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Leah, 96. Photo by Hugh Wesley

Forever youngResearchers are using cutting-edge science in a quest to defy mortality. Howfar should they go? By Larry Krotz

ETHICS May 2015

In 1513, when the Spanish explorer Ponce de León was searching for the fabled fountain ofyouth, he went to Florida. After wading through malarial swamps, the legend goes, he cameupon some disease-free spring water around what would become St. Augustine. He declared itthe fountain of youth, and it became his fame. Five centuries later, when I am looking forsomething similar — an explanation for aging and an answer to the question of whether wemight do something about it — I get on a plane for California. My destination is the BuckInstitute, a stunning building of glass and white travertine stone designed by I.M. Pei and setlike a jewel on 200 hectares of wooded hillside in Marin County, north of San Francisco.

In 1900, the average life expectancy for a Canadian was 50. Some, of course, lived much longer,but those who died as infants or in childbirth or of various infections kept down the averages.By 1990, with improved sanitation, antibiotics, vaccines and better practices during childbirth,average life expectancy had risen to 74 for males and 81 for females. By 2012, it was 77 and 82.Could it improve any further? The low-hanging fruit has already been plucked. Further gainswould require crossing a new frontier: making old people live even longer — perhapsdramatically longer.

The Buck Institute bills itself as the world’s leading private institution dedicated to the study ofaging, and its scientists even coined a term for their investigation — “geroscience.” They dare toask: Why do we age? And is it possible to slow, stop or even reverse that process? Thequestions challenge assumptions that hold sacred places in our culture: that aging is a naturaland inevitable process, and death is as certain as taxes. How much should we tinker with whatmost of us believe is a set limit to the human lifespan?

As I started my research, I felt unsettled. Apparently I’m not totally enthralled about thepossibilities of science transcending nature. I couldn’t escape a feeling of disloyalty to the properrhythms of the universe. The Psalmist pegged the ideal human lifespan at threescore years and10, or even fourscore for the strong (that’s 70 or 80). We are told that Moses lived to 120, Noahto 950 and Methuselah to 969. But I always assumed those numbers were exaggerated — orsomehow from a different calendar. The longevity record in modern times is 122, held by aFrench woman named Jeanne Calment, who died in 1997.

It’s hard to argue that longer life is a negative thing. Yet there have always been opposing

camps. Aristotle described the elderly as those whose “passions have slackened, and they areslaves to the love of gain.” The centuries-long quest to turn nature on its head has includedsome wacky practices, such as implants of goat testicles and ingestion of radium-laced elixirs. In1934, poet W.B. Yeats emerged from what was in effect a vasectomy at age 68 claiming to befrisky as a colt. Scientific research into aging has roots in the 1960s, but it got going in earnestin the early 1990s with a generation of scientists who remain active today — several of them atthe Buck.

The Buck Institute was established by the estate of Marin County philanthropists Beryl andLeonard Buck. Leonard, a pathologist whose family owned an oil company, died in the 1950s.His widow, Beryl, died in 1975 expressing the desire “to extend help towards the problems ofthe aged.” Twenty-four years and several lawsuits later, the Buck Institute opened its doors,funded by income from the estate. Kris Rebillot, director of communications, explains that 17.5percent of the institute’s present annual budget of US$32.5 million comes from the Buck Trust.To support the work of the 229 employees, each of the 23 faculty augment this funding throughgrants.

Rebillot takes me below the gleaming upper floors into an underworld of laboratories chockfull of expensive equipment. Microscopes, freezers and cell-sequencing apparatus share space

UC Observer Buck Institute CEO Brian Kennedy talks to Larry Kro… Share

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with thousands of research subjects: mice and fruit flies, yeasts and microscopic worms. Thesetiny specimens are where the strategies that will someday be applied to humans are tested.Institute CEO Brian Kennedy has spent the past 25 years looking through his microscope atyeast. His colleague, Gordon Lithgow, has spent equivalent time with tiny worms called C.elegans. Judith Campisi and her post-doctoral students work with mice, while Pejmun Haghighispends his days with fruit flies. It’s not that we are reduced to these tiny beings, but the otherway round: to understand how the cells in more complex beings function, you need to startwith the single-cell organisms and work up.

Geroscience is different from research into the various diseases that hit us when we get old,though Haghighi (who is also on the faculty of McGill University in Montreal) looks for cluesto Alzheimer’s in the proteins of his fruit flies, and Campisi (who has a posting at theUniversity of Alberta by virtue of supervising one of its PhD students) hopes to postpone age-related cancer through what she is learning from the cells of her mice. Geroscience also differsfrom gerontology, the examination of everything to do with aging, including the socio-economics.

Lithgow, a Scot who maintains his soft brogue, explains that the beauty of his worms is their

UC Observer Judith Campisi, of the Buck Institute, talks to Larry … Share

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20-day life cycle. “Things go on in the worm during those 20 days that take 80 years in us.” Thehighlight of his career came in 2000 when he and a colleague changed a single gene andmanaged to make one of their worms live not for 20 days, but 40.

Campisi cranks up a PowerPoint presentation to explain what she has learned about how ourcells age and the mischief that leads to heart and vascular conditions, neuro-degeneration,diabetes, organ failures, osteoporosis and cancer. “The occurrence of these diseases risesexponentially after age 50 or 60, and the evidence is mounting that there is something about theprocess of aging itself that is driving them all,” Campisi says. “That is our hypothesis, and ifwe’re right, we will absolutely revolutionize modern medicine.” What she predicts is that thesilo model, where specialists look at one disease at a time, will collapse and geriatricians willinstead treat aging itself. The focus will be on avoiding or postponing disease by creating agenerally more healthy body that deteriorates more slowly. “It’s still a dream that we will be ableto tackle diseases in this way,” Campisi adds, “but it’s no longer science fiction.”

What Campisi, who hails from New York, has figured out over 35 years is that as we get older,multitudes of useless “senescent” cells impede our bodies from attacking all the above-mentioned diseases. In collaboration with colleagues at the Mayo Clinic, she has been able toinject powerful drugs that help mice get rid of senescent cells and, as a result, clear their bodiesof cancer tumours. It’s only a matter of time, she believes, until drugs achieve the same forhumans.

Integral to many theories of longevity is something called caloric restriction (CR). In the 1930s,scientists at Cornell University observed that severely restricting dietary calories in lab rats —while maintaining micronutrient levels — resulted in life extension. In subsequent decades,experiments have been carried out with dogs and primates, in all cases achieving extendedlifespans.

Severe calorie restriction, however, has side effects. No one wants to feel cold and experienceslower healing of wounds or reduced sex drive, acknowledges Brian Kennedy. “People don’twant to be malnourished, and few want to put in the effort to gather the knowledge to do it[CR] properly. You can’t eat two Snickers bars and call it a day.”

The trick, then, is finding a drug that will mimic what was achieved in the rat studies whileletting humans continue to eat normally — what’s known as a “mimetic.” Writer David Stipp,whose book The Youth Pill details research initiatives into human aging, states that CR mimetics

Nell, 88, and Ted, 83. Photo by Hugh Wesley

from the early 2000s began “to transform the anti-agingquest from an endless guessing game into a fairly routineexercise in drug development.”

Some initiatives have stumbled after promising debuts. Anexciting moment in the early 1990s was identifying the so-called French paradox: despite rich diets loaded with saucesand cheese, the French were discovered to have healthierhearts than Americans. Could it be because of the red winethey consumed?

Researchers soon isolated an ingredient called resveratrol.When tested on yeasts and finally on mice, it extendedboth lifespan and energy. Then it was acknowledged thatthe average person would have to drink 300 glasses of wineper day to replicate the dosage and effect.

Something currently considered promising is rapamycin, a member of a class of drugs calledmTOR inhibitors, and already shown to be capable of counteracting aging and delaying age-related diseases in mice and other animals. This is where Kennedy is directing much of hisresearch energy. In one trial, mouse lifespan increased by 38 percent. In 2014, thepharmaceutical company Novartis proved rapamycin safe for humans through a six-week trialwith older people who were also receiving the influenza vaccine. The drug zeroed in on agenetic signalling pathway associated with immune function and aging, and improved theparticipants’ immune reaction to a flu vaccine by as much as 20 percent.

The 25 years of Kennedy’s scientific career match the trajectory of modern aging research. Now51, the Kentucky-born scientist has been, since 2010, CEO of the Buck Institute after stints atMIT in Boston and the University of Washington in Seattle. “Skeptics have always argued thataging is a natural process, and you could never test drugs for aging in humans because youshouldn’t give drugs to healthy humans,” he says. He sees the work of his colleagues, both at theinstitute and in the increasing number of research programs in universities around the world,as preventative medicine. “We don’t want people living longer if it’s just prolonging their timesuffering the diseases of aging. We want to see if we can delay or postpone those. Peopleimagine we’re trying to make rich people live longer. We’re not doing anything different thanpeople targeting one disease at a time. We’re just trying to come up with an intervention that

will prevent multiple diseases at one time, something that will prevent cancer that, by the way,might also prevent Alzheimer’s.”

While the Buck Institute scientists seek pharmaceutical keys to extending longevity, that goalhas already been achieved elsewhere through more natural means. A decade ago, NationalGeographic writer Dan Buettner set out to find “blue zones,” places around the globe wherepeople seemed to live extraordinarily long lives — naturally. Buettner identified five: a corner ofthe Mediterranean island of Sardinia, Okinawa in Japan, Ikaria island in Greece, the NicoyaPeninsula of Costa Rica and — the next stop on my journey — Loma Linda, Calif.

Each blue zone community had its defining characteristic. What distinguishes Loma Linda isthe fact that most of the 23,000 people who live there are Seventh-day Adventists — the churchfounded in the 1860s that, among other things, follows Old Testament rules (no tobacco,alcohol or pork) and observes a strict Saturday Sabbath. Adventists are also deeply committedto health, having established hospitals all over the world. One of their largest health-carefacilities is in Loma Linda where, in 1905, Ellen G. White founded a nursing school thatbecame Loma Linda University; a community grew up around it. White’s 1905 book, The

Ministry of Healing, became a bible of proper nutrition.

Well before the arrival of Buettner, Adventists realized they had something special going on. In1960, 23,000 Californian members of the church joined the Adventist Mortality Study.Through it, they discovered that if the death rate from coronary heart disease in non-Adventists is taken as 100 percent, then deaths among Adventist men were only 66 percent ofwhat was expected (and 98 percent for women). Overall cancer deaths, again with the non-Adventist population as the standard, were 60 percent for Adventist men and 76 percent forAdventist women. Mortality was also lower with specific types of cancer: the lung cancer deathrate among Adventists was 21 percent; the colo-rectal cancer death rate was 62 percent; thebreast cancer death rate for Adventist women was 85 percent; and the prostate cancer deathrate for Adventist men was 92 percent.

In 1974, another study of 34,000 California Adventists began, this time to determine whatcomponents of their lifestyle contributed to the lower rates of diseases. Yet another study waslaunched in 2002, with 96,000 Adventists from across the United States and Canada. This one,which is still ongoing, is exploring the links between lifestyle, diet and disease.

Larry Beeson is a cheerfully relaxed professor at Loma Linda University’s School of PublicHealth. The 68-year-old, who sports steel-framed glasses and mutton-chop whiskers, classifieshimself as a “lifer.” Beeson came to the university as a student and was welcomed onto thefaculty in 1973. He’s been there ever since, teaching generations of students and joining theresearch into their one big question: Why do Adventists live to such a ripe old age? MaleAdventists outlive other men in California by 7.3 years, and female Adventists outlive otherwomen by 4.4 years. And not, emphasizes Beeson, seven and four dragged-out years but, by andlarge, vigorous, healthful, productive years. “We die in the end of the same diseases — heart andstroke and cancer — but we do it later and live well up until that end.”

Adventist studies compare the health and longevity effects of various diets. Beeson (whoconsumes eggs and milk but not meat) notes that vegans have the lowest rates of Alzheimer’sdisease and dementia, a number that climbs as more animal products are introduced. Avegetarian diet is recommended for church members but not enforced. The culture of the townsupports such a lifestyle with lots of vegetarian options and soy milk on restaurant menus andin grocery aisles. School cafeterias are vegetarian.

The conclusions of the studies reveal no mysteries to someone like Beeson who rhymes off theessentials: “Eat a plant-based diet; maintain normal body weight — avoid being obese; don’t

UC Observer Larry Beeson, with Loma Linda University’s School … Share

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smoke or drink, except lots of water; eat lots of nuts; maintain a faith base — bring God into thepicture.” This last point particularly intrigues him. “When Dan Buettner came here,” Beesonobserves, “the one thing that separated Loma Linda from the other blue zones was the 24-hourSabbath. That is, the time to de-stress, put my work aside and replace it with concentrating onmy relationship to God, to my family, to my friends.” In the current ongoing health study, asub-study, designed by psychologists and members of the faculty of religion, will try to quantifythe effect of being a religious practitioner on health and longevity.

What is it like to live in a town with a substantial population of seniors? As I drive around thespanking-clean streets, I note that the civic centre is promoting a scrapbooking workshop forseniors. The organic produce supermarket has basket-mounted scooters for mobility-challenged customers, as does the campus food market. But this is not a seniors’ community likeyou might find in Florida; Loma Linda is definitely mixed. When I peek in the door of theuniversity gym (which is open to the public), I note as many grey-haired persons as studentssweating on the machines. While seniors make up 14 percent of Loma Linda’s population(compared to the California average of 11 percent), there are also the 4,500 students at itsmedical schools (many of whom are Asian), as well as the university’s faculty and staff membersand their families. It is not a homogenous place.

Except in the religious sense. Rev. Randy Speyer, one of 17 pastors at the 6,500-member LomaLinda University Church, tells me that there are almost no churches other than Adventistinside the town limits, and 30 more Adventist churches in a 10-mile radius beyond the town.With those kind of numbers, it’s not hard to keep the Sabbath customs. Speyer spent 20 years asa counsellor in northern California before coming to Loma Linda’s church last year. This is thefirst time he’s been in such a monolithic community, as well as one with such a preponderanceof older people. Five of LLUC’s 17 pastors are dedicated to ministries with seniors. But somenoteworthy things are observable: the generations mix, and seniors teach children in Sabbathschool. Seniors also take leadership roles on committees and are committed to continuededucation. When people are spry and vigorous in their 80s and 90s, it redefines the term“seniors.” Lots of 65-year-olds, Speyer observes, remain working as teachers and doctors,enjoying their professions and the contributions they make.

As a man of a certain age, I’ve decided to embrace John Burroughs’s dictum that “old age isalways 10 years older than I am.” Yet, although I’d be happy to see aging postponed, I also feel Imust be prepared to gracefully leave the stage — not hog it at the expense of those coming afterme. Nothing in the healthy mix of generations in Loma Linda, nor in the modest and

reasonable goals of the Buck Institute scientists, offended that instinct. As Kennedy assured me,they’re not trying to make “rich people live longer.” In fact, they know they have big challengesstill ahead.

Lithgow acknowledged that what has most surprised him in the 15 years since the eurekamoment when his worm doubled its life is how slowly things have moved. “I guess we thoughtthat would be a watershed moment and the walls would come tumbling down,” he said. “Moneywould come into the field; pharmaceutical companies would pop up recognizing that aging anddisease were going hand in hand. It didn’t happen.” Instead, geroscience remains at the edge ofrespectability, with the pharmaceutical industry slow to invest because government regulatorsaren’t yet on board with anti-aging drugs.

“The complexities of humans still encompass huge unknowns,” Lithgow admitted. “There areholes in our understanding. The big challenge remains translating what we know fromstudying worms into something of import for humans. That is painstaking, time-consumingand expensive.”

Coincidentally, while I was travelling through California last February, Time magazine puthuman aging in the public eye, featuring a baby on its cover with the provocative headline,“This baby could live to be 142 years old.” The sensational pronouncement played into thehands of enthusiasts, who love to trumpet the possibilities of 90-year-olds who look and feel 45.

We already do take some things for granted. Today’s medicine prolongs life each time it treatsor cures an individual’s disease. But will a combination of drugs and geroscience prolong life forthe population as a whole? What about the more extreme possibilities of turning back the clock— actually making people younger? This has already been achieved in the labs: blood fromyoung mice has been transfused into old mice, heralding a futuristic horror show where the old,like vampires, might feed on the young. And despite Lithgow’s gloominess about financing,some very big players are showing up. In 2013, the Internet giant Google set up Calico(California Life Company) with an investment reputedly in the range of $1 billion. Thespecifics of Calico remain secret, but its project is generally to “harness advanced technologiesto increase our understanding of the biology that controls lifespan.”

This brought me rudely back to reality. Science will plow forward, but so will theaccompanying implications. In her lead essay in Time, Laura Carstensen, founding director ofStanford University’s Center on Longevity, postulates that “our aging society presents

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challenges every bit as fundamental and pervasive as climate change and globalization.”Carstensen’s centre, established in 2006, has charted how quickly the demographic structure hasbeen reshaped. Once a pyramid, with a small quotient of elderly at the top, it now looks morelike a rectangle, with the aged population equal in number to the young. The implications ofthis shifting demographic are both financial and structural (things like architecture with nostairs or automobiles that drive themselves). But they’re also ethical. How will the changingdemographics affect things like global population pressures, demand for resources and politicaltensions between the young and the old?

The idea of a fountain of youth retains its imaginative power, and the possibilities are moreenticing than ever. But the issues at play are not simply scientific. And we’re going to have tostart talking about them.

Larry Krotz is a journalist and author in Toronto.

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