BIOLOGY

OF

AGING

Research Today 

for a Healthier 

Tomorrow

NATIONAL INSTITUTE ON AGING NATIONAL INSTITUTES OF HEALTH 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 1

AGING UNDER THE 

MICROSCOPE

4 What is aging?

6 Living long and well: 

Can we do both? Are 

they the same?

9 Is what’s good for 

mice good for men?

GENETICS

13 Is aging in our genes?

14 How can we find aging 

genes in humans?

18 What happens when DNA 

becomes damaged?

METABOLISM

23 Does stress really shorten 

your life?

27 Does how much you eat 

affect how long you live?

IMMUNE SYSTEM

31 Can your immune system 

still defend you as you age?

THE PROMISE OF RESEARCH

35 Past, present, and future

36 GLOSSARY

37 BIBLIOGRAPHY

The National Institute on Aging 

(NIA), part of the National 

Institutes of Health at the 

U.S. Department of Health and 

Human Services, was established 

to help improve the health and 

well-being of older people through 

research. NIA conducts and 

supports research on the medical, 

social, and behavioral aspects 

of aging. This mission is carried 

out through NIA’s Intramural 

Research Program composed 

of staff scientists in Baltimore 

and Bethesda, Maryland, and 

through its Extramural Research 

Program, which funds researchers 

at major institutions across the 

United States and internationally. 

Biology of Aging: Research Today 

for a Healthier Tomorrow describes 

some of NIA’s exciting findings 

about the basic biology of aging 

and points to directions for 

future investigation.

BIOLOGY OF AGING

Research Today for a Healthier Tomorrow
2

PHOTO CREDIT: MARTY KATZ, WWW.MARTYKATZ.COM
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 3

We marvel at the 90-year-old who still 

gets up every day and goes to work. 

And, it is a genuine thrill to celebrate 

a relative’s 100th birthday. Yet our 

feelings about aging are complex. 

We may want to live forever, but who looks 

forward to getting old? We hope we’re vigorous right up until the very end. Still, day-today, many of us make unhealthy choices that 

could put our future at risk. 

From the beginning of time, people 

have tried to understand aging. Almost 

every culture has a mythology to explain it. 

As we grow up, tales of eternal youth pique 

our curiosity. And, it is these musings that 

may provide just the spark needed to ignite 

a budding scientist. There’s the little girl, 

excited to visit her grandmother, who asks 

her parents how someone so spunky and 

fun could be so old. Or, the 3rd grader who, 

after watching in awe as a caterpillar spins 

a cocoon and then days later emerges as a 

butterfly, peppers the teacher with questions 

about this magical transformation. These 

are the types of questions and kinds of experiences that could stimulate a lifelong quest to 

explore what happens as we age.

Since the National Institute on Aging (NIA) 

was established at the National Institutes of 

Health (NIH) in 1974, scientists asking just 

such questions have learned a great deal 

about the processes associated with the 

biology of aging. For scientists who study 

aging—called gerontologists—this is an exciting time. Technology today supports research 

that years ago would have seemed possible 

only in a science fiction novel. And, a scientific 

community that values active collaboration as 

well as individual scientific achievement has 

helped to move research forward faster than 

ever before. 

AGING UNDER THE 

MICROSCOPE
4

Over centuries, theories about aging have 

emerged and faded, but the true nature of the 

aging process is still uncertain. The fact is—

aging is a part of everyone’s life. But the facts 

of aging—what is happening on a biochemical, genetic, and physiological level—remain 

rich for exploration. 

This booklet introduces some key areas of 

research into the biology of aging. Each area 

is a part of a larger field of scientific inquiry. 

You can look at each topic individually, or you 

can step back to see how they fit together in 

a lattice-work, interwoven to help us better 

understand aging processes. Research on aging 

is dynamic, constantly evolving based on new 

discoveries, and so this booklet also keeps an 

open eye on the future, as today’s research 

provides the strongest hints of things to come.

What is aging? 

In the broadest sense, aging reflects all the 

changes that occur over the course of life. 

You grow. You develop. You reach maturity. 

To the young, aging is exciting—it leads to 

later bedtimes and curfews, and more independence. By middle age, another candle 

seems to fill up the top of the birthday cake. 

It’s hard not to notice some harmless cosmetic 

changes like gray hair and wrinkles. Middle 

age also is the time when people begin to 

notice a fair amount of physical decline. 

Even the most athletically fit cannot escape 

these changes. Take marathon runners, for 

example. An NIA-funded study found that 

their record times increased with age—aging

literally slowed down the runners. Although 

some physical decline may be a normal result 

of aging, the reasons for these changes are of 

particular interest to gerontologists. 

Gerontologists look for what distinguishes 

normal aging from disease, as well as explore 

why older adults are increasingly vulnerable 

to disease and disability. They also try to 

understand why these health threats take 

a higher toll on older bodies. Since 1958, 

NIA’s Baltimore Longitudinal Study of Aging 

(BLSA) has been observing and reporting on 

these kinds of questions. As with any longitudinal study, the BLSA repeatedly evaluates 

people over time rather than comparing 

a group of young people to a group of old 

people, as in a cross-sectional study. Using this 

approach, BLSA scientists have observed, for 

example, that people who have no evidence 

of ear problems or noise-induced hearing 

loss still lose some of their hearing with 

age—that’s normal. Using brain scans to learn 

if cognitive changes can be related to structural changes in the brain, BLSA scientists 

discovered that even people who remain 

healthy and maintain good brain function 

late in life lose a significant amount of brain 

volume during normal aging. 

However, some changes that we have long 

thought of as normal aging can be, in fact, 

the signs of a potential disease. Take, for

example, sudden changes in personality. 

A common belief is that people become 

cranky, depressed, and withdrawn as they get 

older. But an analysis of long-term data from 

the BLSA showed that an adult’s personality 

AGING UNDER THE MICROSCOPE
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 5

POSSIBLE PATHWAYS

LEADING TO AGING

To answer questions about why and how we age, some scientists look for mechanisms or 

pathways in the body that lead to aging. Our cells constantly receive cues from both inside and 

outside the body, prompted by such things as injury, infection, stress, or even food. To react and 

adjust to these cues, cells send and receive signals through biological pathways. Some of the 

most common are involved in metabolism, the regulation of genes, and the transmission 

of signals. These pathways may also be important to aging.

DNA

NUCLEUS

CELL

SIGNALS TO OTHER CELLS

SIGNALS ENTERING THE CELL

ILLUSTRATION AND INFORMATION ADAPTED FROM WWW.GENOME.GOV
6

generally does not change much after age 30. 

People who are cheerful and assertive when 

they are younger will likely be the same when 

they are age 80. The BLSA finding suggests 

that significant changes in personality are not 

due to normal aging, but instead may be early 

signs of disease or dementia. 

The rate and progression of cellular aging 

can vary greatly from person to person. But 

generally, over time, aging affects the cells of 

every major organ of the body. Changes can 

start early. Some impact our health and function more seriously than others. For instance, 

around the age of 20, lung tissue starts to lose 

elasticity, and the muscles of the rib cage slowly 

begin to shrink. As a result, the maximum 

amount of air you can inhale decreases. In the 

gut, production of digestive enzymes diminishes, affecting your ability to absorb foods 

properly and maintain a nutritional balance. 

Blood vessels in your heart accumulate 

fatty deposits and lose flexibility to varying 

degrees, resulting in what used to be called 

“hardening of the arteries” or atherosclerosis. 

Over time, women’s vaginal fluid production 

decreases, and sexual tissues atrophy. In men, 

aging decreases sperm production, and the 

prostate can become enlarged. 

Scientists are increasingly successful at 

detailing these age-related differences because 

of studies like the BLSA. Yet studies that 

observe aging do not identify the reasons for 

age-related changes, and, therefore, can only 

go so far toward explaining aging. Questions 

remain at the most basic level about what 

triggers aging in our tissues and cells, why it 

occurs, and what are the biological processes 

underlying these changes. Scientists look 

deep into our cells and the cells of laboratory 

animals to find answers. What they learn today 

about aging at the cellular and molecular 

levels may, ultimately, lead to new and better 

ways to live a longer, healthier life.

Living long and well: Can we 

do both? Are they the same?

You can hardly turn on your computer these 

days without being bombarded with advertisements that pop up trying to convince you 

of the power of a pill that will make you live 

longer or a cream that will help to revive your 

youthful vigor and appearance. The search for 

AGING UNDER THE MICROSCOPE
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 7

ways to stop or reverse the aging process is a 

near-obsession in popular culture. The likelihood of discovering a scientifically proven 

“anti-aging” elixir is slim, but researchers 

believe their work will reveal ways to improve 

a person’s ability to live a longer, healthier 

life. They express these goals in terms of 

“lifespan” and “health span,” respectively.

Lifespan is the length of life for an organism. 

For instance, if you live to age 99, that would 

be your lifespan. Maximal lifespan is the 

maximum number of years of life observed in 

a specific population. It differs from species 

to species. The maximum recorded lifespan 

for humans, reported in 2010, was 122.5 years 

for females and 116 years for males. 

Lifespan is a common measurement in 

aging research. That’s because it is clear-cut 

and easy to measure—an organism is either 

alive or dead. Scientists look for factors such 

as genes, environment, and behavioral traits 

(including diet) that may contribute to an 

organism’s lifespan. Altering a factor to see if 

it changes lifespan can provide evidence about 

whether or not that specific factor is important for aging. For instance, when researchers 

suspect that a specific gene has an effect on 

lifespan, they may test their hypothesis by 

modifying the activity of that gene (perhaps 

lower its activity by deleting the gene or 

increase its activity by adding an extra copy 

of it). If the life of the animal with the modified 

gene activity is longer or shorter, then the gene 

probably does play a role in lifespan. 

Researchers are finding that lifespan 

may be influenced by external factors, as well. 

This has been demonstrated in animal studies. NIA’s Interventions Testing Program (ITP) 

examines a variety of compounds for their 

effects on the lifespan of mice. Compounds 

studied include dietary supplements, 

hormones, and anti-inflammatory drugs. 

In one ITP study, male mice treated with 

aspirin, an anti-inflammatory drug, displayed 

a moderately increased lifespan. In another 

ITP study, masoprocol, an anti-inflammatory 

drug that has antioxidant properties, was 

found to increase longevity of male, but not 

female, mice. These and other findings may 

help scientists identify compounds to test in 

ENVIRONMENT

BEHAVIORAL TRAITS

GENES

FACTORS CONTRIBUTING TO LIFESPAN
8

humans for their effects on aging. While some of the 

compounds tested in the ITP already have a clinical 

use for humans, scientists are clear: These compounds 

should be used only as prescribed and not for lifespan 

extension at this time.

The ability to withstand disease could also be 

central to lifespan. Studies of exceptionally long-lived 

people are helping to establish patterns of health 

decline and increased disease (called morbidity) with 

old age. For example, do health problems start around 

the same age in all people and expand over extra years 

of life for the long-lived, or are the problems delayed, 

occurring closer to the end of life among exceptional 

agers? Evidence from a Danish longitudinal study of 

92- to 100-year-olds found that health problems seem 

to be delayed, appearing closer to the end of life. This is 

not a certain outcome, but in many studies, the average 

centenarian seems to be in better health than the average 80-year-old. However, living to 100 does not mean 

never having any health issues. In the New England 

Centenarian Study, researchers have developed three 

categories for their long-lived participants. They are 

characterized as “survivors,” “delayers,” or “escapers,” 

depending on whether they have survived a life-threatening disease, delayed a serious health problem until much 

later in life, and/or escaped any serious health events. 

Scientists used to think that long life was a good 

indicator of health span, or years of good health and 

function. However, some experiments, particularly in 

mice, demonstrate significant improvements in health, 

without actually increasing lifespan. For example, NIA 

scientists and grantees (that is, scientists at a university 

or other institution whose research is funded by NIA) 

examining the effects of the wine-derived compound 

resveratrol in mice on a normal diet found the 

AGING UNDER THE MICROSCOPE

Most of what we know about factors 

that can contribute to a long lifespan 

and health span is based on research 

in animal models. However, NIAfunded research like the Long Life 

Family Study is taking what we’ve 

learned in animals and seeing if it 

applies to human aging. This study 

is collecting data from families with 

at least two siblings who have lived 

to a very old age in relatively good 

health. Along with asking questions 

about their family and health history, 

the researchers conduct physical 

assessments and health screenings 

and collect a small blood sample 

for genetic tests.  What researchers 

learn about common characteristics 

shared by these families could one 

day be used to guide lifestyle advice 

and medical treatments. 

UNCOVERING FAMILY 

SECRETS TO A LONG LIFE
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 9

compound positively influenced the health of the 

mice—resveratrol-treated mice had better bone health, 

heart function, strength, vision, coordination, and 

cholesterol than the control group. But, resveratrol did 

not increase lifespan. (Lifespan was increased, however, 

in mice on a high-fat diet supplemented with resveratrol.) 

Understanding how to extend health span—apart 

from its impact on longevity—is a growing focus of 

many studies, and for good reason. Imagine a society 

where a majority of people live to be 100, but along with 

the added years comes considerably more physical decline. 

While there is still a place for lifespan research, health 

span research holds promise for revealing ways to delay 

or prevent disease and disability so that we can live 

healthier longer. 

Is what’s good for mice 

good for men? 

A lot of research findings seem to tell us what is good—or 

bad—for yeast, mice, roundworms (C. elegans), or fruit 

flies (Drosophila melanogaster). Does that mean it will 

work for you? Animal models are essential to research 

in the biology of aging. Fruit flies and roundworms, 

along with more complex organisms like mice, rats, and 

nonhuman primates, have many biological mechanisms 

and genes that are similar to humans. They also experience 

many of the same physiological changes (changes in the 

body) with aging. Therefore, these animals can be used as 

models of human aging and human physiology, despite 

the obvious differences in appearance. Scientists can use 

some exploratory approaches (like modifying a gene 

to measure its effects on health or longevity) in animal 

models such as worms, flies, and mice that would not be 

possible in humans. They also can better isolate the variable 

ROUNDWORM

C. elegans

FRUIT FLY

Drosophila melanogaster

MOUSE

Mus musculous

RHESUS MONKEY

Macaca mulatta

ANIMAL MODELS

Here are some animals commonly 

studied in aging research.
10

they want to investigate because animal studies 

are conducted in tightly controlled environments. The animals typically have a very structured daily regimen with limited exposure to 

pollutants, stressors, or other elements that 

could otherwise affect lifespan and health span. 

Different types of studies use different 

animal models. Animal models with a short 

lifespan take less time and fewer resources 

to study from birth to death and to test interventions that might affect the aging process. 

Scientists might favor a fruit fly when studying 

a possible genetic target for an intervention to 

increase longevity, for example, because their 

average lifespan is only 30 days. This allows 

researchers to measure the effects in about a 

month. The roundworm’s 2- to 3-week lifespan 

makes it another ideal model for identifying and 

studying genes that might affect longevity. In a 

landmark study, NIA-funded researchers found 

that reducing the activity of a set of genes, called 

daf, increased roundworm lifespan by three- or 

even fourfold. Daf genes are involved in the 

roundworm’s ability to enter a type of hibernation stage, called diapause, to survive periods of 

food scarcity. This research would not have been 

as feasible if conducted using an animal model 

with an average lifespan of 10 or 20 years. 

After scientists establish a possible intervention in one animal model, they then apply 

the intervention to increasingly complex 

organisms. They might work their way up 

from worms or flies to mice and then to larger 

mammals, such as nonhuman primates. At each 

step, researchers carefully study if the intervention has the same effect on the comparable 

biological pathway. Sometimes it does not. 

Part of the reason might be that while mice, 

for example, have only a slightly larger number 

of genes than worms, and the genes in mice 

and worms serve similar functions, the activity of mouse genes is different and somewhat 

more complex than that of worms. As a result, 

a genetic intervention that increases a worm’s 

lifespan by fourfold might have a significantly 

less impressive effect on a mouse’s lifespan. 

For similar reasons, an intervention might be 

promising in mice, but that does not mean it 

will work the same way or at all in humans. 

Studies in animal models closer to 

humans, such as monkeys or other nonhuman 

primates, can be key to understanding how 

basic discoveries might apply to humans. 

They are essential for pre-clinical studies, 

an intermediary step between research in 

animal models like mice and clinical studies 

in humans. Studies in nonhuman primates, for 

example, have demonstrated to NIA researchers 

how normal age-related changes in the heart 

influence risk of heart disease. They have also 

been important for testing interventions to 

lower risks of heart disease, such as drugs to 

decrease blood vessel stiffness. 

So, if something works to slow aging in 

mice, worms, fruit flies, or monkeys, does 

that mean it will definitely work for you? 

The answer is no. Certainly, data from animal 

studies provide critical insights to the aging 

process and can form the basis for testing 

potential interventions. But direct testing in 

humans is essential before an intervention 

can be considered safe and effective. 

AGING UNDER THE MICROSCOPE
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 11

One approach to aging biology research 

is called “comparative biology.” It involves 

comparing two or more similar species that have 

very different lifespans—one lives much longer 

than the other—to understand how the longerlived species has, as one NIA-funded researcher 

puts it, “exceptional resistance to basic aging 

processes.” Comparative biology studies 

generally focus on species that live at least twice 

as long as their close relatives. 

A few possible theories explain what may be 

taking place among these longer-lived animals:

► They experience a slower rate of 

age-related decline.

► They can survive even when their organs and/or 

systems break down and have minimal function. 

► They are better able to tolerate cellular 

damage or diseases. 

The naked mole rat, a mouse-size rodent 

that lives underground, has been widely used 

in comparative research. It lives approximately 

17 years in the wild and more than 28 years 

in captivity. Its relative, the mouse, lives a 

maximum of 4 years. What accounts for this 

startling difference? Naked mole rats have lower 

metabolic rates and body temperature, meaning 

that they require less energy to survive. They 

have low concentrations of blood glucose (blood 

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

less susceptible to certain diseases. Naked mole 

rats are better able to withstand some types 

of biological stress and, at this point, there has 

never been a case of cancer reported in these 

animals. All these factors and likely others yet to 

be determined contribute to their healthier and 

longer life.

A DIFFERENT APPROACH: COMPARATIVE BIOLOGY 

NAKED MOLE RAT

Lifespan: 17 to 28 years

MOUSE

Lifespan: 4 years

NAKED MOLE RAT PHOTO CREDIT: COURTESY OF THOMAS PARK, PH.D., UNIVERSITY OF ILLINOIS AT CHICAGO
12
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 13

Is aging in our genes? 

You may get your hair color from your 

father’s side of the family and your great 

math skills from your mother. These traits 

are “in the genes,” so to speak. Likewise, 

longevity tends to “run in families”—your 

genetic make-up plays an important role 

in how you age. You can see evidence of 

this genetic connection in families with 

siblings who live into their 90s or families 

that have generation after generation of 

centenarians. These long-lived families are 

the basis for many genetic studies.

Identifying the genes associated with any trait 

is difficult. First, just locating the gene requires 

a detailed understanding of the trait, including 

knowledge of most, if not all, of the contributing 

factors and pathways related to that trait. Second, 

scientists must have clear ways of determining 

whether the gene suspected to have a relationship 

with the trait has a direct, indirect, or even no effect 

on that trait. 

GENETICS
14

Identifying longevity genes is even more 

complex than determining genes for height or 

hair color, for example. Scientists do not know 

all the factors and pathways that contribute 

to longevity, and measuring a gene’s effect on 

long-lived animals, including humans, would 

literally take a lifetime! Instead, scientists 

have identified hundreds of genes that affect 

longevity in short-lived animal models, like 

worms and flies. Not all of these genes promote long life. Sometimes mutating or eliminating a gene increases lifespan, suggesting 

that the normal function of the gene limits 

longevity. Findings in animal models point to 

places for scientists to look for the genes that 

may influence longevity in humans.

How can we find aging 

genes in humans?

The human genetic blueprint, or genome, 

consists of approximately 25,000 genes made 

up of approximately 3 billion letters (base 

pairs) of DNA. Small deviations in the base 

pairs naturally occur about once in every 

1,000 letters of DNA code, generating small 

genetic variants. Scientists are finding that 

some of these variants (polymorphisms) are 

actually associated with particular traits or 

chance of developing a specific disease. People 

with a certain trait, for example, those living 

past age 100, may be more likely to have one 

variant of a gene, while people without the 

same trait may be more likely to have another 

variant. While it is very difficult to prove that 

a gene influences aging in humans, a relationship, or “association,” may be inferred based 

upon whether a genetic variant is found more 

frequently among successful agers, such as 

centenarians, compared with groups of people 

who have an average or short lifespan and 

health span. 

Several approaches are used to identify 

possible genes associated with longevity in 

humans. In the candidate gene approach, 

scientists look for genes in humans that serve 

similar functions in the body as genes already 

associated with aging in animal models, socalled “homologs” or “orthologs” to animal 

genes. For instance, after finding longevity 

genes involved in the insulin/IGF-1 pathway 

of animal models, researchers look for the 

comparable genes in the insulin/IGF-1 pathway of humans. Scientists then determine 

whether the genes are linked to longevity in 

humans by looking to see if a variant of the 

genes is prevalent among people who live 

healthy, long lives but not for people who have 

an average health span and lifespan.

In one NIA-funded project, researchers 

studied 30 genes associated with the insulin/

IGF-1 pathway in humans to see if any variants of those genes were more common in 

women over 92 years old compared to women 

who were less than 80 years old. Variants 

of certain genes—like the FOXO3a gene—

predominated among long-lived individuals, 

suggesting a possible role with longer lifespan. 

This finding provides evidence that, like in 

animal models, the insulin/IGF-1 pathway has 

GENETICS
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 15

The human genetic blueprint, or genome, consists of approximately 25,000 genes 

made up of approximately 3 billion letters (base pairs) of DNA. Base pair sequences: 

guanine (G) pairs with cytosine (C); adenine (A) pairs with thymine (T).

C

T

HUMAN GENETIC BLUEPRINT

NUCLEUS GENES

DNA STRAND

BASES

G

T

A

A

G

C

23 PAIRS OF CHROMOSOMES

CELL

ILLUSTRATION ADAPTED FROM ALZHEIMER'S DISEASE: UNRAVELING THE MYSTERY
16 GENETICS

Most longevity genes identified thus far influence one of 

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

In the 1980s, scientists discovered the first gene 

shown to limit lifespan in roundworms, which they named 

age-1. Further investigation revealed that the effects of 

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

scientists “silenced” the age-1 gene’s activity, the insulin/

IGF-1 pathway’s activity also decreased and the worms 

lived longer. Since then, many other genes associated 

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

affect the lifespan of fruit flies and mice, strengthening 

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

important role in the aging process. More research is 

needed to determine if inhibiting this pathway could 

increase longevity in humans or create insulin-related 

health problems like diabetes. A recent report suggests that 

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

may have less risk of developing diabetes and cancer. 

There is also a great deal of interest in the sirtuin 

pathway. Sirtuin genes are present in all species and 

regulate metabolism in the cell. They are crucial for 

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

Massachusetts Institute of Technology found that 

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

increased the lifespan of yeast. Extension of lifespan has 

been replicated in other organisms, including flies and worms. 

However, studies in mice have yielded conflicting results. 

The mTOR pathway—an abbreviation of “mammalian 

target of rapamycin”—plays a role in aging of yeast, 

worms, flies, and mice. This pathway controls the cell’s 

rate of protein synthesis, which is important for proper cell 

function. Researchers have found that inhibiting the pathway 

in mice genetically or pharmacologically (using rapamycin) 

leads to increased longevity and improved health span.

a role in human aging. These genes may be 

important to future development of therapies to support healthy aging. 

Another approach, the genome-wide 

association study, or GWAS, is particularly 

productive in finding genes involved in 

diseases and conditions associated with 

aging. In this approach, scientists scan 

the entire genome looking for variants 

that occur more often among a group 

with a particular health issue or trait. In 

one GWAS study, NIH-funded researchers 

identified genes possibly associated with 

high and low blood fat levels, cholesterol, 

and, therefore, risk for coronary artery 

disease. The data analyzed were collected 

from Sardinians, a small genetically alike 

population living off the coast of Italy in 

the Mediterranean, and from two other 

international studies. The findings 

revealed more than 25 genetic variants 

in 18 genes connected to cholesterol and 

lipid levels. Seven of the genes were not 

previously connected to cholesterol/lipid 

levels, suggesting that there are possibly 

other pathways associated with risk for 

coronary artery disease. Heart disease is 

a major health issue facing older people. 

Finding a way to eliminate or lower risk 

for heart disease could have important 

ramifications for reducing disability 

and death from this particular agerelated condition. 

Scientists are also currently using 

GWAS to find genes directly associated 

with aging and longevity. Because the 

PATHWAYS OF LONGEVITY GENES
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 17

At the center of this research is the 

epigenome—chemical modifications, or 

marks, on our DNA, or in proteins that 

interact with DNA, that tell it what to do, 

where to do it, and when to do it. The marks 

that make up the epigenome are affected 

by your lifestyle and environment and may 

change, for example, based on what you eat 

and drink, if you smoke, what medicines 

you take, and what pollutants you encounter. 

Changes in the epigenome can cause 

changes in gene activity. Most epigenetic 

changes are likely harmless, but some could 

trigger or exacerbate a disease or condition, 

such as your risk for age-related diseases. 

In some cases, scientists find that these 

epigenetic changes driven by the environment can be inherited by the offspring. 

Identical, maternal twins are ideal for 

epigenetic research. At birth, twins have 

nearly the same genetic blueprint; however, 

over time, they may have fewer identical 

traits. Careful study of these changes may 

help scientists better understand environmental and lifestyle’s influence on genes. 

Epigenetics might also explain variations 

in lifespan among laboratory mice that are 

genetically identical and seemingly raised 

in the exact same environment. Scientists 

theorize that the difference in their

lifespans may result from a disparity in the 

amount of nurturing they received when 

very young. The mice with the shorter 

lifespan might have been less adept at feeding and, therefore, got less of their mother’s 

milk, or their mother may have licked them 

less, or they may have slept farther away from 

the center of the litter. Receiving less nurturing may have influenced their epigenetics, 

marking the genes that control aging. 

As epigenetic research moves forward, 

scientists hope to answer three key questions:

• How do changes in the epigenome translate into long-term differences in health 

and aging?

• Do single events influence the epigenome? 

• If single events can change the epigenome, 

does the organism’s age (or stage of development) at the time of the change matter?

An emerging area of research called “epigenetics” opens the door to a scientific 

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

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

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

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

EPIGENETICS

THE FUTURE OF AGING RESEARCH
18 GENETICS

GWAS approach does not require previous 

knowledge of the function of the gene or its 

potential relationship with longevity, it could 

possibly uncover genes involved in cellular 

processes and pathways that were not previously thought to play roles in aging. Since no 

single approach can precisely identify each 

and every gene involved in aging, scientists 

will use multiple methods, including a combination of the GWAS and candidate gene 

approaches to identify genes involved 

in aging.

As scientists continue to explore the genetics 

of aging, its complexity becomes increasingly 

evident. Further studies could illustrate the 

varying ways genes influence longevity. For 

example, some people who live to a very old 

age may have genes that better equip them 

to survive a disease; others may have genes 

that help them resist getting a disease in the 

first place. Some genes may accelerate the rate 

of aging, others may slow it down. Scientists 

investigating the genetics of aging do not 

foresee a “Eureka!” moment when one gene 

is discovered as the principal factor affecting 

health and lifespan. It is more likely that we 

will identify several combinations of many 

genes that affect aging, each to a small degree. 

What happens when DNA

becomes damaged? 

The impact of age, of course, is not limited 

to organisms. You drive a brand new car 

off the lot, and ideally it’s in perfect working condition. But by the time it reaches the 

100,000 mile mark, the car doesn’t run quite 

like it used to. Or, that lovely walking path 

you discovered when you first moved into 

your home has now become weathered, 

the weeds are overgrown, and some of the 

asphalt has buckled. 

Like the car and the walking path, over 

time your DNA accumulates damage. That’s 

normal. Our DNA suffers millions of damaging 

events each day. Fortunately, our cells have 

powerful mechanisms to repair damage and, 

by and large, these mechanisms remain active 

and functional through old age. However, 

over time, some damage will fail to be repaired 

and will stay in our DNA. Scientists think this 

damage—and a decrease in the body’s ability 

to fix itself—may be an important component 

of aging. Most DNA damage is harmless—for 

example, small errors in DNA code, called 

mutations, are harmless. Other types of DNA 

damage, for example, when a DNA strand breaks, 

can have more serious ramifications. Fixing a 

break in a DNA strand is a complex operation 

and it is more likely the body will make mistakes 

when attempting this repair—mistakes that 

could shorten lifespan. 

Another kind of DNA damage build-up 

occurs when a cell divides and passes its 

genetic information on to its two daughter 

cells. During cell division, the telomere, a 

stretch of DNA at each end of a chromosome 

that doesn’t encode any proteins but instead 

protects the protein-encoding part of the 

DNA, becomes shorter. When the telomere 
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 19

becomes too short, it can no longer protect the cell’s 

DNA, leaving the cell at risk for serious damage. In

most cells, telomere length cannot be restored. Extreme 

telomere shortening triggers an SOS response, and 

the cell will do one of three things: stop replicating 

by turning itself off, becoming what is known as 

senescent; stop replicating by dying, called apoptosis; 

or continue to divide, becoming abnormal and potentially dangerous (for example, leading to cancer).

Scientists are interested in senescent cells because, 

although they are turned off, they still work on many 

levels. For instance, they continue to interact with 

other cells by both sending and receiving signals. 

However, senescent cells are different from their 

earlier selves. They cannot die, and they release 

molecules that lead to an increased risk for diseases, 

particularly cancer. 

The relationship among cell senescence, cancer, and 

aging is an area of ongoing investigation. When we are 

young, cell senescence may be critical in helping to 

suppress cancer. Senescence makes the cell stop 

replicating when its telomeres become too short, 

or when the cell cannot repair other damage to its 

DNA. Thus, senescence prevents severely damaged 

cells from producing abnormal and perhaps cancerous daughter cells. However, later in life, cell senescence may actually raise the risk of cancer by releasing 

certain molecules that make the cells more vulnerable 

to abnormal function. 

Consider fibroblasts, cells that divide about 60 times 

before turning off. Normally, fibroblasts hold skin and 

other tissues together via an underlying structure, a 

scaffold outside the cell, called the extracellular matrix. 

The extracellular matrix also helps to control the 

growth of other cells. When fibroblasts turn off, they 

Telomeres shorten each time a cell 

divides. In most cells, the telomeres 

eventually reach a critical length 

when the cells stop proliferating and 

become senescent. 

But, in certain cells, like sperm and egg

cells, the enzyme telomerase restores 

telomeres to the ends of chromosomes. This telomere lengthening 

insures that the cells can continue to 

safely divide and multiply. Investigators have shown that telomerase is 

activated in most immortal cancer 

cells, since telomeres do not shorten 

when cancer cells divide.

TELOMERASE

TELOMERE

TELOMERE SHORTENS AFTER

MULTIPLE REPLICATIONS

TELOMERE AT

SENESCENCE

TELOMERASE

CHROMOSOME OF ADULT CELL

CHROMOSOME OF IMMORTAL CELL
20

emit molecules that can change the extracellular 

matrix and cause inflammation. This disturbs the 

tissue’s function and contributes to aging. At the same 

time, the breakdown of the extracellular matrix may 

contribute to increased risk of cancer with age. 

Learning why—on a biological level—cell senescence 

goes from being beneficial early in life to having detrimental effects later in life may reveal some important 

clues about aging. 

YOUNG FIBROBLASTS

OLD FIBROBLASTS, 

NEARING SENESCENCE

GENETICS

Aging biologists are investigating 

whether humans' telomere length 

is associated with lifespan, health 

span, or both. In one study of people 

age 85 years and older, researchers 

found telomere length was not 

associated with longevity, at least not 

in the oldest-old. In another study, 

researchers analyzing DNA samples 

from centenarians found that 

telomeres of healthy centenarians 

were significantly longer than 

those of unhealthy centenarians, 

suggesting that telomere length may 

be associated with health span.

TELOMERE LENGTH:

HEALTH SPAN VS. LIFESPAN?

FIBROBLASTS PHOTO CREDIT: COURTESY OF LEONARD HAYFLICK, PH.D., UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 21

Stem cells can come from a variety of sources. 

Adult stem cells are candidates for regenerative medicine approaches for several 

reasons—doctors can use the patient’s own 

stem cells; stem cells can develop into nearly 

any type of cell based on where they are 

inserted and other factors; and stem cells 

continue to function normally during an 

almost infinite number of cell divisions, 

making them essentially immortal. Therefore, in theory, if stem cells were inserted in a 

damaged part of the body, they could develop 

into area-specific cells that could potentially 

restore function. But does that work? That’s 

what researchers are trying to find out. 

Findings from early research on regenerative medicine, primarily in animal 

models, show potential for stem cell treatment. For example, inserting mouse ovarian 

cells created from a female donor’s stem 

cells into infertile mice restored the mice’s 

ability to reproduce. Another study in 

mice found that function could be restored 

to injured muscle tissue by reactivating 

existing stem cells rather than transplanting 

new ones. The ability to reactivate dormant 

adult stem cells continues to be investigated. 

In a 2010 Italian study with human participants, researchers restored vision to some 

people with severe burns on the outmost 

layer of their eyes (the cornea) by using 

stem cells grown in the laboratory. 

Researchers are also looking for alternatives to stem cells that have similar healing 

abilities and can be used in regenerative 

medicine. It appears that certain cells, 

like skin cells, can be reprogrammed to 

act as artificial stem cells, called induced 

pluripotent cells. 

Many questions about stem cell (and 

induced pluripotent cell) therapy need to be 

answered: Do older adults have enough stem 

cells for this type of therapy or do they need 

to be donated from someone else? Would 

creating stem cells from an older person’s 

skin cells work? Would stem cell therapy restore 

health and vigor to an older person or only 

work in a younger person? How would stem 

cell therapy work on the cellular level—would 

stem cells replace the non-functioning cells 

or would they reactivate and repair the damaged cells? Would stem cell therapy work in 

all areas of the body, or only in some areas?

While many questions remain, the prospect 

of regenerative medicine could have important implications for the treatment of many 

degenerative diseases. 

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

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

know if regenerative medicine will ever be a reality, research on stem cells 

opens up the possibility. 

STEM CELLS &

REGENERATIVE MEDICINE

THE FUTURE OF AGING RESEARCH
22
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 23

Does stress really 

shorten your life? 

Have you ever looked at side-by-side 

photos of a person before and after a 

particularly trying time in his or her life, 

for instance, before and a few years after 

starting a highly demanding job? The 

person likely appears much older in the 

later photo. The stress of the job is thought 

to contribute to the prematurely aged 

appearance. You might feel stress from 

work or other aspects of your daily life, 

too. Stress is everywhere. Even when you 

feel relaxed, your body is still experiencing 

considerable stress—biological stress. 

And, it is this type of stress that is widely 

studied by gerontologists for its effects on 

aging and longevity. 

Biological stress begins with the very basic 

processes in the body that produce and use energy. 

We eat foods and we breathe, and our body uses 

those two vital elements (glucose from food and 

oxygen from the air) to produce energy, in a process 

known as metabolism. You may already think 

of metabolism as it pertains to eating—“My

metabolism is fast, so I can eat dessert," or “My 

metabolism has slowed down over the years, 

so I’m gaining weight.” Since metabolism is all 

about energy, it also encompasses breathing, 

circulating blood, eliminating waste, controlling 

body temperature, contracting muscles, operating the brain and nerves, and just about every 

other activity associated with living. 

METABOLISM
24 METABOLISM

These everyday metabolic activities that 

sustain life also create “metabolic stress,” which, 

over time, results in damage to our bodies. 

Take breathing—obviously, we could not survive 

without oxygen, but oxygen is a catalyst for 

much of the damage associated with aging 

because of the way it is metabolized inside our 

cells. Tiny parts of the cell, called mitochondria, 

use oxygen to convert food into energy. While 

mitochondria are extremely efficient in doing 

this, they produce potentially harmful byproducts called oxygen free radicals. A variety 

of environmental factors, including tobacco 

smoke and sun exposure, can produce them, 

too. The oxygen free radicals react with and 

create instability in surrounding molecules. 

This process, called oxidation, occurs as a chain 

reaction: the oxygen free radical reacts with 

molecule “A” causing molecule “A” to become 

unstable; molecule “A” attempts to stabilize 

itself by reacting with neighboring molecule “B”; 

then molecule “B” is unstable and attempts to 

become stable by reacting with neighboring 

molecule “C”; and so on. This process repeats 

itself until one of the molecules becomes stable 

by breaking or rearranging itself, instead of 

passing the instability on to another molecule. 

Some free radicals are beneficial. The 

immune system, for instance, uses oxygen free 

radicals to destroy bacteria and other harmful 

organisms. Oxidation and its by-products also 

help nerve cells in the brain communicate. 

But, in general, the outcome of free radicals 

is damage (breaks or rearrangements) to 

other molecules, including proteins and DNA. 

Because mitochondria metabolize oxygen, 

FREE RADICALS

Oxidation chain reaction.

A B

B C

B C

A B
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 25

In the early 1960s, scientists discovered 

that fruit flies exposed to a burst of heat 

produced proteins that helped their cells 

survive the temperature change. Over the 

years, scientists have found these “heat 

shock proteins” in virtually every living 

organism, including plants, bacteria, worms, 

mice, and even humans. Scientists have 

learned that, despite their name, heat shock 

proteins are produced when cells are exposed to a variety of stresses, not just heat. 

The proteins can be triggered by oxidative 

stress and by exposure to toxic substances 

(for example, some chemicals). When heat 

shock proteins are produced, they help cells 

dismantle and dispose of damaged proteins 

and help other proteins keep their structure 

and not become unraveled by stress. They 

also facilitate making and transporting new 

proteins in the body.

Heat shock response to stress changes 

with age. Older animals have a higher everyday level of heat shock proteins, indicating 

that their bodies are under more biological 

stress than younger animals. On the other 

hand, older animals are unable to produce 

an adequate amount of heat shock proteins 

to cope with fleeting bouts of stress from 

the environment. 

Heat shock proteins are being considered as a possible aging biomarker—

something that could predict lifespan or 

development of age-related problems—

in animal models like worms and fruit flies. 

However, the exact role heat shock proteins 

play in the human aging process is not yet clear.

HEAT SHOCK PROTEINS

they are particularly prone to free radical 

damage. As damage mounts, mitochondria 

may become less efficient, progressively 

generating less energy and more free radicals. 

Scientists study whether the accumulation 

of oxidative (free radical) damage in our cells 

and tissues over time might be responsible for 

many of the changes we associate with aging. 

Free radicals are already implicated in many 

disorders linked with advancing age, including cancer, atherosclerosis, cataracts, and 

neurodegeneration.

Fortunately, free radicals in the body do 

not go unchecked. Cells use substances called 

antioxidants to counteract them. Antioxidants 

include nutrients, such as vitamins C and E, as 

well as enzyme proteins produced naturally in 

the cell, such as superoxide dismutase (SOD), 

catalase, and glutathione peroxidase. 

Many scientists are taking the idea that antioxidants counter the negative effects of oxygen 

free radicals a step further. Studies have tested 

whether altering the antioxidant defenses of the 

cell can affect the lifespan of animal models. 

These experiments have had conflicting results. 

NIA-supported researchers found that inserting extra copies of the SOD gene into fruit flies 

extended the fruit flies’ average lifespan by as 

much as 30 percent. Other researchers found 

that immersing roundworms in a synthetic 

form of SOD and catalase extended their 

lifespan by 44 percent. However, in a comprehensive set of experiments, increasing or 

decreasing antioxidant enzymes in laboratory 

mice had no effect on lifespan. Results from a 
26

Scientists also found that age-related damage to DNA and proteins is often reversible 

and does not cause problems until the damage evokes a stress response. This suggests 

that the stress response, rather than the 

damage itself, is partially responsible for 

age-related deterioration. 

Some biologists have started looking 

at stress resistance when choosing animal 

models to study as examples of successful 

aging. Researchers can test stress resistance 

in young animals and then continue studying only those animals demonstrating high 

resistance. Ongoing studies will determine 

if there is a direct cause-effect relationship 

between stress resistance and longevity,

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

In addition, researchers are studying 

the relationship between psychological 

stress and aging. In one study, mothers of 

severely and chronically sick children had 

shorter telomeres, relative to other women. 

In other research, caregivers of people with 

Alzheimer’s disease were found to have 

shortened telomeres. These findings could 

suggest that emotional or psychological 

stress might affect the aging process. More 

research on the mechanisms involved is 

needed before scientists can make any 

conclusions about clinical implications.

The first C. elegans worm genetically manipulated to have a longer lifespan 

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

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

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

compared to animals with an average or shorter lifespan. 

STRESS

THE FUTURE OF AGING RESEARCH

limited number of human clinical trials involving antioxidants generally have not supported 

the premise that adding antioxidants to the 

diet will support longer life. Antioxidant 

supplementation remains a topic of 

continuing investigation.

METABOLISM
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 27

Does how much you eat 

affect how long you live? 

Your body needs food to survive. However, the 

very process of extracting energy from food—

metabolizing food—creates stress on your body. 

Overeating creates even more stress on the 

body. That’s part of the reason why it can lead to 

a shorter lifespan and serious health problems 

common among older people, including cardiovascular disease and type 2 diabetes. 

Calorie restriction, an approach primarily 

(but not exclusively) used in a research setting, is more tightly controlled than normal 

healthy eating or dieting. It is commonly 

defined by at least a 30 percent decrease in 

calorie consumption from the normal diet 

with a balanced amount of protein, fat, vitamins, and minerals. In the 1930s, investigators 

found that laboratory rats and mice lived 

up to 40 percent longer when fed a calorierestricted diet, compared to mice fed a normal 

diet. Since that time, scientists observed that 

calorie restriction increased the lifespan of 

many other animal models, including yeast, 

worms, flies, some (but not all) strains of 

mice, and maybe even nonhuman primates. 

In addition, when started at an early age or as 

a young adult, calorie restriction was found 

to increase the health span of many animal 

models by delaying onset of age-related disease and delaying normal age-related decline. 

Two studies of calorie restriction in nonhuman primates (the animals most closely 

related to humans) have had intriguing 

results. In a study conducted at NIA, monkeys 

fed a calorie-restricted diet had a notably 

decreased and/or delayed onset of age-related 

diseases, compared to the control group of 

“normal” eaters. In a University of Wisconsin 

study supported by NIA, calorie-restricted 

rhesus monkeys had three times fewer agerelated diseases compared to the control 

group. The Wisconsin study also found that 

rhesus monkeys on a restricted diet had fewer 

age-related deaths compared to their normal 

fed controls. In 2007, when the findings from 

the study conducted at NIA were published, 

it was too early to determine whether calorie restriction had any effects on lifespan. 

Research in primates continues.
28

Despite its apparent widespread acceptance, 

calorie restriction does not increase lifespan 

in all animals. In studies of non-laboratory 

(wild) mice, researchers found that on average, calorie restriction did not have any effect 

on lifespan. Some of the calorie-restricted 

mice actually lived shorter than average lives. 

This may be due to differences in the genetics 

of the wild mice. A 2010 NIA-funded study 

provides further evidence that genetics may 

play a role in whether or not calorie restriction will have a positive effect on longevity. 

Looking at 42 closely related strains of laboratory mice, researchers found that only about a 

third of the strains on a calorie-restricted diet 

had an increase in longevity. One-third of the 

strains of mice on a calorie-restricted diet had 

a shortened lifespan, and the other third had 

no significant difference in lifespan compared to mice on a normal diet.

While animal studies are ongoing, researchers 

are also exploring calorie restriction in humans 

to test its safety and practicality, as well as to 

see if it will have positive effects on health. 

Participants in a 2002 pilot of the Comprehensive Assessment of Long-term Effects of 

Reducing Intake of Energy (CALERIE) study 

had, after 1 year, lowered their fasting glucose, 

total cholesterol, core body temperature, body 

weight, and fat. At the cellular level, they had 

better functioning mitochondria and reduced 

DNA damage. However, in terms of practicality, scientists observed that adapting and 

adhering to the regimen could be difficult.

A longer-term trial is underway. 

Given that ample studies have demonstrated mostly positive effects of calorie 

restriction in many organisms, today’s 

scientific studies focus on finding the mechanisms and pathways by which calorie restriction works. Researchers are also studying 

compounds that might act the same way 

in the body, mimicking the benefits of 

calorie restriction. 

A wide range of possible mechanisms for 

calorie restriction are being investigated. 

Some scientists are exploring the possibility 

that metabolizing fewer calories results in less 

oxidative damage to the cells. Other scientists 

are looking at how the relative scarcity of 

nutrients caused by calorie restriction might 

induce heat shock proteins and other defense 

mechanisms that allow the body to better 

withstand other stresses and health problems. 

Some researchers wonder if the effects of calorie restriction are controlled by the brain and 

nervous system. In one NIA-conducted study, 

calorie restriction increased the production 

of brain-derived neurotrophic factor, or 

BDNF, a protein that protects the brain from 

dysfunction and degeneration, and supports 

increased regulation of blood sugar and heart 

function in animal models. Still other studies 

indicate calorie restriction may influence 

hormonal balance, cell senescence, or gene 

expression. It is likely that calorie restriction 

works through a combination of these mechanisms, and others yet to be identified. 

There is an intriguing overlap between 

the pathways that control normal aging and 

METABOLISM
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 29

those that scientists think may be pertinent 

to calorie restriction. The most relevant are 

the sirtuins and mTOR (mammalian target 

of rapamycin) pathways as discussed on 

page 16. In several, but not all cases, disrupting 

these pathways means the organism no longer responds positively to calorie restriction. 

These two pathways have been important 

for identifying at least two compounds that 

may mimic the effects of calorie restriction: 

resveratrol and rapamycin. 

Resveratrol, found naturally in grapes, 

wine, and nuts, activates the sirtuin pathway. 

It has been shown to increase the lifespan 

of yeast, flies, worms, and fish. In 2006, NIA 

researchers, in collaboration with university 

scientists funded by NIA, reported on a study 

comparing mice fed a standard diet, a high 

fat-and-calorie diet, or a high fat-and-calorie 

diet supplemented with resveratrol beginning 

at middle age. Resveratrol appeared to lessen 

the negative effects of the high fat-and-calorie 

diet, both in terms of lifespan and disease. In 

a 2008 follow-up study, investigators found 

that resveratrol improved the health of aging 

mice fed a standard diet. It prevented age- and 

obesity-related decline in heart function. 

Mice on resveratrol had better bone health, 

reduced cataract formation, and enhanced 

balance and motor coordination compared to 

non-treated mice. In addition, resveratrol was 

found to partially mimic the effects of calorie 

restriction on gene expression profiles of 

liver, skeletal muscle, and adipose (fatty) tissue 

in the mice. However, the compound did not 

have an impact on the mice’s overall survival 

or maximum lifespan. These findings suggest 

that resveratrol does not affect all aspects of 

the basic aging process and that there may 

be different mechanisms for health versus 

lifespan. Research on resveratrol continues 

in mice, along with studies in nonhuman 

primates and people. 

Rapamycin, another possible calorie 

restriction mimetic, acts on the mTOR pathway. This compound’s main clinical use is to 

help suppress the immune system of people 

who have had an organ transplant so that 

the transplant can succeed. A study by NIA’s 

Interventions Testing Program, as discussed 

on page 7, reported in 2009 that rapamycin 

extended the median and maximum lifespan 

of mice, likely by inhibiting the mTOR pathway. Rapamycin had these positive effects 

even when fed to the mice beginning at 

early-old age (20 months), suggesting that 

an intervention started later in life may still 

be able to increase longevity. Researchers are 

now looking at rapamycin’s effects on health 

span and if there are other compounds that 

may have similar effects as rapamycin on 

the mTOR pathway. 

Scientists do not yet know how resveratrol, 

rapamycin, and other compounds that demonstrate effects similar to calorie restriction 

will influence human aging. Learning more 

about these calorie restriction mimetics, and 

the mechanisms and pathways underlying 

calorie restriction, may point the way to future 

healthy aging therapies. 
30
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 31

Can your immune system still 

defend you as you age? 

Elementary schools are breeding grounds 

for the common cold. Kids pass their 

germs around as often as they share 

their lunch. For children, catching a cold 

may not be a big deal. They might take it 

easy for a few days while their immune 

system kicks into action and fights off 

infection. But for their older teachers and 

grandparents, each cold can be more of 

a challenge. It may take a week or longer 

to get back to feeling 100 percent. Does 

that mean that the immune system gets 

weaker as we age? That’s what

gerontologists are trying to figure out. 

Our immune system is a complicated network 

of cells, tissues, and organs to keep us healthy 

and fight off disease and infection. The immune 

system is composed of two major parts: the 

innate immune system and the adaptive immune 

system. Both change as people get older. Studies to 

better understand these changes may lead to ways 

of supporting the aging immune system.

IMMUNE 

SYSTEM
32

Innate immunity is our first line of 

defense. It is made up of barriers and certain 

cells that keep harmful germs from entering 

the body. These include our skin, the cough 

reflex, mucous membranes, and stomach 

acid. If germs are able to pass these physical 

barriers, they encounter a second line of 

innate defense, composed of specialized cells 

that alert the body of the impending danger. 

Research has shown that, with age, innate 

immune cells lose some of their ability to 

communicate with each other. This makes 

it difficult for the cells to react adequately to 

potentially harmful germs called pathogens, 

including viruses and bacteria. 

Inflammation is an important part of 

our innate immune system. In a young 

person, bouts of inflammation are vital 

for fighting off disease. But as people age, 

they tend to have mild, chronic inflammation, which is associated with an increased 

risk for heart disease, arthritis, frailty, 

type 2 diabetes, physical disability, and 

dementia, among other problems. Researchers have yet to determine whether inflammation leads to disease, disease leads to 

inflammation, or if both scenarios are true. 

Interestingly, centenarians and other people 

who have grown old in relatively good health 

generally have less inflammation and a 

more efficient recovery from infection and 

inflammation when compared to people 

who are unhealthy or have average health. 

Understanding the underlying causes of 

chronic inflammation in older individuals—

and why some older people do not have this 

problem—may help gerontologists find ways 

to temper its associated diseases. 

The adaptive immune system is more 

complex than the innate immune system 

and includes the thymus, spleen, tonsils, bone 

marrow, circulatory system, and lymphatic 

system. These different parts of the body 

work together to produce, store, and transport 

specific types of cells and substances to combat 

health threats. T cells, a type of white blood 

cell (called lymphocytes) that fights invading 

bacteria, viruses, and other foreign cells, are 

of particular interest to gerontologists. 

T cells attack infected or damaged cells 

directly or produce powerful chemicals that 

mobilize an army of other immune system 

substances and cells. Before a T cell gets 

programmed to recognize a specific harmful 

germ, it is in a “naïve” state. After a T cell is 

assigned to fight off a particular infection, it 

becomes a “memory” cell. Because these cells 

remember how to resist a specific germ, they 

help you fight a second round of infection 

faster and more effectively. Memory T cells 

remain in your system for many decades. 

A healthy young person’s body is like a 

T cell producing engine, able to fight off 

infections and building a lifetime storehouse 

of memory T cells. With age, however, people 

produce fewer naïve T cells, which makes 

them less able to combat new health threats. 

This also makes older people less responsive 

to vaccines, because vaccines generally 

require naïve T cells to produce a protective 

immune response. One exception is the shingles 

vaccine. Since shingles is the reactivation 

IMMUNE SYSTEM
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 33

ORGANS OF THE IMMUNE SYSTEM

BARRIERS —

NOSE, MUCOUS

THYMUS

BONE MARROW

LYMPH NODES

TONSILS

LYMPH NODES

LYMPH NODES

SPLEEN

LYMPHATIC VESSELS

LYMPHATIC VESSELS

ADAPTED FROM WWW.NIAID.NIH.GOV
34

of the chickenpox virus, this particular 

vaccine relies on existing memory T cells 

and has been particularly effective in older 

people. Researchers are investigating ways to 

develop other vaccines that are adjusted for 

the changes that happen in an older person’s 

immune system. 

Negative, age-related changes in our innate 

and adaptive immune systems are known 

collectively as immunosenescence. A lifetime 

of stress on our bodies is thought to contribute to immunosenescence. Radiation, chemical exposure, and exposure to certain diseases 

can also speed up the deterioration of the 

immune system. Studying the intricacies of 

the immune system helps researchers better 

understand immunosenescence and determine which areas of the immune system are 

most vulnerable to aging. Ongoing research 

may shed light on whether or not there is any 

way to reverse the decline and boost immune 

protection in older individuals. 

IMMUNE SYSTEM

ALTERING OLDER

ADULTS' IMMUNITY

THE FUTURE OF AGING RESEARCH

Our ability to survive the germs 

around us is based on a tightly 

controlled immune system. Too 

little of an immune response 

makes us susceptible to infection, 

including life-threatening pneumonia. 

Conversely, an overactive immune response 

is at the root of autoimmune diseases 

common among older people and may 

contribute to age-related chronic diseases 

like Alzheimer’s disease, osteoarthritis, 

diabetes, and heart disease. So, should scientists try to change the immune response 

in older people, or is immunosenescence 

somehow beneficial within the context of 

the aging body? 

Given the delicate balance of the 

immune system, gerontologists suspect that, 

along with its more obvious negative consequences, immunosenescence might have 

a protective role in seniors. More research 

is needed before scientists fully understand 

the aging immune system and determine 

whether changing an immune response 

would lead to an increase or a decrease in 

health span and lifespan in humans. 
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 35

So, in the end, what causes aging? 

Clearly this question has fascinated 

medical researchers, philosophers, 

anthropologists, and the general public 

for centuries. This booklet offers you just 

a glimpse of the journey to understand 

the science of aging. 

In a sense, we are all aging experts—

every day we get older. It’s true that most 

of us cannot explain what’s happening 

under the microscope, but the little girl 

can still be curious about her vivacious 

grandmother without knowing that 

the grandmother’s good health may 

be a sign of what to expect during her 

own golden years. And, the man in 

middle age can know that he looks and 

feels better when making healthy food 

choices and staying physically active 

without understanding the intricacies 

of metabolism and biological stress. 

Aging is part of us, it’s part of life. 

As the field of gerontology matures, 

scientists will continue to learn about 

what happens deep inside our bodies 

during our passage from child to older 

adult. Experiments involving animal 

models that on the surface seem so 

different from us—yeast, fruit flies, 

worms, and mice—will yield insights into 

aspects of aging that could one day lead 

to important clinical, pharmacological, or 

behavioral interventions for humans. 

What is the future of biology of aging 

research? It is not likely that we will see 

a modern-day fountain of youth, that 

mythical elixir promised to restore people 

to their younger selves. But research may 

very well offer us the means to a healthier, 

longer life. And, with that, we may have 

the opportunity to spend more time with 

our loved ones, the opportunity to meet 

our great-great-grandchildren, and the 

opportunity to enjoy more life experiences. 

BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 35

THE PROMISE

OF RESEARCH

PHOTO CREDIT: WWW.BILLDENISONPHOTO.COM

Past, present, and future


36

Antioxidants – Compounds that may protect 

cells from oxygen free radicals by preventing or 

slowing the process of oxidation. Some antioxidants are enzyme proteins like superoxide 

dismutase (SOD) and catalase, while others are 

nutrients, such as vitamin C.

Calorie restriction – A diet that is lower by a 

specific percent of calories than the normal diet, 

but includes all essential nutrients. At this time 

calorie restriction is an experimental intervention being studied to determine its impact on 

health and longevity.

Cell senescence – A process in which a cell 

turns off its capacity to produce new cells, stops 

dividing, and has limited function. Cell senescence may contribute to aging, but it may also 

be a protective mechanism against cancer (a 

disease state in which cells continue to divide 

without control). 

Centenarian – A person who has lived at least 

100 years.

Chromosome –A structure inside cells containing DNA, which carries our genetic information 

and is responsible for heritable traits.

DNA – Abbreviation for deoxyribonucleic acid; 

DNA contains the genetic code for all animals 

and plants, from single-cell organisms to humans. 

Enzyme – A protein that increases the rate of a 

specific chemical reaction. 

Fibroblast – One of the major cell types found 

in skin and other tissues. Fibroblasts secrete 

molecules that have important structural 

properties for tissues and organs, and they 

change with age. 

Free radicals – Unstable molecules that react 

readily with other molecules to try to become 

stable. Oxygen free radicals are produced normally when food is metabolized and may cause 

damage to cells. Over a lifetime, this damage 

may contribute to aging.

Gene – A region of DNA containing code that 

can be read to make proteins in the cell. Genes 

are responsible for many heritable traits. 

Immunosenescence – The age-related decline 

in functions of the immune system. 

Life expectancy – The average number of 

years that members of a population (or species) 

live; also known as average lifespan. 

Lymphocytes –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 population (or species). 

GLOSSARY
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 37

Mitochondria – Cell organelles that 

produce energy necessary for life from the 

foods we eat. Mitochondria contain DNA, 

which may be damaged by oxygen free radicals produced during this process. Damage 

of mitochondrial DNA may contribute to 

aging. Mitochondria also are involved in 

controlling cell death.

Proteins – Molecules arranged in a specific 

order determined by DNA. Proteins are 

essential for all life processes. Certain proteins, 

such as those protecting against free radicals 

and those produced by the immune system, 

are studied extensively by gerontologists.

Stem cells – Cells with the potential 

to become many different types of cells 

found in the body. Stem cells are also able 

to replicate almost indefinitely without 

becoming abnormal. 

Telomerase – An enzyme that restores 

telomeres to the ends of chromosomes in 

certain cells, such as egg and sperm cells. This 

telomere lengthening insures that the cells 

can continue to divide and multiply. 

Telomeres –Repeated short, non-coding 

sequences of DNA at each end of a chromosome. Telomeres protect the chromosome from 

damage and shorten each time a cell divides.

Austad, S.N., “Comparative Biology of Aging,” Journal of 

Gerontology: Biological Sciences, 64A(2): 199-201, 2009. 

Bartke, A., “Insulin and Aging,” Cell Cycle, 7(21): 

3338-3343, 2008. 

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

and Persistent Questions about Practical Implications,” 

Experimental Gerontology, 44(6-7): 372-374, 2009. 

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

Mechanistically Understand the Healthy Life Span Extension Achieved by Calorie Restriction and Modulation of 

Hormones,” Journal of Gerontology: Biological Sciences, 

64A(2): 187-191, 2009. 

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

Review,” NeuroImmunoModulation, 15: 241-250, 2008. 

Baur, J.A., Pearson, K.J., Price, N.L., et al., “Resveratrol 

Improves Health and Survival of Mice on a High-Calorie 

Diet,” Nature, 444: 337-342, 2006. 

Blagozklonny, M.V. and Campisi, J., “Cancer and Aging,” 

Cell Cycle, 7(17): 2615-2618, 2008. 

Buffenstein, R., “The Naked Mole-Rat: A New Long-Living 

Model for Human Aging Research,” Journal of Gerontology: 

Biological Sciences, 60A(11): 1369-1377, 2005. 

Calvanese, V., Lara, E., Kahn, A., and Fraga, M.F., “The Role 

of Epigenetics in Aging and Age-Related Diseases,” Ageing 

Research Reviews, 8: 268-276, 2009. 

Campisi, J. and Yaswen, P., “Aging and Cancer Cell Biology, 

2009,” Aging Cell, 8: 221-225, 2009. 

Centers for Disease Control and Prevention,

Health, United States, 2008, p. 208, http://www.cdc.gov/

nchs/data/hus/hus08.pdf#026 

BIBLIOGRAPHY
38

Chen, W.H., Kozlovsky, B.F., Effros, R.B., et al., “Vaccination 

in the Elderly: An Immunological Perspective,” Trends in 

Immunology, 30(7): 351-359, 2009. 

Christensen, K., Doblhammer, G., Rau, R., and Vaupel, J.W., 

“Ageing Populations: The Challenges Ahead,” Lancet, 374: 

1196-1208, 2009.

Christensen, K., McGue, M., Petersen, I., et al., “Exceptional 

Longevity Does Not Result in Excessive Levels of Disability,” 

Proceedings of the National Academy of Sciences, 105(36): 

13274-13279, 2008. 

Colman, R.J., Anderson, R.M., Johnson, S.C., et al., “Calorie 

Restriction Delays Disease Onset and Mortality in Rhesus 

Monkeys,” Science, 325: 201-204, 2009. 

Cox, L.S. and Mattison, J.A., “Increasing Longevity through 

Caloric Restriction or Rapamycin Feeding in Mammals: 

Common Mechanisms for Common Outcomes?” 

Aging Cell, 8: 607-613, 2009. 

Cuervo, A.M., “Autophagy and Aging: Keeping that Old 

Broom Working,” Trends in Genetics, 24(12): 604-612, 2008. 

Cuervo, A.M., “Calorie Restriction and Aging: The Ultimate 

‘Cleansing Diet,’” Journal of Gerontology: Biological 

Sciences, 63A(6): 547-549, 2008. 

DiCarlo, A.L., Fuldner, R., Kaminski, J., and Hodes, R., “Aging 

in the Context of Immunological Architecture, Function 

and Disease Outcomes,” Trends in Immunology, 30(7): 293-

294, 2009.

Finch, C.E., “Update on Slow Aging and Negligible Senescence—A Mini-Review,” Gerontology, 55: 307-313, 2009.

Fraga, M.F., Ballestar, E., Paz, M.F., et al., “Epigenetic Differences Arise During the Lifetime of Monozygotic Twins,” 

Proceedings of the National Academy of Sciences, 102(30): 

10604-10609, 2005. 

Garinis, G.A., van der Horst, G.T.J., Vijg, J., and Hoeijmakers, 

J.H.J., “DNA Damage and Ageing: New-Age Ideas for an AgeOld Problem,” Nature Cell Biology, 10(11): 1241-1247, 2008. 

Geiger, H. and Rudolph, K.L., “Aging in the Lympho-hematopoietic Stem Cell Compartment,” Trends in Immunology, 

30(7): 360-365, 2009.

Globerson, A. and Barzilai, N., “The Voyage to Healthy 

Longevity: From Experimental Models to the Ultimate 

Goal,” Mechanisms of Ageing and Development, 126: 

225-229, 2005. 

Guarente, L., “Sirtuins in Aging and Disease,” Cold Spring 

Harbor Symposia on Quantitative Biology, 72: 483-488, 2007. 

Guevara-Aguirre, J., Balasubramanian, P., Guevara-Aguirre, 

M., et al., “Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, 

and Diabetes in Humans,” Science Translational Medicine, 

3(70): 70ra13, 2011.

Hadley, E.C., Lakatta, E.G., Morrison-Bogorad, M., et al., 

“The Future of Aging Therapies,” Cell, 120: 557-567, 2005. 

Harrison, D.E., Strong, R., Sharp, Z.D., et al., “Rapamycin 

Fed Late in Life Extends Lifespan in Genetically Heterogeneous Mice,” Nature, 460: 392-395, 2009.

Herbig, U., Ferriera, M., Condel, L., et al., “Cellular

Senescence in Aging Primates,” Science, 311: 1257, 2006. 

Hildt, E., “Living Longer: Age Retardation and Autonomy,” 

Medicine, Health Care, and Philosophy, 12(2): 179-185, 2009.

Kennedy, B.K., “The Genetics of Ageing: Insight from 

Genome-Wide Approaches in Invertebrate Model Organisms,” Journal of Internal Medicine, 263: 142-152, 2008. 

Khrapko, K. and Vijg, J., “Mitochondrial DNA Mutations 

and Aging: Devils in the Details?” Trends in Genetics, 25(2): 

91-98, 2009. 

BIBLIOGRAPHY (continued)
BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 39

Kirkwood, T.B.L., “Understanding the Odd Science of Aging,” 

Cell, 120: 437-447, 2005. 

Leslie, M., “Searching for the Secrets of the Super Old,” 

Science, 321: 1764-1765, 2008. 

Martin, G.M., Bergman, A., and Barzilai, N., “Genetic Determinants of Human Health Span and Life Span: Progress and 

New Opportunities,” PLoS Genetics, 3(7): 1121-1130, 2007.

Mattison, J.A., Roth, G.S., Lane, M.A., and Ingram, D.K., 

“Dietary Restriction in Aging Nonhuman Primates” in 

Mobbs, C.V., Yen, K., Hof, P.R. (eds): Mechanisms of Dietary 

Restriction in Aging and Disease. Interdisciplinary Topics 

in Gerontology. Basel, Karger, 35: 137-158, 2007.

Mattson, M., “Dietary Factors, Hormesis and Health,” 

Ageing Research Reviews, 7: 43-48, 2008. 

Mattson, M., “Energy Intake, Meal Frequency, and 

Health: A Neurobiological Perspective,” Annual Review 

of Nutrition, 25: 237-260, 2005. 

Maue, A.C., Yager, E.J., Swain, S.L., et al., “T cell Immunosenescence: Lessons Learned from Mouse Models of Aging,” 

Trends in Immunology, 30(7): 301-305, 2009.

McElhaney, J.E. and Effros, R.B., “Immunosenescence: 

What Does It Mean to Health Outcomes in Older Adults?” 

Current Opinion in Immunology, 21: 418-424, 2009. 

Melzer, D., “Genetic Polymorphisms and Human Aging: 

Association Studies Deliver,” Rejuvenation Research, 11(2): 

523-526, 2008. 

Michan, S. and Sinclair, D., “Sirtuins in Mammals: Insights 

into Their Biological Function,” Biochemical Journal, 404: 

1-13, 2007. 

Narasimhan, S.D., Yen, K., and Tissenbaum, H.A., “Converging Pathways in Lifespan Regulation,” Current Biology, 

19(15): 657-666, 2009. 

Ostan, R., Bucci, L., Capri, M., et al., “Immunosenescence and 

Immunogenetics of Human Longevity,” NeuroImmunoModulation, 15: 224-240, 2008. 

Panda, A., Arjona, A., Sapey, E., et al., “Human Innate Immunosenscence: Causes and Consequences for Immunity in 

Old Age,” Trends in Immunology, 30(7): 325-333, 2009.

Pawlikowska, L., Hu, D., Huntsman, S., et al., “Association 

of Common Genetic Variation in the Insulin/IGF-1 

Signaling Pathway with Human Longevity,” Aging Cell, 

8: 260-472, 2009. 

Pearson, K.J., Baur, J.A., Lewis, K.N., et al., “Resveratrol Delays 

Age-Related Deterioration and Mimics Transcriptional 

Aspects of Dietary Restriction without Extending Life Span,” 

Cell Metabolism, 8: 157-168, 2008. 

Pedersen, P.L., “Mitochondrial Matters of the Heart: 

A Plethora of Regulatory Modes to Maintain Function 

for a Long Lifetime,” Journal of Bioenergetics and 

Biomembranes, 41: 95-98, 2009. 

Pérez, V.I., Buffenstein, R., Masamsetti V., et al., “Protein Stability and Resistance to Oxidative Stress Are Determinants 

of Longevity in the Longest-Living Rodent, the Naked Mole 

Rat,” Proceedings of the National Academy of Sciences, 106: 

3059-3064, 2009.

Perls, T., “The Different Paths to Age One Hundred,” Annals 

of the New York Academy of Sciences, 1055: 13-25, 2005. 

Perls, T., Kunkel, L., and Puca, A., “The Genetics of Aging,” 

Current Opinion in Genetics & Development, 12: 

362-369, 2002. 

Rama, P., Matuska, S., Paganoni, G., et al., “Limbal Stem-Cell 

Therapy and Long-Term Corneal Regeneration,” The New 

England Journal of Medicine, 363: 147-155, 2010. 
40

Reddien, P.W., Bermange, A.L., Murfitt, K.J., et al., “Identification of Genes Needed for Regeneration, Stem Cell Function, 

and Tissue Homeostasis by Systematic Gene Perturbation 

in Planaria,” Developmental Cell, 8: 635-649, 2005. 

Salmon, A.B., Leonard, S., Masamsetti, V., et al., “The Long 

Lifespan of Two Bat Species Is Correlated with Resistance 

to Protein Oxidation and Enhanced Protein Homeostasis,” 

The Journal of the Federation of American Societies for 

Experimental Biology, 23: 2317-2326, 2009. 

Sierra, F., “Biology of Aging Summit Report,” Journal of 

Gerontology: Biological Sciences, 64A(2): 155-156, 2009. 

Sierra, F., Hadley, E., Suzman, R., and Hodes, R., “Prospects 

for Life Span Extension,” Annual Review of Medicine, 60: 

457-469, 2009. 

Stanfel, M.N., Shamieh, L.S., Kaeberlein, M., and Kennedy, 

B.K., “The TOR Pathway Comes of Age,” Biochimica et 

Biophysica Acta, 1790: 1067-1074, 2009. 

Strong, R., Miller, R.A., Astle, C.M., et al., “Nordihydroguariarietic Acid and Aspirin Increase Lifespan of Genetically 

Heterogeneous Male Mice,” Aging Cell, 7: 641-650, 2008.

Swain, S.L. and Nikolich-Zugich, J., “Key Research Opportunities in Immune System Aging,” Journal of Gerontology: 

Biological Sciences, 64A(2): 183-186, 2009. 

Terry, D.F., Nolan, V.G., Andersen, S.L., et al., “Association 

of Longer Telomeres With Better Health in Centenarians,” 

Journal of Gerontology: Biological Sciences, 63A(8): 

809-812, 2008. 

Tower, J., “Hsps and Aging,” Trends in Endocrinology

and Metabolism, 20(5): 216-222, 2009. 

Vijg, J. and Campisi, J., “Puzzles, Promises and a Cure 

for Aging,” Nature, 454(7208): 1065-1071, 2008. 

Willer, C.J., Sanna, S., Jackson, A.U., et al., “Newly Identified 

Loci that Influence Lipid Concentrations and Risk of 

Coronary Artery Disease,” Nature Genetics, 40(2): 

161-169, 2008. 
DESIGN: LEVINE & ASSOCIATES, WASHINGTON, D.C.
NIH...Turning Discovery into Health

Publication No. 11-7561

November 2011