National Institutes of Health

National Institute on Aging

Office of Communications

and Public Liaison

Building 31, Room 5C27

Bethesda, MD 20892-2292

Phone: 1-301-496-1752

Website: www.nia.nih.gov

NIH Publication No. 02-2756

3Biochemistry

and 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

2

5

4

Introduction 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 Genetic

Connection 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

Physiologic

Clues 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 Future

of Aging 39

Stem Cells: Great Expectations,

but Many Barriers Remain 41-42

Glossary/

Bibliography 43

Glossary 44-45

Bibliography 46-48

TABLE OF CONTENTS
—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 encounter

and after a good shaking make him go your way.”

“

Life is short, so enjoy every minute.

Hang gliding, for me, lifts the spirit

and recharges the old batteries. It is

the greatest sport going, and lots of

exercise too.

— Robert Byrd

hang glider, age 74
i

Aging Under the Microscope

Introduction

The 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 diseases 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.
FindingAnswers

PosingQuestions,

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’s

oldest people were Japanese,

six were American, three

were French, and two were

Italian. Is there something

special about how these 

people live? Mme. Calment

took 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 than

likely, all of these elements—

heredity, environment, and

lifestyle—have complex roles

in determining whether an 

individual will have a long

and healthy life, according to

scientists 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, perhaps

no more than 25 people are

more than 110 years old. So

these super centenarians, as

they are known, are clearly

humanity’s ultimate marathoners. But why? What factors allowed Jeanne Calment,

who was 14 when the Eiffel

Tower was completed and

who once sold painting 

supplies to Vincent Van

Gogh, to live such a long 

life that she herself became

part of history?

Is genetics the key factor?

Mme. Calment’s ancestors

were legendary for their long

“We all make bad deals in

life,” Mme. Calment once

joked to the astounded 

attorney. When her welldocumented life ended on

August 4, 1997 at age 122

years 5 months and 14 days,

she is believed to have lived

longer than any other person

in recorded history. She outlived Shigechiyo Izumi of

Japan, who had held the

unverified longevity record of

120 years, 237 days. She outlived her husband, who died

in 1942, four years before their

50th wedding anniversary. She

outlived her daughter, who

died in 1936. She outlived her

only grandson, who died in

1963. And yes, she outlived

2

Posing Questions, Finding Answers Posing Questions, Finding Answers

At her 120th birthday party, a journalist hesitantly

told 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!”
b

d

c

a

c

b

a

d

Four brothers, below (a) 9 years old,

(b) 7 years old, (c) 5 years old, and 

(d) 3 years old; at lower right, the

brothers pictured 52 years later. 

Visible signs of aging can vary, even

among family members, depending 

on a number of environmental and

genetic factors.

during the lifespan. However,

this definition includes some

changes that aren’t necessarily

problematic, and usually

don’t affect an individual’s

viability. Gray hair and wrinkles, for instance, certainly are

manifestations of aging, but

neither is harmful.

To differentiate these

superficial changes from 

those that increase the risk 

of disease, disability, or 

death, gerontologists prefer 

to use a more precise term—

senescence—to describe

aging. Senescence is the 

progressive deterioration of

many bodily functions over

time. This loss of function is

accompanied by decreased

fertility and increased risk 

of mortality as an individual

Aging Under the Microscope: A Biological Quest

describes what we know 

so far about the answers 

to these questions. It offers

an overview of research 

on aging and longevity,

describing the major puzzle

pieces 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 natural

process potentially involving

every molecule, cell, and

organ in the body. In its

broadest sense, aging merely

refers to changes that occur

lifespan beyond which we

cannot live no matter how

optimal our environment 

or favorable our genes? And

finally for all of us, the most

important question: How 

can insights into longevity 

be used to fight the diseases

and disabilities associated

with old age to make sure

this period of life is healthy,

active, and independent?

Researchers at the

National Institute on Aging

(NIA), part of the National

Institutes of Health, are seeking answers to these and

other important questions.

Established by the Federal

Government in 1974, the 

NIA conducts and supports

research on aging and educates the public about its

findings.

These scientists, called 

gerontologists, ponder other

fundamental questions. Why

do we age? What happens as

we age? Why do some people

age faster or slower and in

different ways than others? 

Is there a maximum human

3

Aging Under the Microscope
Comparative Lifespans (in years)

4 18 20 24 30 30 47 50 62 66 68 70 80 100 122 150 mouse snail dog bat dolphin lion bear monkey ostrich alligator owl elephant eagle human oyster turtle

fairly primitive, and the life

expectancy—the average

number of years from birth

that an individual can expect

to live—was still less than 

50 years worldwide. 

Yet Mme. Calment, perhaps because she was born

with a set of extraordinary

genes or was simply fortunate

enough to elude many of the

illnesses that claim so many

others, beat the odds and set

What is the 

Difference Between

Life Expectancy 

and Lifespan?

When George Washington

celebrated his 60th birthday 

in 1792, he had outlived all 

of his male ancestors, dating

back for several generations.

He had outlived a typical 

Virginian of his era by about

15 years. To achieve this 

relative “old age,” he had

survived smallpox, mumps,

pneumonia, dysentery,

typhoid fever, a staphylococcal infection of the hip, four

bouts of malaria, and two

nearly fatal encounters with

influenza.

When Jeanne Calment

was born in 1875, the illnesses

that plagued Washington’s

generation still took many

lives, health care was still

sexual tissues atrophy with

increasing age. In men,

sperm production decreases

and the prostate enlarges. 

Why these and other

changes occur with advancing age both intrigues and

perplexes gerontologists. 

In fact, senescence is one of

nature’s least understood biological processes. Gerontologists, for instance, disagree

about when senescence

begins. Some argue it begins

at birth. Others contend it

sets in after the peak reproductive years. But clearly,

senescence, whether it begins

at birth or age 20, 30, or 40,

leads to an accumulating 

loss of bodily functions,

which ultimately increases

the probability of death, as

we get older. 

gets older. The rate and progression of this process can

vary greatly from person to

person, but generally over

time every major organ of 

the body is affected. As we

age, for instance, lung tissue

loses much of its elasticity,

and the muscles of the rib

cage shrink. As a result, 

maximum vital breathing

capacity progressively diminishes in each decade of life,

beginning at about age 20.

With age, blood vessels accumulate fatty deposits and

lose much of their flexibility,

resulting in arteriosclerosis or

“hardening of the arteries.”

In the gastrointestinal 

system, production of digestive enzymes diminishes, and

as a result, tissues lose much

of their ability to break down

and absorb foods properly. 

In women, vaginal fluid 

production decreases and

4

Posing 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 show

few outward signs of aging and are

apparently capable of reproducing frequently, even in late life. These differences intrigue some gerontologists.

knowledge, all-encompassing theories of aging are 

giving way to a more 

diverse perspective. 

Aging today is viewed 

as many processes, interactive and interdependent,

that determine lifespan and

health, and gerontologists 

are studying a multitude 

of factors that may be

involved. The rest of this

booklet describes what we

know and don't know about

many of these factors, and

where we think scientists 

are likely to find answers 

to questions about aging 

and longevity.

Why Do We Age?

Gerontologists have proposed many theories to 

explain the diversity of the

aging process in nature.

Pacific salmon, for instance,

reproduce only once and die

within hours of spawning,

while at the other end of 

the spectrum, sea anemones,

which reproduce asexually,

show few, if any, outward

signs of deterioration until

the very end of their long

lives. Most gerontologists

now agree that no single 

theory can account for this

wide spectrum. In fact, with

the tools of biotechnology

and an influx of new 

As part of this quest,

gerontologists are studying 

a variety of life forms including yeast, fruit flies, nematodes, mice, and primates 

in search of clues applicable

to human aging. As they

explore the genes, cells, and

organs involved in aging,

they are uncovering more

and more of the secrets of

longevity. As a result, life

extension may some day be

more than the stuff of myth.

In addition, as gerontologists

apply their expanding knowledge to medicine, the prevention or retardation of the

onset of some age-related 

diseases and disabilities 

may become realistic goals.

the benchmark for maximum

human lifespan—the greatest

age reached by any member

of a species.

Life expectancy in the

United States rose dramatically in the 20th century, from

about 47 years in 1900 to

about 73 years for males and

79 years for females in 1999.

This increase is mostly due 

to improvements in environmental factors—sanitation,

the discovery of antibiotics,

and medical care. Now, as

scientists make headway

against chronic diseases like

cancer and heart disease,

some think life expectancy

can be extended even further

in the 21st century. 

5

Aging Under the Microscope

Next to the miracle of life itself, aging and death 

are perhaps the greatest mysteries.”

—Caleb Finch, Ph.D.

Gerontologist, University of Southern California

“
6

Posing Questions, Finding Answers

Theories of Aging

ERROR THEORIES 

Wear and Tear. Cells and tissues have vital parts that 

wear out.

Rate of Living. The greater an organism's rate of oxygen

basal 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 mitochondrial

DNA might lead to mitochondrial

dysfunction.

Theories of aging fall into two groups. The programmed

theories hold that aging follows a biological timetable,

perhaps a continuation of the one that regulates childhood growth and development. The damage or error 

theories emphasize environmental assaults to our systems

that gradually cause things to go wrong. Many of the 

theories of aging are not mutually exclusive. Here is a

brief and very simplified rundown of the major theories. 

PROGRAMMED THEORIES

Programmed Longevity. Aging is the result of the sequential switching on and off of certain genes, with senescence

being defined as the time when age-associated deficits are

manifested.

Endocrine Theory. Biological clocks act through hormones

to control the pace of aging.

Immunological Theory. A programmed decline in immune

system functions leads to an increased vulnerability to

infectious disease and thus aging and death.

Four generations of a family. Although it is

fairly easy to estimate the approximate ages

of the women in this picture, gerontologists

have 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 gerontologists

now believe no single theory fully explains 

the changes that occur in the aging body.
Connection

TheGenetic

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.
Connection

TheGenetic

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.
Investigators are finding clues to aging and longevity

in yeast, one-celled organisms that have some intriguing genetic similarities to human cells. In a laboratory

at Louisiana State University Medical Center in New

Orleans, Michal Jazwinski, Ph.D., has found genes that

seem to promote longevity in these rapidly dividing,

easy-to-study organisms.

Yeast normally have about 21 cell divisions or generations. Jazwinski observed that over the course of that

lifespan, certain genes in the yeast are more active

or less active as the cells age; in the language of

molecular biology, they are differentially expressed.

So far, Jazwinski has found 14 such genes in yeast.

Selecting one of these genes, Jazwinski tried

two different experiments. First, he introduced the gene into yeast cells in a form

that allowed him to control its activity.

When the gene was activated to a

greater degree than normal, or 

overexpressed, some of the yeast

cells went on dividing for 27 or 28

generations; their period of activity

was extended by 30 percent.

In his second experiment, Jazwinski mutated the gene.

When he introduced this non-working version into a

group 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 divisions

in yeast or, according to some researchers’ ways of

thinking, its longevity. (LAG-1 is short for longevity

assurance 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 a

protein found in cell membranes. One next step is to

study the function of that protein. Similar sequences

have been found in human DNA, so a second investigative path is to clone the human gene and study its

function. If there turns out to be a human LAG-1 counterpart, new insights into aging may be uncovered.

In another laboratory, Leonard Guarente, Ph.D., of 

the Massachusetts Institute of Technology found that

mutation 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 other

animals, produces an enzyme that alters the structure 

of DNA, which, in turn, alters patterns of gene 

expression.

Tracking Down a Longevity Gene

Yeast could help

gerontologists

understand the

genetics of aging.

More than 14 genes

that appear to promote the longevity

of these single-celled

organisms have been

discovered.

9

Aging Under the Microscope
Investigators are finding clues to aging and longevity

in yeast, one-celled organisms that have some intriguing genetic similarities to human cells. In a laboratory

at Louisiana State University Medical Center in New

Orleans, Michal Jazwinski, Ph.D., has found genes that

seem to promote longevity in these rapidly dividing,

easy-to-study organisms.

Yeast normally have about 21 cell divisions or generations. Jazwinski observed that over the course of that

lifespan, certain genes in the yeast are more active

or less active as the cells age; in the language of

molecular biology, they are differentially expressed.

So far, Jazwinski has found 14 such genes in yeast.

Selecting one of these genes, Jazwinski tried

two different experiments. First, he introduced the gene into yeast cells in a form

that allowed him to control its activity.

When the gene was activated to a

greater degree than normal, or 

overexpressed, some of the yeast

cells went on dividing for 27 or 28

generations; their period of activity

was extended by 30 percent.

In his second experiment, Jazwinski mutated the gene.

When he introduced this non-working version into a

group 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 divisions

in yeast or, according to some researchers’ ways of

thinking, its longevity. (LAG-1 is short for longevity

assurance 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 a

protein found in cell membranes. One next step is to

study the function of that protein. Similar sequences

have been found in human DNA, so a second investigative path is to clone the human gene and study its

function. If there turns out to be a human LAG-1 counterpart, new insights into aging may be uncovered.

In another laboratory, Leonard Guarente, Ph.D., of 

the Massachusetts Institute of Technology found that

mutation 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 other

animals, produces an enzyme that alters the structure 

of DNA, which, in turn, alters patterns of gene 

expression.

Tracking Down a Longevity Gene

Yeast could help

gerontologists

understand the

genetics of aging.

More than 14 genes

that appear to promote the longevity

of these single-celled

organisms have been

discovered.

9

Aging Under the Microscope
Age-related Traits 

Are All in the Family

Finding longevity genes is only one of many goals for

gerontologists. An equally important mission is unraveling

the genetic processes involved in age-related traits and diseases.

NIA and Italian investigators are focusing their attention on Sardinia, a

secluded Mediterranean island. Since settlers first occupied the island thousands of years ago, the population has grown without much immigration

from the outside world. Because they are more closely related than people

living in other societies, Sardinians share much of the same genetic information, which makes it easier to track genetic effects through generations. 

When a particular trait exists in a genetically isolated “founder” population

such as Sardinia, it is likely that the same few genes are responsible for the

trait in most or all affected individuals. Once the genes for a certain complex

trait are identified within the founder population, researchers can use this

information to isolate interacting genes and assess their importance in more

genetically 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 Sardinians

for evidence of genetic influences on two traits: severe arterial stiffness and

frequent positive emotions. Vascular stiffness may be an important predictor

of heart disease mortality. Reports also suggest that joyfulness and other

positive emotions can have profound impact on life satisfaction and health as

we age. Gerontologists suspect these traits have strong genetic components.

As the project progresses, investigators plan to conduct genetic analysis on

individuals who share extreme values of these traits and will attempt to 

identify the underlying genes.

Ultimately, gerontologists hope founder population studies yield results that

will help prevent certain age-related diseases.

In the worm, this gene makes

a protein that looks much

like the receptor for the hormone insulin. In humans, this

hormone controls functions

including food utilization

pathways, glucose metabolism, and cell growth. These

and other genetic linkages

are under intense scrutiny,

and ultimately could yield

clues about how genes 

interact with environmental 

factors to influence longevity in humans and other

species. Caloric restriction,

for example, is the only

known intervention shown 

to prolong life in species

ranging from yeast to

rodents. Scientists suspect

this intervention works in

yeast, worms, and other 

species, in part, because it

Gerontologists study many

different animals including

zebrafish (left) and birds like

budgerigars (background) for

genetic clues about aging.

triggers alterations of genetic

activity. Caloric restriction 

also may work, partially, by

altering metabolic pathways

involved in energy utilization.

(See The Next Step: Caloric

Restriction in Primates, page 36).

Many investigators, however, interpret these findings

cautiously because there are

important differences between

human genes and those of

lower animals. In fact, the

structural similarity is only

about 30 percent, which means

that comparing yeast genes to

human genes, for instance, is

like comparing a go-cart to a

high-performance racing car.

The basic machinery may be

similar, but one is far less 

complex than the other. So

while yeast, worms, and 

other simple organisms are

helpful models of aging, they

probably don’t completely

mimic the process that occurs

in humans. For this reason, 

11

Aging Under the Microscope
Age-related Traits 

Are All in the Family

Finding longevity genes is only one of many goals for

gerontologists. An equally important mission is unraveling

the genetic processes involved in age-related traits and diseases.

NIA and Italian investigators are focusing their attention on Sardinia, a

secluded Mediterranean island. Since settlers first occupied the island thousands of years ago, the population has grown without much immigration

from the outside world. Because they are more closely related than people

living in other societies, Sardinians share much of the same genetic information, which makes it easier to track genetic effects through generations. 

When a particular trait exists in a genetically isolated “founder” population

such as Sardinia, it is likely that the same few genes are responsible for the

trait in most or all affected individuals. Once the genes for a certain complex

trait are identified within the founder population, researchers can use this

information to isolate interacting genes and assess their importance in more

genetically 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 Sardinians

for evidence of genetic influences on two traits: severe arterial stiffness and

frequent positive emotions. Vascular stiffness may be an important predictor

of heart disease mortality. Reports also suggest that joyfulness and other

positive emotions can have profound impact on life satisfaction and health as

we age. Gerontologists suspect these traits have strong genetic components.

As the project progresses, investigators plan to conduct genetic analysis on

individuals who share extreme values of these traits and will attempt to 

identify the underlying genes.

Ultimately, gerontologists hope founder population studies yield results that

will help prevent certain age-related diseases.

In the worm, this gene makes

a protein that looks much

like the receptor for the hormone insulin. In humans, this

hormone controls functions

including food utilization

pathways, glucose metabolism, and cell growth. These

and other genetic linkages

are under intense scrutiny,

and ultimately could yield

clues about how genes 

interact with environmental 

factors to influence longevity in humans and other

species. Caloric restriction,

for example, is the only

known intervention shown 

to prolong life in species

ranging from yeast to

rodents. Scientists suspect

this intervention works in

yeast, worms, and other 

species, in part, because it

Gerontologists study many

different animals including

zebrafish (left) and birds like

budgerigars (background) for

genetic clues about aging.

triggers alterations of genetic

activity. Caloric restriction 

also may work, partially, by

altering metabolic pathways

involved in energy utilization.

(See The Next Step: Caloric

Restriction in Primates, page 36).

Many investigators, however, interpret these findings

cautiously because there are

important differences between

human genes and those of

lower animals. In fact, the

structural similarity is only

about 30 percent, which means

that comparing yeast genes to

human genes, for instance, is

like comparing a go-cart to a

high-performance racing car.

The basic machinery may be

similar, but one is far less 

complex than the other. So

while yeast, worms, and 

other simple organisms are

helpful models of aging, they

probably don’t completely

mimic the process that occurs

in humans. For this reason, 

11

Aging Under the Microscope
100 trillion cells, composing

the organ systems that make

our bodies. 

Early in life, nearly all 

of the body’s cells can divide.

But this process doesn’t go

on indefinitely. Researchers

have learned that cells have

finite proliferative lifespans,

at least when studied in test

tubes—in vitro. After a certain number of divisions,

they enter a state in which

they no longer proliferate

and DNA synthesis is

blocked. For example, 

young human fibroblasts—

structural cells that hold skin

and other tissues together—

divide about 50 times and

then stop. This phenomenon

is known as the Hayflick

limit, after Leonard Hayflick,

who with Paul Moorhead

described it in 1961 while at

the Wistar Institute in

Philadelphia. At least 

four genes involved in this

For now, investigators

have found evidence that

some proteins, such as 

antioxidant enzymes, prevent

damage to cells, while others

may repair damaged DNA,

regulate glucose metabolism,

or help cells respond to 

stress. Other gene products

are thought to influence 

replicative senescence.

Cellular Senescence

During the process of cell

division or mitosis, a cell’s

nucleus dissolves, and its

chromosomes condense into

visible thread-like structures

that 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 two

identical daughter cells. It is

this process that allows us to 

grow from a single cell into

In the Lab of the 

Long-Lived Fruit Flies

A laboratory at the University of California, Irvine, is the home of

thousands of Drosophila melanogaster, or fruit flies, that routinely

live for 70 or 80 days, nearly twice the average Drosophila lifespan.

Here evolutionary biologist Michael Rose, Ph.D., has bred the longlived stocks by selecting and mating flies late in life.

To begin the process of genetic selection, Rose first collected eggs

laid by middle-age fruit flies and let them hatch in isolation. The

progeny were then transferred to a communal plexiglass cage to

eat, grow, and breed under conditions ideal for mating. Once they

had reached advanced ages, the eggs laid by older females (and 

fertilized by older males) were again collected and removed to individual hatching vials. The cycle was repeated, but with succeeding

generations, the day on which the eggs were collected was progressively 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 are

involved? Since the first experiments, Rose has bred longer life

spans into fruit flies by selecting for other characteristics, such as

ability 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, superoxide

dismutase (SOD), is involved. Two laboratory studies,

including work by John Tower, Ph.D., at the University of

Southern California, have shown that genetically altered

fruit flies that produce greater amounts of SOD have

extended lifespans. This finding has given a boost to the

hypothesis that antioxidant enzymes like SOD are linked

to aging or longevity. However, to date, similar experiments in other species have been inconclusive.

The eyes of these

genetically altered

fruit flies appear

fluorescent under

the microscope. 

By altering gene

expression in fruit

flies and other

organisms, investigators are learning

much about aging.
100 trillion cells, composing

the organ systems that make

our bodies. 

Early in life, nearly all 

of the body’s cells can divide.

But this process doesn’t go

on indefinitely. Researchers

have learned that cells have

finite proliferative lifespans,

at least when studied in test

tubes—in vitro. After a certain number of divisions,

they enter a state in which

they no longer proliferate

and DNA synthesis is

blocked. For example, 

young human fibroblasts—

structural cells that hold skin

and other tissues together—

divide about 50 times and

then stop. This phenomenon

is known as the Hayflick

limit, after Leonard Hayflick,

who with Paul Moorhead

described it in 1961 while at

the Wistar Institute in

Philadelphia. At least 

four genes involved in this

For now, investigators

have found evidence that

some proteins, such as 

antioxidant enzymes, prevent

damage to cells, while others

may repair damaged DNA,

regulate glucose metabolism,

or help cells respond to 

stress. Other gene products

are thought to influence 

replicative senescence.

Cellular Senescence

During the process of cell

division or mitosis, a cell’s

nucleus dissolves, and its

chromosomes condense into

visible thread-like structures

that 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 two

identical daughter cells. It is

this process that allows us to 

grow from a single cell into

In the Lab of the 

Long-Lived Fruit Flies

A laboratory at the University of California, Irvine, is the home of

thousands of Drosophila melanogaster, or fruit flies, that routinely

live for 70 or 80 days, nearly twice the average Drosophila lifespan.

Here evolutionary biologist Michael Rose, Ph.D., has bred the longlived stocks by selecting and mating flies late in life.

To begin the process of genetic selection, Rose first collected eggs

laid by middle-age fruit flies and let them hatch in isolation. The

progeny were then transferred to a communal plexiglass cage to

eat, grow, and breed under conditions ideal for mating. Once they

had reached advanced ages, the eggs laid by older females (and 

fertilized by older males) were again collected and removed to individual hatching vials. The cycle was repeated, but with succeeding

generations, the day on which the eggs were collected was progressively 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 are

involved? Since the first experiments, Rose has bred longer life

spans into fruit flies by selecting for other characteristics, such as

ability 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, superoxide

dismutase (SOD), is involved. Two laboratory studies,

including work by John Tower, Ph.D., at the University of

Southern California, have shown that genetically altered

fruit flies that produce greater amounts of SOD have

extended lifespans. This finding has given a boost to the

hypothesis that antioxidant enzymes like SOD are linked

to aging or longevity. However, to date, similar experiments in other species have been inconclusive.

The eyes of these

genetically altered

fruit flies appear

fluorescent under

the microscope. 

By altering gene

expression in fruit

flies and other

organisms, investigators are learning

much about aging.
as telomere shortening influence replicative senescence.

Telomeres

Every chromosome has tails

at its ends that get shorter 

as a cell divides. These tails,

called telomeres, all have the

same short sequence of DNA

bases (TTAGGG in humans

and other vertebrates)

repeated thousands of times.

These repetitive snippets do

not contain any vital genetic

information, but acting much

like the hard, plastic covering on the ends of shoestrings, they help keep

chromosomes intact.

During mitosis, the

molecular machinery that

replicates DNA can’t completely copy the extreme

ends of chromosomes. So

each time a cell divides, the

telomeres get shorter. Over

time, scientists theorize,

research and cancer research

intersect. When tumor suppressor genes are inactivated, investigators theorize

it turns on a complex process

that leads to development of

a tumor. So replicative senescence apparently has been

retained through evolution

as a defense against cancer.

Scientists are unraveling

how the products of these

genes promote and suppress

cell proliferation. There are

indications that a multi-layer

control system is at work,

involving a host of intricate

mechanisms that interact to

maintain a balance between

the two kinds of genes. Some

genes, for instance, appear 

to suppress or silence other

genes. Mutations in these

silencing genes have been

shown to affect the lifespan

of C. elegans and yeast. 

Many gerontologists are

studying how silencing 

and other mechanisms such

anti-proliferative gene came

from an eye tumor called

retinoblastoma. When one 

of the genes from retinoblastoma cells—later called the

RB gene—became inactive,

the cells went on dividing

indefinitely and produced 

a tumor. But when the RB

gene product was activated,

the cells stopped dividing.

This gene’s product, in other

words, appeared to suppress

proliferation. Another wellcharacterized gene of this

type is the p53 gene, which

produces a protein that 

also limits cell proliferation.

These genes are called 

tumor suppressor genes.

Limited proliferation 

is the norm in the world of

human cells. In some cases,

however, a cell somehow

escapes this control mechanism and goes on dividing,

becoming, in the terms of 

cell biology, immortal. And

because immortal cells eventually form tumors, this is

one area in which aging

does occur, could, in turn,

indirectly increase an individual’s vulnerability to 

the diseases and disabilities

often associated with aging.

However, no feature of aging

has yet been unequivocally

explained by in vitro cellular

senescence.

Proliferative Genes

Searching for explanations of

proliferation and senescence,

scientists have found certain

genes that appear to trigger

cell proliferation. One example of such a proliferative

gene is c-fos, which encodes 

a short-lived protein that 

is thought to regulate the

expression of other genes

important in cell division.

Proliferative genes, such

as c-fos and others of its kind,

are countered by anti-proliferative genes, which seem 

to interfere with division.

The first evidence of an 

15

Aging Under the Microscope
as telomere shortening influence replicative senescence.

Telomeres

Every chromosome has tails

at its ends that get shorter 

as a cell divides. These tails,

called telomeres, all have the

same short sequence of DNA

bases (TTAGGG in humans

and other vertebrates)

repeated thousands of times.

These repetitive snippets do

not contain any vital genetic

information, but acting much

like the hard, plastic covering on the ends of shoestrings, they help keep

chromosomes intact.

During mitosis, the

molecular machinery that

replicates DNA can’t completely copy the extreme

ends of chromosomes. So

each time a cell divides, the

telomeres get shorter. Over

time, scientists theorize,

research and cancer research

intersect. When tumor suppressor genes are inactivated, investigators theorize

it turns on a complex process

that leads to development of

a tumor. So replicative senescence apparently has been

retained through evolution

as a defense against cancer.

Scientists are unraveling

how the products of these

genes promote and suppress

cell proliferation. There are

indications that a multi-layer

control system is at work,

involving a host of intricate

mechanisms that interact to

maintain a balance between

the two kinds of genes. Some

genes, for instance, appear 

to suppress or silence other

genes. Mutations in these

silencing genes have been

shown to affect the lifespan

of C. elegans and yeast. 

Many gerontologists are

studying how silencing 

and other mechanisms such

anti-proliferative gene came

from an eye tumor called

retinoblastoma. When one 

of the genes from retinoblastoma cells—later called the

RB gene—became inactive,

the cells went on dividing

indefinitely and produced 

a tumor. But when the RB

gene product was activated,

the cells stopped dividing.

This gene’s product, in other

words, appeared to suppress

proliferation. Another wellcharacterized gene of this

type is the p53 gene, which

produces a protein that 

also limits cell proliferation.

These genes are called 

tumor suppressor genes.

Limited proliferation 

is the norm in the world of

human cells. In some cases,

however, a cell somehow

escapes this control mechanism and goes on dividing,

becoming, in the terms of 

cell biology, immortal. And

because immortal cells eventually form tumors, this is

one area in which aging

does occur, could, in turn,

indirectly increase an individual’s vulnerability to 

the diseases and disabilities

often associated with aging.

However, no feature of aging

has yet been unequivocally

explained by in vitro cellular

senescence.

Proliferative Genes

Searching for explanations of

proliferation and senescence,

scientists have found certain

genes that appear to trigger

cell proliferation. One example of such a proliferative

gene is c-fos, which encodes 

a short-lived protein that 

is thought to regulate the

expression of other genes

important in cell division.

Proliferative genes, such

as c-fos and others of its kind,

are countered by anti-proliferative genes, which seem 

to interfere with division.

The first evidence of an 

15

Aging Under the Microscope
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.

Aging

Biochemistry

and
a

ndcombinereadilywith

othermolecules.

Thisprocess,called

oxidation,cansparkachain

reactionresultinginaseries

ofproducts,someofwhich

areactuallybeneficial.The

immunesystem,forinstance,

usesfreeradicalstodestroy

bacteriaandotherpatho-

gens.Anotheroxidizing

molecule,callednitricoxide,

helpsnervecellsinthebrain

communicatewitheachother.

Freeradicals,however,

alsocanbevandalsthat

causeextensivedamageto

proteins,membranes,and

DNA.Mitochondriaare

particularlypronetofree

radicaldamage.Themajor

sourceoffreeradical

by–productsarecalledoxy-

genfreeradicals,alsoknown

asreactiveoxygenspecies.

Afreeradicalcanbe

producedfromalmostany

moleculewhenitlosesan

electronfromoneormore

ofitsatoms.Incells,they

arecommonlycreatedwhen

mitochondriacombineoxy-

genwithhydrogentoform

water.Thistransformation

releasesenergyintothe

cell,butitalsocanshred

electronsfromoxygen.

Whenthishappensitleaves

theoxygenatom—now

anunstableoxygenfree

radical—withoneunpaired

electron.Becauseelectrons

aremoststablewhenthey

arepaired,oxygenfree

radicalsstealmatesfortheir

loneelectronsfromother

molecules.Thesemolecules,

inturn,becomeunstable

OxygenRadicals

Oxygensustainsus.Every

cellinthebodyneedsitto

survive.Yet,paradoxically,

oxygenalsowreakshavoc

inthebodyandmaybea

primarycatalystformuch

ofthedamageweassociate

withaging.Thisdamage

occursasadirectresultof

howcellsmetabolizeit.

Oxygenisprocessed

withinacellbytinyogan-

ellescalledmitochondria.

Mitochondriaconvertoxy-

genandfoodintoadenosine

triphosphate(ATP),an

energy-releasingmolecule

thatpowersmostcellular

processes.Inessence,mito-

chondriaarefurnaces,and

likeallfurnaces,theypro-

ducepotentiallyharmful

by–products.Incells,these

Thismitochondrionisacellularpower-

house,continuouslygeneratingATP,an

energy-r

eleasingmolecule,aswellas

potentiallyharmfulby-productssuchas

oxygenfreeradicals.Hundredsofmito-

chondriaexistineverycell.Withage,

increasingoxidativedamagetothese

organellesmaydecreasetheirefficiency.

18

BiochemistryandAging
Antioxidants and

Aging Nematodes

A worm barely the size of a comma printed on this page

may change how investigators think about oxygen radicals,

antioxidants, and aging. C. elegans nematodes immersed in a

liquid containing a potent antioxidant drug lived 44 percent

longer than worms not treated with this substance. It was

the first time that any drug had extended the lifespan of any

multi-cellular organism. The finding lends credence to the

hypothesis that oxygen radicals have a significant role in

the aging process.

In addition, the international team of investigators, led by

Simon Melov, Ph.D., of the Buck Center for Research in Aging

in California, restored a normal lifespan to mutant worms

that had a mitochondrial defect, which caused increased

oxygen radical production and accelerated aging. The

worms showed no apparent ill effects from the treatment.

EUK-134, the drug used in the experiment, was a

synthetic form of superoxide dismutase (SOD) and catalase, two enzymes that counteract the effects of oxidative

stress. Like other antioxidants, such as vitamin E, these

compounds convert oxygen radicals to water. But they are

much more potent.

While it is only one study, and its results have not been confirmed in other species, this investigation supports the concept

that antioxidant defenses may be critical during aging. It also

suggests that one day it may be possible to use similar

interventions to treat age-related conditions in humans.

Oxygen free radicals, the

bright yellow spots in this

illustration, can attack and

damage DNA, leading to

mutations.

substances called antioxidants to counteract them.

These substances including

nutrients—the familiar

vitamins C and E—as well

as enzymes produced in

the cell, such as superoxide

dismutase (SOD), catalase,

and glutathione peroxidase,

prevent most oxidative damage. Nonetheless, some free

radicals manage to circumvent these defenses and do

harm. As a result, cellular

repair mechanisms eventually falter and some internal

breakdowns are inevitable.

These breakdowns can lead

to cellular senescence, and

eventually may trigger

apoptosis, a form of

programmed cell death.

production in the body, they

are also one of its prime targets. As the damage mounts,

mitochondria become less

efficient, progressively generating less ATP and more

free radicals. Over time,

according to the free radical

theory, oxidative damage

accumulates in our cells

and tissues, triggering many

of the bodily changes that

occur as we age. Free radicals

have been implicated not

only in aging but also in

degenerative disorders,

including cancer, atherosclerosis, cataracts, and

neurodegeneration.

But free radicals, which

also can be produced by

tobacco smoke, sun exposure, and other environmental factors, do not go

unchecked. Cells utilize

19

Aging Under the Microscope
Protein Crosslinking

Human rib cartilage shows the effects of protein

crosslinks, which slowly accumulate through complex

pathways and eventually disrupt cellular function.

With age, as glucose binds to its proteins, the cartilage

turns brown and becomes less supple. This process,

called the Maillard reaction, is similar to what happens

when bread is toasted.

Protein Crosslinking

Blood sugar—glucose—is

another suspect in cellular

deterioration. In a process

called non-enzymatic glycosylation or glycation, glucose

molecules attach themselves

to proteins, setting in motion

a chain of chemical reactions

that ends in the proteins

binding together or crosslinking, thus altering their

biological and structural

roles. The process is slow

and complex, but crosslinked proteins accumulate

with time and eventually

disrupt cellular function.

Investigators suspect

that glycation and oxidation

are interdependent processes

since free radicals and crosslinks seem to accelerate the

formation of one another.

extended their normal lifespan. (See Antioxidants and

Aging Nematodes, page 19).

The discovery of antioxidants raised hopes that

people could retard aging

simply by adding them to

the diet. So far, studies of

antioxidant-laden foods and

supplements in humans

have yielded little support

for this premise. Further

research, including largescale epidemiological studies, might clarify whether

dietary antioxidants can help

people live longer, healthier

lives. For now, however,

the effectiveness of dietary

antioxidant supplementation

remains controversial. In

the meantime, gerontologists

are investigating other

intriguing biochemical

processes affected by free

radicals, including protein

crosslinking.

Support for the free

radical theory, first proposed

in 1956 by chemist Denham

Harman, M.D., Ph.D., comes

from studies of antioxidants,

particularly SOD. SOD converts an oxygen radical

known as superoxide anion

into hydrogen peroxide,

which can be degraded by

an enzyme, called catalase,

into oxygen and water. Studies have shown that inserting extra copies of the SOD

gene into fruit flies extends

their average lifespan by as

much as 30 percent.

Other experimental evidence lends support to the

free radical hypothesis. For

example, higher levels of

SOD and catalase have been

found in long-lived nematodes. In one compelling

study, giving nematodes

synthetic forms of these

antioxidants significantly

20

Biochemistry and Aging

Infant Age 17

Age 45 Age 64

Age 76 Age 88
As anyone who reads beauty magazines knows, sunlight damages

skin in ways that seem similar to aging. It’s well-established that

long-term, sunlight-induced damage causes wrinkles. And in both

normal aging and photoaging—the process initiated by sunlight—

the skin becomes drier and loses elasticity. Although gerontologists think that the normal or intrinsic aging process is

probably not the same as photoaging, there are enough

similarities to make this a tantalizing field of study.

The process of photoaging may hold clues to normal aging

because many of the same cells are affected. Photoaging,

for example, damages collagen and elastin, the two proteins

that give skin its elasticity. These proteins decline as we age,

along with the fibroblast cells that manufacture them. In

addition, the enzymes that break down collagen and

elastin increase.

Other changes occur in keratinocytes, upper-layer skin

cells that are shed and renewed regularly. In the normal

aging process the turnover of keratinocytes slows down

and in photoaging they are damaged. Still other skin cells,

called melanocytes, are also affected by both processes: they

decline with normal aging and are killed in photoaging. (Stopped in

their tracks by sunlight, these normally migratory cells show up as

freckles in light skin.)

What we don’t know yet is exactly how photoaging damages

cells. Ultraviolet light can damage DNA and could be the culprit.

Free radicals could be involved in some way. Researchers continue

to explore these and other factors in the effort to understand

photoaging.

Research on Sunlight May Help Explain

What Happens to Skin as We Age

kidney function (nephropathy), and age-related neurological disorders including

Alzheimer’s disease.

These conditions appear

at younger ages in people

with diabetes, who have

high glucose levels (hyperglycemia). Glycosylated

hemoglobin in red blood

cells, for instance, is an

important marker doctors

use to measure hyperglycemia. While the physiological effects of glycosylated

hemoglobin are unclear,

the disease it helps doctors

detect—diabetes—is sometimes considered an accelerated model of aging. Not

only do the complications

of diabetes mimic the

physiologic changes that

can accompany old age, but

people with this condition

have shorter-than-average

life expectancies. As a result,

much research on crosslinking has focused on its

relationship to diabetes as

well as aging.

Crosslinks, also known as

advanced glycation end

products (AGEs), seem to

“stiffen” tissues and may

cause some of the deterioration associated with aging.

Collagen, for instance, the

most common protein molecule in our bodies, forms the

connective tissue that provides structure and support

for organs and joints. When

glucose binds with collagen—as it tends to do as we

age—this normally supple

protein loses much of its

flexibility. As a result, lungs,

arteries, tendons, and other

tissues stiffen and become

less efficient. In the circulatory system, AGEs may help

trap LDL (the so-called

“bad”) cholesterol in artery

walls, and thus contribute to

the development of atherosclerosis. They also have

been linked to clouded

lenses (cataracts), reduced

21

Aging Under the Microscope
Werner’s

Syndrome

WS patient age 14

WS patient age 48

Genetic defects are believed to be

responsible for Werner’s syndrome

(WS), a disease in which people at a

young chronological age develop some

characteristics associated with aging,

such as gray hair, wrinkled skin,

diabetes, heart disease, and cancer.

Because of the apparent acceleration

of aging in WS, gerontologists are delving into its causes, hoping to shed light

on the disease and the degenerative

processes that occur with normal aging.

Macrophages, such as the one shown

here, recognize foreign bodies such as

bacteria, or altered molecules such as

crosslinked proteins, and remove

them from circulation.

gradually accumulates, leads

to malfunctioning genes,

proteins, cells, and, as the

years go by, deteriorating

tissues and organs.

Not surprisingly, numerous enzyme systems in the

cell have evolved to detect

and repair damaged DNA.

For repair, transcription,

and replication to occur, the

double-helical structure that

makes up DNA must be partially unwound. Enzymes

called helicases do the

unwinding. Investigators

have found that people who

have Werner’s syndrome

(WS), a rare disease with

several features of premature

aging, have a defect in one

of their helicases. George

Martin, M.D., of the University of Washington and other

investigators are exploring

the mechanisms involved

in DNA repair in WS and

crosslinking may play a role

in damage to DNA, which is

another important focus for

research on aging.

DNA Repair

and Synthesis

In the normal wear and tear

of cellular life, DNA undergoes continual damage.

Attacked by oxygen radicals,

ultraviolet light, and other

toxic agents, it suffers damage in the form of deletions,

or deleted sections, and

mutations, or changes in the

sequence of DNA bases that

make up the genetic code.

In addition, sometimes the

DNA replication machinery

makes an error.

Biologists theorize that

this DNA damage, which

Why this happens is not

known, but immunologists

are beginning to learn more

about how the immune system affects, and is affected

by aging (See The Immune

System, page 31). And in

the meantime, diabetes

researchers are investigating

drugs that could supplement

the body’s natural defenses

by blocking AGEs formation.

Crosslinking interests

gerontologists for several

reasons. It is associated with

disorders that are common

among older people, such as

diabetes and heart disease;

it progresses with age; and

AGEs are potential targets

for drugs. In addition,

Just as the body has

antioxidants to fight freeradical damage, it has other

guardians, immune cells

called macrophages, which

combat glycation. Macrophages with special receptors for AGEs seek out and

engulf them. Once AGEs

are broken down, they are

ejected into the blood stream

where they are filtered out

by the kidneys and eliminated in urine.

The only apparent

drawback to this defense

system is that it is not complete and levels of AGEs

increase steadily with age.

One reason is that kidney

function tends to decline

with advancing age. Another

is that macrophages, like

certain other components

of the immune system,

become less active.

22

Biochemistry and Aging
DNA, the double helix cellular molecule that contains thousands of genes

necessary for life, is constantly being damaged and repaired. Gerontologists

suspect DNA repair mechanisms become less efficient with age. Accumulating

DNA damage, including breaks in its structure or changes in its nucleotide

sequences, can lead to some of the physical changes we associate with aging.

production, and cells have

hundreds of them. Investigators suspect mitochondrial

DNA is injured at a much

greater rate than nuclear

DNA, possibly because the

mitochondria produce a

stream of damaging oxygen

radicals during metabolism.

Adding to its vulnerability,

mitochondrial DNA is

unprotected by the protein

coat that helps shield DNA

in the nucleus from damage.

Research has shown

that mitochondrial DNA

damage increases exponentially with age, and as a

result, energy production

in cells diminishes over time.

These changes may cause

declines in physiological

performance, and may play

a role in the development

bility to cancer. If DNA

repair processes decline with

age while damage accumulates as scientists hypothesize, it could help explain

why cancer is more common

among older people.

Gerontologists who

study DNA damage and

repair have begun to uncover

numerous complexities. Even

within a single organism,

repair rates can vary among

cells, with the most efficient

repair going on in germ

(sperm and egg) cells.

Moreover, certain genes are

repaired more quickly than

others, including those that

regulate cell proliferation.

Especially intriguing

is repair to a kind of DNA

that resides not in the cell’s

nucleus but in its mitochondria. These small organelles

are the principal sites of

metabolism and energy

similar disorders, collectively

known as progeroid syndromes. This research could

help explain why DNA repair

becomes less efficient during

normal human aging.

The repair process

interests gerontologists for

many reasons. It is known

that an animal’s ability to

repair certain types of DNA

damage is directly related

to the lifespan of its species.

Humans repair DNA, for

example, more quickly and

efficiently than mice or other

animals with shorter lifespans. This suggests that

DNA damage and repair

are in some way part of

the aging puzzle.

In addition, researchers

have found defects in DNA

repair in people with a

genetic or familial suscepti23

Aging Under the Microscope

The remarkable increase in our

life span during the 20th Century

has been due, in large part to the

contributions of basic biomedical

research...In the 21st Century,

the advances in these basic

sciences should lead to effective

treatments of diseases of our

aging population.”

—Julius Axelrod, Ph.D.

1970 Nobel Laureate in Medicine

“
Unstressed Adult

of a heat shock protein designated HSP-70 than young

animals under similar stress.

Moreover, in laboratory cultures of cells, researchers

have found a striking decline

in HSP-70 production as

cells approach senescence.

Exactly what role HSPs

play in the aging process

is not yet clear. They are

known to help cells dismantle and dispose of damaged

proteins. They also facilitate

the making and transport

of new proteins. But what

proteins are involved and

how they relate to aging is

still the subject of speculation and study.

While at the NIA, Nikki

Holbrook, Ph.D., and other

researchers investigated the

plants, bacteria, worms,

mice, and yes, humans.

Today, the role of these

substances, known as heat

shock proteins, in the aging

process is under scrutiny.

Despite their name,

heat shock proteins (HSPs)

are produced when cells are

exposed to various stresses,

not only heat. Their expression can be triggered by

exposure to toxic substances

such as heavy metals and

chemicals and even by

behavioral and psychological stress.

What attracts aging

researchers to HSPs is the

finding that the levels at

which they are produced

depend on age. Old animals

placed under stress—shortterm, physical restraint, for

example—have lower levels

of age-related diseases.

Investigators are examining

how much mitochondrial

DNA damage occurs in specific parts of the body such

as the brain, what causes

the damage, and whether

it can be prevented.

Heat Shock Proteins

In the early 1960s, investigators noticed fruit flies did

something unusual. When

these insects were exposed

to a burst of heat, they produced proteins that helped

their cells survive the temperature change. Intrigued,

researchers looked for these

proteins in other animals,

and found them in virtually

every living thing including

24

Biochemistry and Aging

In certain circumstances, plants and

animals produce heat shock proteins

(HSPs). These proteins are believed

to have an important role in helping

cells respond to stress. The dark areas

in these illustrations show increased

expression of HSPs in short term, physically restrained rats. With age, genetic

expression of these proteins diminishes.

Heat Shock

Proteins

action of HSP-70 in specific

sites, such as the adrenal

cortex (the outer layer of the

adrenal gland). In this gland

as well as in blood vessels

and possibly other sites,

the expression of HSP-70

appears closely related

to hormones released in

response to stress, such

as the glucocorticoids and

catecholamines. Eventually,

answers to the puzzle of

HSPs may throw light on

some parts of the neuroendocrine system, whose

hormones and growth

factors might have an

important influence on

the aging process.

Plants Bacteria Worms Mice Humans

Since they were first discovered

in fruit flies, heat shock proteins

have been found in virtually

every living thing.

In the Aorta

Stressed Adult

Unstressed Aged

Stressed Aged

In the

Adrenal Gland
Testosterone

Estrogen

hot flashes, long-term use of

these hormones may increase

risk for several major agerelated diseases in some

women, especially when

treatment is started years

after menopause. The finding

that levels of testosterone in

men decreased with aging

raised the question of whether

they too might benefit from

sex hormone treatment.

As a result of these

preliminary observational

findings, the NIA launched a

series of research initiatives

to clarify what influence

hormone replacement therapy

might have on the aging

process. So far, most of these

studies have been inconclusive, but have led many

investigators to question

whether the risks of hormone

replacement may outweigh

increased their lean body

(and presumably muscle)

mass, reduced excess fat,

and thickened skin. When

the injections stopped, these

changes reversed, and the

signs of aging returned.

What the men were taking

was recombinant human

growth hormone (hGH),

a synthetic version of the

hormone that is produced

in the pituitary gland and

plays a critical part in normal childhood growth and

development. At the same

time, evidence was accumulating that menopausal hormone therapy with estrogen

(alone or in combination

with a progestin in women

with a uterus) could benefit

postmenopausal women by

reducing cardiovascular disease, colon cancer, and other

diseases of aging. Further

studies have indicated that,

although estrogen remains

an effective way to control

and immune function.

These glands, including the

pituitary, thyroid, adrenal,

ovaries, and testes, release

various hormones into the

body as needed.

As we age, production

of certain hormones, such

as testosterone and estrogen,

tends to decrease. Hormones

with less familiar names,

like melatonin and dehydroepiandrosterone (DHEA)

are also not as abundant in

older people as in younger

adults. But what influence, if

any, these natural hormonal

declines have on the aging

process is unclear.

Hormone

Replacement

In the late 1980s, at Veterans

Administration hospitals in

Milwaukee and Chicago,

12 men age 60 and older

began receiving injections

three times a week that

dramatically reversed some

signs of aging. The injections

25

Aging Under the Microscope

Hormones

Hormones are powerful

chemicals that help keep our

bodies working normally.

Made by specialized groups

of cells called glands, hormones stimulate, regulate,

and control the function of

various tissues and organs.

They are involved in virtually every biological process

including sexual reproduction, growth, metabolism,

In this colored transmission

electron micrograph, growth

hormone granules (brown)

are visible in the cytoplasm

(yellow) of a growth-hormone

secreting endocrine cell from

the pituitary gland. Visible cell

organelles 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 (image

above). 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 menopausal 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 muscle and bone strength. It is released through the action ofanother 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 arebeing studied for their potential to strengthen muscle andbones and prevent frailty among older people. For now,however, there is no convincing evidence that takinggrowth hormone will improve the health of those who donot 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 thebody. Current research does indicate that melatonin in lowdosages may help some older individuals with their sleep.However, it is recommended that a physician knowledgeable in sleep medicine be consulted before self-medication.Claims that melatonin can slow or reverse aging are farfrom proven. continued >>

Hormones and Research on Aging

Produced 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.

26

Biochemistry and Aging
TERONE 

> In men, testosterone (image 

s produced in the testes (women also produce 

ounts of this hormone). Production peaks in early 

hood. However, the range of normal testosterone

uction is vast. So while there are some declines in

osterone production with age, most older men stay

 within normal limits. The NIA is investigating the

 of testosterone supplementation in delaying or

venting frailty. Preliminary results have been 

clusive, and it remains unclear if supplementation 

s hormone can sharpen memory or help men 

tain stout muscles, sturdy bones, and robust 

al activity. Investigators are also looking at its 

e effects, which may include an increased risk of

rtain cancers, particularly prostate cancer. A small

e of men with profound deficiencies may be helped

ption testosterone supplements. 

Short for dehydroepiandrosterone, DHEA is pro

he adrenal glands. It is a precursor to some other

 including testosterone and estrogen. Production

he mid-20s, and gradually declines with age. What

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

Investigators are working to find more definite

bout DHEA’s effects on aging, muscles, and the

ystem. DHEA supplements, even when taken briefly,

 liver damage and have other detrimental effects

dy.

mones and Research

Estrogen is perhaps the

most well studied of all hormones. Yet results from theWomen’s Health Initiative(WHI), the first majorplacebo-controlled, randomized clinical trial of estrogentherapy with or withoutprogestin to prevent somechronic diseases of aging,surprised the medical community. 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

postmenopausal

women using

estrogen alone,

there were

more cases

of 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 production live substantially longerthan normal mice, whilemice overproducing growthhormone live shorter thanaverage lives. This findingsuggests that even if hGHreplacement therapy is initially beneficial, ultimately itmay be harmful and actuallymight curtail longevity.

Similarly, there is scant

evidence that testosteronesupplementation has anypositive impact in healthyolder men. In fact, somestudies suggest supplementation might trigger excessivered blood cell production insome men. This can increasea man’s risk of stroke. 
action of growth hormone

also 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 complexities 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 important role in longevity determination. In nematodes, forinstance, mutations in atleast two genes in the IGF-Ipathway result in extendedlifespan.

The mechanisms—how

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

Consider growth 

hormone. It begins by 

n

r

ne

se

n

s

28

Biochemistry 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. 
Clues

We 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 measures

of physiological aging. In 

theory, these biomarkers

would be more precise 

indicators of aging than

chronological age itself. 

Once established, these 

biomarkers could make it

easier to study normal aging,

diseases, and possible interventions. So far, however, 

no such biomarkers have

been identified in humans. 

Normal Aging

Unlike most of us, Satchel

Paige was never quite sure 

of his birth year. “My birth

certificate was in our (family) Bible, and the goat ate

the Bible,” he said. But even

had he known his chronological age, it may not have

shed much light on how 

old he was physiologically.

In fact, gerontologists are

discovering that age in years

doesn’t necessarily correlate

with physiological age. 

For decades, investigators at the NIA have compiled data on heart function,

lung capacity, and numerous

other bodily functions in

hopes that this information

may one day be used to

Chronic diseases and disability were once thought inseparable from old age. This

view is changing rapidly as

one disease after another

joins the ranks of those that

can be prevented or at least

controlled, often through

changes in lifestyle.

We now know, for example, that most people can

avoid lung disease by not

smoking. And heart disease

and stroke rates have fallen

at the same time that Americans have lowered their fat

consumption, begun to exercise more, and quit smoking.

So if chronic disease is

not intrinsic to the aging

process, as many gerontologists now believe, then what

is? Are there universal or

“normal” aging processes?

30

Physiologic Clues

ow old would you be if you

didn’t know how old you were?”

—Leroy “Satchel” Paige

Member, Baseball Hall of Fame. The oldest person to pitch 

in the major leagues—he was in his late 50s.

“
Scientists have long known

that these defenses decline

with age; now, some of the

underlying mechanisms are

coming to light.

A multiplicity of cells,

substances, and organs make

up the immune system. The

thymus, spleen, tonsils, bone

marrow, and lymphatic system, for example, produce,

store, and transport a host 

of cells and substances—

B-lymphocytes and T-lymphocytes, antibodies, interleukins, and interferon, to

name a few. Several are of

special interest to gerontologists. These include the class

of white blood cells called

lymphocytes, which fight

invading bacteria and other

foreign cells.

Although this diversity

lessens the likelihood of 

finding biomarkers of aging

in humans, the quest for

these indicators has yielded

many insights into the 

physiology of two organ 

systems that may have

important roles in the aging

process. One of these is 

the endocrine system (See 

Hormones and Research 

on Aging, page 26). The

other is the immune system.

The Immune System

When Shigechiyo Izumi of

Japan contracted pneumonia

and died in 1986 at the

reputed age of 120, it was 

his immune system that

failed. One of the many 

bacteria or viruses that 

cause pneumonia broke

through the elaborate, natural defenses that protect

humans from infection. 

In fact, normal 

physiological aging is 

quite variable, according 

to investigators involved in

the Baltimore Longitudinal

Study of Aging, a long-term

NIA study begun in 1958 that

has tracked the lives of more

than 1,000 people from age

20 to 90 and beyond. Not

only do individuals age overall at vastly different rates, 

it is quite likely that agerelated changes in various

cells, tissues, and organs 

differ as well. For instance,

kidney function may decline

more rapidly in some individuals. In others, bone

strength may diminish faster.

The organs that age fastest in

one person may not age as

rapidly in another. This suggests that genes, lifestyle, and

disease can all affect the rate

of aging and that several distinct processes are involved.

31

Aging Under the Microscope

In the Baltimore Longitudinal Study of

Aging (BLSA), volunteers, age 20 to 90,

are screened every 2 years for physiological and psychological changes. They

undergo a complete physical exam and a

series of tests including muscle strength

(shown), bone density, aerobic capacity,

and glucose tolerance. Each assessment

adds 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 blood

cells—lymphocytes—are key operatives of 

this system. With age, these cells become less

active, making the body more vulnerable to 

bacteria, viruses and other pathogens. 
Physiologic Clues

32

What is Normal Aging?

HEART > Heart muscle thickens with age. Maximal

oxygen consumption during exercise declines in men

by about 10 percent with each decade of adult life and

in women by about 7.5 percent. This decline occurs

because the heart’s maximum pumping rate and the

body’s ability to extract oxygen from blood both

diminish 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 elastic

arteries.

LUNGS > Maximum breathing (vital) capacity may

decline by about 40 percent between the ages of 

20 and 70.

BRAIN > With age, the brain loses some of the

structures (axons) that connect nerve cells (neurons)

to each other, although the actual number of neurons

seems to be less affected. The ability of individual

neurons to function may diminish with age. Recent

studies indicate that the adult nervous system is 

capable of producing new neurons, but the exact 

conditions that are critical for this have yet to be

determined.

KIDNEYS > Kidneys gradually become less 

efficient at extracting wastes from the blood. 

BLADDER > Bladder capacity declines. Urinary

incontinence, 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 one

person, organs and organ systems show different rates of decline.

However, some generalities can be made, based on data from the

Baltimore Longitudinal Study of Aging. 

continued >>
continued >> What is Normal Aging?

BODY FAT > Typically, body fat gradually

increases in adulthood until individuals reach middle

age. Then it usually stabilizes until late life, when

body weight tends to decline. As weight falls, older

individuals tend to lose both muscle and body fat.

With age, fat is redistributed in the body, shifting

from just beneath the skin to deeper organs. Women

typically have a higher percentage of body fat than

men. However, because of differences in how this fat

is distributed—on the hips and thighs in women and

on the abdomen in men—women may be less susceptible to certain conditions including heart disease.

MUSCLES > Without exercise, estimated

muscle mass declines 22 percent for women

and 23 percent for men between the ages of

30 and 70. Exercise can slow this rate of loss.

BONES > Bone mineral is lost and replaced

throughout life; loss begins to outstrip replacement around age 35. This loss accelerates in

women at menopause. Regular weight bearing

exercise—walking, running, strength training—

can slow bone loss.

SIGHT > Difficulty focusing close up may begin in

the 40s; the ability to distinguish fine details may

begin to decline in the 70s. From 50 on, there is

increased 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 hear

higher frequencies with age. Even older individuals

who have good hearing thresholds may experience

difficulty in understanding speech, especially in situations where there is background noise. Hearing

declines more quickly in men than in women.

PERSONALITY > Personality is extraordinarily

stable 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 lifealtering 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 disillusioned

and develop a sullen disposition. But these out-ofcharacter reversals of personality are relatively rare.

33

Aging Under the Microscope
Most research on the

aging immune system now

centers on these cells. One

group of T-cell products,

interleukins, is found at 

different levels as people

age. The interleukins—there

are more than 20 identified

so far—serve as messengers,

relaying signals that regulate

the immune response. Some,

like interleukin-6, rise with

age, and it is speculated that

they interfere in some way

with the immune response.

Others, like interleukin-2,

which stimulates T-cell proliferation, tend to fall with

age. Gerontologists study 

the interleukins, not only 

for clues to the mechanisms

of aging, but also for their

potential in the detection

and treatment of immune

problems.

Meanwhile, compelling

evidence suggests one intervention—caloric restriction—

may counteract some of 

the natural declines in the

powerful chemicals, called

lymphokines, that mobilize

other immune system 

substances and cells. 

T-cells and their lymphokine products have

intrigued gerontologists 

ever since it was learned 

that T-cells—or more precisely the functioning population of T-cells—declines

with age. While the number

of T-cells remains about the

same, the proportion of them

that proliferate and function

declines. Studies have also

shown that in older people,

T-cells destroyed by stresses

such as irradiation or cancer

chemotherapy take longer 

to renew than they do in

younger people.

Lymphocytes fall into

two major classes: B-cells

and T-cells. B-cells mature in

the bone marrow, and one of

their functions is to secrete

antibodies in response to

infectious agents or antigens.

T-cells develop in the thymus, which shrinks in size as

people age; they are divided

into cytotoxic T-cells and

helper T-cells. Cytotoxic 

T-cells attack infected or

damaged cells directly.

Helper T-cells produce 

Feeding animals 30 to 40 percent

fewer calories than normal appears

to delay age-related degeneration 

of nearly every physiological system.

But it remains uncertain whether

caloric restriction could have the

same effect in humans.

immune system as well 

as in other physiological 

systems of aging animals.

Caloric Restriction

An inventor, statesman,

diplomat, and scientist, 

Benjamin Franklin was a true

Renaissance man renowned

for his sage advice. Among

his many pearls of wisdom:

“To lengthen thy life, lessen

thy meals.” Nearly 275 

years later, gerontologists 

are finding those words may

turn out to be amazingly

prophetic. 

Since the 1930s, investigators have consistently

found that laboratory rats 

and mice live up to 40 percent

longer than usual when fed 

a diet that has at least 30 percent fewer calories than they

would normally consume.

The animals that eat this

nutritionally balanced diet,

which provides healthful

34

Physiologic 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 System

3

2

3

1

4

5

7

6

“

To lengthen thy life, lessen thy meals.” 

—Benjamin Franklin, (1706-1790)

8
However, whether caloric

restriction might have the

same effect in primates

remains a major question. 

In studies underway at NIA,

rhesus and squirrel monkeys

are growing up on a calorically restricted diet. Similar

studies are also ongoing at

the University of Wisconsin

and the University of Maryland. Preliminary results 

from these studies show 

some promising early signs of

improved health—including

greater resistance to diabetes

and heart disease—in these

primates as they age. (See

The Next Step: Caloric

Restriction in Primates, 

page 36).

Many gerontologists 

are particularly intrigued 

by findings suggesting that

animals on calorie restricted

diets have reduced rates of

disease. In one of the largest

studies to date, Roderick

Bronson, D.V.M., at Tufts

University found that caloric

restriction not only extended

lifespan in mice, but also

prevented or slowed down

development of every disease and all types of tumors.

Other rodent studies have

found that caloric restriction

may increase resistance 

of neurons in the brain to

dysfunction and death.

These results, described 

as “stunning” by gerontologists, have raised hope

that further study of caloric

restriction will help uncover

the mechanisms responsible

for disease in old age.

reduce oxidative damage 

to cells. Calorie restricted

animals also have less 

glucose circulating in their

blood than their freely feeding counterparts. This may

lessen the potential for 

protein crosslinking, a biochemical process implicated

in cellular aging. And

because caloric restriction

lowers body temperature

slightly, cells may sustain

less genetic damage than at

normal body temperature. In

addition, scientists speculate

that caloric restriction preserves the capacity of cells 

to proliferate, and that it

keeps the immune system

functioning at youthful 

levels. Caloric restriction 

also may work through 

other mechanisms. It may,

for instance, influence hormonal balance, cell senescence, or gene expression.

Or, it might work through 

a combination of all of 

these mechanisms, plus

other factors.

amounts of protein, fat, and

vitamins and minerals, also

appear to be more resistant to

age-related diseases. In fact,

caloric restriction appears to

delay normal age-related

degeneration of almost all

physiological systems. And

so far, caloric restriction has

increased the lifespans of

nearly every animal species

studied including protozoa,

fruit flies, mice, and other

laboratory animals. Now

investigators are exploring

whether and how caloric

restriction will affect aging 

in monkeys and other nonhuman primates, our closest

relatives in the animal 

kingdom.

Why calorically

restricted animals live 

far beyond their normal 

lifespans remains unclear.

Because cutting down on

calories slows metabolism,

and free radicals are byproducts of metabolism,

caloric restriction may

35

Aging Under the Microscope

In the 1930s, investigators discovered

that rats and mice fed fewer calories

lived longer than rodents allowed to eat

as much as they liked. Since then, caloric

restriction has increased the lifespan of

nearly every animal species studied.

Data from animal studies suggests

caloric restriction may help neurons

resist dysfunction and death (top).

Caloric restriction also might help

the body fend off cancer (center),

and other age-related cellular

changes (bottom).
36

Physiologic Clues

The Next Step: Caloric Restriction in Primates

At the NIH Animal Center in Poolesville, Maryland,

about 75 rhesus and squirrel monkeys are on diets;

they eat 30 percent less than they would normally

but get all the necessary nutrients. Another 75 monkeys, the control group, are eating as much as they

want. The differences between the two groups, as

they age, are beginning to provide insights into how

caloric restriction influences lifespan.

The monkeys that arrived at the Poolesville laboratory in 1987 have responded to caloric restriction as

expected; their maturation, measured by factors

such 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 seen

in 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 Center

in Baltimore, where the project is coordinated, are

monitoring dozens of signs of aging, ranging from

immune response to activity level to antioxidant 

levels to fingernail growth. The measurements are

being compared with those of the monkeys in the

control group and should provide leads to some of

the mechanisms at work in caloric restriction.

The monkeys on the restricted diet are smaller and

weigh about 20 percent less than monkeys in the

control group. However, the calorically restricted

monkeys are no less physically active than animals

allowed to eat at will. 

So far, some positive trends have been detected,

including the possibility of reduced incidence of

heart disease and cancer in the calorically

restricted monkeys. But it is important to

keep in mind that these data are preliminary, and investigators caution

that it may be many more years

before it can be determined if

caloric restriction does indeed

improve the health and extend

the lifespan of aging primates.
Regular physical activity may be the most

important thing an older person can do

to stay healthy and self-reliant. In

fact, the more exercise you can do

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

Studies suggest regular, sustained exercise can help

prevent or delay some diseases and disabilities as

people grow older. And, in some cases, it can actually

improve some of these conditions in older people

who already have them. In a study conducted at 

Tufts University in Boston, for instance, some people

age 80 and older were able to progress from using

walkers to using canes after doing simple musclebuilding exercises for just 10 weeks. In addition, 

physical activity can improve your mood, lessen your

risk of developing adult-onset diabetes, slow bone

loss, and reduce your risk of heart attack and stroke.

Endurance exercises such as brisk

walking increase your stamina

and improve the health of your

heart, lungs and circulatory system. Strength exercises build

muscles and reduce your risk of

osteoporosis. Balance exercises help

prevent a major cause of disability in

older adults: falls. Flexibility or

stretching exercises help keep your

body limber. As part of a daily

routine, these exercises and

other physical activities 

you enjoy can make a

difference in your life as 

you get older.

For a nominal fee, an exercise book and a 48-minute

companion video are available from NIA. For more

information about the book and video contact: 

NIA Information Center

P.O. Box 8057

Gaithersburg, MD

1-(800)-222-2225

1-(800)-222-4225 TTY

Exercise: It Works at Any Age

Yet even if caloric restriction is successful in primates, 

it is unlikely that most people could maintain a diet 

of 30 percent fewer calories

without drastic and, in all

probability, unpalatable

changes in their eating

habits. For this reason, most

gerontologists doubt that

caloric restriction will ever

become a widespread means

of extending the human lifespan. But investigators are

exploring the question of

whether drugs might mimic

its effects, negating the need

for sweeping alterations in

diet. In rodent and other 

animal studies, gerontologists are testing a number 

of synthetic substances that

37

Aging Under the Microscope
A balanced diet and regular 

exercise can help strengthen bone

and prevent osteoporosis in later

life. 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 a

major cause of fractures

among older people, frequently resulting in disability, and eventually leading to

institutionalization for many.

In some cases, drugs called 

bisphosphonates help by

slowing calcium loss in bone.

example, help reduce the thinning of bones that accompanies aging in almost everyone

but particularly in older

women, many of whom are 

at high risk for osteoporosis.

Researchers are also

studying exercise as a behavioral factor that may have 

an impact on how long 

we live or at least on how

healthy we are in old age. 

One landmark study at Tufts

University in Boston has

shown that exercise can

strengthen muscles, improve

mobility, and reduce frailty

even among 90-year-olds.

Exercises that put weight

on bones, such as jogging,

walking, and weight-lifting,

have been shown to strengthen

them. Researchers, as a result,

are exploring the potential 

age. These include higher

levels of fats or lipids in the

blood, changing levels of

blood sugar and insulin, a

tendency toward obesity,

and increased central body

fat that settles around the

waist and abdomen. These

changes are so prevalent

among older people that

they have been given a

name, syndrome X. Many

gerontologists are studying

the possible relationship

between this syndrome and

cardiovascular diseases.

Syndrome X may be 

preventable through low-fat

and low-cholesterol diets,

but these are not the only

aspects of nutrition that may

influence life expectancy.

Gerontologists have been

scrutinizing a wide range of

nutrients with an eye toward

their role in aging processes.

Calcium and vitamin D, for

38

Physiologic Clues

produce some of the same

effects as caloric restriction,

such as reducing body 

temperature and lowering

the amount of insulin in the

blood. So far, the preliminary

results have been promising.

However, none of these 

substances has yet proved 

to extend lifespan, and some

have potentially toxic side

effects that may make human

use impractical. Still, the

search goes on. Meanwhile, 

it is becoming increasingly

clear that lifestyle—particularly diet and exercise—can

have a powerful influence 

on how people age.

Behavioral Factors

Diet and exercise are thought

to have a major impact on a

constellation of changes that

are common with advancing
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.

of

TheFuture

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.

of

TheFuture

Aging
41

Aging Under the Microscope

Stem Cells: Great Expectations, but Many Barriers Remain

Colorized scanning electron micrograph of

stem cells collected from human bone marrow. Stem cells are primitive cells that can

multiply indefinitely, migrate to different

parts of the body, and develop into different

types of tissue. Bone marrow retains the 

ability to generate stem cells throughout life.

Bone marrow stem cells typically give rise to

bone, blood, and cartilage.

These versatile cells intrigue investigators because

they are capable of transforming themselves

into many different kinds of body tissue.

Because of this flexibility, stem cells hold

enormous potential for cell replacement or

tissue repair in many age-associated degenerative disorders where loss of cells is currently irreversible, including diabetes,

stroke, heart disease, and Alzheimer’s and

Parkinson’s disease. With millions of older

Americans suffering from these conditions,

gerontologists are scrambling to find out if

these 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 heart

cells, which are dedicated to perform a specific function, stem cells are not specialists. But under certain

circumstances, they can differentiate into specialized

cells. Another unique characteristic of stem cells is

their ability to replicate for indefinite periods without

becoming senescent.

Investigators suspect that embryonic stem cells can

develop into almost any of the many known specialized cell types in the body, including bone, blood, and

brain cells. However, these stem cells are not embryos,

and cannot themselves develop into embryos. Adult

stem cells apparently help repair or replace those 

tissues lost through natural attrition, or when they 

are damaged by injury or disease. Adult stem cells in

bone marrow, for instance, regularly replenish the

body’s supply of red blood cells. Similarly, intestinal

stem 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 fully

match embryonic stem cells’ capacity to differentiate

into vast arrays of replacement cells and tissues. In

animal studies, certain adult stem cells have shown

some potential to develop into multiple cell types,

suggesting that both embryonic and adult stem cells

could have therapeutic applications. NIA-supported

investigators who injected adult mouse bone marrow

cells into the circulatory systems of mice, for instance,

discovered that these cells found their way into the

From the moment they were first isolated in the late 1990s, human

stem cells mesmerized gerontologists. And for good reason.
41

Aging Under the Microscope

Stem Cells: Great Expectations, but Many Barriers Remain

Colorized scanning electron micrograph of

stem cells collected from human bone marrow. Stem cells are primitive cells that can

multiply indefinitely, migrate to different

parts of the body, and develop into different

types of tissue. Bone marrow retains the 

ability to generate stem cells throughout life.

Bone marrow stem cells typically give rise to

bone, blood, and cartilage.

These versatile cells intrigue investigators because

they are capable of transforming themselves

into many different kinds of body tissue.

Because of this flexibility, stem cells hold

enormous potential for cell replacement or

tissue repair in many age-associated degenerative disorders where loss of cells is currently irreversible, including diabetes,

stroke, heart disease, and Alzheimer’s and

Parkinson’s disease. With millions of older

Americans suffering from these conditions,

gerontologists are scrambling to find out if

these 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 heart

cells, which are dedicated to perform a specific function, stem cells are not specialists. But under certain

circumstances, they can differentiate into specialized

cells. Another unique characteristic of stem cells is

their ability to replicate for indefinite periods without

becoming senescent.

Investigators suspect that embryonic stem cells can

develop into almost any of the many known specialized cell types in the body, including bone, blood, and

brain cells. However, these stem cells are not embryos,

and cannot themselves develop into embryos. Adult

stem cells apparently help repair or replace those 

tissues lost through natural attrition, or when they 

are damaged by injury or disease. Adult stem cells in

bone marrow, for instance, regularly replenish the

body’s supply of red blood cells. Similarly, intestinal

stem 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 fully

match embryonic stem cells’ capacity to differentiate

into vast arrays of replacement cells and tissues. In

animal studies, certain adult stem cells have shown

some potential to develop into multiple cell types,

suggesting that both embryonic and adult stem cells

could have therapeutic applications. NIA-supported

investigators who injected adult mouse bone marrow

cells into the circulatory systems of mice, for instance,

discovered that these cells found their way into the

From the moment they were first isolated in the late 1990s, human

stem cells mesmerized gerontologists. And for good reason.
Bibliography Glossaryand
DNA—Abbreviation for deoxyribonucleic acid, the molecule

that contains the genetic code for all life forms except for a

few viruses. It consists of two long, twisted chains made up

of nucleotides. Each nucleotide contains one base, one phosphate molecule, and the sugar molecule deoxyribose. The

bases in DNA nucleotides are adenine, thymine, guanine, and

cytosine.

Enyzme—A protein that promotes a specific biochemical reaction in the body without itself being permanently changed or

destroyed. Enzymes, for instance, are involved in blood clotting and initiate the process of breaking down food.

Fibroblast— One of the major cell types found in skin. Scientists utilize human fibroblast cell cultures to study aging at

the cellular level.

Free radicals—Molecules with unpaired electrons that react

readily with other molecules. Oxygen-free radicals, produced

during metabolism, damage cells and may be responsible for

aging in tissues and organs.

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

Gene expression—The process by which the information

contained in the genes is transcribed and translated into proteins. Age-related changes in gene expression may account

for some of the phenomena of aging.

Glycation—A process by which glucose links with proteins

and causes these proteins to bind together. In some circumstances, this can result in “stiffening” of tissues and may lead

to certain complications of diabetes, and perhaps some of the

physiological problems associated with aging.

Amino acid—A chemical building block of proteins. There

are 20 standard amino acids. A protein consists of a specific

sequence of amino acids.

Antioxidants—Compounds that neutralize oxygen radicals.

Some are enzymes like superoxide dismutase (SOD) and

catalase, while others are nutrients such as vitamin C.

Anti-proliferative genes—Genes that inhibit cell division or

proliferation. 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 aging

process. 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 laboratory settings, the lifespans of animals have been extended

by reducing calories while maintaining the necessary levels

of nutrients.

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

Chromosome—A cellular structure containing genes. Chromosomes are composed of DNA and proteins. Humans have

23 pairs of chromosomes in each body cell, one of each pair

from the mother and the other from the father.

Cytokines—Proteins that are secreted by cells and regulate

the behavior of other cells by binding to receptors on their

surfaces. This binding triggers a variety of responses,

depending on the nature of the cytokine and the target cell.

44

Glossary and Bibliography
Nucleotide—A building block of DNA or RNA. It includes

one base, one phosphate molecule, and one sugar molecule

(deoxyribose in DNA, ribose in RNA).

Photoaging—The process initiated by sunlight through

which the skin becomes drier and loses elasticity. Photoaging

is being studied for clues to aging because it has the same

effect as normal aging on certain skin cells.

Proliferative genes—Genes that promote cell division or

proliferation. These genes can act as oncogenes (genes that

promote cancer growth).

Proteins—Molecules composed of amino acids arranged in a

specific order determined by the DNA sequence of the gene.

Proteins are essential for all life processes. Certain ones, such

as the enzymes that protect against free radicals and the lymphokines, produced in the immune system, are being studied

extensively by gerontologists.

Replicative senescence—The stage at which a cell has permanently stopped dividing.

RNA—Abbreviation for ribonucleic acid, the molecule that

carries out DNA’s instructions for making proteins. It consists of one long chain made up of nucleotides. There are

three main types of RNA: messenger RNA, transfer RNA,

and ribosomal RNA. 

Telomeres—Repeated short DNA sequences occurring at the

end of the chromosomes; telomeres shorten each time a cell

divides.

Tumor suppressor genes—Genes that inhibit cell division or

proliferation.

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 significant

role in normal aging or age-related disorders.

Interleukins—A type of cytokine involved in regulation of

immune function. The levels of some interleukins present in

the body are reported to change with age, but it is unclear

whether these fluctuations are due to aging itself or are a

manifestation of the many conditions and diseases associated

with aging.

Lymphocytes—Small white blood cells that are important to

the immune system. A decline in lymphocyte function with

advancing age is being studied for insights into aging and

disease.

Maximum lifespan—The greatest age reached by any member of a given species.

Mean lifespan—The average number of years that members

of a species live; also known as life expectancy.

Mitochondria—Cell organelles that metabolize glucose and

other sugars to produce biochemical energy. Mitochondria

also contain DNA, which is damaged by the high level of 

free radicals produced during this process.

Mitosis—The process of replicating DNA, and dividing it

into two equal parts to generate two identical “daughter”

cells from one “mother” cell.

45

Aging Under the Microscope
The Genetic Connection

Selected Readings

Blackburn, E.H., “Telomere States and Cell Fates,” Nature

408(6808):53-56, 2000.

Sprott, R.L, and Pereira-Smith, O.M. eds., “The Genetics of

Aging,” 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 Cancer

in Aging Telomerase-Deficient Mice,” Cell, 965: 701-12, 1999.

Hodes, R.J., McCormick, A.M., and Pruzan, M., “Longevity

Assurance Genes: How Do They Influence Aging and Lifespan,” Journal of the American Geriatrics Society, 448:988-991, 1996.

Rubin, H., “Cell Aging In Vivo and In Vitro,” Mechanisms of

Aging and Development, 981:1-35, 1997.

Perls, T., et al., “Exceptional Familial Clustering for Extreme

Longevity in Humans,” Journal of the American Geriatrics

Society, 48(11):1483-1485, 2000.

Harley, C.B., Futcher, A.B., and Greider, C.W., “Telomeres

Shorten During Aging of Human Fibroblasts,” Nature 345:458-

460, 1990.

Posing Questions, Finding Answers

Selected Readings

Clark,W.R., A Means to an End: The Biological Basis of Aging and

Death, New York: Oxford University Press, 2002.

Ricklefs, R.E., and Finch, C.E., Aging: A Natural History, New

York: W.H. Freeman and Company, 1995.

Austad, S.N., Why We Age: What Science Is Discovering about the

Body’s Journey Through Life, New York: John Wiley & Sons, 1997.

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

Press, 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 National

Research Agenda on Aging, Washington, DC: National Academy

Press, 1991.

Martin, G.R., Baker, G.T., “Aging and the Aged: Theories of

Aging 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.

46

Glossary and Bibliography
Tower, J., “Transgenic Methods for Increasing Drosophila Life

Span,” Mechanisms of Aging and Development 118(1-2):1-14, 2000.

Melov, S., et al., “Extension of Life-Span with Superoxide Dismutase/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 PostMitotic Cells,” in Gilchrest, B.A., and Bohr, V.A., eds., The Role

of DNA Damage and Repair in Cell Aging, New York: Elsevier

Science, 2001.

Ames, B.N., “Endogenous DNA Damage as Related to Nutrition 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 Adrenal

Cortex: 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 Responses

by 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 Research

25:585-621, 1961.

Jazwinski, S.M., “Genes of Youth: Genetics of Aging in Baker’s

Yeast,” ASM News 59:172-178, 1993.

Johnson, T.E., “Aging Can Be Genetically Dissected 

into Component Processes Using Long-Lived Lines of

Caenorhabditis elegans,” Proceedings of the National Academy of

Sciences 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 National

Academy of Sciences 85:6042-6046, 1988.

Rose, M.R., “Laboratory Evolution of Postponed Senescence in

Drosophila Melanogaster,” Evolution 38:1004-1010, 1984.

Biochemistry and Aging

Selected Readings

Finkel, T., and Holbrook, N.J., “Oxidants, Oxidative Stress and

the Biology of Aging,” Nature 408(6809):239-247, 2000.

Beckman, K.B., and Ames, B.N., “The Free Radical Theory of

Aging 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

Aging Under the Microscope
Fiatarone, M.A., and Marks, E.C., et al., “High-Intensity

Strength Training in Nonagenarians,” Journal of the American

Medical 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 the

Rate of Aging,” in Goldberg, I., ed., Functional Foods, New

York: 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, Series

P95/01-1, An Aging World: 2001, U.S. Government Printing

Office, 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 and

Human Services, June 2001. http://www.nih.gov/news/

stemcell/scireport.htm 

Rudman, D., Feller, A.G., Nagraj, H.S., et al., “Effects of

Human 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 Aging

and Degenerative Diseases?” Science 256:628-632, 1992.

Physiologic Clues

Selected Readings

Biomarkers of Aging: From Primitive Organisms to Man, 

Workshop Report, International Longevity Center, 2001.

The Aging Factor in Health and Disease, Workshop Report, International Longevity Center, 1999.

Roth, G.S., Ingram, D.K., and Lane, M.A., “Calorie Restriction

in Primates: Will It Work and How Will We Know?” Journal of

the American Geriatrics Society, 47(7):896-903, 1999.

Mattson, M.P., “Neuroprotective Signaling and the Aging

Brain: Take Away My Food and Let Me Run,” Brain Research

886(1-2):47-53, 2000.

Ramsey, J.J., et al., “Dietary Restriction and Aging in Rhesus

Monkeys: The University of Wisconsin Study,” Experimental

Gerontology 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,” in

Powers, D., Morley, J., and Coe, R., eds., Aging, Immunity, and

Infection, New York: Springer, 1993.

48

Glossary and Bibliography
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 Hayflick

photo, courtesy of Dr. Leonard Hayflick, University of

California, 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

WRITER

Doug Dollemore, Office of Communications and Public

Liaison, National Institute on Aging

DESIGN

Randi L. Wright, Levine & Associates, Inc.,

Washington, D.C.

PHOTOGRAPHY / ILLUSTRATIONS

Cover, 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 from

Growing Old Is Not For Sissies II: Portraits of Senior

Athletes, 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 State

University, 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 of

Dr. 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 Is

Not For Sissies II: Portraits of Senior Athletes, by Etta

Clark, 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 for

Bone 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 Communications

and 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)

“
National Institutes of Health

National Institute on Aging

Office of Communications

and Public Liaison

Building 31, Room 5C27

Bethesda, MD 20892-2292

Phone: 301-496-1752

Website: www.nia.nih.gov

NIH Publication No. 02-2756

June 2006 edition

Originally printed September 2002