Biology of Aging NIH

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BIOLOGYOFAGING

Research Todayfor a HealthierTomorrow

NATIONAL INSTITUTE ON AGING NATIONAL INSTITUTES OF HEALTH

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES


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BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 1

AGING UNDER THE

MICROSCOPE

4 What is aging?

6 Living long and well:Can we do both? Are

they the same?

9 Is whats good formice good for men?

GENETICS

13 Is aging in our genes?

14 How can we nd aginggenes in humans?

18 What happens when DNAbecomes damaged?

METABOLISM

23 Does stress really shortenyour life?

27 Does how much you eataffect how long you live?

IMMUNE SYSTEM

31 Can your immune system

still defend you as you age?

THE PROMISE OF RESEARCH

35 Past, present, and future

36 GLOSSARY

37 BIBLIOGRAPHY

The National Institute on Aging

(NIA), part of the National

Institutes of Health at the

U.S. Department of Health and

Human Services, was established

to help improve the health and

well-being of older people through

research. NIA conducts and

supports research on the medical,

social, and behavioral aspects

of aging. This mission is carried

out through NIAs Intramural

Research Program composed

of sta scientists in Baltimore

and Bethesda, Maryland, and

through its Extramural Research

Program, which funds researchers

at major institutions across the

United States and internationally.

Biology of Aging: Research Today

for a Healhier Tomorrow describes

some of NIAs exciting ndings

about the basic biology of aging

and points to directions for

future investigation.

BIOLOGY OF AGINGResearch Today for a Healthier Tomorrow


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PHOTO

CREDIT:

MARTYKATZ,WWW.MA

RTYKATZ.COM


5/44BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 3

We marvel at the 90-year-old who stillgets up every day and goes to work.

And, it is a genuine thrill to celebratea relatives 100th birthday. Yet ourfeelings about aging are complex.

We may want to live forever, but who looksforward to geing old? We hope were vigor-ous right up until the very end. Still, day-to-day, many of us make unhealthy choices thatcould put our future at risk.

From the beginning of time, peoplehave tried to understand aging. Almostevery culture has a mythology to explain it.

As we grow up, tales of eternal youth piqueour curiosity. And, it is these musings thatmay provide just the spark needed to ignitea budding scientist. Theres the lile girl,excited to visit her grandmother, who asksher parents how someone so spunky andfun could be so old. Or, the 3rd grader who,aer watching in awe as a caterpillar spins

a cocoon and then days later emerges as abuery, peppers the teacher with questions

about this magical transformation. Theseare the types of questions and kinds of experi-ences that could stimulate a lifelong quest toexplore what happens as we age.

Since the National Institute on Aging (NIA)was established at the National Institutes ofHealth (NIH) in 1974, scientists asking justsuch questions have learned a great deal

about the processes associated with thebiology of aging. For scientists who studyagingcalled gerontologiststhis is an excit-ing time. Technology today supports researchthat years ago would have seemed possibleonly in a science ction novel. And, a scienticcommunity that values active collaboration aswell as individual scientic achievement has

helped to move research forward faster thanever before.

AGING UNDER THE

MICROSCOPE


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Over centuries, theories about aging haveemerged and faded, but the true nature of theaging process is still uncertain. The fact isaging is a part of everyones life. But the facts

of agingwhat is happening on a biochemi-cal, genetic, and physiological levelremainrich for exploration.

This booklet introduces some key areas ofresearch into the biology of aging. Each areais a part of a larger eld of scientic inquiry.You can look at each topic individually, or you

can step back to see how they t together ina laice-work, interwoven to help us beerunderstand aging processes. Research on agingis dynamic, constantly evolving based on newdiscoveries, and so this booklet also keeps anopen eye on the future, as todays researchprovides the strongest hints of things to come.

What is aging?In the broadest sense, aging reects all thechanges that occur over the course of life.You grow. You develop. You reach maturity.To the young, aging is excitingit leads tolater bedtimes and curfews, and more inde-

pendence. By middle age, another candleseems to ll up the top of the birthday cake.Its hard not to notice some harmless cosmeticchanges like gray hair and wrinkles. Middleage also is the time when people begin tonotice a fair amount of physical decline.Even the most athletically t cannot escapethese changes. Take marathon runners, for

example. An NIA-funded study found thattheir record times increased with ageaging

literally slowed down the runners. Althoughsome physical decline may be a normal resultof aging, the reasons for these changes are ofparticular interest to gerontologists.

Gerontologists look for what distinguishesnormal aging from disease, as well as explorewhy older adults are increasingly vulnerableto disease and disability. They also try tounderstand why these health threats takea higher toll on older bodies. Since 1958,NIAs Baltimore Longitudinal Study of Aging

(BLSA) has been observing and reporting onthese kinds of questions. As with any longi-tudinal study, the BLSA repeatedly evaluatespeople over time rather than comparinga group of young people to a group of oldpeople, as in a cross-sectional study. Using thisapproach, BLSA scientists have observed, forexample, that people who have no evidence

of ear problems or noise-induced hearingloss still lose some of their hearing withagethats normal. Using brain scans to learnif cognitive changes can be related to struc-tural changes in the brain, BLSA scientistsdiscovered that even people who remainhealthy and maintain good brain function

late in life lose a signicant amount of brainvolume during normal aging.

However, some changes that we have longthought of as normal aging can be, in fact,the signs of a potential disease. Take, forexample, sudden changes in personality.A common belief is that people becomecranky, depressed, and withdrawn as they get

older. But an analysis of long-term data fromthe BLSA showed that an adults personality

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POSSIBLE PATHWAYSLEADING TO AGING

To answer questions about why and how we age, some scientists look for mechanisms orpathways in the body that lead to aging. Our cells constantly receive cues from both inside andoutside the body, prompted by such things as injury, infection, stress, or even food. To react andadjust to these cues, cells send and receive signals through biological pathways. Some of themost common are involved in metabolism, the regulation of genes, and the transmissionof signals. These pathways may also be important to aging.

DNA

NUCLEUS

CELL

SIGNALS TO OTHER CELLS

SIGNALS ENTERING THE CELL

ILLUSTRATIONANDINFORMATIONADAPTEDFROMWWW.GENO

ME.GOV


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6

generally does not change much aer age 30.People who are cheerful and assertive whenthey are younger will likely be the same when

they are age 80. The BLSA nding suggeststhat signicant changes in personality are notdue to normal aging, but instead may be earlysigns of disease or dementia.

The rate and progression of cellular agingcan vary greatly from person to person. Butgenerally, over time, aging aects the cells ofevery major organ of the body. Changes can

start early. Some impact our health and func-tion more seriously than others. For instance,around the age of 20, lung tissue starts to loseelasticity, and the muscles of the rib cage slowlybegin to shrink. As a result, the maximumamount of air you can inhale decreases. In thegut, production of digestive enzymes dimin-

ishes, aecting your ability to absorb foodsproperly and maintain a nutritional balance.Blood vessels in your heart accumulatefay deposits and lose exibility to varyingdegrees, resulting in what used to be calledhardening of the arteries or atherosclerosis.Over time, womens vaginal uid productiondecreases, and sexual tissues atrophy. In men,

aging decreases sperm production, and theprostate can become enlarged.

Scientists are increasingly successful atdetailing these age-related dierences becauseof studies like the BLSA. Yet studies thatobserve aging do not identify the reasons forage-related changes, and, therefore, can onlygo so far toward explaining aging. Questions

remain at the most basic level about whattriggers aging in our tissues and cells, why it

occurs, and what are the biological processesunderlying these changes. Scientists lookdeep into our cells and the cells of laboratory

animals to nd answers. What they learn todayabout aging at the cellular and molecularlevels may, ultimately, lead to new and beerways to live a longer, healthier life.

Living long and well: Can wedo both? Are they the same?You can hardly turn on your computer thesedays without being bombarded with adver-tisements that pop up trying to convince youof the power of a pill that will make you livelonger or a cream that will help to revive youryouthful vigor and appearance. The search for



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ways to stop or reverse the aging process is anear-obsession in popular culture. The likeli-hood of discovering a scientically proven

anti-aging elixir is slim, but researchersbelieve their work will reveal ways to improvea persons ability to live a longer, healthierlife. They express these goals in terms oflifespan and health span, respectively.

Lifespan is the length of life for an organism.For instance, if you live to age 99, that would

be your lifespan. Maximal lifespan is themaximum number of years of life observed ina specic population. It diers from speciesto species. The maximum recorded lifespanfor humans, reported in 2010, was 122.5 yearsfor females and 116 years for males.

Lifespan is a common measurement in

aging research. Thats because it is clear-cutand easy to measurean organism is eitheralive or dead. Scientists look for factors suchas genes, environment, and behavioral traits(including diet) that may contribute to anorganisms lifespan. Altering a factor to see ifit changes lifespan can provide evidence aboutwhether or not that specic factor is impor-tant for aging. For instance, when researcherssuspect that a specic gene has an eect onlifespan, they may test their hypothesis bymodifying the activity of that gene (perhapslower its activity by deleting the gene orincrease its activity by adding an extra copyof it). If the life of the animal with the modied

gene activity is longer or shorter, then the geneprobably does play a role in lifespan.

Researchers are nding that lifespanmay be inuenced by external factors, as well.This has been demonstrated in animal stud-ies. NIAs Interventions Testing Program (ITP)examines a variety of compounds for theireects on the lifespan of mice. Compoundsstudied include dietary supplements,hormones, and anti-inammatory drugs.In one ITP study, male mice treated withaspirin, an anti-inammatory drug, displayeda moderately increased lifespan. In anotherITP study, masoprocol, an anti-inammatorydrug that has antioxidant properties, wasfound to increase longevity of male, but not

female, mice. These and other ndings mayhelp scientists identify compounds to test in

ENVIRONMENT

BEHAVIORAL TRAITS

GENES

FACTORS CONTRIBUTING TO LIFESPAN


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8

humans for their eects on aging. While some of thecompounds tested in the ITP already have a clinicaluse for humans, scientists are clear: These compounds

should be used only as prescribed and not for lifespanextension at this time.

The ability to withstand disease could also becentral to lifespan. Studies of exceptionally long-livedpeople are helping to establish paerns of healthdecline and increased disease (called morbidity) withold age. For example, do health problems start around

the same age in all people and expand over extra yearsof life for the long-lived, or are the problems delayed,occurring closer to the end of life among exceptionalagers? Evidence from a Danish longitudinal study of92- to 100-year-olds found that health problems seemto be delayed, appearing closer to the end of life. This isnot a certain outcome, but in many studies, the averagecentenarian seems to be in beer health than the aver-

age 80-year-old. However, living to 100 does not meannever having any health issues. In the New EnglandCentenarian Study, researchers have developed threecategories for their long-lived participants. They arecharacterized as survivors, delayers, or escapers,depending on whether they have survived a life-threaten-ing disease, delayed a serious health problem until muchlater in life, and/or escaped any serious health events.

Scientists used to think that long life was a goodindicator of health span, or years of good health andfunction. However, some experiments, particularly inmice, demonstrate signicant improvements in health,without actually increasing lifespan. For example, NIAscientists and grantees (that is, scientists at a universityor other institution whose research is funded by NIA)

examining the eects of the wine-derived compoundresveratrol in mice on a normal diet found the


Most of what we know about factors

that can contribute to a long lifespan

and health span is based on research

in animal models. However, NIA-

funded research like the Long Life

Family Study is taking what weve

learned in animals and seeing if it

applies to human aging. This study

is collecting data from families with

at least two siblings who have lived

to a very old age in relatively good

health. Along with asking questions

about their family and health history,

the researchers conduct physical

assessments and health screeningsand collect a small blood sample

for genetic tests. What researchers

learn about common characteristics

shared by these families could one

day be used to guide lifestyle advice

and medical treatments.

UNCOVERING FAMILY

SECRETS TO A LONG LIFE


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compound positively inuenced the health of themiceresveratrol-treated mice had beer bone health,heart function, strength, vision, coordination, and

cholesterol than the control group. But, resveratrol didnot increase lifespan. (Lifespan was increased, however,in mice on a high-fat diet supplemented with resveratrol.)

Understanding how to extend health spanapartfrom its impact on longevityis a growing focus ofmany studies, and for good reason. Imagine a societywhere a majority of people live to be 100, but along withthe added years comes considerably more physical decline.While there is still a place for lifespan research, healthspan research holds promise for revealing ways to delayor prevent disease and disability so that we can livehealthier longer.

Is whats good for mice

good for men?A lot of research ndings seem to tell us what is goodorbadfor yeast, mice, roundworms (C. elegans), or fruities (Drosophila melanogaser). Does that mean it willwork for you? Animal models are essential to researchin the biology of aging. Fruit ies and roundworms,along with more complex organisms like mice, rats, and

nonhuman primates, have many biological mechanismsand genes that are similar to humans. They also experiencemany of the same physiological changes (changes in thebody) with aging. Therefore, these animals can be used asmodels of human aging and human physiology, despitethe obvious dierences in appearance. Scientists can usesome exploratory approaches (like modifying a geneto measure its eects on health or longevity) in animal

models such as worms, ies, and mice that would not bepossible in humans. They also can beer isolate the variable

ROUNDWORMC. elegans

FRUIT FLYDrosophila melanogaser

MOUSEMus musculous

RHESUS MONKEY

Macaca mulata

ANIMAL MODELS

Here are some animals commonlystudied in aging research.


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they want to investigate because animal studiesare conducted in tightly controlled environ-ments. The animals typically have a very struc-tured daily regimen with limited exposure to

pollutants, stressors, or other elements thatcould otherwise aect lifespan and health span.

Dierent types of studies use dierentanimal models. Animal models with a shortlifespan take less time and fewer resourcesto study from birth to death and to test inter-ventions that might aect the aging process.

Scientists might favor a fruit y when studyinga possible genetic target for an intervention toincrease longevity, for example, because theiraverage lifespan is only 30 days. This allowsresearchers to measure the eects in about amonth. The roundworms 2- to 3-week lifespanmakes it another ideal model for identifying andstudying genes that might aect longevity. In a

landmark study, NIA-funded researchers foundthat reducing the activity of a set of genes, calleddaf, increased roundworm lifespan by three- oreven fourfold. Dafgenes are involved in theroundworms ability to enter a type of hiberna-tion stage, called diapause, to survive periods offood scarcity. This research would not have been

as feasible if conducted using an animal modelwith an average lifespan of 10 or 20 years.

Aer scientists establish a possible inter-vention in one animal model, they then applythe intervention to increasingly complexorganisms. They might work their way upfrom worms or ies to mice and then to largermammals, such as nonhuman primates. At each

step, researchers carefully study if the interven-tion has the same eect on the comparable

biological pathway. Sometimes it does not.Part of the reason might be that while mice,for example, have only a slightly larger numberof genes than worms, and the genes in mice

and worms serve similar functions, the activ-ity of mouse genes is dierent and somewhatmore complex than that of worms. As a result,a genetic intervention that increases a wormslifespan by fourfold might have a signicantlyless impressive eect on a mouses lifespan.For similar reasons, an intervention might be

promising in mice, but that does not mean itwill work the same way or at all in humans.

Studies in animal models closer tohumans, such as monkeys or other nonhumanprimates, can be key to understanding howbasic discoveries might apply to humans.They are essential for pre-clinical studies,an intermediary step between research in

animal models like mice and clinical studiesin humans. Studies in nonhuman primates, forexample, have demonstrated to NIA researchershow normal age-related changes in the heartinuence risk of heart disease. They have alsobeen important for testing interventions tolower risks of heart disease, such as drugs to

decrease blood vessel stiness.So, if something works to slow aging inmice, worms, fruit ies, or monkeys, doesthat mean it will denitely work for you?The answer is no. Certainly, data from animalstudies provide critical insights to the agingprocess and can form the basis for testingpotential interventions. But direct testing in

humans is essential before an interventioncan be considered safe and eective.



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One approach to aging biology research

is called comparative biology. It involves

comparing two or more similar species that have

very different lifespansone lives much longer

than the otherto understand how the longer-

lived species has, as one NIA-funded researcher

puts it, exceptional resistance to basic aging

processes. Comparative biology studies

generally focus on species that live at least twice

as long as their close relatives.

A few possible theories explain what may be

taking place among these longer-lived animals:

They experience a slower rate of

age-related decline.

They can survive even when their organs and/or

systems break down and have minimal function.

They are better able to tolerate cellular

damage or diseases.

The naked mole rat, a mouse-size rodent

that lives underground, has been widely used

in comparative research. It lives approximately

17 years in the wild and more than 28 years

in captivity. Its relative, the mouse, lives a

maximum of 4 years. What accounts for this

startling difference? Naked mole rats have lower

metabolic rates and body temperature, meaning

that they require less energy to survive. They

have low concentrations of blood glucose (blood

sugar), insulin, and thyroid hormone, so they are

less susceptible to certain diseases. Naked mole

rats are better able to withstand some types

of biological stress and, at this point, there has

never been a case of cancer reported in these

animals. All these factors and likely others yet to

be determined contribute to their healthier and

longer life.

A DIFFERENT APPROACH: COMPARATIVE BIOLOGY

NAKED MOLE RATLifespan: 17 to 28 years

MOUSELifespan: 4 years

NAKEDMOLERATPHOTOCREDIT:

COURTESYOFTHOMASPARK,PH.D.,UNIVERSITYOFILLINOISATCH

ICAGO


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Is aging in our genes?You may get your hair color from yourfathers side of the family and your greatmath skills from your mother. These traitsare in the genes, so to speak. Likewise,longevity tends to run in familiesyour

genetic make-up plays an important rolein how you age. You can see evidence ofthis genetic connection in families withsiblings who live into their 90s or familiesthat have generation after generation ofcentenarians. These long-lived families arethe basis for many genetic studies.

Identifying the genes associated with any traitis dicult. First, just locating the gene requiresa detailed understanding of the trait, includingknowledge of most, if not all, of the contributingfactors and pathways related to that trait. Second,scientists must have clear ways of determiningwhether the gene suspected to have a relationship

with the trait has a direct, indirect, or even no eecton that trait.

GENETICS


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14

Identifying longevity genes is even morecomplex than determining genes for height orhair color, for example. Scientists do not know

all the factors and pathways that contributeto longevity, and measuring a genes eect onlong-lived animals, including humans, wouldliterally take a lifetime! Instead, scientistshave identied hundreds of genes that aectlongevity in short-lived animal models, likeworms and ies. Not all of these genes pro-mote long life. Sometimes mutating or elimi-

nating a gene increases lifespan, suggestingthat the normal function of the gene limitslongevity. Findings in animal models point toplaces for scientists to look for the genes thatmay inuence longevity in humans.

How can we nd aginggenes in humans?The human genetic blueprint, or genome,consists of approximately 25,000 genes madeup of approximately 3 billion leers (basepairs) of DNA. Small deviations in the basepairs naturally occur about once in every

1,000 leers of DNA code, generating smallgenetic variants. Scientists are nding thatsome of these variants (polymorphisms) areactually associated with particular traits orchance of developing a specic disease. Peoplewith a certain trait, for example, those livingpast age 100, may be more likely to have onevariant of a gene, while people without the

same trait may be more likely to have anothervariant. While it is very dicult to prove that

a gene inuences aging in humans, a relation-ship, or association, may be inferred basedupon whether a genetic variant is found more

frequently among successful agers, such ascentenarians, compared with groups of peoplewho have an average or short lifespan andhealth span.

Several approaches are used to identifypossible genes associated with longevity inhumans. In the candidate gene approach,scientists look for genes in humans that servesimilar functions in the body as genes alreadyassociated with aging in animal models, so-called homologs or orthologs to animalgenes. For instance, aer nding longevitygenes involved in the insulin/IGF-1 pathwayof animal models, researchers look for thecomparable genes in the insulin/IGF-1 path-

way of humans. Scientists then determinewhether the genes are linked to longevity inhumans by looking to see if a variant of thegenes is prevalent among people who livehealthy, long lives but not for people who havean average health span and lifespan.

In one NIA-funded project, researchers

studied 30 genes associated with the insulin/IGF-1 pathway in humans to see if any vari-ants of those genes were more common inwomen over 92 years old compared to womenwho were less than 0 years old. Variantsof certain geneslike the FOXO3a genepredominated among long-lived individuals,suggesting a possible role with longer lifespan.

This nding provides evidence that, like inanimal models, the insulin/IGF-1 pathway has

GENETICS


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The human genetic blueprint, or genome, consists of approximately 25,000 genesmade up of approximately 3 billion letters (base pairs) of DNA. Base pair sequences:guanine (G) pairs with cytosine (C); adenine (A) pairs with thymine (T).

C

T

HUMAN GENETIC BLUEPRINT

NUCLEUSGENES

DNA STRAND

BASES

GT

A

A

G

C

23 PAIRS OF CHROMOSOMES

CELL

ILLUSTRATIONAD

APTEDFROMALZHEIMER'SDISEA

SE:UNRAVELINGTHEMYSTERY


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16 GENETICS

Most longevity genes identied thus far inuence one of

three pathways in a cell: insulin/IGF-1, sirtuins, or mTOR.

In the 1980s, scientists discovered the rst gene

shown to limit lifespan in roundworms, which they named

age-1. Further investigation revealed that the effects of

age-1are involved with the insulin/IGF-1 pathway. When

scientists silenced the age-1genes activity, the insulin/

IGF-1 pathways activity also decreased and the worms

lived longer. Since then, many other genes associated

with the insulin/IGF-1 pathway have been found to

affect the lifespan of fruit ies and mice, strengthening

the hypothesis that the insulin/IGF-1 pathway plays an

important role in the aging process. More research is

needed to determine if inhibiting this pathway couldincrease longevity in humans or create insulin-related

health problems like diabetes. A recent report suggests that

people with a mutation related to the insulin/IGF-1 pathway

may have less risk of developing diabetes and cancer.

There is also a great deal of interest in the sirtuin

pathway. Sirtuin genes are present in all species and

regulate metabolism in the cell. They are crucial for

cell activity and cell life. In the 1990s, scientists at the

Massachusetts Institute of Technology found that

inserting an extra copy of a sirtuin equivalent, called Sir2,

increased the lifespan of yeast. Extension of lifespan has

been replicated in other organisms, including ies and worms.

However, studies in mice have yielded conicting results.

The mTOR pathwayan abbreviation of mammalian

target of rapamycinplays a role in aging of yeast,

worms, ies, and mice. This pathway controls the cells

rate of protein synthesis, which is important for proper cell

function. Researchers have found that inhibiting the pathway

in mice genetically or pharmacologically (using rapamycin)

leads to increased longevity and improved health span.

a role in human aging. These genes may beimportant to future development of thera-pies to support healthy aging.

Another approach, the genome-wide

association study, or GWAS, is particularlyproductive in nding genes involved indiseases and conditions associated withaging. In this approach, scientists scanthe entire genome looking for variantsthat occur more oen among a groupwith a particular health issue or trait. In

one GWAS study, NIH-funded researchersidentied genes possibly associated withhigh and low blood fat levels, cholesterol,and, therefore, risk for coronary arterydisease. The data analyzed were collectedfrom Sardinians, a small genetically alikepopulation living o the coast of Italy inthe Mediterranean, and from two other

international studies. The ndingsrevealed more than 25 genetic variantsin 18 genes connected to cholesterol andlipid levels. Seven of the genes were notpreviously connected to cholesterol/lipidlevels, suggesting that there are possiblyother pathways associated with risk forcoronary artery disease. Heart disease isa major health issue facing older people.Finding a way to eliminate or lower riskfor heart disease could have importantramications for reducing disabilityand death from this particular age-related condition.

Scientists are also currently using

GWAS to nd genes directly associatedwith aging and longevity. Because the

PATHWAYS OF LONGEVITY GENES


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At the center of this research is theepigenomechemical modications, ormarks, on our DNA, or in proteins thatinteract with DNA, that tell it what to do,where to do it, and when to do it. The marksthat make up the epigenome are aectedby your lifestyle and environment and maychange, for example, based on what you eatand drink, if you smoke, what medicinesyou take, and what pollutants you encounter.Changes in the epigenome can causechanges in gene activity. Most epigeneticchanges are likely harmless, but some could

trigger or exacerbate a disease or condition,such as your risk for age-related diseases.In some cases, scientists nd that theseepigenetic changes driven by the environ-ment can be inherited by the ospring.

Identical, maternal twins are ideal forepigenetic research. At birth, twins havenearly the same genetic blueprint; however,

over time, they may have fewer identicaltraits. Careful study of these changes mayhelp scientists beer understand environ-mental and lifestyles inuence on genes.

Epigenetics might also explain variationsin lifespan among laboratory mice that aregenetically identical and seemingly raised

in the exact same environment. Scientiststheorize that the dierence in theirlifespans may result from a disparity in theamount of nurturing they received whenvery young. The mice with the shorter

lifespan might have been less adept at feed-ing and, therefore, got less of their mothersmilk, or their mother may have licked themless, or they may have slept farther away fromthe center of the lier. Receiving less nurtur-

ing may have inuenced their epigenetics,marking the genes that control aging.

As epigenetic research moves forward,scientists hope to answer three key questions:

How do changes in the epigenome trans-late into long-term dierences in health

and aging?

Do single events inuence the epigenome? If single events can change the epigenome,does the organisms age (or stage of devel-opment) at the time of the change maer?

An emerging area of research called epigenetics opens the door to a scientic

blending of two worlds that for decades were thought of as totally separate

that is nature and nurture, or more specically genetics and the environment.

Epigenetics research looks at how your environment, over time, can affect how

your genes work and inuence your development, health, and aging.

EPIGENETICSTHE FUTURE OF AGING RESEARCH


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18 GENETICS

GWAS approach does not require previousknowledge of the function of the gene or itspotential relationship with longevity, it could

possibly uncover genes involved in cellularprocesses and pathways that were not previ-ously thought to play roles in aging. Since nosingle approach can precisely identify eachand every gene involved in aging, scientistswill use multiple methods, including a com-bination of the GWAS and candidate geneapproaches to identify genes involved

in aging.As scientists continue to explore the genetics

of aging, its complexity becomes increasinglyevident. Further studies could illustrate thevarying ways genes inuence longevity. Forexample, some people who live to a very oldage may have genes that beer equip them

to survive a disease; others may have genesthat help them resist geing a disease in therst place. Some genes may accelerate the rateof aging, others may slow it down. Scientistsinvestigating the genetics of aging do notforesee a Eureka! moment when one geneis discovered as the principal factor aectinghealth and lifespan. It is more likely that we

will identify several combinations of manygenes that aect aging, each to a small degree.

What happens when DNAbecomes damaged?The impact of age, of course, is not limited

to organisms. You drive a brand new caro the lot, and ideally its in perfect work-

ing condition. But by the time it reaches the100,000 mile mark, the car doesnt run quitelike it used to. Or, that lovely walking path

you discovered when you rst moved intoyour home has now become weathered,the weeds are overgrown, and some of theasphalt has buckled.

Like the car and the walking path, overtime your DNA accumulates damage. Thatsnormal. Our DNA suers millions of damagingevents each day. Fortunately, our cells havepowerful mechanisms to repair damage and,by and large, these mechanisms remain activeand functional through old age. However,over time, some damage will fail to be repairedand will stay in our DNA. Scientists think thisdamageand a decrease in the bodys abilityto x itselfmay be an important component

of aging. Most DNA damage is harmlessforexample, small errors in DNA code, calledmutations, are harmless. Other types of DNAdamage, for example, when a DNA strand breaks,can have more serious ramications. Fixing abreak in a DNA strand is a complex operationand it is more likely the body will make mistakeswhen aempting this repairmistakes that

could shorten lifespan.

Another kind of DNA damage build-upoccurs when a cell divides and passes itsgenetic information on to its two daughtercells. During cell division, the telomere, astretch of DNA at each end of a chromosomethat doesnt encode any proteins but instead

protects the protein-encoding part of theDNA, becomes shorter. When the telomere


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becomes too short, it can no longer protect the cellsDNA, leaving the cell at risk for serious damage. Inmost cells, telomere length cannot be restored. Extreme

telomere shortening triggers an SOS response, andthe cell will do one of three things: stop replicatingby turning itself o, becoming what is known assenescent; stop replicating by dying, called apoptosis;or continue to divide, becoming abnormal and poten-tially dangerous (for example, leading to cancer).

Scientists are interested in senescent cells because,although they are turned o, they still work on manylevels. For instance, they continue to interact withother cells by both sending and receiving signals.However, senescent cells are dierent from theirearlier selves. They cannot die, and they releasemolecules that lead to an increased risk for diseases,particularly cancer.

The relationship among cell senescence, cancer, and

aging is an area of ongoing investigation. When we areyoung, cell senescence may be critical in helping tosuppress cancer. Senescence makes the cell stopreplicating when its telomeres become too short,or when the cell cannot repair other damage to itsDNA. Thus, senescence prevents severely damagedcells from producing abnormal and perhaps cancer-

ous daughter cells. However, later in life, cell senes-cence may actually raise the risk of cancer by releasingcertain molecules that make the cells more vulnerableto abnormal function.

Consider broblasts, cells that divide about 60 timesbefore turning o. Normally, broblasts hold skin andother tissues together via an underlying structure, ascaold outside the cell, called the extracellular matrix.The extracellular matrix also helps to control thegrowth of other cells. When broblasts turn o, they

Telomeres shor ten each time a cell

divides. In most cells, the telomeres

eventually reach a critical length

when the cells stop proliferating and

become senescent.

But, in certain cells, like sperm and eggcells, the enzyme telomerase restores

telomeres to the ends of chromo-

somes. This telomere lengthening

insures that the cells can continue to

safely divide and multiply. Investiga-

tors have shown that telomerase is

activated in most immortal cancer

cells, since telomeres do not shorten

when cancer cells divide.

TELOMERASE

TELOMERE

TELOMERE SHORTENS AFTERMULTIPLE REPLICATIONS

TELOMERE ATSENESCENCE

TELOMERASE

CHROMOSOME OF ADULT CELL

CHROMOSOME OF IMMORTAL CELL


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20

emit molecules that can change the extracellularmatrix and cause inammation. This disturbs thetissues function and contributes to aging. At the sametime, the breakdown of the extracellular matrix maycontribute to increased risk of cancer with age.

Learning whyon a biological levelcell senescencegoes from being benecial early in life to having detri-mental eects later in life may reveal some important

clues about aging.

YOUNG FIBROBLASTS

OLD FIBROBLASTS,

NEARING SENESCENCE

GENETICS

Aging biologists are investigatingwhether humans' telomere length

is associated with lifespan, health

span, or both. In one study of people

age 85 years and older, researchers

found telomere length was not

associated with longevity, at least not

in the oldest-old. In another study,researchers analyzing DNA samples

from centenarians found that

telomeres of healthy centenarians

were signicantly longer than

those of unhealthy centenarians,

suggesting that telomere length may

be associated with health span.

TELOMERE LENGTH:HEALTH SPAN VS. LIFESPAN?

FIBROBLASTSPHOTOCREDIT:

COURTESYOFLEO

NARDHAYFLICK,PH.D.,UNIVERSITYOFCALIFORNIA,SANFRANCISCO


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Stem cells can come from a variety of sources.Adult stem cells are candidates for regen-erative medicine approaches for severalreasonsdoctors can use the patients ownstem cells; stem cells can develop into nearly

any type of cell based on where they areinserted and other factors; and stem cellscontinue to function normally during analmost innite number of cell divisions,making them essentially immortal. There-fore, in theory, if stem cells were inserted in adamaged part of the body, they could developinto area-specic cells that could potentially

restore function. But does that work? Thatswhat researchers are trying to nd out.

Findings from early research on regen-erative medicine, primarily in animalmodels, show potential for stem cell treat-ment. For example, inserting mouse ovariancells created from a female donors stem

cells into infertile mice restored the micesability to reproduce. Another study inmice found that function could be restoredto injured muscle tissue by reactivatingexisting stem cells rather than transplantingnew ones. The ability to reactivate dormantadult stem cells continues to be investigated.In a 2010 Italian study with human partici-

pants, researchers restored vision to some

people with severe burns on the outmostlayer of their eyes (the cornea) by usingstem cells grown in the laboratory.

Researchers are also looking for alterna-tives to stem cells that have similar healingabilities and can be used in regenerativemedicine. It appears that certain cells,like skin cells, can be reprogrammed toact as articial stem cells, called inducedpluripotent cells.

Many questions about stem cell (andinduced pluripotent cell) therapy need to be

answered: Do older adults have enough stemcells for this type of therapy or do they needto be donated from someone else? Wouldcreating stem cells from an older personsskin cells work? Would stem cell therapy restorehealth and vigor to an older person or onlywork in a younger person? How would stemcell therapy work on the cellular levelwould

stem cells replace the non-functioning cellsor would they reactivate and repair the dam-aged cells? Would stem cell therapy work inall areas of the body, or only in some areas?

While many questions remain, the prospectof regenerative medicine could have impor-tant implications for the treatment of many

degenerative diseases.

Imagine if doctors were able to reverse age-related, chronic degeneration

and bring the body back to its original health and vigor. While far too early to

know if regenerative medicine will ever be a reality, research on stem cellsopens up the possibility.

STEM CELLS &REGENERATIVE MEDICINE

THE FUTURE OF AGING RESEARCH


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22


25/44


Does stress really

shorten your life?

Have you ever looked at side-by-side

photos of a person before and after aparticularly trying time in his or her life,for instance, before and a few years afterstarting a highly demanding job? Theperson likely appears much older in thelater photo. The stress of the job is thoughtto contribute to the prematurely aged

appearance. You might feel stress fromwork or other aspects of your daily life,too. Stress is everywhere. Even when youfeel relaxed, your body is still experiencingconsiderable stressbiological stress.And, it is this type of stress that is widelystudied by gerontologists for its effects on

aging and longevity.

Biological stress begins with the very basicprocesses in the body that produce and use energy.We eat foods and we breathe, and our body usesthose two vital elements (glucose from food andoxygen from the air) to produce energy, in a process

known as metabolism. You may already thinkof metabolism as it pertains to eatingMymetabolism is fast, so I can eat dessert," or Mymetabolism has slowed down over the years,so Im gaining weight. Since metabolism is allabout energy, it also encompasses breathing,circulating blood, eliminating waste, controllingbody temperature, contracting muscles, oper-

ating the brain and nerves, and just about everyother activity associated with living.

METABOLISM


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24 METABOLISM

These everyday metabolic activities thatsustain life also create metabolic stress, which,over time, results in damage to our bodies.Take breathingobviously, we could not survivewithout oxygen, but oxygen is a catalyst formuch of the damage associated with agingbecause of the way it is metabolized inside ourcells. Tiny parts of the cell, called mitochondria,use oxygen to convert food into energy. Whilemitochondria are extremely ecient in doingthis, they produce potentially harmful by-

products called oxygen free radicals. A varietyof environmental factors, including tobaccosmoke and sun exposure, can produce them,too. The oxygen free radicals react with andcreate instability in surrounding molecules.This process, called oxidation, occurs as a chainreaction: the oxygen free radical reacts withmolecule A causing molecule A to become

unstable; molecule A aempts to stabilizeitself by reacting with neighboring molecule B;then molecule B is unstable and aempts tobecome stable by reacting with neighboringmolecule C; and so on. This process repeatsitself until one of the molecules becomes stableby breaking or rearranging itself, instead ofpassing the instability on to another molecule.

Some free radicals are benecial. Theimmune system, for instance, uses oxygen freeradicals to destroy bacteria and other harmfulorganisms. Oxidation and its by-products alsohelp nerve cells in the brain communicate.But, in general, the outcome of free radicalsis damage (breaks or rearrangements) to

other molecules, including proteins and DNA.Because mitochondria metabolize oxygen,

FREE RADICALS

Oxidation chain reaction.

A B

B C

B C

A B


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In the early 1960s, scientists discovered

that fruit ies exposed to a burst of heat

produced proteins that helped their cells

survive the temperature change. Over the

years, scientists have found these heat

shock proteins in virtually every living

organism, including plants, bacteria, worms,

mice, and even humans. Scientists have

learned that, despite their name, heat shock

proteins are produced when cells are ex-

posed to a variety of stresses, not just heat.

The pro teins can be triggered by oxidative

stress and by exposure to toxic substances

(for example, some chemicals). When heatshock proteins are produced, they help cells

dismantle and dispose of damaged proteins

and help other proteins keep their structure

and not become unraveled by stress. They

also facilitate making and transporting new

proteins in the body.

Heat shock response to stress changes

with age. Older animals have a higher every-

day level of heat shock proteins, indicating

that their bodies are under more biological

stress than younger animals. On the o ther

hand, older animals are unable to produce

an adequate amount of heat shock proteins

to cope with eeting bouts of stress from

the environment.Heat shock proteins are being consid-

ered as a possible aging biomarker

something that could predict lifespan or

development of age-related problems

in animal models like worms and fruit ies.

However, the exact role heat shock proteins

play in the human aging process is not yet clear.

HEAT SHOCK PROTEINS

they are particularly prone to free radicaldamage. As damage mounts, mitochondriamay become less ecient, progressivelygenerating less energy and more free radicals.

Scientists study whether the accumulationof oxidative (free radical) damage in our cellsand tissues over time might be responsible formany of the changes we associate with aging.Free radicals are already implicated in manydisorders linked with advancing age, includ-ing cancer, atherosclerosis, cataracts, and

neurodegeneration.Fortunately, free radicals in the body do

not go unchecked. Cells use substances calledantioxidants to counteract them. Antioxidantsinclude nutrients, such as vitamins C and E, aswell as enzyme proteins produced naturally inthe cell, such as superoxide dismutase (SOD),

catalase, and glutathione peroxidase.Many scientists are taking the idea that anti-

oxidants counter the negative eects of oxygenfree radicals a step further. Studies have testedwhether altering the antioxidant defenses of thecell can aect the lifespan of animal models.These experiments have had conicting results.NIA-supported researchers found that insert-ing extra copies of the SOD gene into fruit iesextended the fruit ies average lifespan by asmuch as 30 percent. Other researchers foundthat immersing roundworms in a syntheticform of SOD and catalase extended theirlifespan by 44 percent. However, in a com-prehensive set of experiments, increasing or

decreasing antioxidant enzymes in laboratorymice had no eect on lifespan. Results from a


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26

Scientists also found that age-related dam-age to DNA and proteins is oen reversibleand does not cause problems until the dam-age evokes a stress response. This suggeststhat the stress response, rather than thedamage itself, is partially responsible forage-related deterioration.

Some biologists have started looking

at stress resistance when choosing animalmodels to study as examples of successfulaging. Researchers can test stress resistancein young animals and then continue study-ing only those animals demonstrating highresistance. Ongoing studies will determineif there is a direct cause-eect relationshipbetween stress resistance and longevity,

and if these longer-lived animals are resis-tant to all or only certain sources of stress.

In addition, researchers are studyingthe relationship between psychologicalstress and aging. In one study, mothers ofseverely and chronically sick children hadshorter telomeres, relative to other women.In other research, caregivers of people with

Alzheimers disease were found to haveshortened telomeres. These ndings couldsuggest that emotional or psychologicalstress might aect the aging process. Moreresearch on the mechanisms involved isneeded before scientists can make anyconclusions about clinical implications.

The rst C. elegansworm genetically manipulated to have a longer lifespan

was resistant to stress caused by heat. Subsequently, researchers learned

that a common thread among all long-lived animals is that their cells (and in

some cases the animals as a whole) are more resistant to a variety of stresses,

compared to animals with an average or shorter lifespan.

STRESSTHE FUTURE OF AGING RESEARCH

limited number of human clinical trials involv-ing antioxidants generally have not supportedthe premise that adding antioxidants to the

diet will support longer life. Antioxidantsupplementation remains a topic ofcontinuing investigation.

METABOLISM


29/44


Does how much you eataffect how long you live?Your body needs food to survive. However, thevery process of extracting energy from foodmetabolizing foodcreates stress on your body.Overeating creates even more stress on the

body. Thats part of the reason why it can lead toa shorter lifespan and serious health problemscommon among older people, including cardio-vascular disease and type 2 diabetes.

Calorie restriction, an approach primarily(but not exclusively) used in a research set-ting, is more tightly controlled than normal

healthy eating or dieting. It is commonlydened by at least a 30 percent decrease in

calorie consumption from the normal dietwith a balanced amount of protein, fat, vita-mins, and minerals. In the 1930s, investigators

found that laboratory rats and mice livedup to 40 percent longer when fed a calorie-restricted diet, compared to mice fed a normaldiet. Since that time, scientists observed thatcalorie restriction increased the lifespan ofmany other animal models, including yeast,worms, ies, some (but not all) strains ofmice, and maybe even nonhuman primates.

In addition, when started at an early age or asa young adult, calorie restriction was foundto increase the health span of many animalmodels by delaying onset of age-related dis-ease and delaying normal age-related decline.

Two studies of calorie restriction in non-human primates (the animals most closely

related to humans) have had intriguingresults. In a study conducted at NIA, monkeysfed a calorie-restricted diet had a notablydecreased and/or delayed onset of age-relateddiseases, compared to the control group ofnormal eaters. In a University of Wisconsinstudy supported by NIA, calorie-restrictedrhesus monkeys had three times fewer age-

related diseases compared to the controlgroup. The Wisconsin study also found thatrhesus monkeys on a restricted diet had fewerage-related deaths compared to their normalfed controls. In 2007, when the ndings fromthe study conducted at NIA were published,it was too early to determine whether calo-

rie restriction had any eects on lifespan.Research in primates continues.


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28

Despite its apparent widespread acceptance,calorie restriction does not increase lifespanin all animals. In studies of non-laboratory

(wild) mice, researchers found that on aver-age, calorie restriction did not have any eecton lifespan. Some of the calorie-restrictedmice actually lived shorter than average lives.This may be due to dierences in the geneticsof the wild mice. A 2010 NIA-funded studyprovides further evidence that genetics mayplay a role in whether or not calorie restric-

tion will have a positive eect on longevity.Looking at 42 closely related strains of labora-tory mice, researchers found that only about athird of the strains on a calorie-restricted diethad an increase in longevity. One-third of thestrains of mice on a calorie-restricted diet hada shortened lifespan, and the other third had

no signicant dierence in lifespan com-pared to mice on a normal diet.

While animal studies are ongoing, researchersare also exploring calorie restriction in humansto test its safety and practicality, as well as tosee if it will have positive eects on health.Participants in a 2002 pilot of the Compre-hensive Assessment of Long-term Eects of

Reducing Intake of Energy (CALERIE) studyhad, aer 1 year, lowered their fasting glucose,total cholesterol, core body temperature, bodyweight, and fat. At the cellular level, they hadbeer functioning mitochondria and reducedDNA damage. However, in terms of practi-cality, scientists observed that adapting and

adhering to the regimen could be dicult.A longer-term trial is underway.

Given that ample studies have demon-strated mostly positive eects of calorierestriction in many organisms, todaysscientic studies focus on nding the mecha-nisms and pathways by which calorie restric-tion works. Researchers are also studyingcompounds that might act the same wayin the body, mimicking the benets ofcalorie restriction.

A wide range of possible mechanisms forcalorie restriction are being investigated.

Some scientists are exploring the possibilitythat metabolizing fewer calories results in lessoxidative damage to the cells. Other scientistsare looking at how the relative scarcity ofnutrients caused by calorie restriction mightinduce heat shock proteins and other defensemechanisms that allow the body to beer

withstand other stresses and health problems.Some researchers wonder if the eects of calo-rie restriction are controlled by the brain andnervous system. In one NIA-conducted study,calorie restriction increased the productionof brain-derived neurotrophic factor, orBDNF, a protein that protects the brain fromdysfunction and degeneration, and supports

increased regulation of blood sugar and heartfunction in animal models. Still other studiesindicate calorie restriction may inuencehormonal balance, cell senescence, or geneexpression. It is likely that calorie restrictionworks through a combination of these mecha-nisms, and others yet to be identied.

There is an intriguing overlap betweenthe pathways that control normal aging and

METABOLISM


31/44


those that scientists think may be pertinentto calorie restriction. The most relevant arethe sirtuins and mTOR (mammalian targetof rapamycin) pathways as discussed onpage 1. In several, but not all cases, disruptingthese pathways means the organism no lon-ger responds positively to calorie restriction.These two pathways have been importantfor identifying at least two compounds thatmay mimic the eects of calorie restriction:resveratrol and rapamycin.

Resveratrol, found naturally in grapes,wine, and nuts, activates the sirtuin pathway.It has been shown to increase the lifespanof yeast, ies, worms, and sh. In 2006, NIAresearchers, in collaboration with universityscientists funded by NIA, reported on a studycomparing mice fed a standard diet, a highfat-and-calorie diet, or a high fat-and-calorie

diet supplemented with resveratrol beginningat middle age. Resveratrol appeared to lessenthe negative eects of the high fat-and-caloriediet, both in terms of lifespan and disease. Ina 2008 follow-up study, investigators foundthat resveratrol improved the health of agingmice fed a standard diet. It prevented age- andobesity-related decline in heart function.Mice on resveratrol had beer bone health,reduced cataract formation, and enhancedbalance and motor coordination compared tonon-treated mice. In addition, resveratrol wasfound to partially mimic the eects of calorierestriction on gene expression proles ofliver, skeletal muscle, and adipose (fay) tissue

in the mice. However, the compound did nothave an impact on the mices overall survival

or maximum lifespan. These ndings suggestthat resveratrol does not aect all aspects ofthe basic aging process and that there maybe dierent mechanisms for health versuslifespan. Research on resveratrol continuesin mice, along with studies in nonhumanprimates and people.

Rapamycin, another possible calorierestriction mimetic, acts on the mTOR path-way. This compounds main clinical use is tohelp suppress the immune system of people

who have had an organ transplant so thatthe transplant can succeed. A study by NIAsInterventions Testing Program, as discussedon page 7, reported in 2009 that rapamycinextended the median and maximum lifespanof mice, likely by inhibiting the mTOR path-way. Rapamycin had these positive eectseven when fed to the mice beginning at

early-old age (20 months), suggesting thatan intervention started later in life may stillbe able to increase longevity. Researchers arenow looking at rapamycins eects on healthspan and if there are other compounds thatmay have similar eects as rapamycin onthe mTOR pathway.

Scientists do not yet know how resveratrol,rapamycin, and other compounds that dem-onstrate eects similar to calorie restrictionwill inuence human aging. Learning moreabout these calorie restriction mimetics, andthe mechanisms and pathways underlyingcalorie restriction, may point the way to futurehealthy aging therapies.


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30


33/44


Can your immune system still

defend you as you age?

Elementary schools are breeding groundsfor the common cold. Kids pass theirgerms around as often as they sharetheir lunch. For children, catching a coldmay not be a big deal. They might take iteasy for a few days while their immunesystem kicks into action and ghts off

infection. But for their older teachers andgrandparents, each cold can be more ofa challenge. It may take a week or longerto get back to feeling 100 percent. Doesthat mean that the immune system getsweaker as we age? Thats whatgerontologists are trying to gure out.

Our immune system is a complicated networkof cells, tissues, and organs to keep us healthyand ght o disease and infection. The immunesystem is composed of two major parts: theinnate immune system and the adaptive immunesystem. Both change as people get older. Studies tobeer understand these changes may lead to waysof supporting the aging immune system.

IMMUNE

SYSTEM


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32

Innate immunity is our rst line ofdefense. It is made up of barriers and certaincells that keep harmful germs from enteringthe body. These include our skin, the cough

reex, mucous membranes, and stomachacid. If germs are able to pass these physicalbarriers, they encounter a second line ofinnate defense, composed of specialized cellsthat alert the body of the impending danger.Research has shown that, with age, innateimmune cells lose some of their ability tocommunicate with each other. This makes

it dicult for the cells to react adequately topotentially harmful germs called pathogens,including viruses and bacteria.

Inammation is an important part ofour innate immune system. In a youngperson, bouts of inammation are vitalfor ghting o disease. But as people age,

they tend to have mild, chronic inamma-tion, which is associated with an increasedrisk for heart disease, arthritis, frailty,type 2 diabetes, physical disability, anddementia, among other problems. Research-ers have yet to determine whether inam-mation leads to disease, disease leads toinammation, or if both scenarios are true.

Interestingly, centenarians and other peoplewho have grown old in relatively good healthgenerally have less inammation and amore ecient recovery from infection andinammation when compared to peoplewho are unhealthy or have average health.Understanding the underlying causes of

chronic inammation in older individualsand why some older people do not have this

problemmay help gerontologists nd waysto temper its associated diseases.

The adaptive immune system is morecomplex than the innate immune system

and includes the thymus, spleen, tonsils, bonemarrow, circulatory system, and lymphaticsystem. These dierent parts of the bodywork together to produce, store, and transportspecic types of cells and substances to combathealth threats. T cells, a type of white bloodcell (called lymphocytes) that ghts invadingbacteria, viruses, and other foreign cells, are

of particular interest to gerontologists.

T cells aack infected or damaged cellsdirectly or produce powerful chemicals thatmobilize an army of other immune systemsubstances and cells. Before a T cell getsprogrammed to recognize a specic harmfulgerm, it is in a nave state. Aer a T cell is

assigned to ght o a particular infection, itbecomes a memory cell. Because these cellsremember how to resist a specic germ, theyhelp you ght a second round of infectionfaster and more eectively. Memory T cellsremain in your system for many decades.

A healthy young persons body is like aT cell producing engine, able to ght oinfections and building a lifetime storehouseof memory T cells. With age, however, peopleproduce fewer nave T cells, which makesthem less able to combat new health threats.This also makes older people less responsiveto vaccines, because vaccines generallyrequire nave T cells to produce a protective

immune response. One exception is the shinglesvaccine. Since shingles is the reactivation

IMMUNE SYSTEM


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ORGANS OF THE IMMUNE SYSTEM

BARRIERS

NOSE, MUCOUS

THYMUS

BONE MARROW

LYMPH NODES

TONSILS

LYMPH NODES

LYMPH NODES

SPLEEN

LYMPHATIC VESSELS

LYMPHATIC VESSELS

ADAPTEDFROMWWW.NIAID.NIH.GOV


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34

of the chickenpox virus, this particularvaccine relies on existing memory T cellsand has been particularly eective in olderpeople. Researchers are investigating ways todevelop other vaccines that are adjusted for

the changes that happen in an older personsimmune system.

Negative, age-related changes in our innateand adaptive immune systems are knowncollectively as immunosenescence. A lifetimeof stress on our bodies is thought to contrib-

ute to immunosenescence. Radiation, chemi-cal exposure, and exposure to certain diseasescan also speed up the deterioration of theimmune system. Studying the intricacies ofthe immune system helps researchers beer

understand immunosenescence and deter-mine which areas of the immune system aremost vulnerable to aging. Ongoing researchmay shed light on whether or not there is anyway to reverse the decline and boost immuneprotection in older individuals.

IMMUNE SYSTEM

ALTERING OLDER

ADULTS' IMMUNITY

THE FUTURE OF AGING RESEARCH

Our ability to survive the germsaround us is based on a tightlycontrolled immune system. Toolile of an immune responsemakes us susceptible to infection,

including life-threatening pneumonia.

Conversely, an overactive immune responseis at the root of autoimmune diseasescommon among older people and maycontribute to age-related chronic diseaseslike Alzheimers disease, osteoarthritis,diabetes, and heart disease. So, should sci-entists try to change the immune response

in older people, or is immunosenescencesomehow benecial within the context ofthe aging body?

Given the delicate balance of theimmune system, gerontologists suspect that,along with its more obvious negative con-

sequences, immunosenescence might havea protective role in seniors. More researchis needed before scientists fully understandthe aging immune system and determinewhether changing an immune responsewould lead to an increase or a decrease inhealth span and lifespan in humans.

THE PROMISE


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So, in the end, what causes aging?

Clearly this question has fascinated

medical researchers, philosophers,

anthropologists, and the general public

for centuries. This booklet oers you justa glimpse of the journey to understand

the science of aging.

In a sense, we are all aging experts

every day we get older. Its true that most

of us cannot explain whats happening

under the microscope, but the lile girl

can still be curious about her vivacious

grandmother without knowing that

the grandmothers good health may

be a sign of what to expect during her

own golden years. And, the man in

middle age can know that he looks and

feels beer when making healthy food

choices and staying physically active

without understanding the intricacies

of metabolism and biological stress.

Aging is part of us, its part of life.

As the eld of gerontology matures,

scientists will continue to learn about

what happens deep inside our bodies

during our passage from child to older

adult. Experiments involving animalmodels that on the surface seem so

dierent from usyeast, fruit ies,

worms, and micewill yield insights into

aspects of aging that could one day lead

to important clinical, pharmacological, or

behavioral interventions for humans.

What is the future of biology of aging

research? It is not likely that we will see

a modern-day fountain of youth, that

mythical elixir promised to restore people

to their younger selves. But research may

very well oer us the means to a healthier,

longer life. And, with that, we may have

the opportunity to spend more time with

our loved ones, the opportunity to meet

our great-great-grandchildren, and the

opportunity to enjoy more life experiences.


THE PROMISE

OF RESEARCH

PHOTOCREDIT:WWW.BILLDENISONPHOTO.COM

Past, present, and future

GLOSSARY


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36

AntioxidantsCompounds that may protectcells from oxygen free radicals by preventing orslowing the process of oxidation. Some anti-

oxidants are enzyme proteins like superoxidedismutase (SOD) and catalase, while others are

nutrients, such as vitamin C.

Calorie restrictionA diet that is lower by a

specic percent of calories than the normal diet,but includes all essential nutrients. At this time

calorie restriction is an experimental interven-tion being studied to determine its impact on

health and longevity.

Cell senescenceA process in which a cellturns o its capacity to produce new cells, stops

dividing, and has limited function. Cell senes-cence may contribute to aging, but it may alsobe a protective mechanism against cancer (a

disease state in which cells continue to dividewithout control).

CentenarianA person who has lived at least100 years.

ChromosomeA structure inside cells contain-ing DNA, which carries our genetic information

and is responsible for heritable traits.

DNAAbbreviation for deoxyribonucleic acid;DNA contains the genetic code for all animalsand plants, from single-cell organisms to humans.

EnzymeA protein that increases the rate of aspecic chemical reaction.

FibroblastOne of the major cell types foundin skin and other tissues. Fibroblasts secrete

molecules that have important structural

properties for tissues and organs, and they

change with age.

Free radicalsUnstable molecules that reactreadily with other molecules to try to become

stable. Oxygen free radicals are produced nor-

mally when food is metabolized and may cause

damage to cells. Over a lifetime, this damage

may contribute to aging.

GeneA region of DNA containing code thatcan be read to make proteins in the cell. Genesare responsible for many heritable traits.

ImmunosenescenceThe age-related declinein functions of the immune system.

Life expectancyThe average number ofyears that members of a population (or species)

live; also known as average lifespan.

LymphocytesWhite blood cells that areimportant to the immune system. A decline in

lymphocyte function with advancing age is be-

ing studied for insights into aging and disease.

Maximum lifespan The greatest age reached

by any member of a given population (or species).

GLOSSARY

BIBLIOGRAPHY


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MitochondriaCell organelles thatproduce energy necessary for life from thefoods we eat. Mitochondria contain DNA,which may be damaged by oxygen free radi-cals produced during this process. Damageof mitochondrial DNA may contribute toaging. Mitochondria also are involved incontrolling cell death.

ProteinsMolecules arranged in a specicorder determined by DNA. Proteins areessential for all life processes. Certain proteins,such as those protecting against free radicalsand those produced by the immune system,are studied extensively by gerontologists.

Stem cellsCells with the potentialto become many dierent types of cellsfound in the body. Stem cells are also ableto replicate almost indenitely withoutbecoming abnormal.

TelomeraseAn enzyme that restorestelomeres to the ends of chromosomes incertain cells, such as egg and sperm cells. Thistelomere lengthening insures that the cellscan continue to divide and multiply.

TelomeresRepeated short, non-codingsequences of DNA at each end of a chromo-some. Telomeres protect the chromosome fromdamage and shorten each time a cell divides.

Austad, S.N., Comparative Biology of Aging, Journal ofGerontology: Biological Sciences, A(): -, .

Bartke, A., Insulin and Aging, Cell Cycle, ():-, .

Bartke, A., The Somatotropic Axis and Aging: Mechanisms

and Persistent Questions about Practical Implications,Experimental Gerontology, (-): -, .

Barzilai, N. and Bartke, A., Biological Approaches to

Mechanistically Understand the Healthy Life Span Exten-sion Achieved by Calorie Restriction and Modulation of

Hormones, Journal of Gerontology: Biological Sciences,A(): -, .

Bauer, M.E., Chronic Stress and Immunosenescence: A

Review, NeuroImmunoModulation, : -, .

Baur, J.A., Pearson, K.J., Price, N.L., et al., ResveratrolImproves Health and Survival of Mice on a High-Calorie

Diet, Nature, : -, .

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