medita-tion and other techniques to teach students strate-gies to quell anger and hostility.

LES

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ticked off:anger can knock you dead


ment. Heart patients who show theseinflammatory markers might be pre-scribed medication to combat the bac-teria. “Until that time, though, I thinkwe shouldn’t be giving antibiotics toour patients,” Anderson says, becausestudies are still ongoing.

Meanwhile cardiologists are assess-ing whether taking folate and other Bvitamins might lower heart disease rates.Accumulating evidence from the Physi-cians Health Study, the Framingham

Heart Study and others seems to pointto a direct relationship. And homocys-teine levels in blood could be the smok-ing gun. Homocysteine, an amino acidthat results from the body’s metabolismof food, may contribute to atheroscle-rosis and increase clotting because itmakes platelets stickier. In addition, ho-mocysteine may lessen the flexibility ofblood vessels, slowing blood flow. Inpeople such as older adults and post-menopausal women, who typically havehigh levels of homocysteine in theirblood, the risk of heart attack and strokeincreases. Folate and other B vitaminsmay bring about a decrease in heartdisease risk because they break downhomocysteine.

Folate in Your Diet

Randomized, controlled trials areneeded to determine if managinghomocysteine levels, as is done with

cholesterol, could join the list of heartsafeguards. Nevertheless, the AmericanHeart Association currently advocatesthat people who are at high risk forheart disease include more folate andother B vitamins in their diet—at least400 micrograms’ worth. That deed isaccomplished simply by eating a bal-anced diet that includes the already rec-ommended five daily servings of fruitsand vegetables.

High blood pressure, or hypertension,was long ago shown to predispose peo-ple to atherosclerosis, heart attack andstroke. Hypertension is indeed an afflic-tion of aging. The number of men andwomen with high blood pressure rapid-ly escalates in older age groups. Morethan 50 percent of Americans over age65 have high blood pressure. First-linetreatment to control hypertension in-volves a healthy diet, exercise andweight loss. If that fails, physicians pre-scribe antihypertensives such as ACE in-hibitors. Until the 1980s, the presumedand only benefit of ACE inhibitors wasthe foiling of the body’s production ofangiotensin, a chemical that constrictsarteries, so that blood can flow throughvessels easier. But new research indicatesthat ACE inhibitors do more. So muchmore that the HOPE study evaluatingthe effects of the ACE inhibitor ramiprilin 9,541 heart disease patients at multi-

ple medical institutions was stopped sixmonths early and its results released lastNovember, before publication, so thatstudy participants receiving a placebocould also reap the drug’s benefits.

“We got stunning results—more thanwe expected,” says study chairman andcardiologist Salim Yusuf of McMasterUniversity in Ontario. “It is like the dis-covery that cholesterol drugs lower risksof heart attacks.” The data showed a 22percent overall reduction of heart attacks,stroke or death from other cardiovascularcauses. The benefit was independent oframipril’s small reduction in blood pres-sure. In fact, most of the participants didnot have hypertension when they enrolledin the study. Ramipril, Yusuf adds, mayhave an important effect within bloodvessel walls, but it is unknown if otherACE inhibitors work in a similar fashion.Now physicians can offer one more pre-ventive approach to their patients.

But these pills and other advances aremeant for those of us who have flaunt-ed time-tested heart-saving advice orthe few who have only their genes toblame for abnormal lipid levels andsuch. As for waiting for that quick fix,researchers promise none. You can hopeand pray. Take it from the grand pooh-bah of heart health, American Heart As-sociation president Lynn A. Smaha: Newresearch findings hold promise but nocertainty of licking heart disease, so “inthe meantime, take care of yourself.”


Delia K. Cabe is a freelance writer basedin Boston who frequently covers health-related issues.

Further InformationSaving the Heart: The Battle to Con-quer Coronary Disease. Stephen Klaid-man. Oxford University Press, 2000.

The Michigan Electronic Library, a proj-ect of the University of Michigan andthe Library of Michigan, maintains aHeart and Cardiovascular System site:http://mel.org/health/health-disease-heart.html

Research projects on heart disease canbe surveyed at the Web site of the Na-tional Heart, Lung and Blood Insti-tute of the National Institutes of Health:www.nhlbi.nih.gov/

book is required reading in Ketterer’s stressmanagement classes, in hopes that thestudents recognize these tendencies inthemselves.

Blumenthal has also published severalstudies showing that stress serves as atrigger for ischemia. He has found thatstress management graduates experi-enced fewer ischemic episodes. But get-ting in touch with one’s angry side is agradual process among heart disease pa-tients in his classes. “It’s not as if a light-bulb goes off in their heads,” Blumenthalsays. In addition to observing other peo-ple, his relaxation wannabes learn to rec-ognize the physiological reactions to stressand anger, such as increased heart rateand muscle tension.

Once enlightened, the students learnstrategies to deal with their anger andhostility. Altering one’s thought patternsis vital. Easily angered people engage inall-or-nothing thinking, producing exag-gerated reactions to ordinary life eventsand taking everything personally. Blu-menthal teaches them these ABCs inanger management and illustrates with afamiliar situation:

Recognize Antecedents: You are driving,and a car cuts you off.Assess Your Beliefs: He’s out to get me.Know the Consequences: I feel angry.Dispute the Thoughts: The person wasrude, but it wasn’t directed at me.

Notice that there’s no E for yelling Epi-thets. Maybe if those ABCs appear onbumper stickers, road rage will diminish.And those bad drivers won’t give you aheart attack. —D.K.C.

thwarting

major killers



purgatory purgatory promised land orpromised land or


WHETHER OLD AGE IS WORTH LIVING DEPENDS LARGELY

ON MENTAL HEALTH BY CATHERINE JOHNSON

meditations on

quality of life


THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 93THE QUEST TO BEAT AGING

??

Isn’t it great that we’re all going to live to100? Sure ... if we can stay healthy thatlong. Will greater longevity mean 30 yearsof quality old age or a 30-year purgatoryof pain, disability and isolation? Most of

the scientific work on aging concerns the phys-ical body—genes, cells, organs, and plaques inthe arteries and brain. As our bodies last long-er, however, we face an increasingly dauntingchallenge to psychological well-being. Even ifwe live through bone loss, hearing decline,arthritis, heart trouble, cancer and a weak-ened immune system, the daily battles threat-en to wear down our spirit.

ED K

ASH

I


Indeed, with a growing arsenal ofcountermeasures to the physical ail-ments of aging, quality old age will de-pend more and more on good mentalhealth. And that’s a tough nut to crack,because age weakens our minds as muchas our bodies, severely challenging ourability to remain mentally acute andemotionally positive. There is hope,though: science is beginning to provideclues about how to overcome the majormental challenges of old age.

Battling Depression

People are notorious minimizers ofunpleasant realities. As Universityof California at Los Angeles psy-

chologist Shelley E. Taylor and othershave shown, “positive illusions” are astandard feature of the psychologicallyhealthy person. On the face of it, there’sno reason why people shouldn’t simplycontinue deluding themselves into oldage. Many do. When very old and sick

people are asked whether they wouldrather live one year in their current con-dition or die sooner in good health, theychoose quantity over quality.

Still, choosing to live instead of die isa far cry from enjoying a life that ishappy or even marginally satisfactory.The truth is, the elderly suffer very highrates of depression compared with therest of the population. Old age can bea mental grind.

Boston psychiatrist John J. Ratey, au-thor of the forthcoming book A User’sGuide to the Brain, sees a number of el-derly patients in his practice. “Loneli-ness is a huge issue for them. Theydon’t interact as much. They get a littledepressed because they’re losing peo-ple, structure, function and purpose.”Add the physical challenges, and a neg-ative feedback loop begins to spiral.They don’t feel like doing anythingproductive, physically or mentally. AsRatey observes, “They’re losing energy,arousal and vigilance. Going into retire-

ment the large majority of people think,‘Oh, I’m going to have so much time todo stuff,’ and then they end up watch-ing TV. Nonaction begets nonaction—these older people don’t move enoughand slide into lethargy.”

A global state of mental and physicaltorpor is not much of a life. But snap-ping out of depression by means of self-generated positive illusions gets harder,because with advanced age, positive il-lusions become difficult to sustain.

No one knows precisely why this isso, but researchers believe that age-related changes in the serotonin systemplay a key role. Serotonin is the neuro-transmitter most closely linked to feel-ings of happiness, confidence and calm,and it declines with age. Although theneurological basis of emotion is farmore complicated than the relative lev-el of one neurotransmitter, researchersnonetheless find that people with lowlevels of serotonin are more likely tofeel depressed, anxious or angry. Car-


By the time the average American has turned 70, theseven-day pill organizer may be overflowing with col-ored capsules. As medicine finds more fixes for the

maladies of old age, the elderly are in danger of becomingincreasingly dependent on scores of pills, reducing theirquality of life and potentially killing themselves via over-dose or unintended drug interactions.

The Golden Years are exactly the wrong time to face apanoply of pills. Neither our memories nor our kidneys areup to processing half a dozen different prescriptions half a dozen times a day. It’s just too easy to mess up (as thisauthor—a long way from “elderly”—discovered one morn-ing when she took her aging dog’s medication instead ofher own).

One major cause of the problem is polypharmacy—theprescribing of numerous drugs by different doctors for thesame person, often for the same disorder. The marketplaceis also implicated. “The elderly obtain drugs from many dif-ferent sources—over the counter, their local pharmacies,and mail-order sources their insurance companies man-date,” notes Joseph J. Bova, owner of Cary’s Pharmacy inDobbs Ferry, N.Y. “They can end up receiving the samemedication with different names and not realize they aretaking it twice.”

Brian White, a registered nurse at the Community Hospi-tal in Dobbs Ferry, says senior citizens are routinely admit-ted to the emergency room who are in grave danger fromoverdoses of necessary medication. And it doesn’t eventake an overdose to cause serious complications. “As youget older, you don’t metabolize drugs as efficiently,” Whiteexplains, “so medications can build to toxic levels in theblood. Just being dehydrated can cause a dangerouslyhigh level.”

the dangers of

overmedication

CONTRAINDICATION: Too many pills can confuse or harm.

meditations on

quality of life

CO

RBIS


olyn Meltzer, associate professor of ra-diology and psychiatry at the PositronEmission Tomography (PET) Center inPittsburgh, has found a 55 percent re-duction in serotonin receptors in oldersubjects. (Aging women suffer the fur-ther complication of a sharp decline inestrogen after menopause. Estrogen is aprecursor to serotonin in the brain.)

Battling depression becomes harderstill because the elderly find themselvesin the constant company of death. Oldpeople lose friends and loved ones atrates far higher than the rest of us. Andwhen you’re 90, you know that yourown death is likely to be close.

Reducing Stress

Maybe the most ironic fact concern-ing the neurology of aging is thatwhile practically every other sig-

nificant hormone in the body declinesprecipitously with age, cortisol, the stresshormone, shows no drop-off whatso-

ever. In fact, old people may show moresustained cortisol production when sub-jected to stress tests. Apparently, wesimply cannot exhaust the body’s abil-ity to flood itself with cortisol whenlife gets hairy.

This sounds like some malevolentGreek god’s idea of a joke. If so, it getsfunnier: the body’s ability to recoverfrom stress diminishes with age. Thestress from a virus, an argument with afriend or a dip in a cold swimming poolstays with you longer when you’re oldthan when you’re young. As we age, weget better at becoming stressed andworse at letting stress go.

Lower levels of serotonin combinedwith higher levels of cortisol make for aharsh cocktail. This is the very hormon-al makeup found in clinically depressedyoung people. Yet researchers are notsure how meaningful this resemblancemight be. Owen M. Wolkowitz, profes-sor of psychiatry at the University ofCalifornia at San Francisco, points outthat although the elderly have highercortisol levels, they are still within nor-mal limits. The real villain might be adrop in DHEA, a hormone that regu-lates cortisol. “DHEA goes down dra-matically with age,” Wolkowitz says.“The important thing may be the ratiobetween DHEA and cortisol.” The“grumpy old man” view of the agedtakes on new meaning considering thehormonal state elderly men (and wom-en) often endure. If your balance of cor-tisol is off, those crying children in thesupermarket can be really irritating.

Here again, negatives beget negatives.A person whose stress response systemis permanently stuck on high will devel-op strategies designed to limit his expo-sure to stress—strategies that are likelyto result in even less involvement withthe social world than his fading energyhas already decreed.

Stanford University neuroscientistRobert M. Sapolsky observes that whenold people are faced with a difficult situ-ation, they are more likely than youngerpeople to distance themselves from it. Itmay be that the intense stress reaction,accompanied by slow recovery time,makes the cost of a direct approach tolife’s stressors too great. Withdrawingfrom society, however, is one of the worstthings an elderly person can do; study

after study has shown that social sup-port and active engagement with otherpeople combat depression.

Taking Charge

Forcing yourself to fight depressionand stress requires initiative andplanning. But the single most funda-

mental change gerontologists see in thenormal aging brain is a 5 to 10 percentloss of tissue in the frontal lobes, whichare largely responsible for these veryskills, notes Mony J. de Leon, professorof psychiatry at the New York Univer-sity School of Medicine. Although thebrain declines slightly in size overall, noother part undergoes a change of thismagnitude.

The frontal lobes are the seat of whatneuropsychologists call “executive func-tion” (EF), a cognitive capacity definedin the 1990s. Executive function is a per-son’s ability to plan, organize time, stayfocused and motivate oneself. Any de-gree of impairment to EF is going tohamper an elderly person’s ability toward off depression by creating an ac-tive, purposeful and structured exis-tence—or even to want to do so. Rateyobserves that for all people, a sense ofpurpose in life—a mission—is essentialto happiness as well as to good brainfunction.

An impaired EF can also interferewith an individual’s ability to establishand maintain social support. Motiva-tion to see friends and family may wane.Unattractive personality traits may arise,making others less inclined to spendtime with that individual, because an-other EF function is impulse control.The “grump” was there all along, but itwas controlled. Now the older personcan no longer manage this behavior.

Stimulants may help counteract braindeficits such as frontal lobe loss. Rateyand his colleagues have begun to treatthe loss of energy associated with ad-vanced age with the new medicationProvigil, a novel compound that is thefirst to be approved for narcolepsy in 40years. No one has pinned down exactlyhow Provigil affects brain cells, but ithas been shown to promote alertness.Ratey describes one patient as “an 86-year-old woman who would have to re-turn to bed for hours each day because

SCIENTIFIC AMERICAN PRESENTS 95THE QUEST TO BEAT AGING

Better drug management strategiesare the key to safety. Bova cites the BrownBag program sponsored by New YorkState’s Pharmacists Society, available atmost pharmacies, as one approach. “Pa-tients are asked to bring in the contentsof their medicine chests for their phar-macist’s review,” Bova explains. “We canpick up problems such as duplication ofdrug therapy and help avoid mistakes.”Midwesterners can find local Brown Baghelp through the Meijer Online Pharmacy(www.meijer.com/pharmacy/ askpharm_frameset.html).

Ultimately, though, advances in medi-cine itself will provide the best solution.Researchers anticipate that when the Hu-man Genome Project is completed we’lldiscover hidden links among disorderswe have traditionally viewed as distinct. If,say, we find an underlying genetic linkamong heart disease, Type II diabetesand high blood pressure, it’s possiblewe’ll need only one highly refined medi-cation to treat them all.

Until then, if you’re elderly, keep the or-ganizer organized, and if you’re not, offerto help someone who is. —C.J.



of tiredness. Now she is ‘thrilled’ with arestored energy level and sense of well-being. Instead of being slumped over inbed, she is reading, catching up on hercorrespondence and exercising.” Rateyhas also found that Provigil can coun-teract the sedation that often accom-panies the many medications taken byseniors. Soon the elderly may routinelybe given medications like this to treatfrontal-lobe deficits.

Mental Exercise Pays Off

If by now you’re becoming depressedand stressed about the prospects for amentally healthy old age, cheer up.

Help may come from sustaining simpledaily habits in our lives. The key tacticis to keep challenging the brain.

Although some decline in hormonesis inevitable, mental decline is not. Oneof the most fundamental research find-ings of the 1990s—“the decade of thebrain”—is that neurons and their inter-connections can remain remarkably

plastic into one’s 80s and beyond. Thebrain is not a preset, unalterable net-work of cells. Aging connections canremain flexible, and new ones can evenbe formed, regardless of how old thatgray matter becomes. This is extremelyimportant because it indicates that thebrain can reroute connections aroundareas that may be growing rigid withage or even bring those areas back togreater functionality.

“The brain remains plastic untildeath,” says Arnold B. Scheibel, a robust78-year-old professor of neurobiologyand psychiatry at U.C.L.A. and formerdirector of the Brain Research Institute.“With plasticity we can short-circuitevolution. We can force ourselves toevolve within our own lifetimes.”

Scientists are only beginning to un-derstand how we can maintain ourbrain’s plasticity, but a few promisingavenues have been found. Physical ex-ercise is one. Although the mechanismhas not been pinned down, the physicalexertion of the cardiovascular and mus-

cular systems seems to keep the brainmore pliable. One study shows that aer-obic walking improves executive func-tion in people between the ages of 60and 75, and there is no reason to believethat this would not hold true for 80-and 90-year-olds. The subjects’ abilityto switch rapidly from one task to an-other improved, their distractibility de-creased, and their ability to stop doingwhatever they were doing (like takingtheir foot off the accelerator while driv-ing) increased.

All three of these skills, by the way,are the ones affected in childhood dis-orders such as attention-deficit hyper-activity disorder. It is easy to see howthe notion of old age as a second child-hood developed—and how age-relatedbrain deficits may one day be treated inmuch the same way.

There are reams of evidence that oldpeople who stay in touch with family,friends, church and society stay in bettershape physically and mentally. Dataeven show that an active social life bene-


Advocates of the right to die—as well as journalists

covering the issue—routinely raise the horrors of old age as an argument in favor of assisted suicide,

championed by Jack Kevorkian. But oldness, like beauty,is in the eye of the beholder. Although an 80-year-oldmight look miserable to amiddle-ager, she is mostlikely to compare herselfto a 90-year-old—and toconclude that she is doingreasonably well.

This positive outlook isa standard feature of hu-man psychology. Even ma-jor illness and loss cannotput a dent in an ordinaryperson’s sense of well-be-ing for more than a fewyears. In study after study,victims describe them-selves as being as happyoverall as they were be-fore their trauma.

The trick to happiness

may be social contact. Researchers have found that a sickor disabled senior who is surrounded by friends and fam-ily will tend to characterize his or her life as satisfactory.Studies by Joel Tsevat of the University of CincinnatiMedical Center found that 43 percent of his subjects in

the worst physical condi-tion and 51 percent withsevere pain described theirquality of life as good. Inshort, no one can divine anold person’s state of mindby looking at the state ofhis or her body.

It is a slippery slope frombelieving in assisted sui-cide to simply assumingthat a sick old friend orrelative wants someoneto help him or her die. Old-er Americans, who have astrong collective voice inpolitics and culture, shouldbe allowed to speak forthemselves. —C.J.

a right

to die?

ASSISTED SUICIDE CRUSADER: Jack Kevorkian.

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fits brain function as muchas physical fitness does.Staying socially active alsohelps maintain a positiveattitude, by improvingfeelings of self-worth. Onestudy showed that olderadults who attended reli-gious services at least oncea week had a survival ad-vantage over those whodid not attend. Whether itwas the activity or a spiri-tual boost, the message isclear: you’ve got to stayengaged.

Elderly people who sim-ply cannot get around mayfind help from the Inter-net. An aged person whocan no longer walk ordrive can find great cheerin keeping up with friendsand family via exchanginge-mail, electronic photosand on-line chats.

Perhaps the most criticalact in maintaining plasti-city is mental exercise. AsScheibel points out, mentalexercise keeps the brainalive. “We now realize,through some very exhaus-tive work, that the so-called aging brain is justas powerful in learning asyounger brains. The oldphrase ‘You can’t teach anold dog new tricks’ is sim-ply not true.” Indeed, men-tal challenges, from cross-word puzzles to political debates withfriends, keep neuronal connectionsstrong, just as physical exercise keepsmuscle fibers strong. The “workout”lesson is the same: use it or lose it.

Undertaking completely new hob-bies, vocations, or intellectual pursuitscan help even further. Learning in oldage may take a little longer, Scheibelsays, but we remain potential learnersour entire lives.

More exact advice on how to pre-serve mental health will surely expandas millions of baby boomers gray. Thesheer numbers will change everyone’sview of what old age can and shouldbe. Robust mental health will be seen

as an entitlement, not the minor mira-cle it is today. As a result, a significantsegment of medicine will change. “Ger-iatrics as a specialty is only 15 or 20years old—there was such a small clien-

tele until 25 years ago,”Scheibel says. “And re-search interest in aging goesback only another 15 yearsbefore that.”

At the social level, retire-ment will change substan-tially or be done away withaltogether. Scheibel him-self exemplifies the trend:forced retirement has beenabolished in the Universityof California system, andhe has continued to teachand conduct research atU.C.L.A. Scheibel believesthe social custom of retire-ment may itself be respon-sible for the loss of frontal-lobe function that we nowaccept as normal. He notesthat research work at theUniversity of California atBerkeley by his wife, Mari-an Diamond, “has shownthat if you stimulate [brainfunction] you keep it; if youdon’t, you lose it. One ofthe worst things we did forhigh-achieving people wasto make them retire. Nowwe’re developing legislativeacts to reject this.”

At 78 years old, Scheibelis a committed optimist.“In most cases,” he says,“aging brings about wis-dom.” The growing ranksof elderly, he feels, will be“like having a vastly ex-panded senate in our civi-

lization.” We humans will not go gentlyinto a 30-year state of disability and de-spair. Once we know what the prob-lems are going to be, we will do ourbest to figure out how to thrive.

SCIENTIFIC AMERICAN PRESENTS 97THE QUEST TO BEAT AGING

Catherine Johnson of Irvington, N.Y., is co-author with John Ratey of Shadow Syndromes (Pantheon, 1997).

Further InformationWhy Zebras Don’t Get Ulcers. Robert Sapolsky. W. H. Freeman, 1998.

Time of Our Lives: The Science of Human Aging. Tom Kirkwood. OxfordUniversity Press, 1999.

Treatment of Depression with Antiglucocorticoid Drugs. Owen M. Wolkowitzand Victor I. Reus in Psychosomatic Medicine , Vol. 61, pages 698–711; Septem-ber/October 1999.

USE IT OR LOSE IT: Physical exertion helps to keep thebrain supple; mental exercise keeps it sharp.

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How would the option of eternal lifechange the way we view ourselves andthe people close to us? In the epilogue tohis 1999 book Time of Our Lives: TheScience of Human Aging, Tom Kirk-wood explores these issues through animagined future in which people are reg-ularly rejuvenated by a technique calledfraitching. This technology harnesses themutability of stem cells, inducing themto migrate to particular parts of thebody and brain to replace older cells.Although fraitching has the potential to

extend human lives indefinitely, parent-hood comes with certain trade-offs thatprotect society from the perils of a worldin which death is a rarity.

Gregor had entered Miranda’s life ashort time after her ninth fraitch,which, she reflected, would put her

in her late 220s. Gregor himself wasthen nearing his third fraitch, whichmade him about 150 years her junior.Not that it mattered.

Miranda’s love for Gregor had taken

her by surprise. It had been immediateand deep, eclipsing the previous lovesof her long life. Make no mistake, Mi-randa’s earlier loves had lacked neitherwarmth nor joy. One of them even re-sulted in the birth of her cherished son,Nico, now one of her closest friends.But the problem, if problem it had been,was that Miranda had always held some-thing important in reserve.

Holding back from full commitmentwas a habit conditioned by the bound-less possibilities of an unlimited future.


cults of theuThe prospect of living forever, or at

least a millennium, has served as atheme for storytellers throughout

history. Although writers disagree overwhether freedom from death wouldlead to an enchanted existence, an eter-nity of boredom and decrepitude—ormore likely, some amalgam of the two—few doubt its power to fascinate people.The three excerpts from stories we havechosen (two contemporary, one fromthe 18th century) imagine how theachievement of a deathless existence, or the attempt to achieve it at all costs,might affect human society as well asthe tenor of people’s everyday lives.

COMPILED BY EUGENE RAIKHEL


The Immortal in the Mirror

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The only known strategy to cope withthis awesome prospect, short of mind-numbing drugs and escapist diversions,was to cultivate and preserve an exag-gerated love of oneself. In the early cen-turies after fraitch technology was de-veloped, the emotional burden of longlife was poorly understood and the sui-cide rate grew alarmingly high. Psycho-fraitching of the mind quickly becameas important as the regeneration of thecells and tissues of the body.

After their first meeting by the river,and during the heady weeks that fol-lowed, Miranda had been startled todiscover that Gregor loved her with an

intensity and passion that went way be-yond all of her previous experience.Not short of passion herself, Mirandafound her reserve and self-absorptionmelting away. She delighted in Gregor’spresence and he in hers. When Miran-da gave up her farmland home to livepermanently in the limestone caveswhere Gregor had carved his beautifuldwelling, her friends were jolted withthe shock. With the quaint exceptionof the Snuggees, a near-invisible sectthat inhabited the far north-east andpracticed, so it was said, the bizarrehabit of “family living,” most individu-als preferred to live alone, meeting by

choice to share bounded periods of time.Fifteen full and happy years passed

quickly in Miranda’s and Gregor’s lives,their time occupied with creative workand play. During these years, Miranda’slove for Gregor had grown ever strong-er and deeper, until the day finally camethat Miranda made the decision thatwould alter their lives for ever. Mirandadecided that she wanted to share withGregor the making of a child.

In a world freed from the necessity ofaging, the making of children had verygreat significance. Children were stillneeded to replace those who died fromaccidents or suicides, but the accidental


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death rate was so small that their pro-duction had to be strictly controlled.The method was simple and stark.Each individual at birth was geneticallyscreened and assigned the right to sharein the making of a certain number ofchildren. The usual number was two,but sometimes a smaller number wasawarded to limit the spread of harmfulgenotypes. Exceptionally, a person mightbe allowed three children if, for exam-ple, the recent toll of accidents had beenunusually great. The bonus of a thirdchild was awarded by random selection.

To guard against abuse ofthe quota system and to pro-tect against possible geneticdamage to the reproductivecells, which might have a verylong wait before use, all fer-tilizations were carried out in vitro from stored germcells. Once sufficient germcells had been removed tocold storage, the gonads wererendered sterile.

To share in the making of achild, a couple would declaretheir request in a civil cere-mony of great solemnity, andfollowing rigorous checks onquota status and genetic com-patibility, the fertilizationwould be performed. The re-sulting embryo would thenbe raised to term either with-in the womb of the motheror, as was increasingly thecustom, in fetal incubators.

For a person with a quota of two,like Miranda, the making of a firstchild was without major consequence.The parents might choose to participateclosely in the rearing of the infant, orthey might spend only occasional timewith their child, as they preferred. Theymight do so jointly or, more usually, asindividuals. A greater preoccupationwith self had weakened the traditionalbonding of parents with each other andwith their child.

In the interests of all, it had becomeboth custom and law that the primary

responsibility for the welfare and educa-tion of the child rested with the com-munity of which the child would, in duecourse, become a long-term participant.

However, the making of the finalchild of a person’s quota was an entire-ly different matter. The birth of this lastchild signaled the parent’s forfeiture ofthe right to any further fraitches beyondan immediate and final one, at the com-pletion of which a Capsule was im-planted. This terminal fraitch deliveredthe same rejuvenatory effects of the ear-lier fraitches, but the implanted Cap-

sule imposed a delayed sen-tence of death. At a randompoint in time, between 40 and50 years from the date of im-plantation, the Capsule woulddetonate, causing the release ofa sequence of neurotoxins thatwould bring painless death in 5days. Any attempt at surgicalremoval of the Capsule wouldtrigger immediate detonation.The bearer of such a Capsulebecame a Timed One.

It was this fate that Mirandaelected for herself when she de-cided to make a child withGregor.

From Time of Our Lives:The Science of Human Aging,by Tom Kirkwood, copyright©1999 by Thomas Kirkwood.Used by permission of OxfordUniversity Press, Inc., and Ori-on Publishing Group Ltd.


Upgrade or DieThe current obsession with aging mightpale in comparison with that of a soci-ety constructed entirely around the questfor youth, suggests cyberpunk authorBruce Sterling. His 1996 novel Holy Firedepicts a time one century from the pres-ent, where political power is held by“gerontocrats” and the economy fueledby the “medical-industrial complex.” Inthis world, living longer means taking a gamble on an “upgrade” that mightleave you with obsolete hardware.

There were a hundred clever ways tojudge a life-extension upgrade. Staywith the blue chips and you were

practically guaranteed a steady rate ofsurvival. Volunteer early for some bril-liant new start-up, however, and you’dprobably outlive the rest of your gener-ation. Keep in mind, though, that nov-elty and technical sweetness were noguarantees of genuine long-term suc-cess. Many lines of medical advance-ment folded in a spindling crash of

medical vaporware, leaving their sur-vivors internally scarred and psychical-ly wrecked.

Medical upgrades were always im-proving, never steadily, but with con-vulsive organic jumps. Any blue-chipupgrade licensed in the 2090s would be(very roughly speaking) about twice aseffective as the best available in the2080s. . . .

Given these circumstances, it was wiseto postpone your upgrade for as long as


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possible. The longer you waited, the bet-ter your choices would become. Unfor-tunately, the natural aging process neverstopped in the meantime, so waitingtoo long made you subject to serious cu-mulative damage from natural metabolicdecline. Sooner or later you had to holdyour nose and make your choice. Sincethe outcome of leading-edge researchwas unknown by definition, the author-ities could make no guarantees. There-fore, the pursuit of longevity was de-clared a fundamental freedom left tothe choice of the individual. The polityoffered its best advice, consensually de-rived in endless open meetings throughvast thriving packs of experts, but ad-vice was nothing better than advice.

If you were smart or lucky, you chosean upgrade path with excellent long-term potential. Your odds were good.You would be around for quite a while.Your choice would become and remainpopular. The installed base of userswould expand, and that would helpyou quite a lot. If anything went wrongwith your upgrade, there’d be plenty ofexpertise in dealing with it.

If you were unlucky or foolish, yourshort-term gains would reveal seriouslong-term flaws. As the years groundon, you’d become isolated, freakish,obsolescent. The truly bad techniqueswere the ones that complicated yourtransitions to another and better up-grade. Once your quality of life was ir-reparably degraded, you’d have nochoice but to turn your attention to thequality of your death.

There were various methods of hedg-ing your bets. You could, for instance,be conspicuously and repeatedly good.You always voted, you committed nocrimes, you worked for charities, youlooked after your fellow citizens with asmile on your face and a song in yourheart. You joined civil support andserved on net committees. You took atangible wholehearted interest in thebasic well-being of civilization. Thecommunity officially wanted you keptalive. You were probably old, probablywell behaved, and probably a woman.You were awarded certain special con-siderations by a polity that appreciatedyour valuable public spirit. You werethe exact sort of person who had basi-cally seized power in modern society.

If you were responsible in your owndaily health-care practices, the polityappreciated the way in which you easedthe general strain on medical resources.You had objectively demonstrated yourfirm will to live. Your serious-minded,meticulous approach to longevity waseasily verified by anyone, through yourpublic medical records. You had disci-pline and forethought. You could be

kept alive fairly cheaply, because youhad been well maintained. You deservedto live.

Some people destroyed their health,yet they rarely did this through deliber-ate intention. They did it because theylacked foresight, because they were care-less, impatient, and irresponsible. Therewere enormous numbers of medicallycareless people in the world. There hadonce been titanic, earth-shattering num-bers of such people, but hygienicallycareless people had died in their billionsduring the plagues of the 2030s and2040s. The survivors were a permanent-ly cautious and foresightful lot. Care-less people had become a declining in-terest group with a shrinking demo-graphic share.

Once upon a time, having money had

almost guaranteed good health, or atleast good health care. Nowadays merewealth guaranteed very little. People whopublicly destroyed their own health hada rather hard time staying wealthy—notbecause it took good health to becomewealthy, but because it took other peo-ple’s confidence to make and keep mon-ey. If you were on a conspicuously pub-lic metabolic bender, then you weren’t

the kind of person that people trustednowadays. You were a credit risk and abad business partner. You had pointsdemerits and got cheap medical care.

Even the cheap medical treatmentswere improving radically, so you werealmost sure to do very well by historicalstandards. But those who destroyedtheir health still died young, by com-parison with the elite. If you wanted todestroy your health, that was your indi-vidual prerogative. Once you werethoroughly wrecked, the polity wouldencourage you to die.

From Holy Fire, by Bruce Sterling,copyright ©1996 by Bruce Sterling.Used by permission of Bantam Books, adivision of Random House, Inc., andOrion Publishing Group Ltd.

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The Dreadful ProspectGerontology, the science of aging, fo-cuses more on improving mental andphysical health during the time we’vegot than on extending our natural lifespan. And for good reason. To live for-ever may not be to attain the exaltedstatus of the Greek gods. Long beforethe advent of the scientific study of theold, Jonathan Swift documented, in hisclassic account of the Struldbrugs fromGulliver’s Travels, why an eternity ofaging—absent the things that make liv-ing worthwhile—may not be somethingto wish for.

One day, in much good company, Iwas asked by a person of quality,whether I had seen any of their

Struldbrugs, or immortals. I said I hadnot; and desired he would explain tome what he meant by such an appella-tion, applied to a mortal creature. Hetold me that sometimes, though veryrarely, a child happened to be born in afamily with a red circular spot in theforehead, directly over the left eyebrow,

which was an infallible mark that itshould never die....

I freely own myself to have beenstruck with inexpressible delight uponhearing this account…. I cried out as ina rapture, “Happy nation, where everychild hath at least a chance for beingimmortal! Happy people, who enjoy somany living examples of ancient virtue,and have masters ready to instructthem in the wisdom of all former ages!But happiest beyond all comparison arethose excellent Struldbrugs, who, beingborn exempt from that universal calami-ty of human nature, have their mindsfree and disengaged, without the weightand depression of spirits caused by thecontinual apprehension of death!” …

I enlarged upon many other topics,which the natural desire of endless lifeand sublunary happiness could easilyfurnish me with. When I had ended,and the sum of my discourse had beeninterpreted as before to the rest of thecompany, there was a good deal of talkamong them in the language of the

country, not without some laughter atmy expense. At last, the same gentlemanwho had been my interpreter said hewas desired by the rest to set me rightin a few mistakes, which I had falleninto through the common imbecility ofhuman nature, and upon that allowancewas less answerable for them....

After this preface, he gave me a partic-ular account of the Struldbrugs amongthem. He said they commonly acted likemortals till about thirty years old, afterwhich, by degrees, they grew melancholyand dejected, increasing in both till theycame to fourscore. This he learned fromtheir own confession: for otherwise,there not being above two or three ofthat species born in an age, they weretoo few to form a general observationby. When they came to fourscore years,which is reckoned the extremity of liv-ing in this country, they had not only allthe follies and infirmities of other oldmen, but many more which arose fromthe dreadful prospect of never dying.They were not only opinionative, pee-

vish, covetous, morose,vain, talkative, but inca-pable of friendship, anddead to all natural af-fection, which never de-scended below theirgrandchildren. Envy andimpotent desires aretheir prevailing passions.But those objects againstwhich their envy seemsprincipally directed, arethe vices of the youngersort and the deaths of theold. By reflecting on theformer, they find them-selves cut off from allpossibility of pleasure;and whenever they see afuneral, they lament andrepine that others havegone to a harbor of restto which they themselvesnever can hope to arrive.They have no remem-brance of anything butwhat they learned andSTRULDBRUGS (1912), BY MILO WINTER

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observed in their youth andmiddle age, and even that isvery imperfect; and for the truthor particulars of any fact, it issafer to depend on commontraditions than upon their bestrecollections. The least miser-able among them appear to bethose who turn to dotage, andentirely lose their memories;these meet with more pity andassistance, because they wantmany bad qualities whichabound in others.

If a Struldbrug happen tomarry one of his own kind, themarriage is dissolved of courseby the courtesy of the kingdom,as soon as the younger of thetwo comes to be fourscore.For the law thinks it a reason-able indulgence, that thosewho are condemned, withoutany fault of their own, to aperpetual continuance in theworld, should not have theirmisery doubled by the load ofa wife. As soon as they havecompleted the term of eightyyears, they are looked on asdead in law; their heirs imme-diately succeed to their estates;only a small pittance is re-served for their support; andthe poor ones are maintainedat the public charge. After thatperiod, they are held incapableof any employment of trust orprofit; they cannot purchaselands, or take leases; neitherare they allowed to be witness-es in any cause, either civil orcriminal, not even for the deci-sion of meers and bounds.

At ninety, they lose their teethand hair; they have at that ageno distinction of taste, but eat and drinkwhatever they can get, without relish orappetite. The diseases they were subjectto still continue, without increasing ordiminishing. In talking, they forget thecommon appellation of things, and thenames of persons, even of those whoare their nearest friends and relations.

For the same reason, they never canamuse themselves with reading, be-cause their memory will not serve tocarry them from the beginning of a

sentence to the end; and by this defect,they are deprived of the only entertain-ment whereof they might otherwise becapable.

The language of this country beingalways upon the flux, the Struldbrugsof one age do not understand those ofanother; neither are they able, after twohundred years, to hold any conversa-tion (farther than by a few generalwords) with their neighbors the mor-tals; and thus they lie under the disad-

vantage of living like foreigners in theirown country. This was the account giv-en me of the Struldbrugs, as near as Ican remember.

The full electronic text of Gulliver’sTravels, which includes the account ofthe Struldbrugs in chapter 10, can bedownloaded without charge from Proj-ect Gutenberg at ftp://metalab.unc.edu/pub/docs/books/gutenberg/etext97/gltrv10.txt on the World Wide Web.


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My mother, who turns 39 next year (for thesecond time), says of her septuagenarian sta-tus, “I always wanted to look like ElizabethTaylor. And now I do.” Not everyone is sosanguine about getting older. Some of usfight it tooth and nail, both of which lookedwhiter and shinier years ago. A friend of

mine (really, it’s a friend, not me) has embarked on a life-ex-tension regimen that he expects will lead to birthday cakesvisible from space. My buddy gets regular aerobic exercise,avoids stress and eats a remarkably healthful diet consistingin great part of steamed vegetables. And garlic.

Garlic does indeed appear to impart a bounty of healthbenefits. According to published reports, garlic has proved tobe good for you in more than 1,000 studies. It seems to cutthe risk of various cancers; it lowers blood pressure; it wardsoff vampires; it lowers cholesterol; it has antifungal proper-ties. It also richly deserves its nom de fume: the stinking rose.

My friend, on learning of garlic’s health-enhancing powers,replaced the apple with a clove of garlic in the old proverb re-garding methods to keep the doctor away. He then extrapo-lated that if one clove per day was good, two or three mightbe even better. I saw him recently for the first time in weeks.As soon as I entered his apartment, the fragrance slammedme. As I got close to him, my eyes began to water. I instinc-tively (emphasis on the “stinct”) covered my nose with theback of my hand. “How many today?” I asked. “Seven!” hereplied proudly. I struggled for oxygen and muttered duringan exhalation, “Well, you’ll never get an infection, that’s forsure. No one’s ever going to get close enough.” Sitting in hisapartment, I slowly got somewhat used to the rich bouquetthat was making me a bit queasy and light-headed. I took afew sips of what I would have taken to be ordinary tap waterbut was in fact distilled, from his new home water distiller.

We soon left for a drive, during which we stopped at a lo-

cal natural foods store to pick up some supplies. (Apparently,I’m a health-food enabler.) While my friend wandered, pre-sumably examining the latest in garlic presses and garlic sup-plements, I perused the soy goods. Years ago I wrote a storyabout the possible benefits of soy and convinced myself thatthere was enough basic research on its anticancer and choles-terol-lowering powers to make a few of the bean’s products asmall part of my diet. I spotted and bought some soy-basedvegetarian pepperoni. A few hours later I adulterated a per-fectly respectable slice of Bronx-made Sicilian-style pizzawith thin slices of same soy. Though not terrible, it wasn’treal pepperoni. And it probably won’t happen again.

After stopping at my house for a while, we prepared to getback in the car. I then noticed that he had never taken off apair of thin glove liners while in my home. Now, I admit tobeing a lousy housekeeper—like nature, I abhor a vacuum—but I don’t think the place is actually dangerous. “You don’twant to touch anything here, do you?” I asked. He said,“No, I’m just chilly,” which may be true now that his body-fat levels are down to the point where even his nerve cells areprobably losing their insulation. But the sheepish grin on hisface convinced me that at least part of the issue might be my-sophobia (which sounds like fear of soy soup but is actuallydread of germs). “Listen,” I said, “I have one question. Howyou gonna keep those gloves on when your fingernails aretwo inches long, Howard Hughes?”

My friend could have the last laugh. I may be long deadwhen he is still steaming broccoli, distilling water and, ofcourse, gobbling garlic. But I figure, based on genes and mymore moderate but still relatively healthy lifestyle, that I havea solid 85 years in store, maybe more. And I swear to you, agood slice of Bronx-made Sicilian pizza really is to die for.

STEVE MIRSKY is an editor and columnist at Scientific American.

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