A Biological Quest - Glenn Foundation for Medical Research · A Biological Quest National Institutes of Health National Institute on Aging Office of Communications and Public Liaison

N AT I O N A L I N S T I T U T E O N A G I N G N AT I O N A L I N S T I T U T E S O F H E A LT H

A Biological Quest

National Institutes of HealthNational Institute on AgingOffice of Communications

and Public LiaisonBuilding 31, Room 5C27Bethesda, MD 20892-2292Phone: 1-301-496-1752Website: www.nia.nih.gov

NIH Publication No. 02-2756

grow old along with me!The best is yet to be,

The last of life, for which the first was made.”

—Robert Browning, (1812-1889)

“

3Biochemistryand Aging 17

Oxygen Radicals 18

Antioxidants and Aging Nematodes 19

Protein Crosslinking 20

Research on Sunlight May Help Explain

What Happens to Skin as We Age 21

DNA Repair and Synthesis 22

Heat Shock Proteins 24

Hormones 25

Hormone Replacement 25

Hormones and Research on Aging 26-27

Growth Factors 28

1

25

4Introduction i

Posing Questions,Finding Answers 1

What is Aging? What is Senescence? 3

What is the Difference Between Life

Expectancy and Lifespan? 4

Why Do We Age? 5

Theories of Aging 6

The GeneticConnection 7

Longevity Genes 8

Tracking Down A Longevity Gene 9

Age-related Traits Are All in the Family 11

Microarrays in Action 12

In the Lab of the Long-Lived Fruit Flies 13

Cellular Senescence 13

Proliferative Genes 15

Telomeres 15 6

PhysiologicClues 29

Normal Aging 30

The Immune System 31

What Is Normal Aging? 32-33

Caloric Restriction 34

The Next Step: Caloric Restriction

in Primates 36

Behavioral Factors 38

Exercise: It Works at Any Age 37

The Futureof Aging 39

Stem Cells: Great Expectations,

but Many Barriers Remain 41-42

Glossary/Bibliography 43

Glossary 44-45

Bibliography 46-48

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—William Osler, 1913

One of two things happens after sixty,when old age takes a fellow by the hand.

Either the rascal takes charge as general factotum,and you are in his grip body and soul;

or you take him by the neck at the first encounterand after a good shaking make him go your way.”

“

Life is short, so enjoy every minute.Hang gliding, for me, lifts the spiritand recharges the old batteries. It isthe greatest sport going, and lots ofexercise too.

— Robert Byrdhang glider, age 74

i

Aging Under the Microscope

IntroductionThe study of aging is not what it used to be. Gerontology was a young science when

Congress created the National Institute on Aging (NIA) in 1974 as part of the National

Institutes of Health (NIH). At that time, theories of aging abounded, but data was scant.

Gerontology lacked, or was just in the early stages of developing, ways to explore the

fundamentals of the aging process. Knowledge of aging clustered around specific dis-

eases associated with advancing age; indeed the notion that aging equated with decline

and illness was widespread.

Now, nearly 30 years later, the science base has grown in depth, breadth, and detail.

And, with this growth have come new insights into the processes and experience of

aging. Where gerontologists once looked for a single, all-encompassing theory to explain

aging—a single gene, for instance, or the decline of the immune system—they are now

finding multiple processes, combining and interacting on many levels. Cells, proteins,

tissues, and organ systems are all involved, and gerontologists are now able to discern

many more of the mechanisms by which these components cause or react to aging.

Much of this research has been supported or conducted by the NIA. In addition

to research in its laboratories in Baltimore and Bethesda, Maryland, the Institute

sponsors basic, clinical, epidemiological, and social research on aging at universities,

medical centers, and other sites worldwide. As this work evolves and new knowledge

accumulates, gerontologists hope to move closer to their ultimate goal of promoting

health and independence throughout the lifespan.

FindingAnswersQuestions,Posing

In 1965, a lawyer made an unusual deal with one of his older

clients, Jeanne Calment of Arles, France. In exchange for

ownership of her apartment, he agreed to pay her a monthly

pension for the rest of her life. Because Mme. Calment was

90 years old at the time, it seemed likely that the lawyer

would only have to make a few payments before her demise.

As it turned out, however, it was a much better bargain for

Mme. Calment. During the next 32 years of her extraordinary

life, she was paid three times the worth of the apartment.

lives. Is it where people live?As of 2001, ten of the world’soldest people were Japanese,six were American, threewere French, and two wereItalian. Is there somethingspecial about how these people live? Mme. Calmenttook up fencing lessons at 85,still rode a bicycle at age 100,smoked until she was 117,and ate a diet rich in olive oil all of her life. In truth,there probably is no single“secret” of aging. More thanlikely, all of these elements—heredity, environment, andlifestyle—have complex rolesin determining whether an individual will have a longand healthy life, according toscientists who study aging.

her lawyer who died—at age 77—soon after Mme. Calment’s 120th birthday.

Long lives like Mme. Calment’s are a wonder. Of the planet’s current 6 billion inhabitants, perhapsno more than 25 people aremore than 110 years old. Sothese super centenarians, asthey are known, are clearlyhumanity’s ultimate mara-thoners. But why? What fac-tors allowed Jeanne Calment,who was 14 when the EiffelTower was completed andwho once sold painting supplies to Vincent VanGogh, to live such a long life that she herself becamepart of history?

Is genetics the key factor?Mme. Calment’s ancestorswere legendary for their long

“We all make bad deals inlife,” Mme. Calment oncejoked to the astounded attorney. When her well-documented life ended onAugust 4, 1997 at age 122years 5 months and 14 days,she is believed to have livedlonger than any other personin recorded history. She out-lived Shigechiyo Izumi ofJapan, who had held theunverified longevity record of120 years, 237 days. She out-lived her husband, who diedin 1942, four years before their50th wedding anniversary. Sheoutlived her daughter, whodied in 1936. She outlived heronly grandson, who died in1963. And yes, she outlived

2

Posing Questions, Finding AnswersPosing Questions, Finding Answers

At her 120th birthday party, a journalist hesitantlytold Mme. Calment, “Well, I guess I’ll see you next year.”

Instantly, she shot back, “I don’t see why not. You look to be in pretty good health to me!”

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d

Four brothers, below (a) 9 years old,(b) 7 years old, (c) 5 years old, and (d) 3 years old; at lower right, thebrothers pictured 52 years later. Visible signs of aging can vary, evenamong family members, depending on a number of environmental andgenetic factors.

during the lifespan. However,this definition includes somechanges that aren’t necessarilyproblematic, and usuallydon’t affect an individual’sviability. Gray hair and wrin-kles, for instance, certainly aremanifestations of aging, butneither is harmful.

To differentiate thesesuperficial changes from those that increase the risk of disease, disability, or death, gerontologists prefer to use a more precise term—senescence—to describeaging. Senescence is the progressive deterioration ofmany bodily functions overtime. This loss of function isaccompanied by decreasedfertility and increased risk of mortality as an individual

Aging Under the Micro-scope: A Biological Questdescribes what we know so far about the answers to these questions. It offersan overview of research on aging and longevity,describing the major puzzlepieces already in place and, to the extent possible,the shapes of those that are missing.

What Is Aging? What Is Senescence?Aging is a complex naturalprocess potentially involvingevery molecule, cell, andorgan in the body. In itsbroadest sense, aging merelyrefers to changes that occur

lifespan beyond which wecannot live no matter howoptimal our environment or favorable our genes? Andfinally for all of us, the mostimportant question: How can insights into longevity be used to fight the diseasesand disabilities associatedwith old age to make surethis period of life is healthy,active, and independent?

Researchers at theNational Institute on Aging(NIA), part of the NationalInstitutes of Health, are seek-ing answers to these andother important questions.Established by the FederalGovernment in 1974, the NIA conducts and supportsresearch on aging and edu-cates the public about itsfindings.

These scientists, called gerontologists, ponder otherfundamental questions. Whydo we age? What happens aswe age? Why do some peopleage faster or slower and indifferent ways than others? Is there a maximum human

3


Comparative Lifespans (in years)

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fairly primitive, and the lifeexpectancy—the averagenumber of years from birththat an individual can expectto live—was still less than 50 years worldwide.

Yet Mme. Calment, per-haps because she was bornwith a set of extraordinarygenes or was simply fortunateenough to elude many of theillnesses that claim so manyothers, beat the odds and set

What is the Difference BetweenLife Expectancy and Lifespan?When George Washingtoncelebrated his 60th birthday in 1792, he had outlived all of his male ancestors, datingback for several generations.He had outlived a typical Virginian of his era by about15 years. To achieve this relative “old age,” he hadsurvived smallpox, mumps,pneumonia, dysentery,typhoid fever, a staphylococ-cal infection of the hip, fourbouts of malaria, and twonearly fatal encounters withinfluenza.

When Jeanne Calmentwas born in 1875, the illnessesthat plagued Washington’sgeneration still took manylives, health care was still

sexual tissues atrophy withincreasing age. In men,sperm production decreasesand the prostate enlarges.

Why these and otherchanges occur with advanc-ing age both intrigues andperplexes gerontologists. In fact, senescence is one ofnature’s least understood bio-logical processes. Gerontolo-gists, for instance, disagreeabout when senescencebegins. Some argue it beginsat birth. Others contend itsets in after the peak repro-ductive years. But clearly,senescence, whether it beginsat birth or age 20, 30, or 40,leads to an accumulating loss of bodily functions,which ultimately increasesthe probability of death, aswe get older.

gets older. The rate and pro-gression of this process canvary greatly from person toperson, but generally overtime every major organ of the body is affected. As weage, for instance, lung tissueloses much of its elasticity,and the muscles of the ribcage shrink. As a result, maximum vital breathingcapacity progressively dimin-ishes in each decade of life,beginning at about age 20.With age, blood vessels accu-mulate fatty deposits andlose much of their flexibility,resulting in arteriosclerosis or“hardening of the arteries.”In the gastrointestinal system, production of diges-tive enzymes diminishes, andas a result, tissues lose muchof their ability to break downand absorb foods properly. In women, vaginal fluid production decreases and

4Posing Questions, Finding Answers

Pacific salmon, above, live about 5 years and reproduce only once. They

undergo rapid physical deterioration and die soon after breeding. In contrast,Rougheye rockfish, right, are estimated

to live more than 200 years, yet showfew outward signs of aging and are

apparently capable of reproducing fre-quently, even in late life. These differ-

ences intrigue some gerontologists.

knowledge, all-encompass-ing theories of aging are giving way to a more diverse perspective.

Aging today is viewed as many processes, inter-active and interdependent,that determine lifespan andhealth, and gerontologists are studying a multitude of factors that may beinvolved. The rest of thisbooklet describes what weknow and don't know aboutmany of these factors, andwhere we think scientists are likely to find answers to questions about aging and longevity.

Why Do We Age?Gerontologists have pro-posed many theories to explain the diversity of theaging process in nature.Pacific salmon, for instance,reproduce only once and diewithin hours of spawning,while at the other end of the spectrum, sea anemones,which reproduce asexually,show few, if any, outwardsigns of deterioration untilthe very end of their longlives. Most gerontologistsnow agree that no single theory can account for thiswide spectrum. In fact, withthe tools of biotechnologyand an influx of new

As part of this quest,gerontologists are studying a variety of life forms includ-ing yeast, fruit flies, nema-todes, mice, and primates in search of clues applicableto human aging. As theyexplore the genes, cells, andorgans involved in aging,they are uncovering moreand more of the secrets oflongevity. As a result, lifeextension may some day bemore than the stuff of myth.In addition, as gerontologistsapply their expanding know-ledge to medicine, the pre-vention or retardation of theonset of some age-related diseases and disabilities may become realistic goals.

the benchmark for maximumhuman lifespan—the greatestage reached by any memberof a species.

Life expectancy in theUnited States rose dramati-cally in the 20th century, fromabout 47 years in 1900 toabout 73 years for males and79 years for females in 1999.This increase is mostly due to improvements in environ-mental factors—sanitation,the discovery of antibiotics,and medical care. Now, asscientists make headwayagainst chronic diseases likecancer and heart disease,some think life expectancycan be extended even furtherin the 21st century.

5


Next to the miracle of life itself, aging and death are perhaps the greatest mysteries.”

—Caleb Finch, Ph.D.Gerontologist, University of Southern California

“

6Posing Questions, Finding Answers

Theories of AgingERROR THEORIES Wear and Tear. Cells and tissues have vital parts that wear out.

Rate of Living. The greater an organism's rate of oxygenbasal metabolism, the shorter its life span.

Crosslinking. An accumulation of crosslinked proteins damages cells and tissues, slowing down bodily processes.

Free Radicals. Accumulated damage caused by oxygen radicals causes cells, and eventually organs, to stop functioning.

Somatic DNA Damage. Genetic mutations occur and accumulate with increasing age, causing cells to deteriorate and malfunction. In particular, damage to mitochondrialDNA might lead to mitochondrialdysfunction.

Theories of aging fall into two groups. The programmedtheories hold that aging follows a biological timetable,perhaps a continuation of the one that regulates child-hood growth and development. The damage or error theories emphasize environmental assaults to our systemsthat gradually cause things to go wrong. Many of the theories of aging are not mutually exclusive. Here is abrief and very simplified rundown of the major theories.

PROGRAMMED THEORIESProgrammed Longevity. Aging is the result of the sequen-tial switching on and off of certain genes, with senescencebeing defined as the time when age-associated deficits aremanifested.

Endocrine Theory. Biological clocks act through hormonesto control the pace of aging.

Immunological Theory. A programmed decline in immunesystem functions leads to an increased vulnerability toinfectious disease and thus aging and death.

Four generations of a family. Although it isfairly easy to estimate the approximate agesof the women in this picture, gerontologistshave not yet found any reliable way to measure these stark differences in human age under the microscope — either at the cellular or molecular level. Most gerontologistsnow believe no single theory fully explains the changes that occur in the aging body.

“

Mary Lavigne, age 102, shares alaugh in her home with ThomasPerls, M.D., founder and directorof the New England CentenarianStudy. Ms. Lavigne has lived inthree centuries. Perls and his colleagues are studying centen-arians and their siblings for signsof longevity genes and othergenetic traits.

Idon’t think the trick is staying young. I think the trick is aging well.”

— Thomas Perls, M.D.Director, New England Centenarian Study

can perform nearly 2,000roundworm studies in thetime it would take them to do one human study.

Under normal condi-tions, some genes arethought to manufacture proteins that limit lifespan.But when these same genesare mutated, they either produce defective proteins or no proteins at all. The net effect is these mutationspromote longevity.

about human aging andlongevity (See TrackingDown a Longevity Gene,page 9).

Longevity GenesResearchers have found evidence of several genes that seem to be related tolongevity determination.Longevity-related genes have been found in tinyroundworms called nema-todes, in fruit flies, and evenin mice. Like yeast, nema-todes and fruit flies haveattracted a lot of attentionfrom gerontologists becausetheir short lifespans and theirwell-characterized geneticcomposition make them relatively easy to study.Investigators, for instance,

There is little doubt that genes have a tremen-dous impact on aging andlongevity. Based on studiesof identical twins, who sharethe exact same set of genes,scientists now suspect thatlifespan is determined byboth environmental andgenetic factors, with geneticsaccounting for up to 35 per-cent of this complex interac-tion. Although differentanimal species vary up to 100 times in lifespan—humans live five timeslonger than cats, forinstance—scientists are dis-covering some surprisingsimilarities between ourgenes and those of otherspecies. Even single-celledyeast, one of nature’s simplest organisms, mayprovide scientists withimportant genetic clues

Some families seemblessed with long lives. Infact, siblings of centenarians have a four times greaterchance of living into theirearly nineties than most peo-ple, according to researchersat the New England Cente-narian Study in Boston. Acoincidence? Hardly. Whatlikely helps set these hardyindividuals apart are extra-ordinary sets of genes, thecoded segments of DNA(deoxyribonucleic acid),which are strung like beadsalong the chromosomes ofnearly every living cell. Inhumans, the nucleus of eachcell holds 23 pairs of chromo-somes, and together thesechromosomes contain about30,000 genes.

8The Genetic Connection

ConnectionGeneticThe

Each year on her birthday, Jeanne Calment sent her lawyer

a note, which read, “Excuse me if I’m still alive, but my

parents didn’t raise shoddy goods.” Her brother, who died

at age 97, apparently wasn’t too “shoddy” himself. When

another super centenarian, Sarah Knauss of Allentown,

Pennsylvania, died in 1999 at age 119, her daughter was 96.

“

Mary Lavigne, age 102, shares alaugh in her home with ThomasPerls, M.D., founder and directorof the New England CentenarianStudy. Ms. Lavigne has lived inthree centuries. Perls and his colleagues are studying centen-arians and their siblings for signsof longevity genes and othergenetic traits.

Idon’t think the trick is staying young. I think the trick is aging well.”

— Thomas Perls, M.D.Director, New England Centenarian Study

can perform nearly 2,000roundworm studies in thetime it would take them to do one human study.

Under normal condi-tions, some genes arethought to manufacture proteins that limit lifespan.But when these same genesare mutated, they either produce defective proteins or no proteins at all. The net effect is these mutationspromote longevity.

about human aging andlongevity (See TrackingDown a Longevity Gene,page 9).

Longevity GenesResearchers have found evidence of several genes that seem to be related tolongevity determination.Longevity-related genes have been found in tinyroundworms called nema-todes, in fruit flies, and evenin mice. Like yeast, nema-todes and fruit flies haveattracted a lot of attentionfrom gerontologists becausetheir short lifespans and theirwell-characterized geneticcomposition make them relatively easy to study.Investigators, for instance,

There is little doubt that genes have a tremen-dous impact on aging andlongevity. Based on studiesof identical twins, who sharethe exact same set of genes,scientists now suspect thatlifespan is determined byboth environmental andgenetic factors, with geneticsaccounting for up to 35 per-cent of this complex interac-tion. Although differentanimal species vary up to 100 times in lifespan—humans live five timeslonger than cats, forinstance—scientists are dis-covering some surprisingsimilarities between ourgenes and those of otherspecies. Even single-celledyeast, one of nature’s simplest organisms, mayprovide scientists withimportant genetic clues

Some families seemblessed with long lives. Infact, siblings of centenarians have a four times greaterchance of living into theirearly nineties than most peo-ple, according to researchersat the New England Cente-narian Study in Boston. Acoincidence? Hardly. Whatlikely helps set these hardyindividuals apart are extra-ordinary sets of genes, thecoded segments of DNA(deoxyribonucleic acid),which are strung like beadsalong the chromosomes ofnearly every living cell. Inhumans, the nucleus of eachcell holds 23 pairs of chromo-somes, and together thesechromosomes contain about30,000 genes.


ConnectionGeneticThe

Each year on her birthday, Jeanne Calment sent her lawyer

a note, which read, “Excuse me if I’m still alive, but my

parents didn’t raise shoddy goods.” Her brother, who died

at age 97, apparently wasn’t too “shoddy” himself. When

another super centenarian, Sarah Knauss of Allentown,

Pennsylvania, died in 1999 at age 119, her daughter was 96.

YOUNG WORMEarly in its brief lifespan, C. elegans, a small nematode (roundworm),moves rapidly and feeds vigorously.The worm is transparent, making iteasier to study physiological andgenetic changes that occur during its lifespan.

OLD WORMNear the end of its typical 2-to-3-weeklifespan, the worm loses muscle toneand eventually stops moving. By thetime it dies, its body appears tatteredand worn out. But by altering certaingenes, gerontologists have been ableto keep some of these worms sleek andvibrant for much longer than normal.

Investigators are finding clues to aging and longevityin yeast, one-celled organisms that have some intrigu-ing genetic similarities to human cells. In a laboratoryat Louisiana State University Medical Center in NewOrleans, Michal Jazwinski, Ph.D., has found genes thatseem to promote longevity in these rapidly dividing,easy-to-study organisms.

Yeast normally have about 21 cell divisions or genera-tions. Jazwinski observed that over the course of thatlifespan, certain genes in the yeast are more activeor less active as the cells age; in the language ofmolecular biology, they are differentially expressed.So far, Jazwinski has found 14 such genes in yeast.

Selecting one of these genes, Jazwinski triedtwo different experiments. First, he intro-

duced the gene into yeast cells in a formthat allowed him to control its activity.

When the gene was activated to agreater degree than normal, or overexpressed, some of the yeastcells went on dividing for 27 or 28generations; their period of activitywas extended by 30 percent.

In his second experiment, Jazwinski mutated the gene.When he introduced this non-working version into agroup of yeast cells, they had only about 12 divisions.

The two experiments made it clear that the gene, now called LAG-1, influences the number of divisionsin yeast or, according to some researchers’ ways ofthinking, its longevity. (LAG-1 is short for longevityassurance gene.) But how it works is still a mystery.One small clue lies in its sequence of DNA bases—its genetic code—which suggests that it produces aprotein found in cell membranes. One next step is tostudy the function of that protein. Similar sequenceshave been found in human DNA, so a second inves-tigative path is to clone the human gene and study itsfunction. If there turns out to be a human LAG-1 coun-terpart, new insights into aging may be uncovered.

In another laboratory, Leonard Guarente, Ph.D., of the Massachusetts Institute of Technology found thatmutation of a silencing gene—a gene that “turns off” other genes—delayed aging 30 percent in yeast. The gene, which is also found in C. elegans and otheranimals, produces an enzyme that alters the structure of DNA, which, in turn, alters patterns of gene expression.

Tracking Down a Longevity Gene

Yeast could helpgerontologistsunderstand thegenetics of aging.More than 14 genesthat appear to pro-mote the longevityof these single-celledorganisms have beendiscovered.

Kenyon’s team found lifespanof well-fed worms, which didnot form a dauer, could bedoubled. Other investigatorshave detected mutations insimilar daf genes that increasenematode lifespan three oreven four-fold.

The genes isolated so far are only a few of what scientists think may bedozens, perhaps hundreds, of longevity- and aging-related genes. But trackingthem down in organisms like nematodes and fruit fliesis just the beginning. The next big question for manygerontologists is whethercounterparts in people—human homologs—of thegenes found in laboratoryanimals have similar effects.The daf-2 gene in C. elegans, for instance, is similar to agene found in humans thatfunctions in hormone control.

worms. One of these genes,called daf-2, controls a specialstage in the worm’s develop-ment called dauer formation.A dauer forms, if, in the firstfew hours of its brief life, aworm finds food scarce. Inthis state, C. elegans grows acuticle for protection and can go into hibernation forseveral months. When thefood supply is ample again,the worm emerges from this metabolically slowed,non-aging state and contin-ues its normal life cycle. The protein produced by thedaf-2 gene drives the worm’sdevelopment past or out ofthe dauer state. But CynthiaKenyon, Ph.D., and her colleagues at the Universityof California, San Francisco,found that daf-2 does muchmore. It also can regulate thelifespan of normal, fertileadults. By altering this geneso that its activity is reduced,

For instance, a mutation of a gene whimsically named“I’m Not Dead Yet” or INDY,can double the lifespan offruit flies. In studies sup-ported by the NIA, these fruitflies not only lived longer,they thrived. By the time that80 to 90 percent of normalflies were dead, many of theINDY flies were still vigorousand capable of reproduction.At least two other life-extend-ing genetic mutations havebeen detected in the fruit fly genome.

In C. elegans, a nematode(roundworm), researchershave found yet another treas-ure trove of genetic cluesabout the aging process. By altering certain genes,researchers can substantiallyextend the normal 2-to-3-week lifespan of these tiny


9


Worms, Genes, and Aging

YOUNG WORMEarly in its brief lifespan, C. elegans, a small nematode (roundworm),moves rapidly and feeds vigorously.The worm is transparent, making iteasier to study physiological andgenetic changes that occur during its lifespan.

OLD WORMNear the end of its typical 2-to-3-weeklifespan, the worm loses muscle toneand eventually stops moving. By thetime it dies, its body appears tatteredand worn out. But by altering certaingenes, gerontologists have been ableto keep some of these worms sleek andvibrant for much longer than normal.

Investigators are finding clues to aging and longevityin yeast, one-celled organisms that have some intrigu-ing genetic similarities to human cells. In a laboratoryat Louisiana State University Medical Center in NewOrleans, Michal Jazwinski, Ph.D., has found genes thatseem to promote longevity in these rapidly dividing,easy-to-study organisms.

Yeast normally have about 21 cell divisions or genera-tions. Jazwinski observed that over the course of thatlifespan, certain genes in the yeast are more activeor less active as the cells age; in the language ofmolecular biology, they are differentially expressed.So far, Jazwinski has found 14 such genes in yeast.

Selecting one of these genes, Jazwinski triedtwo different experiments. First, he intro-

duced the gene into yeast cells in a formthat allowed him to control its activity.

When the gene was activated to agreater degree than normal, or overexpressed, some of the yeastcells went on dividing for 27 or 28generations; their period of activitywas extended by 30 percent.

In his second experiment, Jazwinski mutated the gene.When he introduced this non-working version into agroup of yeast cells, they had only about 12 divisions.

The two experiments made it clear that the gene, now called LAG-1, influences the number of divisionsin yeast or, according to some researchers’ ways ofthinking, its longevity. (LAG-1 is short for longevityassurance gene.) But how it works is still a mystery.One small clue lies in its sequence of DNA bases—its genetic code—which suggests that it produces aprotein found in cell membranes. One next step is tostudy the function of that protein. Similar sequenceshave been found in human DNA, so a second inves-tigative path is to clone the human gene and study itsfunction. If there turns out to be a human LAG-1 coun-terpart, new insights into aging may be uncovered.

In another laboratory, Leonard Guarente, Ph.D., of the Massachusetts Institute of Technology found thatmutation of a silencing gene—a gene that “turns off” other genes—delayed aging 30 percent in yeast. The gene, which is also found in C. elegans and otheranimals, produces an enzyme that alters the structure of DNA, which, in turn, alters patterns of gene expression.

Tracking Down a Longevity Gene

Yeast could helpgerontologistsunderstand thegenetics of aging.More than 14 genesthat appear to pro-mote the longevityof these single-celledorganisms have beendiscovered.

Kenyon’s team found lifespanof well-fed worms, which didnot form a dauer, could bedoubled. Other investigatorshave detected mutations insimilar daf genes that increasenematode lifespan three oreven four-fold.

The genes isolated so far are only a few of what scientists think may bedozens, perhaps hundreds, of longevity- and aging-related genes. But trackingthem down in organisms like nematodes and fruit fliesis just the beginning. The next big question for manygerontologists is whethercounterparts in people—human homologs—of thegenes found in laboratoryanimals have similar effects.The daf-2 gene in C. elegans, for instance, is similar to agene found in humans thatfunctions in hormone control.

worms. One of these genes,called daf-2, controls a specialstage in the worm’s develop-ment called dauer formation.A dauer forms, if, in the firstfew hours of its brief life, aworm finds food scarce. Inthis state, C. elegans grows acuticle for protection and can go into hibernation forseveral months. When thefood supply is ample again,the worm emerges from this metabolically slowed,non-aging state and contin-ues its normal life cycle. The protein produced by thedaf-2 gene drives the worm’sdevelopment past or out ofthe dauer state. But CynthiaKenyon, Ph.D., and her colleagues at the Universityof California, San Francisco,found that daf-2 does muchmore. It also can regulate thelifespan of normal, fertileadults. By altering this geneso that its activity is reduced,

For instance, a mutation of a gene whimsically named“I’m Not Dead Yet” or INDY,can double the lifespan offruit flies. In studies sup-ported by the NIA, these fruitflies not only lived longer,they thrived. By the time that80 to 90 percent of normalflies were dead, many of theINDY flies were still vigorousand capable of reproduction.At least two other life-extend-ing genetic mutations havebeen detected in the fruit fly genome.

In C. elegans, a nematode(roundworm), researchershave found yet another treas-ure trove of genetic cluesabout the aging process. By altering certain genes,researchers can substantiallyextend the normal 2-to-3-week lifespan of these tiny


9


Worms, Genes, and Aging

Age-related Traits Are All in the FamilyFinding longevity genes is only one of many goals forgerontologists. An equally important mission is unravelingthe genetic processes involved in age-related traits and diseases.

NIA and Italian investigators are focusing their attention on Sardinia, asecluded Mediterranean island. Since settlers first occupied the island thou-sands of years ago, the population has grown without much immigrationfrom the outside world. Because they are more closely related than peopleliving in other societies, Sardinians share much of the same genetic informa-tion, which makes it easier to track genetic effects through generations.

When a particular trait exists in a genetically isolated “founder” populationsuch as Sardinia, it is likely that the same few genes are responsible for thetrait in most or all affected individuals. Once the genes for a certain complextrait are identified within the founder population, researchers can use thisinformation to isolate interacting genes and assess their importance in moregenetically diverse cultures, like the United States. Other large founder populations exist in Finland, Iceland, and French-speaking Quebec.

In a study called the Progenia project, gerontologists are studying Sardiniansfor evidence of genetic influences on two traits: severe arterial stiffness andfrequent positive emotions. Vascular stiffness may be an important predictorof heart disease mortality. Reports also suggest that joyfulness and otherpositive emotions can have profound impact on life satisfaction and health aswe age. Gerontologists suspect these traits have strong genetic components.As the project progresses, investigators plan to conduct genetic analysis onindividuals who share extreme values of these traits and will attempt to identify the underlying genes.

Ultimately, gerontologists hope founder population studies yield results thatwill help prevent certain age-related diseases.

In the worm, this gene makesa protein that looks muchlike the receptor for the hor-mone insulin. In humans, thishormone controls functionsincluding food utilizationpathways, glucose metabo-lism, and cell growth. Theseand other genetic linkagesare under intense scrutiny,and ultimately could yieldclues about how genes interact with environmental factors to influence longe-vity in humans and otherspecies. Caloric restriction,for example, is the onlyknown intervention shown to prolong life in speciesranging from yeast torodents. Scientists suspectthis intervention works inyeast, worms, and other species, in part, because it

All cells have the same complement of genes.The form and function of any given cell isdetermined by which of these genes are turnedon and off. As a cell grows, matures and ages,the pattern of genes turned on and off changes.Detecting these changes was once a tedious processthat involved testing one gene at a time. No longer.

Gene expression microarray technology, a potent scientifictool, is helping gerontologists rapidly clarify what geneticchanges occur in cells as they get older. Also known as “genechips,” microarrays allow researchers to survey the expressionof thousands of genes at once. The match-box size glass chipscontain DNA that has been exposed to messenger RNA(mRNA), a nucleic acid that translates information contained in DNA into proteins. Each kind of mRNA binds to its corre-sponding DNA probe, and the amount of mRNA that binds to each gene’s DNA on the chip is an indicator of the activitylevel of that gene.

Investigators using this technology have found relatively fewchanges in gene expression occur in aging tissues. In somestudies, comparing tissue taken from young animals versusolder animals, fewer than two of every 100 genes have shownmajor changes in activity over time. But these limited changesmay have significant impact on the ability of aging tissues and organs to function properly. In time, microarrays mighthelp gerontologists to more precisely characterize the genesinvolved in the aging of specific tissues or organs, and accelerate our understanding of its underlying mechanisms.

Gerontologists study manydifferent animals includingzebrafish (left) and birds likebudgerigars (background) forgenetic clues about aging.

Microarrays in Actiontriggers alterations of geneticactivity. Caloric restriction also may work, partially, byaltering metabolic pathwaysinvolved in energy utilization.(See The Next Step: CaloricRestriction in Primates, page 36).

Many investigators, how-ever, interpret these findingscautiously because there areimportant differences betweenhuman genes and those oflower animals. In fact, thestructural similarity is onlyabout 30 percent, which meansthat comparing yeast genes tohuman genes, for instance, islike comparing a go-cart to ahigh-performance racing car.The basic machinery may besimilar, but one is far less complex than the other. Sowhile yeast, worms, and other simple organisms arehelpful models of aging, theyprobably don’t completelymimic the process that occursin humans. For this reason,

11


The proteins expressedby genes carry out a multi-tude of functions in each celland tissue in the body, andsome of these functions arerelated to aging. So, when we ask what longevity oraging-related genes do, we are actually asking whattheir protein products do atthe cellular and tissue levels.Increasingly, gerontologistsalso are asking how alter-ations in the process of gene expression itself mayaffect aging. Technologicaladvances, which allowresearchers to observe theexpression of thousands ofgenes at once, are speedingthe investigation of thisprocess. In time, this emerg-ing technology could helpclarify what changes areoccurring simultaneously in diverse cells, as they getolder. (See Microarrays in Action, at right).

gerontologists study thegenetics of mice, primates,and other mammals that aremore closely related to us.Some researchers are alsostudying human cells formore precise clues about how genes regulate humanlongevity and aging.

Other unanswered questions concern the rolesplayed by these genes. Whatexactly do they do? Howand when are they activated?On one level, all genes function by transcribing their “codes”—actually DNA base sequences—intoanother nucleic acid calledmessenger ribonucleic acidor mRNA. Messenger RNA is then translated intoproteins. Transcription andtranslation together consti-tute the process known asgene expression.


Age-related Traits Are All in the FamilyFinding longevity genes is only one of many goals forgerontologists. An equally important mission is unravelingthe genetic processes involved in age-related traits and diseases.

NIA and Italian investigators are focusing their attention on Sardinia, asecluded Mediterranean island. Since settlers first occupied the island thou-sands of years ago, the population has grown without much immigrationfrom the outside world. Because they are more closely related than peopleliving in other societies, Sardinians share much of the same genetic informa-tion, which makes it easier to track genetic effects through generations.

When a particular trait exists in a genetically isolated “founder” populationsuch as Sardinia, it is likely that the same few genes are responsible for thetrait in most or all affected individuals. Once the genes for a certain complextrait are identified within the founder population, researchers can use thisinformation to isolate interacting genes and assess their importance in moregenetically diverse cultures, like the United States. Other large founder populations exist in Finland, Iceland, and French-speaking Quebec.

In a study called the Progenia project, gerontologists are studying Sardiniansfor evidence of genetic influences on two traits: severe arterial stiffness andfrequent positive emotions. Vascular stiffness may be an important predictorof heart disease mortality. Reports also suggest that joyfulness and otherpositive emotions can have profound impact on life satisfaction and health aswe age. Gerontologists suspect these traits have strong genetic components.As the project progresses, investigators plan to conduct genetic analysis onindividuals who share extreme values of these traits and will attempt to identify the underlying genes.

Ultimately, gerontologists hope founder population studies yield results thatwill help prevent certain age-related diseases.

In the worm, this gene makesa protein that looks muchlike the receptor for the hor-mone insulin. In humans, thishormone controls functionsincluding food utilizationpathways, glucose metabo-lism, and cell growth. Theseand other genetic linkagesare under intense scrutiny,and ultimately could yieldclues about how genes interact with environmental factors to influence longe-vity in humans and otherspecies. Caloric restriction,for example, is the onlyknown intervention shown to prolong life in speciesranging from yeast torodents. Scientists suspectthis intervention works inyeast, worms, and other species, in part, because it

All cells have the same complement of genes.The form and function of any given cell isdetermined by which of these genes are turnedon and off. As a cell grows, matures and ages,the pattern of genes turned on and off changes.Detecting these changes was once a tedious processthat involved testing one gene at a time. No longer.

Gene expression microarray technology, a potent scientifictool, is helping gerontologists rapidly clarify what geneticchanges occur in cells as they get older. Also known as “genechips,” microarrays allow researchers to survey the expressionof thousands of genes at once. The match-box size glass chipscontain DNA that has been exposed to messenger RNA(mRNA), a nucleic acid that translates information contained in DNA into proteins. Each kind of mRNA binds to its corre-sponding DNA probe, and the amount of mRNA that binds to each gene’s DNA on the chip is an indicator of the activitylevel of that gene.

Investigators using this technology have found relatively fewchanges in gene expression occur in aging tissues. In somestudies, comparing tissue taken from young animals versusolder animals, fewer than two of every 100 genes have shownmajor changes in activity over time. But these limited changesmay have significant impact on the ability of aging tissues and organs to function properly. In time, microarrays mighthelp gerontologists to more precisely characterize the genesinvolved in the aging of specific tissues or organs, and accelerate our understanding of its underlying mechanisms.

Gerontologists study manydifferent animals includingzebrafish (left) and birds likebudgerigars (background) forgenetic clues about aging.

Microarrays in Actiontriggers alterations of geneticactivity. Caloric restriction also may work, partially, byaltering metabolic pathwaysinvolved in energy utilization.(See The Next Step: CaloricRestriction in Primates, page 36).

Many investigators, how-ever, interpret these findingscautiously because there areimportant differences betweenhuman genes and those oflower animals. In fact, thestructural similarity is onlyabout 30 percent, which meansthat comparing yeast genes tohuman genes, for instance, islike comparing a go-cart to ahigh-performance racing car.The basic machinery may besimilar, but one is far less complex than the other. Sowhile yeast, worms, and other simple organisms arehelpful models of aging, theyprobably don’t completelymimic the process that occursin humans. For this reason,

11


The proteins expressedby genes carry out a multi-tude of functions in each celland tissue in the body, andsome of these functions arerelated to aging. So, when we ask what longevity oraging-related genes do, we are actually asking whattheir protein products do atthe cellular and tissue levels.Increasingly, gerontologistsalso are asking how alter-ations in the process of gene expression itself mayaffect aging. Technologicaladvances, which allowresearchers to observe theexpression of thousands ofgenes at once, are speedingthe investigation of thisprocess. In time, this emerg-ing technology could helpclarify what changes areoccurring simultaneously in diverse cells, as they getolder. (See Microarrays in Action, at right).

gerontologists study thegenetics of mice, primates,and other mammals that aremore closely related to us.Some researchers are alsostudying human cells formore precise clues about how genes regulate humanlongevity and aging.

Other unanswered questions concern the rolesplayed by these genes. Whatexactly do they do? Howand when are they activated?On one level, all genes function by transcribing their “codes”—actually DNA base sequences—intoanother nucleic acid calledmessenger ribonucleic acidor mRNA. Messenger RNA is then translated intoproteins. Transcription andtranslation together consti-tute the process known asgene expression.


changes in the genes theyexpress might actually pro-mote unregulated growthand tumor formation. Thisconcept that genes, whichhave beneficial effects earlyin life, can also have detri-mental effects later is knownas antagonistic pleiotropy.Some gerontologists specu-late that a better understand-ing of antagonistic pleiotropymight reveal much aboutwhat aging is, and how cellular senescence contributes to it.

But for now, many major questions about cellular senescence remainunanswered. Investigators,for example, are uncertainwhether senescent cells accumulate in all tissues and organs with increasingage, thus contributing to thegradual loss of the body’scapacity to heal wounds,maintain strong bones, andfend off infections. Accumu-lation of senescent cells, if it

instance, senescent cells areresistant to dying and, as aresult, they occur more oftenin aging bodies. Cellularsenescence also triggersimportant changes in geneexpression. Normally, fibro-blasts are responsible for creating an underlying struc-ture, called the extracellularmatrix, which controls thegrowth of other cells. Butsenescent fibroblasts secreteenzymes that actuallydegrade this matrix. Geron-tologists suspect the break-down of this structure maycontribute to the increasedrisk of cancer as we age. So,cellular senescence may becritical early in life because itlimits cell proliferation andhelps suppress cancer. But aswe get older, senescent cellsmight be harmful because

process have been identified.This special aspect of cellularsenescence is known asreplicative senescence.

However, we do not diebecause we run out of cells(even the oldest people haveplenty of proliferating fibrob-lasts and other types of cells).In fact, most senescent cellsare not dead or dying. Theycontinue to respond to hor-mones and other outsidestimuli, but can’t proliferate.Evidence suggests they cancontinue to work at manylevels for some time afterthey cease dividing. Senes-cence, however, can causeradical shifts in some impor-tant cellular functions. For


100 trillion cells, composingthe organ systems that makeour bodies.

Early in life, nearly all of the body’s cells can divide.But this process doesn’t goon indefinitely. Researchershave learned that cells havefinite proliferative lifespans,at least when studied in testtubes—in vitro. After a cer-tain number of divisions,they enter a state in whichthey no longer proliferateand DNA synthesis isblocked. For example, young human fibroblasts—structural cells that hold skinand other tissues together—divide about 50 times andthen stop. This phenomenonis known as the Hayflicklimit, after Leonard Hayflick,who with Paul Moorheaddescribed it in 1961 while atthe Wistar Institute inPhiladelphia. At least four genes involved in this

For now, investigatorshave found evidence thatsome proteins, such as antioxidant enzymes, preventdamage to cells, while othersmay repair damaged DNA,regulate glucose metabolism,or help cells respond to stress. Other gene productsare thought to influence replicative senescence.

Cellular SenescenceDuring the process of celldivision or mitosis, a cell’snucleus dissolves, and itschromosomes condense intovisible thread-like structuresthat replicate. The resulting 92 chromosomes separate,migrating to opposite sides of the cell where new nuclei—each with 46 chromosomes—are formed. Once this occurs,the original cell, following the chromosomes’ lead, pulls apart and forms twoidentical daughter cells. It isthis process that allows us to grow from a single cell into

In the Lab of the Long-Lived Fruit FliesA laboratory at the University of California, Irvine, is the home ofthousands of Drosophila melanogaster, or fruit flies, that routinelylive for 70 or 80 days, nearly twice the average Drosophila lifespan.Here evolutionary biologist Michael Rose, Ph.D., has bred the long-lived stocks by selecting and mating flies late in life.

To begin the process of genetic selection, Rose first collected eggslaid by middle-age fruit flies and let them hatch in isolation. Theprogeny were then transferred to a communal plexiglass cage toeat, grow, and breed under conditions ideal for mating. Once theyhad reached advanced ages, the eggs laid by older females (and fertilized by older males) were again collected and removed to indi-vidual hatching vials. The cycle was repeated, but with succeedinggenerations, the day on which the eggs were collected was pro-gressively postponed. After 2 years and 15 generations, the laboratory had stocks of Drosophila with longer lifespans.

The next question is what genes and what gene products areinvolved? Since the first experiments, Rose has bred longer life

spans into fruit flies by selecting for other characteristics, such asability to resist starvation, so the flies‘ long lifespans are not

necessarily tied to their fertility late in life.

One possibility is that the antioxidant enzyme, superoxidedismutase (SOD), is involved. Two laboratory studies,including work by John Tower, Ph.D., at the University ofSouthern California, have shown that genetically alteredfruit flies that produce greater amounts of SOD haveextended lifespans. This finding has given a boost to thehypothesis that antioxidant enzymes like SOD are linked

to aging or longevity. However, to date, similar experi-ments in other species have been inconclusive.

The eyes of thesegenetically alteredfruit flies appearfluorescent underthe microscope. By altering geneexpression in fruitflies and otherorganisms, investi-gators are learningmuch about aging.

Limits To Growth

YOUNG FIBROBLASTSThese human lung fibroblasts, shown after about the 10th in vitro population doubling,grow vigorously and completethe replication process more rapidly than older cells.

OLD FIBROBLASTSNearing senescence, these lungfibroblasts are noticeably larger andtend to divide more slowly than theiryounger counterparts. After about 50in vitro population doublings, thesecells stop dividing. This phenomenonis known as the Hayflick limit.

For decades, researchers believed normal plant andanimal cells could be propagated forever in test tubes(in vitro). But in 1961, Leonard Hayflick, Ph.D., (below)disproved this idea in experiments with skin and lungfibroblast cells. Hayflick is a professor of anatomy atthe University of California, San Francisco.

CELL DIVISIONDaughter cells divide duringmitosis. Early in life, nearly all cells can divide. But overtime, this capacity diminishes.Cellular senescence is one ofmany biological processes that gerontologists study.

changes in the genes theyexpress might actually pro-mote unregulated growthand tumor formation. Thisconcept that genes, whichhave beneficial effects earlyin life, can also have detri-mental effects later is knownas antagonistic pleiotropy.Some gerontologists specu-late that a better understand-ing of antagonistic pleiotropymight reveal much aboutwhat aging is, and how cellular senescence contributes to it.

But for now, many major questions about cellular senescence remainunanswered. Investigators,for example, are uncertainwhether senescent cells accumulate in all tissues and organs with increasingage, thus contributing to thegradual loss of the body’scapacity to heal wounds,maintain strong bones, andfend off infections. Accumu-lation of senescent cells, if it

instance, senescent cells areresistant to dying and, as aresult, they occur more oftenin aging bodies. Cellularsenescence also triggersimportant changes in geneexpression. Normally, fibro-blasts are responsible for creating an underlying struc-ture, called the extracellularmatrix, which controls thegrowth of other cells. Butsenescent fibroblasts secreteenzymes that actuallydegrade this matrix. Geron-tologists suspect the break-down of this structure maycontribute to the increasedrisk of cancer as we age. So,cellular senescence may becritical early in life because itlimits cell proliferation andhelps suppress cancer. But aswe get older, senescent cellsmight be harmful because

process have been identified.This special aspect of cellularsenescence is known asreplicative senescence.

However, we do not diebecause we run out of cells(even the oldest people haveplenty of proliferating fibrob-lasts and other types of cells).In fact, most senescent cellsare not dead or dying. Theycontinue to respond to hor-mones and other outsidestimuli, but can’t proliferate.Evidence suggests they cancontinue to work at manylevels for some time afterthey cease dividing. Senes-cence, however, can causeradical shifts in some impor-tant cellular functions. For


100 trillion cells, composingthe organ systems that makeour bodies.

Early in life, nearly all of the body’s cells can divide.But this process doesn’t goon indefinitely. Researchershave learned that cells havefinite proliferative lifespans,at least when studied in testtubes—in vitro. After a cer-tain number of divisions,they enter a state in whichthey no longer proliferateand DNA synthesis isblocked. For example, young human fibroblasts—structural cells that hold skinand other tissues together—divide about 50 times andthen stop. This phenomenonis known as the Hayflicklimit, after Leonard Hayflick,who with Paul Moorheaddescribed it in 1961 while atthe Wistar Institute inPhiladelphia. At least four genes involved in this

For now, investigatorshave found evidence thatsome proteins, such as antioxidant enzymes, preventdamage to cells, while othersmay repair damaged DNA,regulate glucose metabolism,or help cells respond to stress. Other gene productsare thought to influence replicative senescence.

Cellular SenescenceDuring the process of celldivision or mitosis, a cell’snucleus dissolves, and itschromosomes condense intovisible thread-like structuresthat replicate. The resulting 92 chromosomes separate,migrating to opposite sides of the cell where new nuclei—each with 46 chromosomes—are formed. Once this occurs,the original cell, following the chromosomes’ lead, pulls apart and forms twoidentical daughter cells. It isthis process that allows us to grow from a single cell into

In the Lab of the Long-Lived Fruit FliesA laboratory at the University of California, Irvine, is the home ofthousands of Drosophila melanogaster, or fruit flies, that routinelylive for 70 or 80 days, nearly twice the average Drosophila lifespan.Here evolutionary biologist Michael Rose, Ph.D., has bred the long-lived stocks by selecting and mating flies late in life.

To begin the process of genetic selection, Rose first collected eggslaid by middle-age fruit flies and let them hatch in isolation. Theprogeny were then transferred to a communal plexiglass cage toeat, grow, and breed under conditions ideal for mating. Once theyhad reached advanced ages, the eggs laid by older females (and fertilized by older males) were again collected and removed to indi-vidual hatching vials. The cycle was repeated, but with succeedinggenerations, the day on which the eggs were collected was pro-gressively postponed. After 2 years and 15 generations, the laboratory had stocks of Drosophila with longer lifespans.

The next question is what genes and what gene products areinvolved? Since the first experiments, Rose has bred longer life

spans into fruit flies by selecting for other characteristics, such asability to resist starvation, so the flies‘ long lifespans are not

necessarily tied to their fertility late in life.

One possibility is that the antioxidant enzyme, superoxidedismutase (SOD), is involved. Two laboratory studies,including work by John Tower, Ph.D., at the University ofSouthern California, have shown that genetically alteredfruit flies that produce greater amounts of SOD haveextended lifespans. This finding has given a boost to thehypothesis that antioxidant enzymes like SOD are linked

to aging or longevity. However, to date, similar experi-ments in other species have been inconclusive.

The eyes of thesegenetically alteredfruit flies appearfluorescent underthe microscope. By altering geneexpression in fruitflies and otherorganisms, investi-gators are learningmuch about aging.

Limits To Growth

YOUNG FIBROBLASTSThese human lung fibroblasts, shown after about the 10th in vitro population doubling,grow vigorously and completethe replication process more rapidly than older cells.

OLD FIBROBLASTSNearing senescence, these lungfibroblasts are noticeably larger andtend to divide more slowly than theiryounger counterparts. After about 50in vitro population doublings, thesecells stop dividing. This phenomenonis known as the Hayflick limit.

For decades, researchers believed normal plant andanimal cells could be propagated forever in test tubes(in vitro). But in 1961, Leonard Hayflick, Ph.D., (below)disproved this idea in experiments with skin and lungfibroblast cells. Hayflick is a professor of anatomy atthe University of California, San Francisco.

CELL DIVISIONDaughter cells divide duringmitosis. Early in life, nearly all cells can divide. But overtime, this capacity diminishes.Cellular senescence is one ofmany biological processes that gerontologists study.

TELOMERESAt each end of every chromosome (blue)are telomeres (red), repetitive DNAsequences that appear to help regulatecellular replication. Gerontologists areworking to learn more about telomerestructure and function.

Germ Cell

Adult Cell

Senescent Cell

Cell Immortality and Cancer

telomerase

telomere chromosomes

TELOMERES: The Cancer Connection

enabling cells to replace lost telomeric sequences and divide indefinitely. Thisfinding has led to speculationthat if a drug could be devel-oped to block telomeraseactivity, it might aid in cancer treatment.

Whether cell senescenceis explained by abnormalgene products, telomereshortening, or other factors,the question of what senescence has to do with the aging of organisms continues to be the focus of rigorous study.

while others with long, but“frayed” telomeres under-go senescence. Telomereresearchers also are explor-ing other possible ways inwhich these chromosomeends regulate cellular life-span, and believe that proteins associated withtelomeres play a role.

Telomere research isanother territory where can-cer and aging research merge.In immortal cancer cells,telomeres act abnormally—they no longer shrink witheach cell division. In thesearch for clues to this phe-nomenon, researchers havediscovered an enzyme calledtelomerase. This enzyme,which is not active in mostadult cells (egg and spermcells are among the excep-tions), seems to swing intoaction in advanced cancers,

telomeres become so shortthat their function is dis-rupted, and this, in turn,leads the cell to stop prolif-erating. Average telomerelength, therefore, gives someindication of how manydivisions the cell has alreadyundergone and how manyremain before it can nolonger replicate.

This apparent countingmechanism, almost like anabacus keeping track of the cell’s age, has led tospeculation that telomeresserve as molecular meters of cell division. But somescientists suspect telomerelength is just one aspect of a complex mechanism. Elizabeth Blackburn, Ph.D.,of the University of Califor-nia, San Francisco, forinstance, has accumulatedevidence that some cellswith extremely short, butstructurally sound telomeres continue to proliferate,


as telomere shortening influ-ence replicative senescence.

TelomeresEvery chromosome has tailsat its ends that get shorter as a cell divides. These tails,called telomeres, all have thesame short sequence of DNAbases (TTAGGG in humansand other vertebrates)repeated thousands of times.These repetitive snippets donot contain any vital geneticinformation, but acting muchlike the hard, plastic cover-ing on the ends of shoe-strings, they help keepchromosomes intact.

During mitosis, themolecular machinery thatreplicates DNA can’t com-pletely copy the extremeends of chromosomes. Soeach time a cell divides, thetelomeres get shorter. Overtime, scientists theorize,

research and cancer researchintersect. When tumor sup-pressor genes are inacti-vated, investigators theorizeit turns on a complex processthat leads to development ofa tumor. So replicative senes-cence apparently has beenretained through evolutionas a defense against cancer.

Scientists are unravelinghow the products of thesegenes promote and suppresscell proliferation. There areindications that a multi-layercontrol system is at work,involving a host of intricatemechanisms that interact tomaintain a balance betweenthe two kinds of genes. Somegenes, for instance, appear to suppress or silence othergenes. Mutations in thesesilencing genes have beenshown to affect the lifespanof C. elegans and yeast. Many gerontologists arestudying how silencing and other mechanisms such

anti-proliferative gene camefrom an eye tumor calledretinoblastoma. When one of the genes from retinoblas-toma cells—later called theRB gene—became inactive,the cells went on dividingindefinitely and produced a tumor. But when the RBgene product was activated,the cells stopped dividing.This gene’s product, in otherwords, appeared to suppressproliferation. Another well-characterized gene of thistype is the p53 gene, whichproduces a protein that also limits cell proliferation.These genes are called tumor suppressor genes.

Limited proliferation is the norm in the world ofhuman cells. In some cases,however, a cell somehowescapes this control mecha-nism and goes on dividing,becoming, in the terms of cell biology, immortal. Andbecause immortal cells even-tually form tumors, this isone area in which aging

does occur, could, in turn,indirectly increase an indi-vidual’s vulnerability to the diseases and disabilitiesoften associated with aging.However, no feature of aginghas yet been unequivocallyexplained by in vitro cellularsenescence.

Proliferative GenesSearching for explanations ofproliferation and senescence,scientists have found certaingenes that appear to triggercell proliferation. One exam-ple of such a proliferativegene is c-fos, which encodes a short-lived protein that is thought to regulate theexpression of other genesimportant in cell division.

Proliferative genes, suchas c-fos and others of its kind,are countered by anti-prolif-erative genes, which seem to interfere with division.The first evidence of an

15


Certain cells, such as egg and sperm cells, use telomerase,an enzyme, to restore telomeres to the ends of their chro-mosomes, insuring that they can continue to reproduceand promote survival of the species. But most adult cellslack this capacity, and when telomeres reach a criticallength, these cells stop proliferating. In immortal cancercells, telomeres act abnormally—they cease shorteningwith each cell division. Investigators suspect telomerase is somehow activated in cancer cells.

TELOMERESAt each end of every chromosome (blue)are telomeres (red), repetitive DNAsequences that appear to help regulatecellular replication. Gerontologists areworking to learn more about telomerestructure and function.

Germ Cell

Adult Cell

Senescent Cell

Cell Immortality and Cancer

telomerase

telomere chromosomes

TELOMERES: The Cancer Connection

enabling cells to replace lost telomeric sequences and divide indefinitely. Thisfinding has led to speculationthat if a drug could be devel-oped to block telomeraseactivity, it might aid in cancer treatment.

Whether cell senescenceis explained by abnormalgene products, telomereshortening, or other factors,the question of what senescence has to do with the aging of organisms continues to be the focus of rigorous study.

while others with long, but“frayed” telomeres under-go senescence. Telomereresearchers also are explor-ing other possible ways inwhich these chromosomeends regulate cellular life-span, and believe that proteins associated withtelomeres play a role.

Telomere research isanother territory where can-cer and aging research merge.In immortal cancer cells,telomeres act abnormally—they no longer shrink witheach cell division. In thesearch for clues to this phe-nomenon, researchers havediscovered an enzyme calledtelomerase. This enzyme,which is not active in mostadult cells (egg and spermcells are among the excep-tions), seems to swing intoaction in advanced cancers,

telomeres become so shortthat their function is dis-rupted, and this, in turn,leads the cell to stop prolif-erating. Average telomerelength, therefore, gives someindication of how manydivisions the cell has alreadyundergone and how manyremain before it can nolonger replicate.

This apparent countingmechanism, almost like anabacus keeping track of the cell’s age, has led tospeculation that telomeresserve as molecular meters of cell division. But somescientists suspect telomerelength is just one aspect of a complex mechanism. Elizabeth Blackburn, Ph.D.,of the University of Califor-nia, San Francisco, forinstance, has accumulatedevidence that some cellswith extremely short, butstructurally sound telomeres continue to proliferate,


as telomere shortening influ-ence replicative senescence.

TelomeresEvery chromosome has tailsat its ends that get shorter as a cell divides. These tails,called telomeres, all have thesame short sequence of DNAbases (TTAGGG in humansand other vertebrates)repeated thousands of times.These repetitive snippets donot contain any vital geneticinformation, but acting muchlike the hard, plastic cover-ing on the ends of shoe-strings, they help keepchromosomes intact.

During mitosis, themolecular machinery thatreplicates DNA can’t com-pletely copy the extremeends of chromosomes. Soeach time a cell divides, thetelomeres get shorter. Overtime, scientists theorize,

research and cancer researchintersect. When tumor sup-pressor genes are inacti-vated, investigators theorizeit turns on a complex processthat leads to development ofa tumor. So replicative senes-cence apparently has beenretained through evolutionas a defense against cancer.

Scientists are unravelinghow the products of thesegenes promote and suppresscell proliferation. There areindications that a multi-layercontrol system is at work,involving a host of intricatemechanisms that interact tomaintain a balance betweenthe two kinds of genes. Somegenes, for instance, appear to suppress or silence othergenes. Mutations in thesesilencing genes have beenshown to affect the lifespanof C. elegans and yeast. Many gerontologists arestudying how silencing and other mechanisms such

anti-proliferative gene camefrom an eye tumor calledretinoblastoma. When one of the genes from retinoblas-toma cells—later called theRB gene—became inactive,the cells went on dividingindefinitely and produced a tumor. But when the RBgene product was activated,the cells stopped dividing.This gene’s product, in otherwords, appeared to suppressproliferation. Another well-characterized gene of thistype is the p53 gene, whichproduces a protein that also limits cell proliferation.These genes are called tumor suppressor genes.

Limited proliferation is the norm in the world ofhuman cells. In some cases,however, a cell somehowescapes this control mecha-nism and goes on dividing,becoming, in the terms of cell biology, immortal. Andbecause immortal cells even-tually form tumors, this isone area in which aging

does occur, could, in turn,indirectly increase an indi-vidual’s vulnerability to the diseases and disabilitiesoften associated with aging.However, no feature of aginghas yet been unequivocallyexplained by in vitro cellularsenescence.

Proliferative GenesSearching for explanations ofproliferation and senescence,scientists have found certaingenes that appear to triggercell proliferation. One exam-ple of such a proliferativegene is c-fos, which encodes a short-lived protein that is thought to regulate theexpression of other genesimportant in cell division.

Proliferative genes, suchas c-fos and others of its kind,are countered by anti-prolif-erative genes, which seem to interfere with division.The first evidence of an

15


Certain cells, such as egg and sperm cells, use telomerase,an enzyme, to restore telomeres to the ends of their chro-mosomes, insuring that they can continue to reproduceand promote survival of the species. But most adult cellslack this capacity, and when telomeres reach a criticallength, these cells stop proliferating. In immortal cancercells, telomeres act abnormally—they cease shorteningwith each cell division. Investigators suspect telomerase is somehow activated in cancer cells.

As important as genes are, they do not act in a vacuum.

Everyday metabolic activities—even breathing—expose

cells to biochemical substances that can promote random

DNA damage and other cellular breakdowns. Of these

factors, oxygen radicals and crosslinking of proteins have

become focal points of scientific exploration. Gerontologists

also are studying other important proteins—heat shock

proteins, hormones, and growth factors—that may play a

role in aging and longevity. In short, the biochemistry of

aging is a rich territory with an expanding frontier.

AgingBiochemistry

and

and combine readily withother molecules.

This process, calledoxidation, can spark a chainreaction resulting in a seriesof products, some of whichare actually beneficial. Theimmune system, for instance,uses free radicals to destroybacteria and other patho-gens. Another oxidizingmolecule, called nitric oxide,helps nerve cells in the braincommunicate with each other.

Free radicals, however,also can be vandals thatcause extensive damage toproteins, membranes, andDNA. Mitochondria areparticularly prone to freeradical damage. The majorsource of free radical

by–products are called oxy-gen free radicals, also knownas reactive oxygen species.

A free radical can beproduced from almost anymolecule when it loses anelectron from one or moreof its atoms. In cells, theyare commonly created whenmitochondria combine oxy-gen with hydrogen to formwater. This transformationreleases energy into thecell, but it also can shredelectrons from oxygen.When this happens it leavesthe oxygen atom—nowan unstable oxygen freeradical—with one unpairedelectron. Because electronsare most stable when theyare paired, oxygen freeradicals steal mates for theirlone electrons from othermolecules. These molecules,in turn, become unstable

Oxygen RadicalsOxygen sustains us. Everycell in the body needs it tosurvive. Yet, paradoxically,oxygen also wreaks havocin the body and may be aprimary catalyst for muchof the damage we associatewith aging. This damageoccurs as a direct result ofhow cells metabolize it.

Oxygen is processedwithin a cell by tiny ogan-elles called mitochondria.Mitochondria convert oxy-gen and food into adenosinetriphosphate (ATP), anenergy-releasing moleculethat powers most cellularprocesses. In essence, mito-chondria are furnaces, andlike all furnaces, they pro-duce potentially harmfulby–products. In cells, these

This mitochondrion is a cellular power-house, continuously generating ATP, anenergy-releasing molecule, as well aspotentially harmful by-products such asoxygen free radicals. Hundreds of mito-chondria exist in every cell. With age,increasing oxidative damage to theseorganelles may decrease their efficiency.

18

Biochemistry and Aging

Antioxidants andAging NematodesA worm barely the size of a comma printed on this pagemay change how investigators think about oxygen radicals,antioxidants, and aging. C. elegans nematodes immersed in aliquid containing a potent antioxidant drug lived 44 percentlonger than worms not treated with this substance. It wasthe first time that any drug had extended the lifespan of anymulti-cellular organism. The finding lends credence to thehypothesis that oxygen radicals have a significant role inthe aging process.

In addition, the international team of investigators, led bySimon Melov, Ph.D., of the Buck Center for Research in Aging

in California, restored a normal lifespan to mutant wormsthat had a mitochondrial defect, which caused increasedoxygen radical production and accelerated aging. Theworms showed no apparent ill effects from the treatment.

EUK-134, the drug used in the experiment, was asynthetic form of superoxide dismutase (SOD) and cata-

lase, two enzymes that counteract the effects of oxidativestress. Like other antioxidants, such as vitamin E, these

compounds convert oxygen radicals to water. But they aremuch more potent.

While it is only one study, and its results have not been con-firmed in other species, this investigation supports the conceptthat antioxidant defenses may be critical during aging. It alsosuggests that one day it may be possible to use similarinterventions to treat age-related conditions in humans.

Oxygen free radicals, thebright yellow spots in thisillustration, can attack anddamage DNA, leading tomutations.

substances called antioxi-dants to counteract them.These substances includingnutrients—the familiarvitamins C and E—as wellas enzymes produced inthe cell, such as superoxidedismutase (SOD), catalase,and glutathione peroxidase,prevent most oxidative dam-age. Nonetheless, some freeradicals manage to circum-vent these defenses and doharm. As a result, cellularrepair mechanisms eventu-ally falter and some internalbreakdowns are inevitable.These breakdowns can leadto cellular senescence, andeventually may triggerapoptosis, a form ofprogrammed cell death.

production in the body, theyare also one of its prime tar-gets. As the damage mounts,mitochondria become lessefficient, progressively gen-erating less ATP and morefree radicals. Over time,according to the free radicaltheory, oxidative damageaccumulates in our cellsand tissues, triggering manyof the bodily changes thatoccur as we age. Free radicalshave been implicated notonly in aging but also indegenerative disorders,including cancer, athero-sclerosis, cataracts, andneurodegeneration.

But free radicals, whichalso can be produced bytobacco smoke, sun expo-sure, and other environ-mental factors, do not gounchecked. Cells utilize

19


Protein Crosslinking

Human rib cartilage shows the effects of proteincrosslinks, which slowly accumulate through complexpathways and eventually disrupt cellular function.With age, as glucose binds to its proteins, the cartilageturns brown and becomes less supple. This process,called the Maillard reaction, is similar to what happenswhen bread is toasted.

Protein CrosslinkingBlood sugar—glucose—isanother suspect in cellulardeterioration. In a processcalled non-enzymatic glyco-sylation or glycation, glucosemolecules attach themselvesto proteins, setting in motiona chain of chemical reactionsthat ends in the proteinsbinding together or cross-linking, thus altering theirbiological and structuralroles. The process is slowand complex, but cross-linked proteins accumulatewith time and eventuallydisrupt cellular function.

Investigators suspectthat glycation and oxidationare interdependent processessince free radicals and cross-links seem to accelerate theformation of one another.

extended their normal life-span. (See Antioxidants andAging Nematodes, page 19).

The discovery of anti-oxidants raised hopes thatpeople could retard agingsimply by adding them tothe diet. So far, studies ofantioxidant-laden foods andsupplements in humanshave yielded little supportfor this premise. Furtherresearch, including large-scale epidemiological stud-ies, might clarify whetherdietary antioxidants can helppeople live longer, healthierlives. For now, however,the effectiveness of dietaryantioxidant supplementationremains controversial. Inthe meantime, gerontologistsare investigating otherintriguing biochemicalprocesses affected by freeradicals, including proteincrosslinking.

Support for the freeradical theory, first proposedin 1956 by chemist DenhamHarman, M.D., Ph.D., comesfrom studies of antioxidants,particularly SOD. SOD con-verts an oxygen radicalknown as superoxide anioninto hydrogen peroxide,which can be degraded byan enzyme, called catalase,into oxygen and water. Stud-ies have shown that insert-ing extra copies of the SODgene into fruit flies extendstheir average lifespan by asmuch as 30 percent.

Other experimental evi-dence lends support to thefree radical hypothesis. Forexample, higher levels ofSOD and catalase have beenfound in long-lived nema-todes. In one compellingstudy, giving nematodessynthetic forms of theseantioxidants significantly

20


Infant Age 17

Age 45 Age 64

Age 76 Age 88

As anyone who reads beauty magazines knows, sunlight damagesskin in ways that seem similar to aging. It’s well-established thatlong-term, sunlight-induced damage causes wrinkles. And in bothnormal aging and photoaging—the process initiated by sunlight—

the skin becomes drier and loses elasticity. Although geron-tologists think that the normal or intrinsic aging process isprobably not the same as photoaging, there are enoughsimilarities to make this a tantalizing field of study.

The process of photoaging may hold clues to normal agingbecause many of the same cells are affected. Photoaging,

for example, damages collagen and elastin, the two proteinsthat give skin its elasticity. These proteins decline as we age,

along with the fibroblast cells that manufacture them. Inaddition, the enzymes that break down collagen andelastin increase.

Other changes occur in keratinocytes, upper-layer skincells that are shed and renewed regularly. In the normal

aging process the turnover of keratinocytes slows downand in photoaging they are damaged. Still other skin cells,

called melanocytes, are also affected by both processes: theydecline with normal aging and are killed in photoaging. (Stopped intheir tracks by sunlight, these normally migratory cells show up asfreckles in light skin.)

What we don’t know yet is exactly how photoaging damagescells. Ultraviolet light can damage DNA and could be the culprit.Free radicals could be involved in some way. Researchers continueto explore these and other factors in the effort to understandphotoaging.

Research on Sunlight May Help ExplainWhat Happens to Skin as We Age

kidney function (nephropa-thy), and age-related neuro-logical disorders includingAlzheimer’s disease.

These conditions appearat younger ages in peoplewith diabetes, who havehigh glucose levels (hyper-glycemia). Glycosylatedhemoglobin in red bloodcells, for instance, is animportant marker doctorsuse to measure hyper-glycemia. While the physio-logical effects of glycosylatedhemoglobin are unclear,the disease it helps doctorsdetect—diabetes—is some-times considered an accele-rated model of aging. Notonly do the complicationsof diabetes mimic thephysiologic changes thatcan accompany old age, butpeople with this conditionhave shorter-than-averagelife expectancies. As a result,much research on cross-linking has focused on itsrelationship to diabetes aswell as aging.

Crosslinks, also known asadvanced glycation endproducts (AGEs), seem to“stiffen” tissues and maycause some of the deteriora-tion associated with aging.Collagen, for instance, themost common protein mole-cule in our bodies, forms theconnective tissue that pro-vides structure and supportfor organs and joints. Whenglucose binds with colla-gen—as it tends to do as weage—this normally suppleprotein loses much of itsflexibility. As a result, lungs,arteries, tendons, and othertissues stiffen and becomeless efficient. In the circula-tory system, AGEs may helptrap LDL (the so-called“bad”) cholesterol in arterywalls, and thus contribute tothe development of athero-sclerosis. They also havebeen linked to cloudedlenses (cataracts), reduced

21


Werner’sSyndrome

WS patient age 14

WS patient age 48

Genetic defects are believed to beresponsible for Werner’s syndrome(WS), a disease in which people at ayoung chronological age develop somecharacteristics associated with aging,such as gray hair, wrinkled skin,diabetes, heart disease, and cancer.Because of the apparent accelerationof aging in WS, gerontologists are delv-ing into its causes, hoping to shed lighton the disease and the degenerativeprocesses that occur with normal aging.

Macrophages, such as the one shownhere, recognize foreign bodies such asbacteria, or altered molecules such ascrosslinked proteins, and removethem from circulation.

gradually accumulates, leadsto malfunctioning genes,proteins, cells, and, as theyears go by, deterioratingtissues and organs.

Not surprisingly, numer-ous enzyme systems in thecell have evolved to detectand repair damaged DNA.For repair, transcription,and replication to occur, thedouble-helical structure thatmakes up DNA must be par-tially unwound. Enzymescalled helicases do theunwinding. Investigatorshave found that people whohave Werner’s syndrome(WS), a rare disease withseveral features of prematureaging, have a defect in oneof their helicases. GeorgeMartin, M.D., of the Univer-sity of Washington and otherinvestigators are exploringthe mechanisms involvedin DNA repair in WS and

crosslinking may play a rolein damage to DNA, which isanother important focus forresearch on aging.

DNA Repairand SynthesisIn the normal wear and tearof cellular life, DNA under-goes continual damage.Attacked by oxygen radicals,ultraviolet light, and othertoxic agents, it suffers dam-age in the form of deletions,or deleted sections, andmutations, or changes in thesequence of DNA bases thatmake up the genetic code.In addition, sometimes theDNA replication machinerymakes an error.

Biologists theorize thatthis DNA damage, which

Why this happens is notknown, but immunologistsare beginning to learn moreabout how the immune sys-tem affects, and is affectedby aging (See The ImmuneSystem, page 31). And inthe meantime, diabetesresearchers are investigatingdrugs that could supplementthe body’s natural defensesby blocking AGEs formation.

Crosslinking interestsgerontologists for severalreasons. It is associated withdisorders that are commonamong older people, such asdiabetes and heart disease;it progresses with age; andAGEs are potential targetsfor drugs. In addition,

Just as the body hasantioxidants to fight free-radical damage, it has otherguardians, immune cellscalled macrophages, whichcombat glycation. Macro-phages with special recep-tors for AGEs seek out andengulf them. Once AGEsare broken down, they areejected into the blood streamwhere they are filtered outby the kidneys and elimi-nated in urine.

The only apparentdrawback to this defensesystem is that it is not com-plete and levels of AGEsincrease steadily with age.One reason is that kidneyfunction tends to declinewith advancing age. Anotheris that macrophages, likecertain other componentsof the immune system,become less active.

22


DNA, the double helix cellular molecule that contains thousands of genesnecessary for life, is constantly being damaged and repaired. Gerontologistssuspect DNA repair mechanisms become less efficient with age. AccumulatingDNA damage, including breaks in its structure or changes in its nucleotidesequences, can lead to some of the physical changes we associate with aging.

production, and cells havehundreds of them. Investiga-tors suspect mitochondrialDNA is injured at a muchgreater rate than nuclearDNA, possibly because themitochondria produce astream of damaging oxygenradicals during metabolism.Adding to its vulnerability,mitochondrial DNA isunprotected by the proteincoat that helps shield DNAin the nucleus from damage.

Research has shownthat mitochondrial DNAdamage increases exponen-tially with age, and as aresult, energy productionin cells diminishes over time.These changes may causedeclines in physiologicalperformance, and may playa role in the development

bility to cancer. If DNArepair processes decline withage while damage accumu-lates as scientists hypothe-size, it could help explainwhy cancer is more commonamong older people.

Gerontologists whostudy DNA damage andrepair have begun to uncovernumerous complexities. Evenwithin a single organism,repair rates can vary amongcells, with the most efficientrepair going on in germ(sperm and egg) cells.Moreover, certain genes arerepaired more quickly thanothers, including those thatregulate cell proliferation.

Especially intriguingis repair to a kind of DNAthat resides not in the cell’snucleus but in its mitochon-dria. These small organellesare the principal sites ofmetabolism and energy

similar disorders, collectivelyknown as progeroid syn-dromes. This research couldhelp explain why DNA repairbecomes less efficient duringnormal human aging.

The repair processinterests gerontologists formany reasons. It is knownthat an animal’s ability torepair certain types of DNAdamage is directly relatedto the lifespan of its species.Humans repair DNA, forexample, more quickly andefficiently than mice or otheranimals with shorter life-spans. This suggests thatDNA damage and repairare in some way part ofthe aging puzzle.

In addition, researchershave found defects in DNArepair in people with agenetic or familial suscepti-

23


The remarkable increase in ourlife span during the 20th Centuryhas been due, in large part to thecontributions of basic biomedicalresearch…In the 21st Century,the advances in these basicsciences should lead to effectivetreatments of diseases of ouraging population.”

—Julius Axelrod, Ph.D.1970 Nobel Laureate in Medicine

“

Unstressed Adult

of a heat shock protein des-ignated HSP-70 than younganimals under similar stress.Moreover, in laboratory cul-tures of cells, researchershave found a striking declinein HSP-70 production ascells approach senescence.

Exactly what role HSPsplay in the aging processis not yet clear. They areknown to help cells disman-tle and dispose of damagedproteins. They also facilitatethe making and transportof new proteins. But whatproteins are involved andhow they relate to aging isstill the subject of specula-tion and study.

While at the NIA, NikkiHolbrook, Ph.D., and otherresearchers investigated the

plants, bacteria, worms,mice, and yes, humans.Today, the role of thesesubstances, known as heatshock proteins, in the agingprocess is under scrutiny.

Despite their name,heat shock proteins (HSPs)are produced when cells areexposed to various stresses,not only heat. Their expres-sion can be triggered byexposure to toxic substancessuch as heavy metals andchemicals and even bybehavioral and psycho-logical stress.

What attracts agingresearchers to HSPs is thefinding that the levels atwhich they are produceddepend on age. Old animalsplaced under stress—short-term, physical restraint, forexample—have lower levels

of age-related diseases.Investigators are examininghow much mitochondrialDNA damage occurs in spe-cific parts of the body suchas the brain, what causesthe damage, and whetherit can be prevented.

Heat Shock ProteinsIn the early 1960s, investiga-tors noticed fruit flies didsomething unusual. Whenthese insects were exposedto a burst of heat, they pro-duced proteins that helpedtheir cells survive the tem-perature change. Intrigued,researchers looked for theseproteins in other animals,and found them in virtuallyevery living thing including

24


In certain circumstances, plants andanimals produce heat shock proteins(HSPs). These proteins are believedto have an important role in helpingcells respond to stress. The dark areasin these illustrations show increasedexpression of HSPs in short term, physi-cally restrained rats. With age, geneticexpression of these proteins diminishes.

Heat ShockProteins

action of HSP-70 in specificsites, such as the adrenalcortex (the outer layer of theadrenal gland). In this glandas well as in blood vesselsand possibly other sites,the expression of HSP-70appears closely relatedto hormones released inresponse to stress, suchas the glucocorticoids andcatecholamines. Eventually,answers to the puzzle ofHSPs may throw light onsome parts of the neuro-endocrine system, whosehormones and growthfactors might have animportant influence onthe aging process.

Plants Bacteria Worms Mice Humans

Since they were first discoveredin fruit flies, heat shock proteinshave been found in virtuallyevery living thing.

In the Aorta

Stressed Adult

Unstressed Aged

Stressed Aged

In theAdrenal Gland

Testosterone

Estrogen

hot flashes, long-term use ofthese hormones may increaserisk for several major age-related diseases in somewomen, especially whentreatment is started yearsafter menopause. The findingthat levels of testosterone inmen decreased with agingraised the question of whetherthey too might benefit fromsex hormone treatment.

As a result of thesepreliminary observationalfindings, the NIA launched aseries of research initiativesto clarify what influencehormone replacement therapymight have on the agingprocess. So far, most of thesestudies have been inconclu-sive, but have led manyinvestigators to questionwhether the risks of hormonereplacement may outweigh

increased their lean body(and presumably muscle)mass, reduced excess fat,and thickened skin. Whenthe injections stopped, thesechanges reversed, and thesigns of aging returned.What the men were takingwas recombinant humangrowth hormone (hGH),a synthetic version of thehormone that is producedin the pituitary gland andplays a critical part in nor-mal childhood growth anddevelopment. At the sametime, evidence was accumu-lating that menopausal hor-mone therapy with estrogen(alone or in combinationwith a progestin in womenwith a uterus) could benefitpostmenopausal women byreducing cardiovascular dis-ease, colon cancer, and otherdiseases of aging. Furtherstudies have indicated that,although estrogen remainsan effective way to control

and immune function.These glands, including thepituitary, thyroid, adrenal,ovaries, and testes, releasevarious hormones into thebody as needed.

As we age, productionof certain hormones, suchas testosterone and estrogen,tends to decrease. Hormoneswith less familiar names,like melatonin and dehy-droepiandrosterone (DHEA)are also not as abundant inolder people as in youngeradults. But what influence, ifany, these natural hormonaldeclines have on the agingprocess is unclear.

HormoneReplacementIn the late 1980s, at VeteransAdministration hospitals inMilwaukee and Chicago,12 men age 60 and olderbegan receiving injectionsthree times a week thatdramatically reversed somesigns of aging. The injections

25

Aging Under the MicroscopeAging Under the Microscope

HormonesHormones are powerfulchemicals that help keep ourbodies working normally.Made by specialized groupsof cells called glands, hor-mones stimulate, regulate,and control the function ofvarious tissues and organs.They are involved in virtu-ally every biological processincluding sexual reproduc-tion, growth, metabolism,

In this colored transmissionelectron micrograph, growthhormone granules (brown)are visible in the cytoplasm(yellow) of a growth-hormonesecreting endocrine cell fromthe pituitary gland. Visible cellorganelles include mitochondria(round, green) and the nucleus(purple, center).

ESTROGEN > Although it is primarily associated with

women, men also produce small amounts of this sex hormone.

Among its many roles, estrogen slows the bone thinning

that accompanies aging. In premenopausal women the

ovaries are the main manufacturers of estrogen (imageabove). After menopause, fat tissue is the major source

of smaller amounts and weaker forms of estrogen than

that produced by the ovaries. While many women with

menopausal symptoms are helped by hormone therapy

during and after menopause, some are placed at higher

risk for certain diseases if they take it. The results of the

WHI are prompting further studies about the usefulness

and safety of this therapy when used by younger meno-

pausal and postmenopausal women to control symptoms,

such as hot flashes, and to prevent chronic diseases.

GROWTH HORMONE > This product of the pituitary

gland appears to play a role in body composition and mus-

cle and bone strength. It is released through the action of

another trophic factor called growth hormone releasing

hormone, which is produced in the brain. It works, in part,

by stimulating the production of insulin-like growth factor,

which comes mainly from the liver. All three hormones are

being studied for their potential to strengthen muscle and

bones and prevent frailty among older people. For now,

however, there is no convincing evidence that taking

growth hormone will improve the health of those who do

not suffer a profound deficiency of this hormone.

MELATONIN > Contrary to some claims, secretion

of this hormone, made by the pineal gland, does not

necessarily diminish with age. Instead, a number of factors,

including light, can affect production of this hormone,

which seems to regulate various seasonal changes in the

body. Current research does indicate that melatonin in low

dosages may help some older individuals with their sleep.

However, it is recommended that a physician knowledge-

able in sleep medicine be consulted before self-medication.

Claims that melatonin can slow or reverse aging are far

from proven. continued >>

Hormones and Research on AgingProduced by glands, organs, and tissues, hormones are the body’s chemical messengers,flowing through the blood stream and searching out cells fitted with special receptors.Each receptor, like a lock, can be opened by the specific hormone that fits it and also, toa lesser extent, by closely related hormones. Here are some of the hormones and othergrowth factors of special interest to gerontologists.

26Biochemistry and Aging

TESTOSTERONE > In men, testosterone (image below) is produced in the testes (women also produce

small amounts of this hormone). Production peaks in early

adulthood. However, the range of normal testosterone

production is vast. So while there are some declines in

testosterone production with age, most older men stay

well within normal limits. The NIA is investigating the

role of testosterone supplementation in delaying or

preventing frailty. Preliminary results have been

inconclusive, and it remains unclear if supplementation

of this hormone can sharpen memory or help men

maintain stout muscles, sturdy bones, and robust

sexual activity. Investigators are also looking at its

side effects, which may include an increased risk of

certain cancers, particularly prostate cancer. A small

percentage of men with profound deficiencies may be helped

by prescription testosterone supplements.

DHEA > Short for dehydroepiandrosterone, DHEA is pro-

duced in the adrenal glands. It is a precursor to some other

hormones, including testosterone and estrogen. Production

peaks in the mid-20s, and gradually declines with age. What

this drop means or how it affects the aging process, if at all,

is unclear. Investigators are working to find more definite

answers about DHEA’s effects on aging, muscles, and the

immune system. DHEA supplements, even when taken briefly,

may cause liver damage and have other detrimental effects

on the body.

continued >> Hormones and ResearchEstrogen is perhaps the

most well studied of all hor-mones. Yet results from theWomen’s Health Initiative(WHI), the first majorplacebo-controlled, random-ized clinical trial of estrogentherapy with or withoutprogestin to prevent somechronic diseases of aging,surprised the medical com-munity. There were morecases of stroke, blood clots,heart disease, and breastcancer in postmenopausalwomen using estrogen andprogestin in the study, andmore cases of possibledementia in women over age 65, than in those usingthe placebo. But, there werealso fewer bone fracturesand cases of colon cancer. In

postmenopausalwomen using

estrogen alone,there were

more casesof stroke

any benefit. Supplements ofhGH, for instance, can promotediabetes, joint pain, carpaltunnel syndrome, and poolingof fluid in the skin and othertissues, which may lead tohigh blood pressure and heartfailure. Studies in mice haveraised other concerns aboutthe hormone. Investigatorshave found that mice deficientin growth hormone produc-tion live substantially longerthan normal mice, whilemice overproducing growthhormone live shorter thanaverage lives. This findingsuggests that even if hGHreplacement therapy is ini-tially beneficial, ultimately itmay be harmful and actuallymight curtail longevity.

Similarly, there is scantevidence that testosteronesupplementation has anypositive impact in healthyolder men. In fact, somestudies suggest supplemen-tation might trigger excessivered blood cell production insome men. This can increasea man’s risk of stroke.

27


action of growth hormonealso may be intertwined witha cluster of other factors—exercise, for example, whichstimulates a certain amountof hGH secretion on its own,and obesity, which depressesproduction of hGH. Even theway fat is distributed in thebody may make a difference;lower levels of hGH havebeen linked to excess abdominal fat but not tolower body fat.

stimulating production ofIGF-I. Produced primarily in the liver, IGF-I enters andflows through the bloodstream, seeking out specialIGF-I receptors on the surfaceof various cells, includingmuscle cells. Through thesereceptors it signals the muscle cells to increase insize and number, perhaps by stimulating their genes to produce more of special,muscle-specific proteins. Alsoinvolved at some point in thisprocess are one or more ofthe six known proteins thatspecifically bind with IGF-I;their regulatory roles are stilla mystery.

As if the cellular com-plexities weren’t enough, the

many of the actions of hGH.Another trophic factor ofinterest to gerontologists isgrowth hormone releasinghormone, which stimulatesthe release of hGH. Growthfactors might have an impor-tant role in longevity deter-mination. In nematodes, forinstance, mutations in atleast two genes in the IGF-Ipathway result in extendedlifespan.

The mechanisms—howhormones and growth factorsproduce their effects—are still a matter of intense specu-lation and study. Scientistsknow that these chemicalmessengers selectively stimulate cell activities,which in turn affect criticalevents, such as the size andfunctioning of skeletal mus-cle. However, the pathwayfrom hormone to muscle iscomplex and still unclear.

Consider growth hormone. It begins by

and fewer bone fractures thanin those women on placebo.Other studies indicate thatmenopausal hormonetherapy is effective in con-trolling moderate-to-severemenopausal symptoms, so research is ongoing toevaluate benefits and risks in menopausal and youngerpostmenopausal women.

As research continues,the pros and cons of hormonereplacement may becomemore precisely defined. Thesehormonal supplementsappear to increase risk andprovide few clear-cut bene-fits for healthy individualsand do not seem to slow the aging process.

Growth FactorsSome types of hormones canbe referred to as growth ortrophic factors. These factorsinclude substances such asinsulin-like growth factor(IGF-I), which mediates

28Biochemistry and Aging

friends…drinking lots of good water, no alcohol, staying positive, and lots of singing

will keep you alive for a long time.”

—Chris Mortensen (1882-1998), America’s oldest man, on his 115th birthday.

-“

Like many hormones, bloodlevels of progesterone, areproductive hormone, (right)diminish with age. But whatinfluence, if any, the naturaldecline in progesterone andother hormones has on theaging process in middle andlate life is unclear.

CluesWe don’t know very much about the few men and women

who have lived to 115 years of age or more, but we can

assume that they eluded the diseases that kill many people in

their 70s and 80s. At 122, Jeanne Calment, for instance,

had lived a relatively disease-free life. In fact, escape from

infectious disease is the most common reason that all of us

can now expect to live longer than our grandparents.

Physiologic

establish definitive measuresof physiological aging. In theory, these biomarkerswould be more precise indicators of aging thanchronological age itself. Once established, these biomarkers could make iteasier to study normal aging,diseases, and possible inter-ventions. So far, however, no such biomarkers havebeen identified in humans.

Normal AgingUnlike most of us, SatchelPaige was never quite sure of his birth year. “My birthcertificate was in our (fam-ily) Bible, and the goat atethe Bible,” he said. But evenhad he known his chrono-logical age, it may not haveshed much light on how old he was physiologically.In fact, gerontologists arediscovering that age in yearsdoesn’t necessarily correlatewith physiological age.

For decades, investiga-tors at the NIA have com-piled data on heart function,lung capacity, and numerousother bodily functions inhopes that this informationmay one day be used to

Chronic diseases and disabil-ity were once thought insep-arable from old age. Thisview is changing rapidly asone disease after anotherjoins the ranks of those thatcan be prevented or at leastcontrolled, often throughchanges in lifestyle.

We now know, for exam-ple, that most people canavoid lung disease by notsmoking. And heart diseaseand stroke rates have fallenat the same time that Ameri-cans have lowered their fatconsumption, begun to exer-cise more, and quit smoking.

So if chronic disease isnot intrinsic to the agingprocess, as many gerontolo-gists now believe, then whatis? Are there universal or“normal” aging processes?

30Physiologic Clues

ow old would you be if youdidn’t know how old you were?”

—Leroy “Satchel” PaigeMember, Baseball Hall of Fame. The oldest person to pitch in the major leagues—he was in his late 50s.

“

Scientists have long knownthat these defenses declinewith age; now, some of theunderlying mechanisms arecoming to light.

A multiplicity of cells,substances, and organs makeup the immune system. Thethymus, spleen, tonsils, bonemarrow, and lymphatic sys-tem, for example, produce,store, and transport a host of cells and substances—B-lymphocytes and T-lym-phocytes, antibodies, inter-leukins, and interferon, toname a few. Several are ofspecial interest to gerontolo-gists. These include the classof white blood cells calledlymphocytes, which fightinvading bacteria and otherforeign cells.

Although this diversitylessens the likelihood of finding biomarkers of agingin humans, the quest forthese indicators has yieldedmany insights into the physiology of two organ systems that may haveimportant roles in the agingprocess. One of these is the endocrine system (See Hormones and Research on Aging, page 26). Theother is the immune system.

The Immune SystemWhen Shigechiyo Izumi ofJapan contracted pneumoniaand died in 1986 at thereputed age of 120, it was his immune system thatfailed. One of the many bacteria or viruses that cause pneumonia brokethrough the elaborate, natu-ral defenses that protecthumans from infection.

In fact, normal physiological aging is quite variable, according to investigators involved inthe Baltimore LongitudinalStudy of Aging, a long-termNIA study begun in 1958 thathas tracked the lives of morethan 1,000 people from age20 to 90 and beyond. Notonly do individuals age over-all at vastly different rates, it is quite likely that age-related changes in variouscells, tissues, and organs differ as well. For instance,kidney function may declinemore rapidly in some indi-viduals. In others, bonestrength may diminish faster.The organs that age fastest inone person may not age asrapidly in another. This sug-gests that genes, lifestyle, anddisease can all affect the rateof aging and that several dis-tinct processes are involved.

31


In the Baltimore Longitudinal Study ofAging (BLSA), volunteers, age 20 to 90,are screened every 2 years for physiologi-cal and psychological changes. Theyundergo a complete physical exam and aseries of tests including muscle strength(shown), bone density, aerobic capacity,and glucose tolerance. Each assessmentadds detail and focus to the BLSA’s slowly growing picture of how we age.

The organs of the immune system are located throughout the body. White bloodcells—lymphocytes—are key operatives of this system. With age, these cells become lessactive, making the body more vulnerable to bacteria, viruses and other pathogens.

Physiologic Clues32

Physiologic Clues

What is Normal Aging?

HEART > Heart muscle thickens with age. Maximaloxygen consumption during exercise declines in menby about 10 percent with each decade of adult life andin women by about 7.5 percent. This decline occursbecause the heart’s maximum pumping rate and thebody’s ability to extract oxygen from blood bothdiminish with age.

ARTERIES > Arteries tend to stiffen with age. The older heart, in turn, needs to supply more force to propel the blood forward through the less elasticarteries.

LUNGS > Maximum breathing (vital) capacity maydecline by about 40 percent between the ages of 20 and 70.

BRAIN > With age, the brain loses some of thestructures (axons) that connect nerve cells (neurons)to each other, although the actual number of neuronsseems to be less affected. The ability of individualneurons to function may diminish with age. Recentstudies indicate that the adult nervous system is capable of producing new neurons, but the exact conditions that are critical for this have yet to bedetermined.

KIDNEYS > Kidneys gradually become less efficient at extracting wastes from the blood.

BLADDER > Bladder capacity declines. Urinaryincontinence, which may occur after tissues atrophy,particularly in women, can often be managed through exercise and behavioral techniques.

Individuals age at extremely different rates. In fact even within oneperson, organs and organ systems show different rates of decline.However, some generalities can be made, based on data from theBaltimore Longitudinal Study of Aging.

continued >>

continued >> What is Normal Aging?

BODY FAT > Typically, body fat graduallyincreases in adulthood until individuals reach middleage. Then it usually stabilizes until late life, whenbody weight tends to decline. As weight falls, olderindividuals tend to lose both muscle and body fat.With age, fat is redistributed in the body, shiftingfrom just beneath the skin to deeper organs. Womentypically have a higher percentage of body fat thanmen. However, because of differences in how this fatis distributed—on the hips and thighs in women andon the abdomen in men—women may be less suscep-tible to certain conditions including heart disease.

MUSCLES > Without exercise, estimatedmuscle mass declines 22 percent for womenand 23 percent for men between the ages of30 and 70. Exercise can slow this rate of loss.

BONES > Bone mineral is lost and replacedthroughout life; loss begins to outstrip replace-ment around age 35. This loss accelerates inwomen at menopause. Regular weight bearingexercise—walking, running, strength training—

can slow bone loss.

SIGHT > Difficulty focusing close up may begin inthe 40s; the ability to distinguish fine details maybegin to decline in the 70s. From 50 on, there isincreased susceptibility to glare, greater difficulty in seeing at low levels of illumination, and more difficulty in detecting moving objects.

HEARING > It becomes more difficult to hearhigher frequencies with age. Even older individualswho have good hearing thresholds may experiencedifficulty in understanding speech, especially in situa-tions where there is background noise. Hearingdeclines more quickly in men than in women.

PERSONALITY > Personality is extraordinarilystable throughout adulthood. Generally, it does not change radically, even in the face of major events in life such as retirement, job loss, or death of loved ones. However, there are exceptions. Certain individuals facing these and other life-altering circumstances can and do show signs of personality change during the final years of life. An easy-going individual who loses a job after many years, for instance, may become disillusionedand develop a sullen disposition. But these out-of-character reversals of personality are relatively rare.

33


Most research on theaging immune system nowcenters on these cells. Onegroup of T-cell products,interleukins, is found at different levels as peopleage. The interleukins—thereare more than 20 identifiedso far—serve as messengers,relaying signals that regulatethe immune response. Some,like interleukin-6, rise withage, and it is speculated thatthey interfere in some waywith the immune response.Others, like interleukin-2,which stimulates T-cell pro-liferation, tend to fall withage. Gerontologists study the interleukins, not only for clues to the mechanismsof aging, but also for theirpotential in the detectionand treatment of immuneproblems.

Meanwhile, compellingevidence suggests one inter-vention—caloric restriction—may counteract some of the natural declines in the

powerful chemicals, calledlymphokines, that mobilizeother immune system substances and cells.

T-cells and their lym-phokine products haveintrigued gerontologists ever since it was learned that T-cells—or more pre-cisely the functioning popu-lation of T-cells—declineswith age. While the numberof T-cells remains about thesame, the proportion of themthat proliferate and functiondeclines. Studies have alsoshown that in older people,T-cells destroyed by stressessuch as irradiation or cancerchemotherapy take longer to renew than they do inyounger people.

Lymphocytes fall intotwo major classes: B-cellsand T-cells. B-cells mature inthe bone marrow, and one oftheir functions is to secreteantibodies in response toinfectious agents or antigens.T-cells develop in the thy-mus, which shrinks in size aspeople age; they are dividedinto cytotoxic T-cells andhelper T-cells. Cytotoxic T-cells attack infected ordamaged cells directly.Helper T-cells produce

Feeding animals 30 to 40 percentfewer calories than normal appearsto delay age-related degeneration of nearly every physiological system.But it remains uncertain whethercaloric restriction could have thesame effect in humans.

immune system as well as in other physiological systems of aging animals.

Caloric RestrictionAn inventor, statesman,diplomat, and scientist, Benjamin Franklin was a trueRenaissance man renownedfor his sage advice. Amonghis many pearls of wisdom:“To lengthen thy life, lessenthy meals.” Nearly 275 years later, gerontologists are finding those words mayturn out to be amazinglyprophetic.

Since the 1930s, investi-gators have consistentlyfound that laboratory rats and mice live up to 40 percentlonger than usual when fed a diet that has at least 30 per-cent fewer calories than theywould normally consume.The animals that eat thisnutritionally balanced diet,which provides healthful

34Physiologic Clues

1 Tonsils and Adenoids

2 Thymus

3 Lymph Nodes

4 Spleen

5 Appendix

6 Peyer’s Patches

7 Lymphatic Vessels

8 Bone Marrow

The Immune System3

2

3

1

4

5

7

6

“To lengthen thy life, lessen thy meals.” —Benjamin Franklin, (1706-1790)

8

However, whether caloricrestriction might have thesame effect in primatesremains a major question. In studies underway at NIA,rhesus and squirrel monkeysare growing up on a calori-cally restricted diet. Similarstudies are also ongoing atthe University of Wisconsinand the University of Mary-land. Preliminary results from these studies show some promising early signs ofimproved health—includinggreater resistance to diabetesand heart disease—in theseprimates as they age. (SeeThe Next Step: CaloricRestriction in Primates, page 36).

Many gerontologists are particularly intrigued by findings suggesting thatanimals on calorie restricteddiets have reduced rates ofdisease. In one of the largeststudies to date, RoderickBronson, D.V.M., at TuftsUniversity found that caloricrestriction not only extendedlifespan in mice, but alsoprevented or slowed downdevelopment of every dis-ease and all types of tumors.Other rodent studies havefound that caloric restrictionmay increase resistance of neurons in the brain todysfunction and death.These results, described as “stunning” by geron-tologists, have raised hopethat further study of caloricrestriction will help uncoverthe mechanisms responsiblefor disease in old age.

reduce oxidative damage to cells. Calorie restrictedanimals also have less glucose circulating in theirblood than their freely feed-ing counterparts. This maylessen the potential for protein crosslinking, a bio-chemical process implicatedin cellular aging. Andbecause caloric restrictionlowers body temperatureslightly, cells may sustainless genetic damage than atnormal body temperature. Inaddition, scientists speculatethat caloric restriction pre-serves the capacity of cells to proliferate, and that itkeeps the immune systemfunctioning at youthful levels. Caloric restriction also may work through other mechanisms. It may,for instance, influence hor-monal balance, cell senes-cence, or gene expression.Or, it might work through a combination of all of these mechanisms, plusother factors.

amounts of protein, fat, andvitamins and minerals, alsoappear to be more resistant toage-related diseases. In fact,caloric restriction appears todelay normal age-relateddegeneration of almost allphysiological systems. Andso far, caloric restriction hasincreased the lifespans ofnearly every animal speciesstudied including protozoa,fruit flies, mice, and otherlaboratory animals. Nowinvestigators are exploringwhether and how caloricrestriction will affect aging in monkeys and other non-human primates, our closestrelatives in the animal kingdom.

Why caloricallyrestricted animals live far beyond their normal lifespans remains unclear.Because cutting down oncalories slows metabolism,and free radicals are by-products of metabolism,caloric restriction may

35


In the 1930s, investigators discoveredthat rats and mice fed fewer calorieslived longer than rodents allowed to eatas much as they liked. Since then, caloricrestriction has increased the lifespan ofnearly every animal species studied.

Data from animal studies suggestscaloric restriction may help neuronsresist dysfunction and death (top).Caloric restriction also might helpthe body fend off cancer (center),and other age-related cellularchanges (bottom).

36Physiologic Clues

The Next Step: Caloric Restriction in PrimatesAt the NIH Animal Center in Poolesville, Maryland,about 75 rhesus and squirrel monkeys are on diets;they eat 30 percent less than they would normallybut get all the necessary nutrients. Another 75 mon-keys, the control group, are eating as much as theywant. The differences between the two groups, asthey age, are beginning to provide insights into howcaloric restriction influences lifespan.

The monkeys that arrived at the Poolesville labora-tory in 1987 have responded to caloric restriction asexpected; their maturation, measured by factorssuch as skeletal development and onset of puberty,has been delayed by about a year or year and a half.This is comparable to the delays in maturation seenin calorically restricted rodents.

As the monkeys continue to grow into middle age and beyond, Donald Ingram, Ph.D., and his colleagues at the NIA’s Gerontology Research Centerin Baltimore, where the project is coordinated, aremonitoring dozens of signs of aging, ranging fromimmune response to activity level to antioxidant levels to fingernail growth. The measurements are

being compared with those of the monkeys in thecontrol group and should provide leads to some ofthe mechanisms at work in caloric restriction.

The monkeys on the restricted diet are smaller andweigh about 20 percent less than monkeys in thecontrol group. However, the calorically restrictedmonkeys are no less physically active than animalsallowed to eat at will.

So far, some positive trends have been detected,including the possibility of reduced incidence ofheart disease and cancer in the caloricallyrestricted monkeys. But it is important tokeep in mind that these data are pre-liminary, and investigators cautionthat it may be many more yearsbefore it can be determined ifcaloric restriction does indeedimprove the health and extendthe lifespan of aging primates.

Regular physical activity may be the mostimportant thing an older person can do

to stay healthy and self-reliant. Infact, the more exercise you can do

in later life, the better off you’ll be.

Studies suggest regular, sustained exercise can helpprevent or delay some diseases and disabilities aspeople grow older. And, in some cases, it can actuallyimprove some of these conditions in older peoplewho already have them. In a study conducted at Tufts University in Boston, for instance, some peopleage 80 and older were able to progress from usingwalkers to using canes after doing simple muscle-building exercises for just 10 weeks. In addition, physical activity can improve your mood, lessen yourrisk of developing adult-onset diabetes, slow boneloss, and reduce your risk of heart attack and stroke.

Endurance exercises such as briskwalking increase your staminaand improve the health of yourheart, lungs and circulatory sys-tem. Strength exercises buildmuscles and reduce your risk ofosteoporosis. Balance exercises helpprevent a major cause of disability in

older adults: falls. Flexibility orstretching exercises help keep yourbody limber. As part of a dailyroutine, these exercises andother physical activities you enjoy can make adifference in your life as you get older.

For a nominal fee, an exercise book and a 48-minutecompanion video are available from NIA. For moreinformation about the book and video contact:

NIA Information CenterP.O. Box 8057Gaithersburg, MD1-(800)-222-22251-(800)-222-4225 TTY

Exercise: It Works at Any AgeYet even if caloric restric-

tion is successful in primates, it is unlikely that most peo-ple could maintain a diet of 30 percent fewer calorieswithout drastic and, in allprobability, unpalatablechanges in their eatinghabits. For this reason, mostgerontologists doubt thatcaloric restriction will everbecome a widespread meansof extending the human life-span. But investigators areexploring the question ofwhether drugs might mimicits effects, negating the needfor sweeping alterations indiet. In rodent and other animal studies, gerontolo-gists are testing a number of synthetic substances that

37


A balanced diet and regular exercise can help strengthen boneand prevent osteoporosis in laterlife. Normal bone (bottom inset)and osteoporotic bone (top).

Reproduced from J Bone Miner Res 1986; 1:16-21 with permision of the American Society for Bone and Mineral Research.

of exercise to reduce the risk of osteoporosis. This condition, with its fragile,easily broken bones, is amajor cause of fracturesamong older people, fre-quently resulting in disabil-ity, and eventually leading toinstitutionalization for many.In some cases, drugs called bisphosphonates help byslowing calcium loss in bone.

example, help reduce the thin-ning of bones that accompa-nies aging in almost everyonebut particularly in olderwomen, many of whom are at high risk for osteoporosis.

Researchers are alsostudying exercise as a behav-ioral factor that may have an impact on how long we live or at least on howhealthy we are in old age. One landmark study at TuftsUniversity in Boston hasshown that exercise canstrengthen muscles, improvemobility, and reduce frailtyeven among 90-year-olds.

Exercises that put weighton bones, such as jogging,walking, and weight-lifting,have been shown to strengthenthem. Researchers, as a result,are exploring the potential

age. These include higherlevels of fats or lipids in theblood, changing levels ofblood sugar and insulin, atendency toward obesity,and increased central bodyfat that settles around thewaist and abdomen. Thesechanges are so prevalentamong older people thatthey have been given aname, syndrome X. Manygerontologists are studyingthe possible relationshipbetween this syndrome andcardiovascular diseases.

Syndrome X may be preventable through low-fatand low-cholesterol diets,but these are not the onlyaspects of nutrition that mayinfluence life expectancy.Gerontologists have beenscrutinizing a wide range ofnutrients with an eye towardtheir role in aging processes.Calcium and vitamin D, for

38Physiologic Clues

produce some of the sameeffects as caloric restriction,such as reducing body temperature and loweringthe amount of insulin in theblood. So far, the preliminaryresults have been promising.However, none of these substances has yet proved to extend lifespan, and somehave potentially toxic sideeffects that may make humanuse impractical. Still, thesearch goes on. Meanwhile, it is becoming increasinglyclear that lifestyle—particu-larly diet and exercise—canhave a powerful influence on how people age.

Behavioral FactorsDiet and exercise are thoughtto have a major impact on aconstellation of changes thatare common with advancing

longevity determination.Experiments involving yeast,fruit flies, nematodes, mice,and primates continue toyield insights into variousaspects of aging that couldone day be applicable tohumans.

Still, many of the funda-mental underpinnings ofaging and longevity determi-nation remain elusive. Therole of telomeres in cellularsenescence and aging, forinstance, is poorly under-stood. It is unclear what, if any, effects diminishinghormone levels in later life have on aging,longevity, and health.

Audrey Stubbart, shown at right in 1920,and below with her great-great grand-daughter, told friends work kept her alive.During her long life, she taught school,raised five children, and operated a 2,000-acre sheep ranch in Wyoming with herhusband. At 66, she took a job at the Independence (Mo.) Examiner, where she was a copy editor and columnist for nearly 40 years. She retired shortlybefore her death at age 105.

The question has been asked countless times in the 12 months since her 100th birthday…“What’s the secret?”

—The Independence (Mo.) Examiner on centenarian Audrey Stubbart’s 101st birthday.

Gerontologists have unraveled many of the secrets of aging thanks to experi-ments with simple organisms such asyeast (below, left). Still, much remainsunknown about the processes thatunderlie the journey from young to old,including the roles that macrophages, a part of the immune system (center) and telomeres (right) may play.

others predict that robusthealth in later life will bemore common as fewer andfewer older Americans livewith disabilities. Whetherany of these visions becomereality will greatly dependon the emerging science of aging.

As investigators delvemore deeply into how andwhy we age, its secrets arebeing deciphered at anunparalleled rate. Scientificunderstanding of the genetic,biochemical, and physiologi-cal aspects of this dynamicprocess has never beengreater. Microarray technol-ogy has enabled gerontolo-gists to characterize theexpression of vast numbersof genes potentially impor-tant in human aging and

This remarkable burst oflongevity, unprecedented in human history, has beenpossible because of equallyremarkable improvements insanitation, health care, andlifestyle. These advanceshave led to much conjectureabout how aging will evolvein the 21st century. Somegerontologists suspect anaverage life expectancy of 85 years or more may bepossible in the not-so-distantfuture. Others have specu-lated that the first persondestined to live 130 years or more is alive today. Still

40The Future of Aging

The aging boom is upon us. Life expectancy nearly doubled

in the 20th century. Since 1900, the number of Americans age

65 and older has increased 10-fold. The oldest-old—people

age 85 and older—constitute the fastest growing segment

of the U.S. population. By 2050, this population— currently

about 4 million people—could top 19 million. Living to 100

likely will become more commonplace. In 1950, only about

3,000 Americans were centenarians; by 2050, there could be

nearly one million.

ofFutureThe

Aging

longevity determination.Experiments involving yeast,fruit flies, nematodes, mice,and primates continue toyield insights into variousaspects of aging that couldone day be applicable tohumans.

Still, many of the funda-mental underpinnings ofaging and longevity determi-nation remain elusive. Therole of telomeres in cellularsenescence and aging, forinstance, is poorly under-stood. It is unclear what, if any, effects diminishinghormone levels in later life have on aging,longevity, and health.

Audrey Stubbart, shown at right in 1920,and below with her great-great grand-daughter, told friends work kept her alive.During her long life, she taught school,raised five children, and operated a 2,000-acre sheep ranch in Wyoming with herhusband. At 66, she took a job at the Independence (Mo.) Examiner, where she was a copy editor and columnist for nearly 40 years. She retired shortlybefore her death at age 105.

The question has been asked countless times in the 12 months since her 100th birthday…“What’s the secret?”

—The Independence (Mo.) Examiner on centenarian Audrey Stubbart’s 101st birthday.

Gerontologists have unraveled many of the secrets of aging thanks to experi-ments with simple organisms such asyeast (below, left). Still, much remainsunknown about the processes thatunderlie the journey from young to old,including the roles that macrophages, a part of the immune system (center) and telomeres (right) may play.

others predict that robusthealth in later life will bemore common as fewer andfewer older Americans livewith disabilities. Whetherany of these visions becomereality will greatly dependon the emerging science of aging.

As investigators delvemore deeply into how andwhy we age, its secrets arebeing deciphered at anunparalleled rate. Scientificunderstanding of the genetic,biochemical, and physiologi-cal aspects of this dynamicprocess has never beengreater. Microarray technol-ogy has enabled gerontolo-gists to characterize theexpression of vast numbersof genes potentially impor-tant in human aging and

This remarkable burst oflongevity, unprecedented in human history, has beenpossible because of equallyremarkable improvements insanitation, health care, andlifestyle. These advanceshave led to much conjectureabout how aging will evolvein the 21st century. Somegerontologists suspect anaverage life expectancy of 85 years or more may bepossible in the not-so-distantfuture. Others have specu-lated that the first persondestined to live 130 years or more is alive today. Still


The aging boom is upon us. Life expectancy nearly doubled

in the 20th century. Since 1900, the number of Americans age

65 and older has increased 10-fold. The oldest-old—people

age 85 and older—constitute the fastest growing segment

of the U.S. population. By 2050, this population— currently

about 4 million people—could top 19 million. Living to 100

likely will become more commonplace. In 1950, only about

3,000 Americans were centenarians; by 2050, there could be

nearly one million.

ofFutureThe

Aging

they will likely uncovermany more secrets of aging.These discoveries may leadto extended life-spans, andalmost certainly will con-tribute to better health, less disability, and greaterindependence in later life.

Further study is needed toclarify how caloric restrictionworks, and to determinewhether this intervention—or drugs that mimic itseffects—might be effectiveand safe for humans.

These and other linger-ing research challengesunderscore the enormity of the quest facing geron-tologists. It is becomingincreasingly clear that agingis an intricate bundle ofinterdependent processes,some of which are betterunderstood than others. As gerontologists untanglethese interconnectinggenetic, biochemical, andphysiological processes,


41


Stem Cells: Great Expectations, but Many Barriers Remain

Colorized scanning electron micrograph ofstem cells collected from human bone mar-row. Stem cells are primitive cells that canmultiply indefinitely, migrate to differentparts of the body, and develop into differenttypes of tissue. Bone marrow retains the ability to generate stem cells throughout life.Bone marrow stem cells typically give rise tobone, blood, and cartilage.

These versatile cells intrigue investigators becausethey are capable of transforming themselves

into many different kinds of body tissue.Because of this flexibility, stem cells holdenormous potential for cell replacement ortissue repair in many age-associated degen-erative disorders where loss of cells is cur-rently irreversible, including diabetes,stroke, heart disease, and Alzheimer’s and

Parkinson’s disease. With millions of olderAmericans suffering from these conditions,

gerontologists are scrambling to find out ifthese cells will yield any practical interventions

that might help promote healthy aging.

Stem cells can be derived from an embryo or an adult.Unlike most cells in the body, such as skin or heartcells, which are dedicated to perform a specific func-tion, stem cells are not specialists. But under certaincircumstances, they can differentiate into specializedcells. Another unique characteristic of stem cells istheir ability to replicate for indefinite periods withoutbecoming senescent.

Investigators suspect that embryonic stem cells candevelop into almost any of the many known special-ized cell types in the body, including bone, blood, andbrain cells. However, these stem cells are not embryos,and cannot themselves develop into embryos. Adultstem cells apparently help repair or replace those tissues lost through natural attrition, or when they are damaged by injury or disease. Adult stem cells inbone marrow, for instance, regularly replenish thebody’s supply of red blood cells. Similarly, intestinalstem cells help maintain the lining of the intestines,which is frequently sloughed off in a natural process.

It is not clear, however, if adult stem cells can fullymatch embryonic stem cells’ capacity to differentiateinto vast arrays of replacement cells and tissues. Inanimal studies, certain adult stem cells have shownsome potential to develop into multiple cell types,suggesting that both embryonic and adult stem cellscould have therapeutic applications. NIA-supportedinvestigators who injected adult mouse bone marrowcells into the circulatory systems of mice, for instance,discovered that these cells found their way into the

brains of the rodentsand within 1-to-6 monthsbecame neuronal cells. Asecond study showed thatadult mouse bone marrow cells could also develop into heart cells and vascular structures, resulting in the substantial replacement of damaged heart tissuewithin 2 weeks.

Despite these preliminary successes, many formidablehurdles must be overcome. Investigators still under-stand very little about how stem cells work, so deter-mining how to get stem cells to do what investigatorswant them to do in the body remains a mystery. Inadults, stem cells appear to become less spontaneouslyactive with age, and some gerontologists suspect thatinactivation of these cells may play a prominent role inthe normal aging process. For investigators, findingways to reactivate these cells and get them to wherethey are needed in the body are significant challenges.

Still, the discovery of human stem cells is an importantscientific breakthrough that clearly has the potential toimprove the quality and length of life.

From the moment they were first isolated in the late 1990s, humanstem cells mesmerized gerontologists. And for good reason.

for the first time in human history the prospect of living a long, healthy and productive

life has become a reality for the majority of people...What was the privilege of the few

has become the destiny of the many.” —Robert Butler, M.D., Gerontologist

Will robust aging as shown bythis man, be the norm in thefuture? Jeanne Calment, theworld’s longest-lived person, still rode a bicycle at age 100.

“--

they will likely uncovermany more secrets of aging.These discoveries may leadto extended life-spans, andalmost certainly will con-tribute to better health, less disability, and greaterindependence in later life.

Further study is needed toclarify how caloric restrictionworks, and to determinewhether this intervention—or drugs that mimic itseffects—might be effectiveand safe for humans.

These and other linger-ing research challengesunderscore the enormity of the quest facing geron-tologists. It is becomingincreasingly clear that agingis an intricate bundle ofinterdependent processes,some of which are betterunderstood than others. As gerontologists untanglethese interconnectinggenetic, biochemical, andphysiological processes,


41


Stem Cells: Great Expectations, but Many Barriers Remain

Colorized scanning electron micrograph ofstem cells collected from human bone mar-row. Stem cells are primitive cells that canmultiply indefinitely, migrate to differentparts of the body, and develop into differenttypes of tissue. Bone marrow retains the ability to generate stem cells throughout life.Bone marrow stem cells typically give rise tobone, blood, and cartilage.

These versatile cells intrigue investigators becausethey are capable of transforming themselves

into many different kinds of body tissue.Because of this flexibility, stem cells holdenormous potential for cell replacement ortissue repair in many age-associated degen-erative disorders where loss of cells is cur-rently irreversible, including diabetes,stroke, heart disease, and Alzheimer’s and

Parkinson’s disease. With millions of olderAmericans suffering from these conditions,

gerontologists are scrambling to find out ifthese cells will yield any practical interventions

that might help promote healthy aging.

Stem cells can be derived from an embryo or an adult.Unlike most cells in the body, such as skin or heartcells, which are dedicated to perform a specific func-tion, stem cells are not specialists. But under certaincircumstances, they can differentiate into specializedcells. Another unique characteristic of stem cells istheir ability to replicate for indefinite periods withoutbecoming senescent.

Investigators suspect that embryonic stem cells candevelop into almost any of the many known special-ized cell types in the body, including bone, blood, andbrain cells. However, these stem cells are not embryos,and cannot themselves develop into embryos. Adultstem cells apparently help repair or replace those tissues lost through natural attrition, or when they are damaged by injury or disease. Adult stem cells inbone marrow, for instance, regularly replenish thebody’s supply of red blood cells. Similarly, intestinalstem cells help maintain the lining of the intestines,which is frequently sloughed off in a natural process.

It is not clear, however, if adult stem cells can fullymatch embryonic stem cells’ capacity to differentiateinto vast arrays of replacement cells and tissues. Inanimal studies, certain adult stem cells have shownsome potential to develop into multiple cell types,suggesting that both embryonic and adult stem cellscould have therapeutic applications. NIA-supportedinvestigators who injected adult mouse bone marrowcells into the circulatory systems of mice, for instance,discovered that these cells found their way into the

brains of the rodentsand within 1-to-6 monthsbecame neuronal cells. Asecond study showed thatadult mouse bone marrow cells could also develop into heart cells and vascular structures, resulting in the substantial replacement of damaged heart tissuewithin 2 weeks.

Despite these preliminary successes, many formidablehurdles must be overcome. Investigators still under-stand very little about how stem cells work, so deter-mining how to get stem cells to do what investigatorswant them to do in the body remains a mystery. Inadults, stem cells appear to become less spontaneouslyactive with age, and some gerontologists suspect thatinactivation of these cells may play a prominent role inthe normal aging process. For investigators, findingways to reactivate these cells and get them to wherethey are needed in the body are significant challenges.

Still, the discovery of human stem cells is an importantscientific breakthrough that clearly has the potential toimprove the quality and length of life.

From the moment they were first isolated in the late 1990s, humanstem cells mesmerized gerontologists. And for good reason.

for the first time in human history the prospect of living a long, healthy and productive

life has become a reality for the majority of people...What was the privilege of the few

has become the destiny of the many.” —Robert Butler, M.D., Gerontologist

Will robust aging as shown bythis man, be the norm in thefuture? Jeanne Calment, theworld’s longest-lived person, still rode a bicycle at age 100.

“--

BibliographyGlossaryand

DNA—Abbreviation for deoxyribonucleic acid, the moleculethat contains the genetic code for all life forms except for afew viruses. It consists of two long, twisted chains made upof nucleotides. Each nucleotide contains one base, one phos-phate molecule, and the sugar molecule deoxyribose. Thebases in DNA nucleotides are adenine, thymine, guanine, andcytosine.

Enyzme—A protein that promotes a specific biochemical reac-tion in the body without itself being permanently changed ordestroyed. Enzymes, for instance, are involved in blood clot-ting and initiate the process of breaking down food.

Fibroblast— One of the major cell types found in skin. Scien-tists utilize human fibroblast cell cultures to study aging atthe cellular level.

Free radicals—Molecules with unpaired electrons that reactreadily with other molecules. Oxygen-free radicals, producedduring metabolism, damage cells and may be responsible foraging in tissues and organs.

Gene—A segment of DNA that contains the “code” for a spe-cific protein.

Gene expression—The process by which the informationcontained in the genes is transcribed and translated into pro-teins. Age-related changes in gene expression may accountfor some of the phenomena of aging.

Glycation—A process by which glucose links with proteinsand causes these proteins to bind together. In some circum-stances, this can result in “stiffening” of tissues and may leadto certain complications of diabetes, and perhaps some of thephysiological problems associated with aging.

Amino acid—A chemical building block of proteins. Thereare 20 standard amino acids. A protein consists of a specificsequence of amino acids.

Antioxidants—Compounds that neutralize oxygen radicals.Some are enzymes like superoxide dismutase (SOD) andcatalase, while others are nutrients such as vitamin C.

Anti-proliferative genes—Genes that inhibit cell division orproliferation. These genes can act as tumor suppressor genes.

Base—Part of a nucleotide. In DNA, the bases are adenine(abbreviated A), thymine (T), cytosine (C), and guanine (G).RNA contains uracil (U) instead of thymine.

Biomarkers—Biological changes that characterize the agingprocess. So far, no reliable biomarkers have been identified in humans.

Caloric restriction—An experimental intervention that is being studied to determine its impact on longevity. In labo-ratory settings, the lifespans of animals have been extendedby reducing calories while maintaining the necessary levelsof nutrients.

Centenarian—a person who has lived at least 100 years.

Chromosome—A cellular structure containing genes. Chro-mosomes are composed of DNA and proteins. Humans have23 pairs of chromosomes in each body cell, one of each pairfrom the mother and the other from the father.

Cytokines—Proteins that are secreted by cells and regulatethe behavior of other cells by binding to receptors on theirsurfaces. This binding triggers a variety of responses,depending on the nature of the cytokine and the target cell.

44Glossary and Bibliography

Nucleotide—A building block of DNA or RNA. It includesone base, one phosphate molecule, and one sugar molecule(deoxyribose in DNA, ribose in RNA).

Photoaging—The process initiated by sunlight throughwhich the skin becomes drier and loses elasticity. Photoagingis being studied for clues to aging because it has the sameeffect as normal aging on certain skin cells.

Proliferative genes—Genes that promote cell division orproliferation. These genes can act as oncogenes (genes thatpromote cancer growth).

Proteins—Molecules composed of amino acids arranged in aspecific order determined by the DNA sequence of the gene.Proteins are essential for all life processes. Certain ones, suchas the enzymes that protect against free radicals and the lym-phokines, produced in the immune system, are being studiedextensively by gerontologists.

Replicative senescence—The stage at which a cell has per-manently stopped dividing.

RNA—Abbreviation for ribonucleic acid, the molecule thatcarries out DNA’s instructions for making proteins. It con-sists of one long chain made up of nucleotides. There arethree main types of RNA: messenger RNA, transfer RNA,and ribosomal RNA.

Telomeres—Repeated short DNA sequences occurring at theend of the chromosomes; telomeres shorten each time a celldivides.

Tumor suppressor genes—Genes that inhibit cell division orproliferation.

Hayflick limit—The finite number of divisions a cell is capable of when cultured in a laboratory setting (in vitro). A cell reaching this limit is considered to be senescent, at least when in vitro. However, to date there is no evidence that replicative senescence plays a physiologically significantrole in normal aging or age-related disorders.

Interleukins—A type of cytokine involved in regulation ofimmune function. The levels of some interleukins present inthe body are reported to change with age, but it is unclearwhether these fluctuations are due to aging itself or are amanifestation of the many conditions and diseases associatedwith aging.

Lymphocytes—Small white blood cells that are important tothe immune system. A decline in lymphocyte function withadvancing age is being studied for insights into aging anddisease.

Maximum lifespan—The greatest age reached by any mem-ber of a given species.

Mean lifespan—The average number of years that membersof a species live; also known as life expectancy.

Mitochondria—Cell organelles that metabolize glucose andother sugars to produce biochemical energy. Mitochondriaalso contain DNA, which is damaged by the high level of free radicals produced during this process.

Mitosis—The process of replicating DNA, and dividing itinto two equal parts to generate two identical “daughter”cells from one “mother” cell.

45


The Genetic ConnectionSelected Readings

Blackburn, E.H., “Telomere States and Cell Fates,” Nature408(6808):53-56, 2000.

Sprott, R.L, and Pereira-Smith, O.M. eds., “The Genetics ofAging,” Generations: Journal of the American Society on Aging,24:11-88, 2000.

Guarente, L., and Kenyon, C., “Genetic Pathways That Regulate Aging in Model Organisms,” Nature 408(6809): 255-262, 2000.

Finch C.E., and Tanzi, R.E., “Genetics of Aging,” Science,278(5337): 407-411, 1997.

Rudolph, K.L., et al., “Longevity, Stress Response, and Cancerin Aging Telomerase-Deficient Mice,” Cell, 965: 701-12, 1999.

Hodes, R.J., McCormick, A.M., and Pruzan, M., “LongevityAssurance Genes: How Do They Influence Aging and Lifes-pan,” Journal of the American Geriatrics Society, 448:988-991, 1996.

Rubin, H., “Cell Aging In Vivo and In Vitro,” Mechanisms ofAging and Development, 981:1-35, 1997.

Perls, T., et al., “Exceptional Familial Clustering for ExtremeLongevity in Humans,” Journal of the American GeriatricsSociety, 48(11):1483-1485, 2000.

Harley, C.B., Futcher, A.B., and Greider, C.W., “TelomeresShorten During Aging of Human Fibroblasts,” Nature 345:458-460, 1990.

Posing Questions, Finding AnswersSelected Readings

Clark,W.R., A Means to an End: The Biological Basis of Aging andDeath, New York: Oxford University Press, 2002.

Ricklefs, R.E., and Finch, C.E., Aging: A Natural History, NewYork: W.H. Freeman and Company, 1995.

Austad, S.N., Why We Age: What Science Is Discovering about theBody’s Journey Through Life, New York: John Wiley & Sons, 1997.

Kirkwood, T., Time of Our Lives, New York: Oxford UniversityPress, 2000.

Rowe, J.W., and Kahn, R.L., Successful Aging, New York: Random House, 1998.

Hayflick, L., How and Why We Age, New York: Ballantine, 1994.

Finch, C.E., Longevity, Senescence and the Genome, Chicago: University of Chicago Press, 1991.

Institute of Medicine, Extending Life, Enhancing Life: A NationalResearch Agenda on Aging, Washington, DC: National AcademyPress, 1991.

Martin, G.R., Baker, G.T., “Aging and the Aged: Theories ofAging and Life Extension,” Encyclopedia of Bioethics, New York:MacMillan, 1993.

Warner, H.R., Butler, R.N., Sprott, R.L., and Schneider, E.L., eds.,Modern Biological Theories of Aging, New York: Raven, 1987.


Tower, J., “Transgenic Methods for Increasing Drosophila LifeSpan,” Mechanisms of Aging and Development 118(1-2):1-14, 2000.

Melov, S., et al., “Extension of Life-Span with Superoxide Dis-mutase/Catalase Mimetics,” Science 289(5484):1567-1569, 2000.

Knight, J.A., “The Biochemistry of Aging,” Advances In Clinical Chemistry, 35:1-62, 2000.

Campisi, J., and Warner, H.R., “Aging in Mitotic and Post-Mitotic Cells,” in Gilchrest, B.A., and Bohr, V.A., eds., The Roleof DNA Damage and Repair in Cell Aging, New York: ElsevierScience, 2001.

Ames, B.N., “Endogenous DNA Damage as Related to Nutri-tion and Aging,” in Ingram, D.K., Baker, G.T., and Shock, N.W.,eds., The Potential for Nutritional Modulation of Aging Processes,Trumbull, CT: Food and Nutrition Press, 1991.

Blake, M.J., Udelsman, R., Feulner, G.J., Norton, D.D., and Holbrook, N.J., “Stress-Induced HSP70 Expression in AdrenalCortex: A Glucocorticoid Sensitive, Age-Dependent Response,”Proceedings of the National Academy of Sciences 87:846-850, 1991.

Cerami, A., “Hypothesis: Glucose as a Mediator of Aging,”Journal of the American Geriatrics Society 33:626-634, 1985.

Daynes R.A., and Araneo, B.A., “Prevention and Reversal of Some Age-Associated Changes in Immunologic Responsesby Supplemental Dehydroepiandrosterone Sulfate Therapy,”Aging: Immunology, and Infectious Disease 3:135-153, 1992.

Harman, D., “The Free Radical Theory of Aging,” in Warner,H.R., et al., eds., Modern Biological Theories of Aging, New York: Raven, 1987.

Hayflick, L., and Moorhead, P.S., “The Serial Cultivation of Human Diploid Cell Strains,” Experimental Cell Research25:585-621, 1961.

Jazwinski, S.M., “Genes of Youth: Genetics of Aging in Baker’sYeast,” ASM News 59:172-178, 1993.

Johnson, T.E., “Aging Can Be Genetically Dissected into Component Processes Using Long-Lived Lines ofCaenorhabditis elegans,” Proceedings of the National Academy ofSciences 84:3777-3781, 1987.

McCormick, A.M., and Campisi, J., “Cellular Aging and Senescence,” Current Opinion in Cell Biology 3:230-234, 1991.

Pereira-Smith, O.M., and Smith, J.R., “Genetic Analysis of Indefinite Division in Human Cells: Identification of Four Complementation Groups,” Proceedings of the NationalAcademy of Sciences 85:6042-6046, 1988.

Rose, M.R., “Laboratory Evolution of Postponed Senescence inDrosophila Melanogaster,” Evolution 38:1004-1010, 1984.

Biochemistry and AgingSelected Readings

Finkel, T., and Holbrook, N.J., “Oxidants, Oxidative Stress andthe Biology of Aging,” Nature 408(6809):239-247, 2000.

Beckman, K.B., and Ames, B.N., “The Free Radical Theory ofAging Matures,” Physiological Reviews 78(2): 547-581, 1998.

Phillips, J.P., Parkes, T.L., and Hilliker, A.J., “Targeted Neuronal Gene Expression and Longevity in Drosophila,”Experimental Gerontology 35(9-10):1157-1164, 2000.

47


Fiatarone, M.A., and Marks, E.C., et al., “High-IntensityStrength Training in Nonagenarians,” Journal of the AmericanMedical Association 263:3029-3034, 1990.

National Institute on Aging, Research on Older Women: Highlights from the Baltimore Longitudinal Study of Aging,Bethesda, MD: National Institutes of Health, 1991.

Shock, N.W., Greulich, R.G., Andres, R.A., Arenberg, D., Costa, P.T., Lakatta, E.G., and Tobin, J.P., Normal Human Aging: The Baltimore Longitudinal Study of Aging, Washington, DC: U.S. Government Printing Office, 1984.

Warner, H.R., and Kim, S.K., “Dietary Factors Modulating theRate of Aging,” in Goldberg, I., ed., Functional Foods, NewYork: Van Nostrand Reinhold, 1993.

Weindruch, R., and Walford, R.L., The Retardation of Aging and Disease by Dietary Restriction, Springfield, IL: Charles C.Thomas, 1988.

The Future of Aging Selected Readings

K. Kinsella and V.A. Velkoff, U.S. Census Bureau, SeriesP95/01-1, An Aging World: 2001, U.S. Government PrintingOffice, Washington, D.C. 2001.

Federal Interagency Forum on Aging-Related Statistics. Older Americans 2000: Key Indicators of Well-Being. Federal Interagency Forum on Aging-Related Statistics, Washington,DC: U.S. Government Printing Office. August 2000.

Stem Cells: Scientific Progress and Future Research Directions,National Institutes of Health, Department of Health andHuman Services, June 2001. http://www.nih.gov/news/stemcell/scireport.htm

Rudman, D., Feller, A.G., Nagraj, H.S., et al., “Effects ofHuman Growth Hormone in Men Over 60 Years Old,” The New England Journal of Medicine 323(1):1-6, 1990.

Stadtman, E.R., “Protein Oxidation and Aging,” Science 257:1220-1224, 1992.

Wallace, D.C., “Mitochondrial Genetics: A Paradigm for Agingand Degenerative Diseases?” Science 256:628-632, 1992.

Physiologic CluesSelected Readings

Biomarkers of Aging: From Primitive Organisms to Man, Workshop Report, International Longevity Center, 2001.

The Aging Factor in Health and Disease, Workshop Report, Inter-national Longevity Center, 1999.

Roth, G.S., Ingram, D.K., and Lane, M.A., “Calorie Restrictionin Primates: Will It Work and How Will We Know?” Journal ofthe American Geriatrics Society, 47(7):896-903, 1999.

Mattson, M.P., “Neuroprotective Signaling and the AgingBrain: Take Away My Food and Let Me Run,” Brain Research886(1-2):47-53, 2000.

Ramsey, J.J., et al., “Dietary Restriction and Aging in RhesusMonkeys: The University of Wisconsin Study,” ExperimentalGerontology 35(9-10):1131-1149, 2000.

Adler, W., Song, L., Chopra, R.K., Winchurch, R.A., Waggie,K.S., and Nagel, J.E., “The Immune Deficiency of Aging,” inPowers, D., Morley, J., and Coe, R., eds., Aging, Immunity, andInfection, New York: Springer, 1993.


Page 10, 19 — Aging worm photos, courtesy of Dr. Cynthia Kenyon, University of California, San Francisco

Page 11 — Sardinian man, courtesy of Askos Edizioni,and Dr. Giuseppe Pilia of the L’Instituto sulle Talassemie ed Anemie Mediterranee, Cagliari, Sardinia, Italy

Page 11 — Zebrafish, courtesy of Dr. Glenn Gerhard,VA Medical Center, White River Junction, VT

Page 12 — Microarray photo, courtesy of Dr. Minoru Ko, Laboratory of Genetics, National Institute on Aging

Page 13-14 — Dividing cell, courtesy of Dr. Elizabeth Blackburn, University of California, San Francisco

Page 13 — Fruit Fly photo, courtesy of Dr. John Tower,University of Southern California, Los Angeles

Page 14 — Fibroblast photos and Dr. Leonard Hayflickphoto, courtesy of Dr. Leonard Hayflick, University ofCalifornia, San Francisco

Page 15, 18 — Scientists, courtesy of Max Hirshfeld

Page 18, 22, 25, 31, 35, 40, 41 — Photo Researchers Inc.

Page 19 — Free radical illustration, courtesy of Stacy Janis

Page 20 — Protein crosslinking photos, courtesy of Dr. John W. Baynes, University of South Carolina,Columbia, SC

Page 22 — Werner’s syndrome photos, courtesy of Dr. George Martin, University of Washington, Seattle

WRITERDoug Dollemore, Office of Communications and PublicLiaison, National Institute on Aging

DESIGNRandi L. Wright, Levine & Associates, Inc.,Washington, D.C.

PHOTOGRAPHY / ILLUSTRATIONSCover, inside front and back covers, page 4, 5, 13, 17,18, 19, 20, 21, 23, 26, 27, 29, 30, 34, 35, 37, 39, 42, 43 —courtesy of Getty Images, Inc.

Introduction — Robert Byrd photos, reproduced fromGrowing Old Is Not For Sissies II: Portraits of SeniorAthletes, by Etta Clark, Pomegranate Art Books, San Francisco, (1995) with permission of Etta Clark

Page 2, 30 — Jeanne Calment and Leroy “Satchel”Paige, courtesy of the Associated Press

Page 3 — Four brothers photos, courtesy of Doug Dollemore, National Institute on Aging

Page 5 — Rockfish, courtesy of Dr. Gregor M. Cailliet,Moss Landing Marine Laboratories, California StateUniversity, Moss Landing, CA

Page 6 — Four generations photo, courtesy of Dr. Huber Warner, Biology of Aging Program, National Institute on Aging

Page 8 — Dr. Thomas T. Perls and centenarian, Rick Friedman Photography, © 2002 Rick Friedman All Rights Reserved

Page 9, 40 — Yeast photos, courtesy of Dr. Michal S. Jazwinski, Louisiana State University Medical Center, New Orleans

Page 23 — DNA stock art, courtesy of Dr. Paul A.Thiessen, www.Chemicalgraphics.com

Page 24 — Heat shock protein illustrations, courtesy ofDr. Nikki Holbrook, Yale University, New Haven, CT

Page 26, 27, 28 — Hormones and Molecular Expressions, Michael W. Davidson,http://micro.magnet.fsu.edu

Page 31 — BLSA participant, courtesy of Kay Churnush

Page 35 — Illustration of neurons, courtesy of Dr. Mark Mattson, Laboratory of Neurosciences,National Institute on Aging

Page 36 — Monkey illustrations, courtesy of Dr. Don Ingram, Laboratory of Neurosciences, National Institute on Aging

Page 37 — Rowers, reproduced from Growing Old IsNot For Sissies II: Portraits of Senior Athletes, by EttaClark, Pomegranate Art Books, San Francisco, (1995)with permission of Etta Clark

Page 38 — reproduced from J. Bone Miner Res., 1986;1:16-21 with permission of the American Society forBone and Mineral Research

Page 40 — Audrey Stubbart photos, courtesy of Carol Kroeck and The Examiner

Back cover — Electron microscope, courtesy of Max Hirshfeld

All other photos from the Office of Communicationsand Public Liaison, National Institute on Aging

Special thanks to Dr. Huber Warner, Associate Director, Biology of Aging Program, National Institute on Aging

Acknowledgements

grow old along with me!The best is yet to be,

The last of life, for which the first was made.”

—Robert Browning, (1812-1889)

“

N AT I O N A L I N S T I T U T E O N A G I N G N AT I O N A L I N S T I T U T E S O F H E A LT H

A Biological Quest

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NIH Publication No. 02-2756

June 2006 edition

Originally printed September 2002

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