antioxidants, mitochondrial damage, and human aging

8/12/2019 ANTIOXIDANTS, Mitochondrial Damage, And Human Aging

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ANTIOXIDANTS,MitochondrialD amage, and Human ging Y Edward R. Rosick, DO, MPH, MS

Ihroughout history, scientists have sought strategies forwarding off the seemingly inevitable processes of agingand death. In recent decades, the free radicaltheory of

aginghas shed light on the de gene rative changes that occur aspeople grow older.This theory holds that the body produces reactive, unstableagents known I s, free radicals during normal metabolism andfollowing exposure to ultraviolet l ight or environmental tox-

i n s While natural antidotes to these free radicalsinternallyproduced antioxidautsare ab un dan t in you th, their levelsdec line with age. T h e imba lance be tw ee n free radicals and theant ioxidants need ed to inact ivate, or que nch , them leads toa generalized state of oxidative stress that can da mag e l ipids,proteins, DNA, and mitochondria throughout the body. Oxida-tive stress has been associated with myriad disease processes,including cancer, heart disease, and Alzheimer's .

Scientific research suggests that minimizing deleterious freeradieal reactions by ensuring optimal antioxidant levels may holdthe key to extending the healthy human life span. Studies haveshown that people who live to be 100 years or older often demon-strate higher blood levels of antioxidants than their m uch youngercounterparts. Furthermore, antioxidants may help protect againstmitochondrial dysfunction, another harmful condition thatcommonly accompanies aging and disease states.Numerous antioxidantslipoic acid, green tea polyphenols,lycopene, and vitamins A, G, and Ehave been associated withprotection against many affiictions that commonly accompanyaging, such as Alzheimer's disease, muscle loss (sarcopenia),cataracts, and memor>' impairment. By protecting against theaberrant biochemical changes that occur with aging, antioxidantsmay thus repre sent a veritable fountain of youth. > > >


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Thirty years a g o most mainstreammedical doctors viewed anti-agingmedicine as sheer quackery. Theaccep ted do gma of the time, taught inall medical schools, was that agingand its associated degenerative pro-cesses were unavoidable. Conditionssuch as such as memoryloss,muscledegeneration, and vision deteriora-tion were considered inevitable, notpreventable. T o even speak of ways toslow aging or prevent its physiologi-cal changes was akin to religiousheresy in tbe Middle Ages.

Now, at the dawn of tbe twenty-first century, there seems to be abegrudg ing , r e l uc t an t , and ye tvery real cbange in mainstreammedicine's perception of anti-agingor age-management medicine. Tbereasons for tbis cbange are multi-faceted and include: An explosion in knowledge of tbeintricate biocbemical and physio-logical proces ses involved in aging. Growing dem and from th e rapidlyaging, multimillion-strong baby-boo me r gene ration for scientifical-ly valid ways to ward off aging'smo st deb ilitating effects. (By 2030,approximately 70 million Ameri-cans will be aged 65 or older, rep-resenting a doubling of tbis agegroup since 1998.) Cover articles in mainstrea m p ub -lications such as TIMEmagazinetbat bave seriously examined age-management medicine. Mult iple studies demonstrat ingtbat safe, readily available nutri-t i ona l supp l ement s may be lpcounter m any comm on diseases ofaging such as heart disease, cancer,and Alzheimer's, and may even

retard tbe aging processitselfo W e Def ine

While most peo ple can tell b y sigbtalone wbetber someone is young orold, tbe medical com mun ity remainsdivided over wbat constitutes aging.Tbe mo st widely accep ted idea todayis tbat aging is a multifactorial bio-chemical and pbysiological processtbat leads to overall cellular break-down and deatb. Aging not onlyalters our pbysical app eara nce d ue to

cbanges in skin, bones, and muscletone, but also affects our internalorgans. Tbe beart and immune sys-tem become less efficient, and dis-eases that are rare in young peoplebecome increasingly more prevalentin older adults.Several competing theories seekto explain wbicb biocbemical pro-cesses cause tbe pbys iologica lchanges seen in aging. In one tbeorybeld in bigb regard by many geron-tolo gist s^tb e so-called error tbeoryof aging aging is primarily causedby external or enviro nm ental factorsthat inflict cellular damage, ultimate-ly leading to organ damage anddea tb. One way tbese errors canoccur is tbrough biochemical pro-cesses induced by tbe formation offree radicals, tbe unstable biocbemi-cal entities formed wben energy isproduced in tbecells.While tbe bod ycan partly neutralize tbe damagingeffects of these radicals, its defensesbeco me less efficient w itb adva ncing

a g e . Tbis can lead to dam aged cells,tissues, and organs, wbicb manifestas tbe pbysical de clines of aging.Free Radical 1ndueedOxidative D amage

Free radicals are thought to causecellular degeneration by means of achemical process known as oxida-tion. The concept tbat free radical-induced oxidative damage is a majorcontributor to aging was first pro-posed in 1955 by Denbam Harman,M D . PbD.' Dr. Harm an suggestedtbat tbe sum of tbe deleteriou s free

radical reactions going on conously tbrougbout tbe cells andsues constitutes the aging proceis a major contrib utor to it. -Another well-known scientisproponent of tbe free radical thof agingisBruceAmes,PbD, a wrenowned researcbera ttb eUnity ofCalifornia, Berkeley. In m upapers. Dr.Ames and bis collecon tend tbat oxidant byp rodu cnormal metabolism cause extendamage to DNA, protein, and liAn increasing number of scienargue tbat tbis damag e (tbe samtbat produced by radiat ion) major contributor to aging.'D r s . Harman and Ames are noonly respected scientists to givedence to tbe free radical tbeor

aging. Numerous research padetail tbe ways in wbicb free radincrease oxidative stress in abumans and cause numerous ease states associated witb agBesides damaging cells and orgfree radicals may adversely amitochondria, tb eorganelles in cell tbat literally provide tbe enneeded to sustain life.Energy Man ifarturing

MitochondriaMitocbondr ia are specia lstructures tbat produce energyconverting oxygen and nu trients adenosine tripbosphate, or ATPessential biochemical tbat po wersme tabolic activities of the b ody's cMitochondria are uniquely difent from other cellular organelle


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they contain their own DNA, topostulate that were free- taken up and larger organisms. evolutionary time span,

th e mito- oxygen and nutrients,

ATP .The old adage that there's no suchasa free lunch appliestoener- produc t ion by mi tochond r i a .energy is produc ed inside th e free radi- including superoxide anions

inflict damage to the cellular of mitochondria as well as

How Free Radicals DamageMitochondriaMany medical researchers now that free radical - induced is an importantAmes,. Harman, and other scientists

th e bio- DNA contributes func-that defines aging. '

This process was succinctly sum- by researchers at National University in Taipei,Tai-rote: It has been shown rate of production of super-anions and hy drogen peroxide age. levels of free enzymes are sig- altered in the aging pro- These t w o c o m p o u n d i n g an age-dependent . . . free radicals that may an t iox idan tcause ever-oxidative damage tovari-s biomolecules in mitochondria

dth ecellas awhole . . .we suggest this vicious cycle plays an

important role in human aging andin the pathogenesis of age-relateddegenerative diseases. 'Indeed , mu ltiple lines of evidenceimplicate free radicals in ma ny of thediseases associated with aging, suchas heart disease, visionloss,sarcope-nia, cancer, and Alzheimer's disease. ntioxidants Retardthe ging rocess

To further com plicate m atters,research h as confirmed that levels ofendogenous {internally generated)antioxidantsincluding superoxidedismutase, catalase, and glutathioneperoxidasedecline with advancinga g e . The question is, what can bedone to guard against the biochemi-cal onslaught of free radicals?

One approach e mbraced by holis-tically oriented physicians and theirpatie nts is to increase daily intake ofan t iox idan t sbiochemica l s t ha tcounteract the effects of free radi-calsthrough dietary sources andnut r i t i ona l supplement s . Whi l emany mainstream physicians stillscoff at this idea, a growing body ofresearch validates the importance ofsupplementing with antioxidants.D r s . Harm an and Ames have pro-posed that ant ioxidants can helpdefend against many age-relateddiseases and perhaps against aging

its lf According to Dr. Harm an, thefree radical theory of aging predictsthat the healthy life span can beincreased by minimizing deleteri-ous free radical reactions . . . thedata now available indicate this canbe done by keeping body weightdown . . . while ingesting diets a de-quate in essent ia l nut r ients butdesigned to minimize random freeradical reactions in the hody. Suchdie t s would [ con ta in ] m in im alamounts of components prone toen han ce free radical re actions . . .and increased amounts of sub-stances capable of decreasing freeradical reaction damage, such asa l p h a - t o c o p h e r o l [ v i t a m i n E | ,ascorbic acid [vitamin C|, selenium ,and one or more of the syntheticantioxidants. I t is reasonable toexpect this approach will decrease

th e morbidity and mortality due todegenerative diseases and nonspecific age changes . . . so as to resulinan extension of 5or more yearsinthe span ofhealthy productive life. ^An Italian study in 2000 lends cre-dence to Dr. Harman's conclusionsAlthough bloodlevelsofantioxidanttendto decrease w ithage, theItalianresearchers found that centenarian(people aged 100 or older} hadmarkedlyhigher blood levelsof vitamins A an d E than their youngecounterparts. They conclu ded, it ievident that heal thy centenarianshow a particular profile in whichhigh levelsofvitamin A and vitaminE seem to be important in guaranteeing their extremelongevity.

Protecting the MitochondriaEven mainstream scientific publications now recognize the importance of mitochondrial function in

aging and disease. A study in th nnals of tlie New York cademof Sciences highlighted how mitochondrial dysfunction causedby freradical-induced oxidative damage ia comm on marker in both aging andage-related diseases such as cancerThe authors notethatc ancer is associated with aging, and that adultaged 6 5 or older account for 6 0 of alcancers and 7 0 of all cancer death sAccording to the authors, not onlyiis likely that increased susceptibilitof mitochondrial DNA to oxidative


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damage and l imi ted DNA repaircapacity of the proteins involved inmitochondrial repair play a signifi-cant role in mutagenesis of aging,but mitochon drial dysfunction thataccompaniesagingmay exert a m ajorinfluence on carcinogenesis. '-F o r t u n a t e l y , a m p l e e v i d e n c esuggests that diets rich in fruits andvegetablesand th us high in antiox-idantshave significant protectiveeffectsagainst many age-related dis-eases. In addition, preliminary evi-dence indicates antioxidants exertdirect protec tive effects aga instmito-chondrial damage caused by freeradicals. In another article in th eAnnals of the New ork Academy ofSciences, the authors reviewed howcertain antioxidants such as coen-zyme QIO, N-acetylcysteine, andlipoic acid m ay neutralizethe excessproduction offree radicals inside themitochondria. ' '

Betiefits ofJjpo icAciff,\ cetyl-l. -Cam iriueLipoic acid is cons ide red animportant antioxidant and crucialfor a variety of mitochondrial reac-tions. In F.urope, doctors prescribe

lipoic acid to treat liver diseases andpoiyneuropathies. Recent researchhas shown that lipoic acid may be auseful adjunct in the fight againstpa tho log i ca l and age - r e l a t edchanges seenin the hrain.One study examined how lipoicacid mod ulatesneurotransmitters inthe b rains of aged rats. Theolder ratsgiven l ipoic ac id supplementsincreased their levels of severalimportant neurotransmitters, includ-

ing dopamine, serotonin, and nore-p inephr ine . Postulat ing that thisincrease could be due to lipoic acid'santioxidant action, the authors con-cluded, supp lem entation of lipoicacid could represent a viable thera-peuticapp roach to diminish oxidativestress in the central nervous systemand thereby modulate the levels ofneurotransmitters during [aging].Anotherstudy,coau thored hy Dr.Ames,found that inaged rats, lipoicacid and acetyl-L-carnitine signifi-cant ly protected mitochond ria from

oxidative damage and age-associat-ed decay. According to the authors, feeding old rats acetyl-L-carnitineplus lipoic acid restores mitochon-drial function, lowers oxidants . . .improves the age-associated declinein ambulatory activity and memory. . . and prevents mitochond ria fromoxidative decay and dysfunction. '^

Aiitioxidauts I hat Comb atAlzheimer sIn addition to lipoic acid, other

antioxidants can help protect thebrain against the ravages of aging.Beta-carotene and vitamins C and Eshow great promise in the fightagains t Alzheimer 's d i sease .Alzheimer's, the most co mm on causeof dementia in adults aged 65 andolder, affects more than 15 millionpeop l e wor ldwide . One ma jo rchange that occurs in the brains ofAlzheimer's sufferers is generalizedoxidative damage to neurons. How-ever, current prescription medica-tions for Alzheimer's focus only onincreasing levels of the neurochemi-cal acetylcholine, not on combatingoxidative damage to neurons. Multi-ple studies support the idea thatantioxidants have a place as a front-line therapy against Alzheimer's.

One such study of 442 elderlySwiss patients directly correlatedhigher hlood levels of two commonan t iox idan t s (be t a - ca ro t ene andvitamin C) with better memory. 'A study published in theArchives of

Neurology in 2004 examAlzheimer's risk in people who antioxidant supplements. The sfound that use of vitamin Eandmin Csupp lements in com binatassociated with reduced prevaan d in cide nce of AD [Alzheimer'ease[.Antioxidant supp lemen tsit further study as agents inprimary prevention of A D .

Vita m if E May PreventMuscle LossAs people age, not only do bones become brittle, but their cle tissues shrink and atrophy, adition known as sarcopenia. Ibeen estimated that between theof 20 and 80, skeletal muscle decreases by 35-40% in menwom en. While brittle bon es seconto osteoporosis certainly contributhe greater incidence of hip fracand other debilitating injuries inelderly, leg weakness caused by

copeniaisa major contribu ting fto the falls that cause hip fractWhen sarcopenia robs peop le ofability towalk climbstairs,or pethe simple taskofgetting in and oa chair, i t confines them tounhealthy, seden tary lifestyle.While studies are ongoing, researchers believe that intramular mi tochondr ia l DNA damcaused byfree radicals may beanificant factor in the loss of mmass seen in the aged.' The usantioxidantsspecifically, vitam in


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sarcopenia in the A report from Jobns Hopkins tbe relationship betweenstrength inwomen aged 70- Higher carotenoid and alpha E) levels were witbmusclestrengtb,"' leading tbe adults may result in part t ba te protective.

thiti Protect VisionMany longitudinal studies sbow

in vegetablescan protect age-related diseaseincluding visionloss. T w o of tbe useful carotenoids for combat- age-related vision loss caused byarelutein and zeaxanthin.Tbese potent ant ioxidants are to belp prevent cataractsprotec t ing tbe eye lens from the

and endogenous f r ee format ion. Three r ecen t d e m o n s t r a t e d t b a t a bigb intake of lutein bave significantly risks of developing cataracts lowIn addit ion, researcb bas even in people who already developed cataracts ,

ConclusionAge-management med ic ine i sabout more tban just extending theyea rs of life. Its goal is to lengthen andoptimize tbe years of bealtby, func-tional living by preventing the dis-eases tbat commonly afflict olderadults. Witb a little common senseand bealtby everyday behaviorsincluding regular exercise, a diet richin fruit, vege tables, and lean p rotein,and use of ant ioxidant supple-mentsyou can ensure tbat youbave botb tbe cbance and the capac-ity to enjoy a long, hea lthy life.

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7 . WeiYH, luCY, LecH CPa ngC Y. MaYS.Oxidative dama ge and m utation lo mito-chondrial DNA and age-dep enden t declineof mitochondrial respiratory function. An nNY Acad Sci.1998 Nov 20;854:155-70.

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1 7 . Zandi PI Anthon y IC, Kliachaturian AS,et al. Reduced risk of Alzheimer diseas ein users of antioxidant vitamin supple-men ts: the Cache County Study.ArchNenro/. 2004 lan:(il(l}:82-8.

1 8 . Semb a RU, Blaum C, Guralnik )M, el al.CarotL'noid and v itamin E status areassociated with indicators of sarcopeniaam ong older wome n living in the com -munity.Agin^ Clin Exp R e s 2003Dec;15(6):482-7.

1 9 . Lyle BJ, Ma res-P erlm an |A, Klein BE,Klein R, Greger |L. Antioxidant intakeand risk of incident age-related nuclearcataracts in tbe Beaver Dam Fye Study.Am I Epidemiol. 1999 May l;149(9):801-9.

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antioxidants, mitochondrial damage, and human aging

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