NATIONAL INSTITUTES OF HEALTH NATIONAL INSTITUTE ON AGING

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
THE MISSION OF THE NATIONAL INSTITUTE ON AGING

“...the conduct and support of biomedical, social and behavioral

research, training, health information dissemination, and other

programs with respect to the aging process and the diseases and

other special problems and needs of the aged.”

RESEARCH ON AGING ACT OF 1974, AS AMENDED IN 1990 BY P.L. 101-557
3 Preface

4 A Host of Interconnections

4 The Intricate Pump

5 Anatomy of the Heart

6 Age, Change, and Adaptation

7 In the Beginning

7 The Next Steps

9 The Aging Heart

10 The Effects of Normal Aging

10 Structural Changes

11 Heart Dynamics

12 In a Heart Beat

12 Heart Filling 

14 Pumping At Rest

14 Pumping During Exercise

18 When the Brain Talks to the Heart

21 Cellular Clues

i

3 Introduction

4 A Host of Interconnections

4 The Intricate Pump

5 Anatomy of the Heart ✦

6 Age, Change, and Adaptation

7 In the Beginning

7 The Next Steps

9 The Aging Heart

10 The Effects of Normal Aging

10 Structural Changes

11 Heart Dynamics ✦

12 In a Heart Beat ✦

12 Heart Filling 

14 Pumping at Rest

15 The Heart: Young and Old ✦

16 Pumping During Exercise

18 When the Brain Talks to the Heart ✦★

1 Cellular Clues

22 The Marvelous Calcium Pump

23 How a Myocyte Contracts ✦

24 When a Good Pump Goes Bad

25 Age Lengthens Action Potential

26 Free Radical Damage

27 Nitric Oxide

27 Contractile Proteins ✦

28 Opposing Pressures: Heart Cavity

Pressure vs. Aortic Pressure ✦

28 Bigger Heart Cells...

29 ...But Fewer of Them

30 The Untapped Promise of

the Aging Heart

3

TABLE OF CONTENTS

✦ INFORMATIONAL GRAPHIC ★ INFORMATIONAL SIDEBAR

30 The Untapped Promise of

the Aging Heart

3 Blood Vessels and Aging:

The Rest of the Journey

34 In Search of a Connection

35 What Happens During 

Atherosclerosis? ✦★

36 Age and Arteries ✦

38 Inside Every Artery...

38 ...Time Takes its Toll

39 The Nitty Gritty of High Blood

Pressure

40 Production of Nitric Oxide in Arteries ✦

41 Arteries: Young and Old ✦

41 Stuck in the Middle with You

42 From Balloon to Bicycle Tire

43 Can Gene Therapy be Used

to Treat Heart Problems? ★

44 New Blood Test May Help Doctors

Detect Emerging Heart Disease ★

45 Keeping Your Arteries Healthy

47 Exercise: Your Heart’s Best Friend ★

48 Metabolic Syndrome Accelerates 

Aging of Arteries ✦★

49 Healthy Foods, Healthy Arteries:

Is There a Connection?

53 What Lies Ahead

54 Glossary

58 Bibliography

64 Acknowledgements

3

RICHARD J. HODES, MD, DIRECTOR, NATIONAL INSTITUTE ON AGING

Age is the major risk factor for cardiovascular disease. Heart disease and stroke 

incidence rises steeply after age 65, accounting for more than 40 percent of all deaths

among people age 65 to 74 and almost 60 percent at age 85 and above. People age 65

and older are much more likely than younger people to suffer a heart attack, to have a

stroke, or to develop coronary heart disease and high blood pressure leading to heart

failure. Cardiovascular disease is also a major cause of disability, limiting the activity

and eroding the quality of life of millions of older people each year. The cost of these

diseases to the Nation is in the billions of dollars.

To understand why aging is so closely linked to cardiovascular disease, and ultimately

to understand the causes and develop cures for this group of diseases, it is essential to

understand what is happening in the heart and arteries during normal aging—aging

in the absence of disease. This understanding has moved forward dramatically in the

past 30 years. The purpose of this booklet is to tell the story of this progress, describe

some of the most important findings, and give a sense of what may lie ahead.

While we know a great deal about cardiovascular disease and its risk factors, new areas

of research are beginning to shed further light on the link between aging and the development and course of the disease. For instance, scientists at the National Institute on

Aging (NIA) are paying special attention to certain age-related changes that occur in the

arteries and their influence on cardiac function. Many of these changes, once considered

a normal part of aging, may put people at increased risk for cardiovascular disease.

This and other compelling research on the aging heart and blood vessels takes place at

many different research centers. A great deal of the work is being done by researchers

in the Laboratory of Cardiovascular Science at the NIA or by NIA-funded scientists at

other institutions. Others have worked at or been funded by the National Heart, Lung,

and Blood Institute (NHLBI). NIA and NHLBI are two of 27 research institutes and

centers at the National Institutes of Health, and their work is complementary. NIA

research focuses on the effects of aging on the heart, blood vessels, and other parts of

the body, while NHLBI works to understand the diseases and risk factors that affect

the heart and blood vessels.

Both perspectives are bringing us closer to the possibility that heart disease and stroke

will someday be defeated. Research on the basic biology of the aging cardiovascular

system nurtures hope that we as a Nation need not accept the high rates of death and

disability and the enormous health care costs imposed by cardiovascular disease

among older people in our society.

INTRODUCTION
4

A Host OF INTERCONNECTIONS

The heart is purest theater...throbbing in its cage

palpably as any nightingale.

RICHARD SELZER, MD, AMERICAN SURGEON AND AUTHOR

It is scarcely as big as the palm of your hand yet it

sustains life, pumping up to 5 quarts or more of

blood per minute to the body’s organs, tissues,

and cells. In a typical day, it beats 100,000 times.

And in a lifetime, it beats more than 2.5 billion

times. Even as you rest, your heart is working

twice as hard as your leg muscles would if you

were running at full speed.

Little wonder then that from earliest mythology to

modern medicine, the heart has fascinated and

perplexed us. Fortunately, today we know far

more about the heart and the blood vessels than

was known even a decade ago. Yet for all scientists

have learned, there is still much more to unravel.

Investigators, for instance, now know that the cardiovascular system undergoes significant changes

as we age, and the heart and arteries that we are

born with are surprisingly different in later life.

But how and why do these changes occur? What

influence do these changes have on our risk of

developing heart disease and other cardiovascular

disorders as we get older? Are there any underlying

signs—even in people who appear to have healthy

hearts—that precede and predict who will develop

severe cardiovascular disease and who won’t?

Scientists called gerontologists, who study aging,

are seeking to answer these and other questions.

As a result of this probing, some old ideas about 

the aging cardiovascular system are giving way to

new theories. In other cases, gerontologists are just

beginning to explore some questions, and the heart

and arteries are yielding their secrets grudgingly.

But to truly understand what is emerging and what

remains mysterious, we’ll need to start where these

gerontologists began: in the normal, healthy heart.

The Intricate Pump

The heart is a marvel of coordination and timing.

Almost completely composed of muscle called

myocardium, it is well-equipped for its life-long

marathon of ceaseless beating. It is essentially two

pumps in one. The right side pumps blood to the

lungs to load up on oxygen and dispose of carbon

dioxide. The left side pumps oxygen-rich blood to

the body.

To accomplish these tasks, the heart depends on a

precise sequence of contractions involving its two

upper chambers—the right and left atria—and its

two lower ones, the right and left ventricles.

Between these chambers are two valves, each with 
5

RIGHT ATRIUM

receives blood from veins

depleted of oxygen.

AORTA

largest artery in the body;

carries blood away from the

heart, branching into smaller

arteries that carry blood to

the rest of the body.

LEFT ATRIUM

receives blood from lungs

with fresh oxygen.

LEFT VENTRICLE

pumps blood into the aorta.

RIGHT VENTRICLE

pumps blood to lungs 

to pick up oxygen.

To the lungs

To the body

From the lungs

To the lungs

From the lungs

A

A

B

D

E

C

B

C E

D

Anatomy of the Heart

Heart muscle relaxes to

receive blood; contracts

to pump blood out.

Pulmonary

Artery

Aorta
6

quarter of a second. As they travel, the impulses

are relayed through switching stations at precise

intervals, eventually causing millions of interlocked

cells to contract in near unison.

Age, Change, and Adaptation

The major sequences in this ever-moving picture

of the heart beat have been known for nearly 400

years. But gerontologists are uncovering another

influence on this chain of events—age—and the

picture appears to be even more complex. Aging,

it turns out, brings not a simple slowing down of

heart function, as one might expect, but a set of

intricate alterations: a slowing here, an enhancement there, a minor adjustment elsewhere. The

result of these numerous small alterations is adaptation. In various ingenious, important ways, the

heart at age 65 has adapted to meet the needs of

the 65-year-old body.

However, these refinements have a downside. In

recent years, gerontologists have learned that

some changes in the structure and function of the

aging cardiovascular system, even in a healthy

older person without any diagnosed medical condition, can actually greatly increase the risk of

developing cardiovascular diseases, including high

blood pressure, atherosclerosis, and heart failure.

In fact, these changes can create the nearly perfect

setting for the onset of severe cardiovascular disease in some healthy older people.

Gerontologists seeking to reconcile these two 

conflicting pictures of cardiovascular aging are

intensely studying the fundamental underpinnings of the age-associated changes in the heart

and arteries in hopes of discovering new ways to

effectively prevent and treat cardiovascular disease

in older people. This quest—from the impact of

the smallest molecule to the influence of diet and

exercise—is radically changing how scientists

think about the cardiovascular system.

The notion, for instance, that heart cells can’t

replicate themselves is being reconsidered.

Gerontologists now know far more about how

two or three flaps, also known as cusps. The tricuspid valve separates the right atrium and the right

ventricle. Its counterpart, separating the left atrium

and the left ventricle, is called the mitral valve. The

pulmonic valve controls blood flow out of the right

ventricle to the lungs where it picks up oxygen. The

aortic valve controls the flow of oxygenated blood

out of the left ventricle into the body. Normally

these valves let blood flow in just one direction.

The heart beats in two synchronized stages. First,

the right and left atria contract at the same time

pumping blood into the right and left ventricles.

Then the mitral and tricuspid valves close. A 

split second later, the ventricles contract (beat)

simultaneously to pump blood out of the heart.

Together, these coordinated contractions produce

the familiar “lub-dub” sound of a heart beat—

slightly faster than once a second.After contracting,

the heart muscles momentarily relax, allowing

blood to refill the heart.

To picture how this all works, imagine that as the

heart relaxes dark red blood returning from the

body flows into the right atrium. This blood carries

little oxygen and is laden with carbon dioxide,

which is produced by body tissues. When the right

atrium contracts, it propels oxygen-poor blood

through the tricuspid valve into the right ventricle.

In turn, the right ventricle pumps blood into the

pulmonary artery. From there, it flows into the

lungs where it picks up oxygen and returns to the

left atrium. When it contracts, the left atrium

pumps the now bright red oxygenated blood

through the mitral valve into the left ventricle,

which pumps it into the aorta, from which it is

distributed to other arteries to nourish your cells,

tissues, and organs. Then the cycle begins again.

This cardiac cycle is regulated by nerve impulses,

generated by the heart’s internal pacemaker called

the sinoatrial node (SA node), a small bundle of

specialized cells located in the right atrium. These

impulses cause the heart to beat. Once generated by

the SA node, the impulses spread in a coordinated

fashion across the heart muscle in less than a
7

aging affects blood vessels and how this process

influences the development of atherosclerosis.

They are learning much more about how 

physical activity, diet, and other lifestyle factors

influence the “rate of aging” in the healthy older

heart and arteries.

In the Beginning

Untangling the effects of age from those of disease

and lifestyle is a theme that appears again and

again in modern studies of aging. It wasn’t always

so. In the 1940s and 50s, clinical gerontologists

had to conduct most of their studies in chronic

care hospitals or nursing homes. The people they

studied lived sedentary lives, and many may have

had undetected heart disease or other illnesses.

From this perspective, it appeared as if virtually 

all bodily functions, including the cardiovascular 

system, deteriorated markedly with age.

Then, in 1958, the National Institutes of Health

(NIH) launched the Baltimore Longitudinal Study

of Aging (BLSA). This ongoing investigation, now

part of the National Institute on Aging (NIA), has

tracked the lives of more than 3,000 people from

age 20 to 90 and older in an effort to document

the normal or usual physiological changes that

occur in a stable population of people who live in

the community rather than institutions. BLSA

data have been valuable to scientists searching for

different ways in which aging, lifestyle, and disease

affect the heart and blood vessels.

The modern era of heart research has also

depended heavily on the development of powerful,

non-invasive technologies, such as echocardiography, magnetic resonance imaging, and radionuclide

imaging, which have allowed investigators to easily

see valves, walls, and chambers of the heart and

the flow of blood through these chambers. Two

techniques, thallium scintigraphy, a highly sensitive

radionuclide stress test that can detect hidden

coronary artery disease, and stress electrocardiogram (ECG), a measurement of the electrical

activity of the heart, are particularly useful. In

combination, these two tests allow researchers to

differentiate between the effects of age and the

effects of coronary disease that is so prevalent

among older people—effects that were once

entangled and indistinguishable.

The Next Steps

As you explore this booklet, you will find that scientists have learned a tremendous amount about

aging. Today, more than ever, they understand

what causes your blood vessels and heart to age

and know a lot about how this process interacts

with cardiovascular disease-related changes. In

addition, they have even pinpointed risk factors

that increase the odds a person will develop cardiovascular disease as well as other illnesses. And

while many mysteries of the aging heart and arteries remain unsolved, gerontologists have discovered much about how to prevent or postpone

heart disease in later life.

Scientists have been fascinated with the heart for centuries. Left: This 1523 woodcut by Jacopo Berengario

da Carpi was sophisticated for its time. Right: Today, researchers use magnetic resonance imaging (MRI)

and other high-tech tools to study the living heart.

9

For 92-year-old John Bicknell, this is the best of

times. A long-retired English professor, he remains

mentally and physically active. In addition to

singing in community choirs and performing in

local musical theater productions, he continues to

mow his own large yard and often walks up to a

mile or two a day around his island home in Maine.

As he walks around his property, Bicknell sometimes gathers small twigs and branches for kindling, and makes a mental note of larger deadfall

so he and his son-in-law can return later to cut it

up and haul it back to the house in a truck. An

avid boater, he frequently motors between the

island and the mainland. In the summer, he enjoys

swimming with his grandchildren in the brisk, but

invigorating waters of a nearby cove.

After a recent trip to England and France, he

returned home to a brewing winter storm. The

next morning, he shoveled 9-inches of snow off

his deck and front porch.

He looks healthy; his muscles are strong; he has no

excess fat. And while gerontologists now know

that John Bicknell’s 92-year-old heart is not quite

the same as it was when he was 22, it continues to

serve him extraordinarily well.

On one level, it’s not surprising that an older 

person who exercises regularly is more physically

fit and better able to care for himself than most

other people his age. But below the surface of that

assumption lie intriguing questions that scientists

are just beginning to answer. “We know that older

people who exercise regularly can do more aerobic

work, meaning they are more physically fit,” says

Edward Lakatta, MD, who is chief of the

Laboratory of Cardiovascular Science at the NIA.

“But for decades gerontologists have wanted to

know what changes in the

aging heart and arteries

allow this to happen.

Fortunately, in the past few

years, we have uncovered

some remarkable new clues

that have clarified how and

why these changes occur.

At the same time, however,

we have detected some

intriguing evidence that

transforms much of what

we once thought of as normal cardiovascular aging.”

Many of these adjustments are remarkably efficient, helping the older heart work as well as possible. But some ultimately may be detrimental. In

particular, some gerontologists suspect several of

these age-related changes may lower the heart’s

resistance to disease and compromise its ability 

to respond to increased demands for blood and

oxygen during stress.

THE Aging HEART

The heart is a tough organ: a marvelous mechanism that,

mostly without repairs, will give valiant pumping service 

up to a hundred years.

WILLIS JOHN POTTS, MD, AMERICAN SURGEON, 1895-1968

John Bicknell
researchers knew about the older heart mainly

through chest x-rays and autopsy studies of people

who were institutionalized, often with chronic 

illnesses. These people’s hearts, which were affected

by disease or extremely sedentary lives, often were

smaller than those of younger, healthier people.

Then, in the late 1950s, gerontologists began to

study healthy volunteers, such as those who participate in the BLSA. Soon afterward, scientists

devised new technologies like echocardiography

and radionuclide imaging. While x-rays provide a

static, shadowy silhouette, echocardiography and

other imaging techniques clearly show thickness,

diameter, volume, and in some cases, shape of the

heart and how these change with time during a

given heart beat. Recently, gerontologists have

begun using magnetic resonance imaging (MRI)

to get a better look at the aging heart. MRI is a

type of body scan that uses magnets and computers to provide high-quality images based on varying characteristics of the body’s tissues. The technology allows physicians to noninvasively study

the beating heart’s overall structure and function

continuously in three dimensions.

The thicker left ventricular walls supplied the first

clue that the heart might be adjusting rather than

simply declining with age. Scientists think that the

increased thickness allows the walls to compensate for the extra stress they bear with age (stress

imposed by pumping blood into stiffer blood vessels, for instance). When walls thicken, stress is

spread out over a larger area of heart muscle.

10

“Fortunately, in the past few years, we have uncovered some

remarkable new clues that have clarified how and why these

changes occur. At the same time, however, we have detected

some intriguing evidence that transforms much of what we

once thought of as normal cardiovascular aging.”

EDWARD LAKATTA, MD, CHIEF OF THE LABORATORY OF CARDIOVASCULAR SCIENCE, NIA

The Effects of Normal Aging

The emerging methods of studying the heart have

led to the growing realization that the many factors

influencing the aging heart and blood vessels are

interdependent. At least six major factors affect

how the heart fills with blood and pumps it out.

When scientists first discovered these factors, they

thought they operated independently. But as

investigators more closely examined these factors,

they discovered that these six factors influence

each other in various direct and indirect ways.

The diagram on the facing page illustrating their

interdependence is deceptively simple. It shows only

the six broad categories, but each of these terms

encompasses a host of related factors. Many of these

factors are the focus of rigorous research, including

structural changes in the normal aging heart.

Structural Changes

The NIA’s studies of normal aging have revealed a

series of fine-tuned adjustments that allow the

heart to meet the needs of the aging body. This

picture is radically different from the one that 

prevailed several decades ago when marked

declines in overall heart function were thought to

be the norm. The revolution in perspective began

in the 1970s when researchers came upon their

first surprise: The walls of the left ventricle, as it

ages, grow thicker.

Up until then, gerontologists thought that the

heart shrank with age. One reason was that early
11

CORONARY

FLOW

HEART RATE

CONTRACTILITY

PRELOAD

AFTERLOAD

Heart Dynamics:

Autonomic Nervous System

CONTRACTILITY — the ability of the heart

muscle cells to contract in response to an

increase in calcium in their cytosol.

HEART RATE — the number of beats per minute;

it affects the amount of blood getting to every

organ in the body. It is regulated by the autonomic nervous system.

Six broad factors determine how much blood the heart pumps per minute (cardiac output). 

All six are highly interdependent. The following definitions include just a few examples of their

interconnections.

AUTONOMIC NERVOUS SYSTEM DISCHARGES NEUROTRANSMITTERS — part of the nervous

system that controls involuntary muscles such as the heart; it modulates the other five factors in

many ways.

PRELOAD — stretch on the heart cells prior to

excitation; it is affected by the amount of blood

in the left pumping chamber, or ventricle, before

contraction.

CORONARY FLOW — the flow of blood through

the coronary arteries to the heart muscle itself.

Since the coronary flow determines how much

oxygen reaches the heart muscle cells, it helps

determine their contractility, which affects all

other factors.

AFTERLOAD — the forces that resist contraction once it begins; these forces include resistance by the arteries to pulsing and steady blood

flow, which depends partly on the “tightness” or

stiffness of arteries. This tightness depends, in

part, on the contractility of vascular smooth

cells with the arteries.
pool of blood and come together to close the passage. If this valve were closing more slowly in older

people, as the echocardiograms indicated, then

perhaps the ventricle was filling more slowly.

To figure out why this occurs and if it makes any

difference, investigators turned their attention to

the fraction of a second between heart beats.

During this momentary lull, called the diastole,

the heart relaxes, fills with blood, and readies for

the next contraction or systole.

Heart researchers divide the moments of diastole into even shorter periods. There is the early

filling phase when blood from the left atrium

pushes the mitral valve open, flows rapidly into

the left ventricle, and floats the valve shut. This

early diastolic filling is the phase that takes

longer as people grow older, according to the

Gerstenblith study. Then comes the late filling

phase, when the left atrium contracts, forces

open the mitral valve a second time, and delivers

a last surge of blood to the ventricle, just before

it too contracts.

Heart Filling

Other findings about the left side of the heart soon

followed.While at the NIA, Gary Gerstenblith, MD,

and his colleagues studied the left ventricle and

the left atrium, the receiving chamber into which

blood flows from the lungs before passing into the

ventricle. Their echocardiograms with BLSA 

volunteers showed that in addition to the left ventricular wall growing thicker, the cavity of the left

atrium increased.

This study also yielded one other finding, a curious

one: The mitral valve—the gateway between the

left atrium and ventricle—appeared to

close more slowly in

older people. As the

ventricle fills, the

two flaps of the

mitral valve—like a

trap door with two

separate panels—

Gary Gerstenblith, MD float up on the rising

In a Heart Beat

12

1

Heart muscle relaxes and 

valves open (early diastole)

2

Valves float nearly shut and

ventricles fill with blood

3

Electrical impulse begins in sinoatrial

node (the heart’s pacemaker); Atria

contract, adding more blood to 

ventricles (late diastole)
Why should early diastolic filling slow down as people age? Could it be because the

ventricle wall was not relaxing between heart beats as quickly as it once had?

Why should early diastolic filling slow down as

people age? Could it be because the ventricle

wall was not relaxing between heart beats as

quickly as it once had? 

This possibility intrigued NIA investigators

because it fit neatly with another stray piece to the

puzzle. In animal studies several years earlier,

Dr. Lakatta had learned that rat hearts studied 

in the laboratory took longer to relax after a 

contraction when they were from older rats.

Later imaging studies in humans confirmed the

animal studies: Between beats, the aging ventricle

fills with blood more slowly because it is relaxing

more slowly than it did when young.

But now another piece of the diastolic puzzle

needed to be fit into place. If the older left

ventricle fills more slowly with blood, does this

mean it has less blood pooled at the end of diastole

and thus less to send out to the body during the

next contraction? The answer is no, and the reason

was found in another of the adjustments that the

heart makes with age. NIA investigators found

that the heart compensates for the slower early

filling rate by filling more quickly in the late 

diastolic period.

It happens like this: As the mitral valve slowly 

closes, incoming blood from the lungs pools in the

left atrium, which is now larger and holds more

blood than when young. In the last moments of

the diastole, the SA node—the heart’s pacemaker—triggers the first electrical impulse (the action

potential), which will lead to contraction. The

impulse spreads across the cells of the two atria.

13

4

Electrical impulse spreads to 

ventricles via atrioventricular node

5

Ventricles contract, aortic

valve opens, blood is ejected

from the heart (systole) 
14

the blood in the heart is pumped out at once. A

portion remains in the ventricle, and this is called

the end systolic volume. The proportion of blood

that is pumped out during each beat compared 

to the amount that remains in the heart at the

beginning of the next beat is called the ejection

fraction. Doctors frequently use the ejection fraction

to estimate how well the heart is pumping.

These measurements are important because the

links between end diastolic volume, stroke volume,

end systolic volume, and ejection fraction make

up a complex set of dynamics that researchers had

to sort out as they attempted to understand what

differences aging makes in the heart’s pumping

ability. The various cardiac volumes differ according

to age, gender, body size and composition, and

degree of physical activity. However, keep in mind

that the various changes discussed in this section

are what occur, on average, in older hearts. As we

age, the differences in these measures between one

individual and another will vary much more than

in younger people. So, for instance, among 65 

to 70-year-old women the range of end diastolic

volumes and stroke volumes can be quite vast.

Pumping at Rest

When you are sitting in a chair reading a book or

watching television, your heart—regardless of

age—usually works well below its full capacity.

Instead, the heart saves or reserves most of its

capacity for times when it is really needed, such as

playing tennis or shoveling snow.

In fact, at first glance, healthy young and old hearts

don’t seem very different—at least when resting.

For instance, cardiac output—the amount of blood

pumped through the heart each minute—averages

4 to 6 quarts per minute at rest depending on

body size and doesn’t change much with age.

Similarly, while resting, both young and old hearts

eject about two-thirds of the blood in the left 

ventricle during each heart beat.

The left atrium, stretched with a greater volume of

blood in older hearts, contracts harder, pushing

open the valves and propelling the blood into the

ventricle. The late diastolic surge of blood into the

left ventricle from the atrium’s contraction occurs

at all ages but is stronger in older hearts and delivers

a greater volume of blood to the left ventricle. As a

result, at the end of diastole, the volume of blood

in older hearts is about the same (in women) or

slightly greater (in men) than in younger hearts. In

younger people, about twice as much blood flows

into the ventricle during the early filling period

than during late filling. But as we age, this ratio

changes so blood flow during early and late filling

is about equal.

The next step in this chain of events is contraction or systole, and here the puzzle becomes

more complex.

Picture the left ventricle at the end of diastole

filled with a volume of blood that is equal to or

slightly greater than the volume in younger hearts;

this is called end diastolic volume. When the 

contraction occurs, it forces out a certain amount

of blood—the stroke volume. However, not all of

The heart requires more energy and more blood during exertion or other times of stress. These metabolic

images dramatically show the difference in blood flow

through the heart at rest and during stress. Red indicates greater blood flow to that portion of the heart.

AT REST STRESS
15

But on closer examination, there is at least one

important difference between a healthy resting

young heart and an older one: heart rate. When

we’re lying down, the rates of young and old hearts

remain about the same. But when we’re sitting,

heart rate is less in older people compared to

younger men and women, in part, because of

age-associated changes in the sympathetic nervous

system’s signals to the heart’s pacemaker. As we age,

some of the pathways in this system may develop

fibrous tissue and fat deposits. The SA node, the

heart’s natural pacemaker, loses some of its cells.

At Rest During Vigorous Exercise

At Rest During Vigorous Exercise

Size at the start of

heart beat is the

same as at rest.

Size at the end of

heart beat is smaller

than at rest.

At the start of 

heart beat, at rest.

At the end of 

heart beat, at rest.

In men, the heart compensates partly for this

decline in two ways. First, the increase in end 

diastolic volume that comes with age, means there

is more blood to pump; and second, the greater

volume stretches the ventricular walls and brings

into play a peculiar property of muscle cells—the

more they are stretched, the more they contract.

This phenomenon is called the Frank-Starling

mechanism and together with the greater volume

of blood to be pumped, it helps to make up for the

lower heart rate.

At the start of 

heart beat, at rest.

At the end of 

heart beat, at rest.

Size at the start of

heart beat is larger

than at rest.

Size at the end of

heart beat is the

same as at rest.

Young

Heart

Old

Heart

The Heart: Young and Old
16

age 80, a person can only muster about two times

as much cardiac output as at rest.

Yet the aging heart still must respond to many of

the same demands as the younger heart. To do so,

it takes advantage of its natural flexibility. The

heart, which is composed of elastic-like material,

can readily alter shape and size depending on the

amount of blood within its chambers.

At rest, only a small portion of the body’s blood

supply is flowing into the heart at any given

moment. But with exertion, your body sends out

signals that increase blood flow from the veins

back to the heart initially stretching and swelling

it. This triggers the Frank-Starling mechanism. In

response, the young heart pumps harder. Then the

brain kicks in, releasing neurotransmitters that

elevate heart rate, increase contraction strength,

and boost ejection fraction. In addition, the young

heart returns to its small, resting size at the start of

each beat. All of these reactions help the young

heart work more efficiently. (See When the Brain

Talks to the Heart, page 18)

But the older heart doesn’t respond in the same

way. Although the brain still releases neurotransmitters that stimulate the heart to work harder

during vigorous exercise, the older heart is less

responsive to these signals than the younger heart.

And unlike the young heart, it can’t squeeze down

to a small size at the end of a heart beat. So its 

ejection fraction increases only slightly from its

resting level of about 65 percent during vigorous

exercise. In addition, you might recall that the

older heart can’t increase its rate as much as the

younger heart during exertion. So if it can’t beat as

fast or squeeze down as hard, then how does the

older heart respond to the demands of exercise?

The answer is: it adapts.

In women, end diastolic volume while sitting does

not increase with age, so stroke volume does 

not increase. The difference between the sexes

probably reflects their different needs rather than

a difference in their hearts’ pumping abilities.

But while the resting older heart can keep pace

with its younger counterpart, the older heart—

even if in peak condition—is no match for a

younger one during exercise or stress.

Pumping During Exercise

It’s no secret that the ability to run, swim, and

exert ourselves in other ways diminishes as we get

older. In fact, the body’s capacity to perform vigorous exercise declines by about 50 percent between

the ages of 20 and 80. About half of this decline can

be attributed to changes in the typical aging heart.

During any kind of activity—even moving from a

sitting to a standing position—the heart must

pump more blood to the working muscles. In

younger people it does this by increasing the heart

rate and squeezing harder during contractions,

sending more blood with each beat. But age 

brings changes. Heart rate still rises, but it can no

longer rise as high. In your 20s, for instance, your

maximum heart rate is typically about 190 to 200

beats per minute; by age 80, this rate has diminished to about 145 beats per minute. A reduced

response of heart cells to signals from the brain

result in a substantial decline in the peak rate at

which the older heart can beat. In addition, force of

contraction during vigorous exercise increases, but

not as much in older people as in younger ones.

As a result, the heart’s cardiovascular reserve

diminishes. Put another way, a typical 20-year-old

can increase cardiac output during exercise to

31/2-4 times over resting levels. In comparison, by

...the aging heart must respond to many of the same demands as the younger

heart. To do so, it takes advantage of its natural flexibility.
17

Because its pumping rate increases less during

exercise, the older heart has more time than a

younger heart to fill with blood between beats.

This additional filling time, combined with a lower

ejection fraction, causes the older heart to expand

to a larger size during diastole than a young heart.

As a result, during exercise the older, bigger heart

has more blood in its chambers at the start of each

beat than a younger heart. This extra blood volume

allows the older heart to pump out just about as

much blood with each beat as a younger, smaller

heart, even though it has a lower ejection fraction.

This represents the Frank-Starling mechanism

working at its finest. However during vigorous

exercise the older heart is still pumping less blood

overall because it can’t beat as fast as a young heart.

While this adaptation certainly helps the heart

meet the immediate needs of the exercising older

body, it does so at a cost. As the older heart dilates

between beats, wall tension and pressure within its

cavities rises. This increases load on the heart and

forces it to work harder. In the long run, persistently elevated pressure promotes thickening and

stiffening of the ventricular walls. As a result, the

ventricles don’t fully relax between beats, and

this—combined with a greater filling volume—

causes end diastolic left ventricular pressure to

increase. When this happens the left atrial pressure

increases and this pressure increase is transmitted

to the lungs. As pressure rises, oxygenated blood

has trouble getting from your lungs into the left

side of your heart so it can be pumped out to the

body. One outward sign of this scenario within

the lungs is that you begin to feel short of breath

while exerting yourself. How much exercise you

can do before you experience this symptom

depends, in part, on how much of the left ventricle’s

pumping capacity has been eroded. Regular aerobic

exercise can help diminish the impact of many of

these age-related changes.

Changes in the aging heart result in reduced cardiac output during exertion. However, regular

aerobic exercise, such as swimming or water aerobics, can improve fitness and diminish the effects

of these age-related changes.
Parasympathetic Nerve

Slows the heart rate

Spinal

Cord

Chain of Sympathetic Ganglia

Runs parallel to the neck and trunk spine.

Contains nerve cells that relay sympathetic signals

between the brain and the heart and blood vessels.

Brain-heart communication controls how fast and hard the heart beats.

Sympathetic Nerve

Increases the heart rate 

and strength of contraction

When the Brain Talks to the Heart: 

Does Age Make a Difference?

18

Brain
able than a younger heart to increase its heart rate,

augment its contraction strength or boost its cardiac

output to meet the needs of the body.

At first, researchers suspected that the diminished

supply of catecholamines and other neurotransmitters might be the problem. To test this theory,

NIA investigators infused catecholamines into the

blood streams of older and younger volunteers to

simulate the effects of exercise. As expected, the

heart rates of the young men increased. But the

older men’s rates increased less, even though they

received the same supply of catecholamines. So

the problem wasn’t supply.

Could the problem then be somewhere in the

aging cardiovascular system’s response to catecholamines? Studies show that this is probably the

case. There is a drug called propranolol which

blocks the body’s response to catecholamines by

blocking the beta adrenergic receptors on heart

and blood vessel cells. Propranolol and aging have

the same effects, according to a number of studies.

Older hearts and blood vessels, apparently, have

blocked some of these beta adrenergic receptors.

Investigators soon found that with age the number

of beta adrenergic receptors on heart cells did

diminish. But this reduction was only modest.

Instead, studies now suggest that something else

about these receptors changes with age: the 

number of them that are capable of binding with

catecholamines, i.e., those in a “high affinity state,”

seems to decline with age. 

The reason for the reduced response could lie anywhere in the cascade of events in heart muscle

cells that occurs after catecholamine binds to the

receptor. Scientists are finding a host of possible

cellular mechanisms that might explain the

reduced response. They hope once these mechanisms are better understood, they will be able to

find a way to mend the link or prevent it from disrupting messages in the first place. Eventually

such findings could lead to new ways to prevent

heart failure. •

The brain talks to the heart through the nervous

system, using the language of biochemistry.

Substances called neurotransmitters travel from

nerve cell to heart cell, deliver the brain’s messages by binding with special receptors on the

membranes of heart cells, and set off a chain of

molecular events that ends with a faster beating

heart, stronger contractions, and faster relaxation

between beats. Or, depending on what neurotransmitter is used, the brain can tell the heart to

reverse all of these effects.

This heart-brain dialogue occurs through the autonomic nervous system without you having to think

about it. This system automatically regulates all of

the body’s processes like breathing or digestion

that don’t require conscious control. But as we age,

some of these lines of communication begin to fray,

and the heart doesn’t respond to the brain’s messages as promptly or as well as it once did. 

For years, scientists were puzzled by this phenomenon, but they may be getting closer to understanding how and why these messages get muffled.

In particular, investigators are looking at the sympathetic nervous system, the part of the autonomic

nervous system that signals the heart to speed up.

This subsystem helps regulate the heart beat

through a series of signals passed from neurotransmitters to receptors on the membranes of heart

cells. One of these important signaling cascades

starts when neurotransmitters, such as catecholamines, bind to special protein molecules,

called beta adrenergic receptors, on the heart cell

membrane. Once activated by a neurotransmitter,

these beta adrenergic receptors set off a chain of

molecular events that allows more calcium to enter

heart cells. Increased calcium within these cells

can lead to a stronger and more rapid heart beat.

But as we get older, something goes awry in this

signaling cascade. As a result, the older heart

can’t respond to these neurotransmitters, so it

doesn’t react to stress as well as a younger heart.

During exercise, for instance, an older heart is less

19

21

that changes an electrical impulse into a muscle

contraction. These discoveries have led to novel

hypotheses about aging and disease. Scientists have

found that age-related changes in heart muscle

cells (myocytes) help explain alterations in the

heart as a whole. For instance, they’ve learned there

are fewer myocytes to

do the work as we age

and those that remain

enlarge, compromising

their ability to pump

blood efficiently. They’ve

also discovered much

about how these changes

could interact with disease processes and found

clues to how exercise

affects the biochemistry

of cells. Scientists have

begun to question some

of the long-held theories

about the nature of the

aging heart, including

whether some myocytes can replicate and what

role aging may have in this process. And they’ve

learned a great deal more about the critical role

calcium plays in the drama of the aging heart.

CELLULAR Clues

Under a microscope, the true grandeur of the heart

reveals itself. Magnified, a rod-shaped heart muscle

cell taps out a constant beat.A closer look within the

cell reveals a series of thin contractile fibers called

myofilaments that are the machinery driving these

contractions. In the left ventricle alone, there are

nearly 5 billion of these cells beating rhythmically, as

if they are all listening to the same snappy tune.

The chemical chain of events that underlies the

beating of these cells and of the heart as a whole is

truly remarkable. First, there’s the electrical

impulse along the cell’s membrane; then channels

open in the cell membrane allowing sodium to

flow into the cell. After that, more channels open

and calcium enters and binds to a tiny structure

near the membrane; then, much more calcium

explodes out of that structure into the cell’s inner

fluid and combines with a myofilament protein

called troponin. Troponin then changes shape to

allow two other proteins, actin and myosin, to come

together. The joined proteins slide past each other

in such a way as to shorten the cell, pulling the ends

of the cell inward—this is the actual contraction—

and then the whole process reverses itself as the

heart relaxes in preparation for the next beat.

During the past 30 years, scientists have made

some intriguing discoveries about the process 

The sustained dependability of a tireless heart relies...on the 

performance of the trillions of chemical reactions occurring in its

aggregate of cells every instant of its function.

SHERWIN NULAND, MD, AUTHOR OF THE WISDOM OF THE BODY, 1997

Magnified, a rod-shaped heart

muscle cell (myocyte) contracts its

myofilaments. Billions of these

cells contracting in synchronization produce a heart beat.
22

The Marvelous Calcium Pump

Scientists have long known that calcium—the

mineral that helps keep your teeth and bones

strong—also has an important job within your

heart. Calcium entering the myocyte’s inner fluid

or cytosol binds with other contractile proteins to

bring about contraction. Calcium leaving the

cytosol allows the cell to relax. It’s this constantly

changing ebb and flow of calcium in and out of the

cytosol of heart muscle cells that is the essence of the

heart beat. (See How a Myocyte Contracts, page 23)

At the beginning of the calcium cycle—which

coincides with the heart filling with blood—

calcium in the cytosol and surrounding the contractile filaments of each myocyte is at least 10,000

times lower than calcium levels in your blood and

in other fluids between your cells,called the intercellular spaces. As the cycle progresses, pores (or

channels) in cell membranes open and close,

allowing various salts to flow in and out of the cell.

This activity triggers momentary fluctuations in

the positive and negative electrical charges across

the cell’s membrane. When these fluctuations

reach a particular threshold, an electrical discharge

occurs. This discharge, called the action potential,

essentially flips a switch on the myocyte’s membrane to open pores that allow a small amount of

calcium to enter the cell.

This tiny bit of calcium binds to openings called

calcium release channels on the sarcoplasmic

reticulum, an organelle (a small cellular “organ”)

that serves as a storage bin for calcium. In

response, the sarcoplasmic reticulum releases a

large amount of its stored calcium into the cell.

The calcium released from this storage compartment binds to the cell’s myofilaments, causing

them to tighten or shorten. As the myofilaments

tighten, the myocyte compresses (shrinking in

length and fattening in width). This process

occurs almost simultaneously in every cell in the

heart wall, causing them to contract and pump

blood out of the heart.

In order for the heart to relax, the cycle winds

down and calcium detaches from the myofilaments.

A cellular mechanism kicks in and pumps most of

the calcium back into the storage bins located in

the sarcoplasmic reticulum. Any residual calcium

is driven out of the cell through specialized exit

calcium carriers located on the cell’s membrane.

These carriers are proteins that swap calcium

inside the cell for sodium outside of it. Then the

cycle restarts in preparation for the next heart beat.

If this system fails, and calcium cycling gets out of

whack, chaos can ensue. The heart, for instance,

can’t relax and fill with blood properly and diastolic

pressure in the heart increases. In addition, individual cells may fire off rapidly and independently,

resulting in arrhythmias—variations from the

normal heart beat rhythm—and fibrillation,

which is a very rapid twitching of individual 

muscle fibers. In particular, older hearts are more

susceptible to spontaneous calcium oscillations

than younger hearts, and it takes fewer oscillations

to bring about fibrillation. Fibrillation in the left

ventricle leads quickly to acute heart failure and to

death if not treated.

Heart failure occurs when the heart loses its ability

to pump enough blood to meet the body’s

requirements. In particular, heart failure causes

the heart to gradually lose its reserve pumping

Between heart beats, calcium levels (red) diminish in a myocyte’s

inner fluid or cytosol, allowing it to relax (left). During contraction, a large amount of calcium surges out of a myocyte’s

sarcoplasmic reticulum, right, triggering tightening or shortening of the cell’s muscle fibers (right). This process occurs

almost simultaneously in every cell in the heart wall, causing

them to contract and pump blood out of the heart.
Ca

4

5

6

How a Myocyte Contracts

Sarcoplasmic

Reticulum

Contractile Protein

(before contraction)

Contractile Protein

(during contraction)

Calcium 

Pump Protein

Calcium Releasing

Channel Protein

3

1

1 2

Sodium ( ) channels

open in membrane

causing change in 

electrical charge. 

This causes surface

membrane Calcium 

( ) channels to open,

causing small Ca influx.

Ca

Na

3 Calcium binds 

to calcium releasing

channel protein on

sarcoplasmic reticulum.

4 A large amount of 

calcium is released from 

sarcoplasmic reticulum.

Calcium activates the

contractile proteins.

Cell contracts.

Calcium disengages

from the contractile

proteins. Most is

pumped back into the

sarcoplasmic reticulum.

Some calcium leaves

the cell.

Cell relaxes and cycle

renews.

Action Potential

CONTRACTS IN LENGTH 

FATTENS IN WIDTH

Contracted

Relaxed

7

2

6

7

5

23
24

capacity and work less efficiently. Blood pressure

and flow to body organs drops. The kidneys sense

this and send out signals prompting retention of

body fluid, which contributes to swelling. This can

cause a backup of fluid into the lungs and body

tissues triggering shortness of breath, swelling of

the legs and feet, and other symptoms. As heart

failure progresses the effects can become quite

severe, and patients often lose the ability to perform even modest physical activity. Eventually, the

heart's reduced pumping capacity may interfere

with routine tasks, and individuals may become

unable to care for themselves. Heart failure rises

exponentially with advancing age, and studies of

the calcium cycle in heart cells suggest a number

of possible reasons.

When a Good Pump Goes Bad

Imagine sitting calmly in a living room chair when

the smoke detector goes off. As you scramble to

quickly get out of the house, your heart starts

beating faster. A few moments later, after you 

discover it was a false alarm, you return to your

comfortable chair, and your heart rate slows

again. As this scenario suggests, your heart beat

can vary from moment to moment. And your

heart’s ability to respond to these changes depends

a lot on calcium. The more calcium your heart

cells release from their intracellular storage bins,

the greater the force of the heart’s contractions.

But how well these mechanisms work depends on

how much calcium can be pumped from these

storage bins between heart beats. In young hearts,

these calcium pumps work quite well, but in older

hearts these pumps are much less efficient.

After the heart beat,if you recall,most of the calcium

returns to the storage bins in the sarcoplasmic

reticulum and then awaits the next signal to do its

job again. Scientists began taking a closer look at

this mechanism when they learned that muscle

from older hearts takes longer to relax than muscle

from younger hearts. One of the prime suspects

for this phenomenon was calcium. To test this

idea, Dr. Lakatta and his colleagues at the NIA used

a protein that binds to calcium and gives off a blue

light to detect how much calcium is in a cell at any

one time. When they injected this calcium-sensing

protein into myocytes within heart muscle in laboratory dishes, the blue light showed that calcium

levels, after a contraction, fell more slowly in older

myocytes. Or, putting it in biologists’ terms, the

cytosolic calcium transit was longer. But why?

Could the calcium be spending longer in the inner

fluid because the sarcoplasmic reticulum wasn’t

removing it as quickly in older cells?

The answer was yes. In experiments, NIA scientists

isolated the sarcoplasmic reticulum from the rest

of the heart cell, placed it in a test tube, and then

added calcium. The sarcoplasmic reticulum took

up the calcium more slowly in samples from older

animals than those from younger ones.

Subsequent studies confirmed that the sarcoplasmic

reticulum—or more precisely, a protein on this

organelle—removes calcium more slowly in older

hearts. Researchers have found that older cells

have lower amounts of this particular protein,

often called the calcium pump protein because it

removes the calcium in a series of repeated movements. In essence, the sarcoplasmic reticulum

removes calcium from the inner fluid more slowly

in older hearts because there are fewer pumps,

and those that remain don’t work as well because

of communication breakdowns between the brain

and the heart.

Like other changes, the longer calcium transient appears to be one way that the heart

adjusts to age, or more specifically to the stiffer arteries that accompany aging.

Unfortunately, like those other changes, this adjustment also has a cost.
25

If these pumps aren’t working properly or have

shut down, the sarcoplasmic reticulum won’t fill

as well as it should with calcium, and there won’t

be enough calcium to fulfill the heart cells’ needs,

particularly during exercise or stress.

Once scientists learned about the pump protein,

the next question was about that protein’s gene.

Proteins make up a huge category that includes

enzymes, growth factors, hormones—almost all

the substances that are responsible for the day-today functioning of living organisms. Proteins are

produced by genes in the nucleus of every cell.

Each protein has its own gene. Cells translate gene

codes into proteins through a complex, multistep

process called gene expression. Any alteration in

this process can lead to changes in the end product,

the protein.

In the case of the pump protein, the gene that 

produces it is only about half as active in older

hearts as in younger hearts. The end result of all of

these changes is a decline with age in the maximum strength of the heart beat during strenuous

activity. Reduced calcium pumping also prolongs

the time it takes for heart cells—and in turn, the

heart as a whole—to return to a relaxed state. As a

consequence, the heart can’t fill with blood as

readily as it once did and prepare for the next

heart beat.

Like other changes, the longer calcium transient

appears to be one way that the heart adjusts to age,

or more specifically to the stiffer arteries that

accompany aging. Unfortunately, like those other

changes, this adjustment also has a cost.

“It makes sense from an engineering standpoint

to have a longer contraction if you’re pumping

blood into stiffer vessels,” Dr. Lakatta says. “The

downside is that when you alter the dynamics of

calcium, various stresses can more easily throw

the calcium out of balance. One consequence of

this is that an older person is more apt to feel short

of breath during vigorous exercise.”

Age Lengthens Action Potential

In addition to calcium transit, two other clusters

of events in myocytes seem to be affected by age.

One is the action potential. This is a transient

alteration in the amounts of positive and negative

charges on either side of the myocyte membrane.

As mentioned earlier, the action potential triggers

the opening of sodium and then calcium channels

in the membrane.

The action potential is prolonged in older hearts

and may contribute to the longer calcium transient. This occurs because as the heart ages, there

are coordinated declines in both the activity 

and number of proteins involved in the action

potential as well as the proteins that respond to its

signals. A longer action potential generates a

longer calcium transit, which in turn, produces 

a longer contraction. Each of these processes is

controlled by specific proteins.

The prolonged action potential helps older hearts

work well in most situations. It does this in two

ways. First, pores on the myocyte’s membrane

stay open longer to allow more calcium to enter

the cell between beats. Second, the proteins that

carry calcium out of the cell and sodium back 

in work more slowly. The net result is that more

calcium is available within the cell. These effects

allow the weaker sarcoplasmic reticulum—which

has fewer pumps—to load up on calcium in preparation for the next beat. But these adjustments,

like so many other cardiovascular adaptations,

may have a downside. For instance, in an aging

heart the long action potential adaptation works

well at slower heart rates. But during a rapid heart

rate, the longer action potential contributes to 

calcium dysregulation of myocytes. As a result,

the older heart doesn’t respond as dynamically 

to the needs of the body as a young heart. So, a

prolonged action potential is yet another possible

reason that an older person usually can’t do as

much exercise as someone younger.
26

actually help the older heart work more efficiently.

That’s because slower and longer contractions

don’t use as much energy. Prolonged contractions

also allow the older heart to eject blood into the

arteries later in the heartbeat. This adaptation is

good because it improves the blood flow through

an older person’s stiffer arteries.

Free Radical Damage

Myocytes produce free radicals, unstable oxygen

molecules that can disrupt a cell’s inner workings.

As the heart ages, these free radicals can greatly

alter how well the cellular calcium pumps on the

sarcoplasmic reticulum work.

In myocytes, most free radicals are produced in tiny

cellular organelles called mitochondria and by an

enzyme in cell membranes called NADPH oxidase.

Mitochondria convert oxygen and food into an

energy-releasing molecule that powers most cellular

processes. But during this process they also produce

potentially harmful byproducts such as oxygen free

radicals. A free radical can be produced by almost

any molecule when it loses an electron from one or

more of its atoms. In heart muscle cells, they are

commonly created when mitochondria combine

oxygen with hydrogen to form water. Free radicals

can cause extensive damage to proteins, membranes,

and DNA. As we age, mitochondria become less

efficient, progressively generating less energyreleasing molecules and more free radicals.

In the aging heart, free radicals damage proteins,

membranes, and calcium pumps on the sarcoplasmic reticulum that myocytes need to produce

contractions. As a result of this cellular damage,

myocytes can’t process calcium as well. As calcium builds up in the cell, it can begin to contract 

Contractile Proteins

The other mechanisms that change with age

involve contractile proteins—actin, myosin, troponin, and others—that interact to shorten, or

contract, the myocyte. These contractile proteins

pass through a series of steps, triggered by 

calcium, which bring actin and myosin together

into crossbridges. The crossbridges use energy

released during the transaction to shorten the cell.

With age, one part of the crossbridge alters—the

part called the myosin heavy chain.

The myosin heavy chain can be produced in two

slightly different forms, one dubbed alpha, the

other beta. In experimental animals, the alpha

myosin heavy chain decreases with age, while the

beta increases. The same seems to be true in the

human atrium. When the proportion of alpha

myosin heavy chain is reduced in isolated cells, the

contraction speed is slower.

Changes in the myosin heavy chain have been

traced back to the genes involved—alpha is

expressed less with age, beta more. The expression

of these genes is regulated by proteins called 

transcription factors that start or regulate the 

first steps of cellular reproduction. One of the

transcription factors for the myosin gene is the

same as that for the sarcoplasmic reticulum pump,

suggesting that there is a common aging link

between the two cellular mechanisms. Studies in

rodents suggest the activity of these factors declines

with age. Because of these changes the expression

of genes in the aging heart tends to go back to 

patterns of gene expression seen in the fetus.

These age-related changes in myosin and other

contractile proteins, in conjunction with alterations in calcium transit and action potential,

Prolonged contractions also allow the older heart to eject blood into the arteries later

in the heartbeat. This adaptation is good because it improves the blood flow through

an older person’s stiffer arteries. 
27

erratically,causing an arrhythmia.If this arrhythmia

spreads to other cells, it can eventually disrupt

beating throughout the heart and lead to serious

complications.

Nitric Oxide 

Calcium isn’t the only factor that helps the heart

respond to the body’s increased need for blood

and oxygen during sustained exertion or times of

stress. Nitric oxide, a potent chemical messenger

that helps regulate blood flow in the arteries, also

signals the heart to pump harder at critical times.

As we just learned, heart cells can increase their

contraction force by releasing more calcium from

the sacroplasmic reticulum. Once released from

this cellular storage bin, calcium binds to troponin

and other contractile proteins, which trigger the

heart beat. The more calcium that binds to these

contractile proteins, the greater the force of the

contraction. But there’s at least one other pathway,

the Frank-Starling mechanism, that can increase

the force of these contractions. This mechanism

kicks in when increased blood flow into the heart

stretches myocytes, signaling them to contract

harder and produce more force. Normally, these

two pathways work independently to tap the heart’s

reserve capacity. But if cell stretch is sustained

for prolonged periods, the amount of calcium

released into heart cells during contractions gradually increases. This suggests that some coordinating

mechanism is operating to ensure that, even

under duress, the heart continues to pump

enough blood to the body. But what this link

might be mystified scientists for many years.

Steven Sollott, MD and his colleagues at the NIA

theorized that sustained cell stretch prompts an

enzyme, nitric oxide synthase, to produce nitric

oxide. Nitric oxide, in turn, binds to the calcium

release channels in the sarcoplasmic reticulum

and promotes the release of calcium into the cell.

To test this theory, the investigators conducted a

series of experiments with adult rats and mice—

mammals with cardiovascular systems similar to

humans. Some rodents were genetically altered so

they could not produce the enzyme that makes nitric

oxide. Others were given drugs that blocked the

production of the chemical messenger.In both cases,

sustained cell stretch no longer triggered increased

calcium release in heart cells. Previous studies have

shown that nitric oxide levels may be diminished

in heart failure and other cardiovascular diseases.

“Knowing that this nitric oxide mechanism exists

and how it functions in the normal heart may help

us understand what happens to it with age and disease,” Dr. Sollott says. “This discovery offers scientists an opportunity to consider whether therapies

that sustain or enhance the functioning of this

mechanism might help aging hearts stay healthy

and continue working properly.”

Before contraction During contraction

Contractile Proteins
28

New ideas are also emerging about two other 

phenomena that have puzzled gerontologists and

cardiovascular scientists for decades. As heart cells

get older, there are fewer of them to do the necessary

work, and those that remain get bigger.

Bigger Heart Cells...

To efficiently pump blood, the stiffness of the

heart changes as it beats. When it is filling, the

heart needs to be as relaxed as possible to allow

blood to freely flow into it. When it contracts, it

stiffens so that the pressure it exerts is greater than

that found in the arteries. When this happens,

blood is forced into the arteries with a minimal

amount of effort. If there is a load mismatch—

meaning the force differential between the heart

and arteries isn’t very good—the heart can’t

empty as well as it once did. As a result, the heart

has to work harder to get blood into the arteries.

If this occurs on a regular basis, some heart cells

die, others enlarge, and the heart walls thicken.

This problem gradually increases as we get older.

In some cases, the cells that remain enlarge up to 

40 percent. The enlargement of these remaining

myocytes seems to be the principal mechanism

for the thickening of the heart walls—the hypertrophy—that occurs with normal aging.

Much evidence suggests that myocyte enlargement

and the consequent thickening of the heart walls

are ways that the heart adjusts to increased loads,

especially from the growing stiffness of the arteries.

Extra loads also may develop as the result of disease.

One reason cardiovascular researchers are so

intrigued by myocyte enlargement is because of its

possible links to disease. While enlargement seems

to occur in response to aging and stiffening of the

arteries, it is exaggerated by disease, such as coronary artery disease and high blood pressure.

(However, enlargement occurs with high blood

pressure at any age).

Opposing Pressures:

Heart Cavity Pressure

vs. Aortic Pressure

Aortic pressure, which increases as

blood is pumped into it, impedes further ejection of blood from the heart.

Heart cavity pressure, 

due to contraction of heart

muscle cells within the wall, 

is exerted against blood.

1

1

2

2
29

While myocyte enlargement seems to be one way

that the heart adapts to increased loads, there is

also evidence that at the oldest ages, it no longer

adapts as much. Older animals, for instance, have

less enlargement in response to heart overloads

than younger animals. This failure or slowing of the

adaptive response may explain why 80-year-olds

are much more likely to experience heart failure

following a heart attack than 60-year-olds.

These findings are yet another clue suggesting that

specific age-associated changes in healthy hearts

and blood vessels compromise their ability to

respond to everyday stress and strain. In turn, these

changes gradually lower the heart’s resistance to

certain cardiovascular conditions including left

ventricular hypertrophy, atrial fibrillation, and

congestive heart failure.

...But Fewer of Them

As we age, even the healthiest hearts lose cells. In 

a robust 70-year-old man without heart disease 

or high blood pressure, these age-related losses 

are estimated to account for up to a 30 percent

reduction in the total number of myocytes in the

heart. Although it’s unclear whether this loss of

heart cells is good or bad for the body as a whole,

evidence suggests that loss of a significant number

of heart cells may contribute to the decline in 

cardiovascular health in older people.

Cardiovascular scientists are exploring why some

myocytes die while others continue to thrive.

Injury, due to a lack of oxygen or ischemia, seems

to be one of the prime killers. But studies suggest

that programmed cell death—apoptosis—could

be a significant factor as well.

Apoptosis is a process in which a cell orders itself

to stop functioning, shrink, and ultimately dissolve.

It has been observed in other cells in the body,

where it may be a mechanism for adjusting to

development or removing unwanted or potentially

dangerous cells, such as cancer cells, from the

body. At least one study suggests that apoptosis in

the heart becomes more common with age. And

other research has found that excessive apoptosis

may contribute to decline in the aging cardiovascular system.

A number of molecular processes, such as

increased free radical production, can activate a

cell’s apoptotic or self-destruct mechanism. In

rodents, for instance, NIA grantee Christiaan

Leewenburgh, PhD, of the University of Florida

and his colleagues found that cytochrome c, a

mitochrondial protein, becomes a signal for cell

death if it “leaks” from the mitochondria. The

hearts of older rats

released greater

amounts of that

cell-death signal

than did the hearts

of younger rats.

This difference may

be partly responsible for the increase

in heart cell death.

Cardiovascular scientists studying apoptosis are

particularly interested in the role of a process

called cardiac stretch. Myocytes are connected, so

when one dies—for whatever reason—others

must stretch to maintain the connections. As

myocytes are stretched, they release chemical 

substances called growth factors, such as norepinephrine and angiotensin. These growth factors

may not only help explain why these cells enlarge,

but also why some of them die. In laboratory dishes,

for instance, the same growth factors that regulate

heart cell growth also trigger apoptosis in some

myocytes. However, these and other growth factors may have an equally important role in a

process that was once thought to be impossible:

the replication and regeneration of heart cells.

Christiaan Leewenburgh, PhD
30

The Untapped Promise of

the Aging Heart

For decades it was believed that the heart had a set

number of myocytes, and once one of these cells

died, they couldn’t be replaced. Because these cells

were thought to be unable to divide, according to

this view, their numbers progressively decreased

with age and ultimately impaired heart function.

While this view was widely accepted, it was never

proven. And now, compelling but controversial

evidence raises new questions about its validity.

One of the first challenges to this dogma came

in 2001 when scientists from New York Medical

College in Valhalla, New York found large scale

replication of heart

muscle cells in two

regions of the heart,

and identified several

other key indicators

of cell regeneration.

These scientists, led

by NIA-grantee Piero

Anversa, MD studied

myocytes from the

hearts of 13 patients,

4 to 12 days after their heart attacks, and from the

hearts of 10 patients who did not have cardiovascular disease. Samples were obtained from the border zone near the site of the heart attack and from

a more distant site from the damaged tissue.

By viewing these areas of the heart with a high resolution confocal microscope, the investigators

were able to measure the expression of a protein

found in the nucleus of dividing heart muscle cells.

This protein is expressed during all phases of a

cell’s life cycle and is a strong indicator of ongoing

cell division.

The scientists also obtained images of cell division

and found other evidence of myocyte replication,

including the formation of the mitotic spindle,

and contractile ring, critical structural indicators

of cell division. In comparison with normal

hearts, the number of myocytes multiplying in

diseased hearts was 70 times higher in the border

zone and 24 times higher in the remote tissue.

But where were these new hearts cells coming

from? Subsequent studies—in both animals and

humans—suggested that, although most adult

heart cells probably aren’t able to replicate, a small

core of adult stem cells might exist in the heart or in

the bone marrow that are capable of replenishing

and replacing damaged or dying myocytes.

However, other scientists have had difficulty

duplicating these results. So for now, the notion

that adult stem cells can regenerate heart muscle

remains a tantalizing, but unproven, possibility.

Some cardiologists theorize that adult stem cells

in young hearts might be able to produce enough

new myocytes to replace those that are naturally

dying. In effect, these stem cells might help keep

the total number of myocytes stable in the young

heart. But mounting evidence suggests that even if

these stem cells exist, their numbers decline with

age. As a result, some scientists suspect there are

fewer new heart cells to replace older ones which

are dying in greater numbers due to age, injury,

and other problems. So the deterioration of the

older heart could be related, in part, to the inability

of aging cardiac stem cells to replace dead and

dying myocytes with new ones.

Gerontologists exploring this exciting new area of

research have many questions, but few answers at

this point. For instance, does the number of cardiac

stem cells really decline with age? What role do

growth factors play in regulating the activity of these

cells? How are the changes in cardiac stem cells

linked to other age-related alterations in the heart

and arteries? Why are scientists having so much

difficulty replicating the earlier findings? Are the

myocytes in the heart of an 80-year-old basically

the same ones present in his or her heart at birth

or have the cells been gradually replaced over the

Piero Anversa, MD 
years like the skin? And perhaps most importantly,

if these stem cells exist, can anything be done to

stimulate them to produce new myocytes that will

counteract the effects of age in the older heart?

The key to answering this final question lies in

learning more about stem cells and how they

work. Investigators already know that stem cells

have important characteristics that distinguish

them from other types of cells. Unlike most cells in

the body, such as skin or brain cells, which are dedicated to performing a specific function, stem cells

are not specialists. But under certain physiologic or

experimental conditions, they can be induced to

become cells with special functions such as the

beating cells of the heart muscle or the insulinproducing cells of the pancreas. Another unique

characteristic of stem cells is their ability to renew

themselves for long periods through cell division.

Scientists primarily work with two kinds of stem

cells from animals and humans: embryonic stem

cells and adult stem cells. Most of the basic science

research discoveries on embryonic and adult stem

cells come from research involving animals,

particularly mice. Embryonic stem cells are

derived from embryos. Specifically, embryonic

stem cells are derived from embryos that develop

from eggs that have been fertilized in vitro.

Adult stem cells typically generate the cell types of

the tissue in which they reside. A blood-forming

adult stem cell in the bone marrow, for example,

normally produces many types of blood cells such

as red blood cells, white blood cells, and platelets.

Until recently, it had been thought that a bloodforming cell in the bone marrow—which is called

a hematopoietic stem cell—could not give rise to

the cells of a very different tissue, such as myocytes

in the heart. However, a number of experiments

over the last several years have raised the possibility that stem cells from one tissue may be able to

make cell types of a completely different tissue, a

phenomenon known as plasticity.

Because of this flexibility, stem cells hold enormous

potential for cell replacement or tissue repair in

heart disease and many other age-associated 

disorders. Gerontologists are seeking to find out if

these cells will yield any practical interventions

that might promote healthy aging.

“We’ve made substantial progress, but there is a lot

more to be learned,” according to Dr. Lakatta.

“Finding ways to activate these cells and get them

to where they are needed in the heart and ensuring

that they develop into heart cells are significant

challenges.”

While daunting, these and other challenges are

motivating gerontologists to investigate many

new interventions that in the future could help

keep aging hearts and arteries healthy.

As we age, for instance, pressure increases in the

arteries, and this can affect the structure and function of the left ventricle. In fact, a growing number

of scientists suspect that age-related changes in

the blood vessels may actually instigate many of

the transformations that occur in the older heart.

31

In this microscopic image, adult myocytes (red) surround a cluster of stem cells (blue) growing to maturity in the heart. Many questions remain about

these cells and their potential role in the aging heart.

33

Blood Vessels and Aging:

THE REST OF THE JOURNEY

Stretched end-to-end, the arteries, veins, and

other vessels of the human circulatory system

would measure about 60,000 miles. On any given

day, the heart pumps about 1,800 gallons of blood

through this vast network. In an average lifetime,

the heart pumps approximately one million barrels

of blood—enough to fill more than 3 supertankers—through the circulatory system.

No doubt about it, the heart and arteries are

remarkable. But as we age, the cardiovascular system becomes more susceptible to diseases including high blood pressure and atherosclerosis.

Nearly 40 percent of all deaths among those 65

and older can be attributed to heart problems. By

age 80, men are nine times more likely to die of

chronic heart failure than they were at age 50.

Among women, this risk increases 11-fold over

the same time period.

Certainly, poor lifestyle—smoking, little or no

regular exercise, a diet laden with fat, cholesterol,

and sodium—contribute to the development of

these cardiovascular disorders. But it is becoming

more apparent that like the heart, blood vessels

undergo changes with advancing age, and these

changes, including arterial stiffening and thickening, are major risk factors for these diseases.

This relationship is complex. In fact, studies—in

both animals and humans—have found that

many of the factors that underlie the age-related

changes in the arteries are also implicated in the

development of cardiovascular disease. This suggests that there are some common links between

these two distinct, but intertwined processes.

Based on these and other findings, some investigators theorize that aging is the driving force in

a cycle that begins with age-related changes in

the blood vessels. These changes create an environment that promotes arterial stiffening, which

A man is as old as his arteries.

THOMAS SYDENHAM, MD, ENGLISH PHYSICIAN, 1624-1689

In a healthy artery, the lumen (dark center), where

blood flows, is surrounded by arterial wall (red).

Age-related changes in the arteries, such as arterial

thickening and stiffening, can make them more susceptible to cardiovascular diseases.
34

contributes to development of hypertension (high

blood pressure). At the same time, age-related

changes also make it easier for fatty deposits to build

up on the inside of arteries. This accumulation, part

of a process known as atherosclerosis, can accelerate

the aging of the arteries, which, in turn, leads to further fatty build up and narrowing of the vessel. (See

What Happens During Atherosclerosis? page 35)

In essence, aging arteries form an alliance with risk

factors for atherosclerosis, hypertension, and other

precursors of heart disease and stroke to profoundly

elevate the risk of developing these conditions.

However, as scientists learn more about the changes

that occur in aging blood vessels, they are making

some key discoveries. For instance, in some people

these changes occur at an accelerated rate; in others,

they occur much more slowly than average. This

suggests that how well your arteries perform as you

get older depends on a series of complex interactions among age, disease, lifestyle, and genetics,

Dr. Lakatta says. In any case, epidemiological studies

have consistently shown that people with the greatest

amount of arterial stiffening and thickening are at

the highest risk for developing stroke, heart attack,

and other cardiovascular events.

But investigators also now know that several of

these changes, such as arterial stiffening and thickening, don’t occur to the same extent in all people.

In fact, studies strongly suggest that exercise, good

nutrition, and emerging drug therapies can slow

the aging of the blood vessels, even among people

who are genetically at risk. These interventions

could delay or prevent the onset of cardiovascular

diseases in many older people.

“We’re moving into an era when it will be

imperative to find out what your blood vessels

are like before clinical disease sets in so that, if

necessary, appropriate measures can be taken to

keep your cardiovascular system as healthy as

possible,” Dr. Lakatta says.

In Search of a Connection

So, what made scientists think there might be a

connection between stiffening and thickening of

arteries and heart function? It goes back to what

they have learned in the past few decades, partly

through NIA’s Baltimore Longitudinal Study of

Aging. By comparing younger and older volunteers, scientists have been able to put together a

picture of what happens both in the heart and in

the blood vessels as people age.

The heart, they have learned, adjusts in many subtle and interconnecting ways: It develops thicker

walls, and it fills with blood and pumps the blood

out in a different pattern and even by somewhat

different mechanisms than when young. But it is

also becoming clear that many of these adjustments are made in response to changes in the

structure of the aging blood vessels, particularly

the arteries. For instance, NIA studies show that

among those with the stiffest arteries, heart walls

are thicker.

To picture how these and other changes influence

cardiovascular health, imagine an animated computer graphic of the arteries at, say, age 25, when

the walls are still fairly smooth, slick, and compliant. As the heart contracts, the aortic valve opens

and blood is pumped into the aorta, the largest

artery in the body, and flows up toward the neck,

where the carotid artery branches off to take blood

to the head and brain, and then down toward the

rest of the body. When the aorta receives the rushing pulse of blood from the heart, it also receives

pressure spreading from the walls of the heart to its

own walls. This pressure travels along the aorta’s

walls in wave after wave until it reaches the walls of

the smaller branching arteries that take the blood

to the rest of the body. There, the speed of these

pressure waves—known as pulse wave velocity—

slows, and some are sent back through the aorta

walls, becoming what are called wave reflections.
What Happens During Atherosclerosis?

Inflammation is a key factor in the development of atherosclerosis. As LDL cholesterol accumulates in the

arterial wall, it undergoes chemical changes and signals to endothelial cells to latch onto white blood cells

circulating in the blood. These immune cells penetrate the intima and trigger an inflammatory response,

devouring LDLs, to become fat-laden “foam cells” and form a fatty streak, the earliest stage of atherosclerotic plaque. The plaque continues to grow and forms a fibrous cap. Substances released by foam cells can

eventually destabilize the cap, allowing it to rupture, causing a blood clot which can block blood flow and 

trigger a heart attack.

A therosclerosis (ath-er-o-skle-RO-sis) is the 

build-up of fatty deposits called plaque on

the inside walls of arteries. Plaque is a combination of cholesterol, other fatty materials, calcium,

and blood components that stick to the artery

wall lining. A hard shell or scar covers the

plaque. As plaque builds up in an artery, the

artery gradually narrows and can become

clogged. As an artery becomes more and more

narrowed, less blood can flow through. The artery

may also become less elastic.

Most plaque buildup occurs in medium to large

arteries and many investigators suspect that this

buildup begins with changes in the endothelium,

the innermost layer of the artery. These changes

cause white blood cells to stick to the endothelial

cells, weakening the barrier between the endothelium and the other layers of the artery. This allows

fats, cholesterol, calcium, platelets, and cellular

debris to accumulate in artery walls. In turn, this

accumulation can stimulate other arterial wall

changes that lead to the additional thickening of

the endothelium and the formation of plaques.

Plaques have various sizes and shapes. Some

plaques are unstable and can rupture or burst.

When this happens, it causes blood clotting

inside the artery. If a blood clot totally blocks the

artery, it stops blood flow completely. This is

what happens in most heart attacks and strokes.

There are usually no symptoms, such as pain,

until one or more artery is so clogged with plaque

that blood flow is severely reduced.

All of this takes time. In fact, atherosclerosis is a

slow, progressive condition that often starts in

childhood. But by age 65 it affects one out of

every two adults. Scientists at the National

Heart, Lung, and Blood Institute are studying

why and how the arteries become damaged with

age, how plaques develops and changes over

time, and why plaques can break open and lead

to blood clots. In particular, they have identified

the age-related changes in the arteries discussed

in this booklet as the major catalyst for the development of atherosclerosis. Research is underway

to find drugs that might delay or prevent these

age-related vascular changes and, in turn, reduce

the risk of atherosclerosis.

There are a number of other risk factors, such as

smoking, high blood pressure, and high blood

cholesterol that can be modified with a diet,

exercise, and other lifestyle changes. The more

risk factors you have, the more likely it is that you

have atherosclerosis. Talk with your health care

provider about your risks for atherosclerosis and

cardiovascular disease and what you can do to

reduce them. • 35

1

1

2

2

3

3
RESISTANCE TO 

PULSATILE FLOW

As arteries stiffen, 

they resist the flow 

of blood, especially 

the pulsatile flow 

in the large arteries 

nearest the heart. 

This resistance, 

called impedance, 

is a key factor in 

rising systolic blood

pressures with age.

ARTERIES

Large arteries such as the aorta stiffen

with age; no longer expand as much

during exercise. In the intima, the

inner layer of these blood vessels,

endothelial cell function is impaired

with age. Angiogenesis, the ability to

form new blood vessels, declines in 

small arteries.

Age and Arteries 

Blood flows from the heart through the arteries (red blood vessels) and back to the heart through

veins (blue blood vessels). Age brings numerous changes to the arteries including:

BARORECEPTOR

RESPONSE

Pressure sensitive

nerves in the aorta

help regulate 

heart rate; the

response grows

weaker with age.

PERIPHERAL 

VASCULAR RESISTANCE

Farther away from the heart,

resistance to the smoother 

flow of blood in the arteries,

governed by arterioles, 

determines peripheral 

vascular resistance. With 

age, resistance increases only

slightly in most people who

do not have hypertension. It

increases usually in people

with high blood pressure,

particularly high diastolic

pressure.

36
Now, add 50 years to this picture. The arteries,

including the aorta, grow stiffer and dilate; their

walls become thicker, their diameter larger. As a

result, the stiffer vessels no longer expand and

contract as much as they once did with each heart

beat. Eventually, the opposition to the flow of blood

by the stiffer aorta walls increases significantly.

Along the walls of the stiffer aorta, the pressure

waves move more rapidly, and as a result, the

wave reflections occur sooner than they did

before. The timing of the wave reflection, in fact,

is one of the effects of arterial stiffness that can be

measured noninvasively. Epidemiological studies

using these measures have determined that high

aortic pulse wave velocity (aPWV) is an independent predictor of arterial stiffness and cardiovascular disease and death.

As the walls of the large arteries become stiffer,

diastolic blood pressure tends to drop and systolic

blood pressure rises. The difference between these

two numbers is called pulse pressure. High pulse

pressure—greater than 60 millimeters of mercury—

is associated with greater thickening and stiffening

of arterial walls. In turn, arterial stiffening and

thickening contribute to increased pulse pressure.

Many studies have found that elevated pulse pressure is also an important risk factor for stroke and

heart attack.

Next, picture the effects of movement—when 

a person sits up, stands up, or begins to walk 

or run—the heart rate increases and blood pressure changes. A group of pressure sensitive nerves

in the base of the carotid artery respond by

sending a message to the brain. The brain in turn

sends a message back to the heart, which changes

its rate and strength of contraction. This

arterial/brain/heart message system is called the

baroreceptor response. Blood vessels also dilate to

allow for the extra blood flow. In addition, blood

is turned away temporarily from those organs that

don’t need it (for instance, the stomach), so that

more can be delivered to the working muscles.

A sectional view of the arterial wall. On the right

is the intima, topped by a layer of cells called the

endothelium. The endothelium acts as a barrier to

prevent certain substances from entering the vessel

wall. In the center, the media is composed of

smooth muscle cells and a network of fibrous proteins. The outermost layer, the adventitia, is composed of connective tissue.

In the older picture, the baroreceptor response is

blunted with age, perhaps as a result of stiffer

arteries. Also, at maximum exercise, the large

arteries do not dilate as much as in the younger

picture. In essence, this age-related stiffening

impedes pulsing blood flow from the heart and

places an increased workload on the heart.

As the blood moves into the smaller arteries, the

hydraulics change. The pulse smoothes out, the

flow becomes more steady. The opposition to this

steady flow is known as peripheral vascular resistance or PVR; so far studies show that among men,

resting PVR does not change with normal aging,

but that it does rise somewhat in women. PVR is

actually elevated in people who have high diastolic

blood pressure, but is also elevated, to a lesser

extent, in people who have high systolic and nearly

normal diastolic blood pressure. This condition,

called systolic hypertension, is so common that 

a person age 55 or older has about a 65 percent

chance of developing it. However, PVR is not Adventitia Media Intima Endothelium

37
38

usually directly measured outside of a research

laboratory setting because of the complexities

involved. Instead, physicians monitor diastolic

blood pressure. If it remains steady or increases

rather than dropping in the presence of aortic

stiffening, it’s a sign of elevated PVR. (See The

Nitty Gritty of High Blood Pressure, page 39)

Inside Every Artery...

Scientists are still sorting out why these aging

changes in blood pressure and PVR occur and what

can be done to prevent them.But one key focal point

of research is the inner workings of the arterial wall.

At first glance a large artery resembles a simple

rubber tube. But like many first impressions, this

is a bit deceiving. The arterial wall is actually comprised of three intricate layers of tissue. The innermost layer, closest to the blood, is called the intima.

The part of the intima nearest to the blood is a

single layer of specialized cells, called endothelial

cells, which sits atop the sub-endothelial space

and a wall called the basement membrane. These

endothelial cells act as a barrier to prevent certain

substances from entering the vessel wall through

the intima. Endothelial cells sense mechanical

signals, such as blood pressure and flow, and

chemical signals, such as oxygen tension, and temperature. In reaction to these signals, they secrete

proteins called cytokines and chemokines as well

as growth factors and other substances that help

regulate the structure and function of the arteries.

The smooth muscle cells in the media, the middle

layer of the artery, are surrounded by a network of

fibers primarily made of two proteins, collagen

and elastin. The elastin forms concentric rings

within the vessel wall. The outermost layer, the

aventitia, is composed of connective tissue and

small blood vessels that feed the walls of large

arteries. Together, these three layers of artery wall

surround the lumen, the opening that blood flows

through on its journey throughout the body. With

age, each of these layers change in complex ways.

...Time Takes its Toll

Aging, for instance, triggers thickening of the intima

and stiffening of the arterial walls. This occurs, in

part, because of a fierce molecular struggle.

Healthy endothelial cells produce nitric oxide, an

important signaling molecule that helps keep

arteries supple. When nitric oxide enters a cell, it

stimulates a biochemical process that relaxes and

dilates blood vessels. Nitric oxide also helps keep

atherosclerosis in check by preventing platelets

and white blood cells from sticking to the blood

vessel walls. The molecule also can curb the

abnormal growth of vascular muscle, which can

thicken blood vessel walls.

But unhealthy endothelial cells are a different

story. In these cells, nitric oxide regulation is

impaired. To make nitric oxide, endothelial cells

need L-arginine, an amino acid that is one of the

basic building blocks of proteins, and an enzyme

called nitric oxide synthase (NOS). Normally,

endothelial cells have plenty of L-arginine and NOS.

But NOS is often in short supply in aging blood

vessels. In addition, people who have heart disease

or who are at high risk of developing it produce a

modified amino acid called asymmetric dimethylarginine (ADMA). ADMA blocks the production

of nitric oxide from L-arginine. Even if sufficient

amounts of nitric oxide are produced, it can be

inactivated by oxygen free radicals, unstable molecules that injure vascular tissue.In any case,without

adequate levels of biologically available nitric

oxide, endothelial cells in the intima can’t function

properly. In fact, some researchers consider

decreased availability of nitric oxide in the

endothelium as one of the earliest signs of arterial

aging and a pathological sign of atherosclerosis

and high blood pressure. However, much of this

complex process remains a mystery and scientists

continue to explore precisely how nitric oxide

production and bioavailability affect blood vessels.
By age 60, high blood pressure affects one in

every two Americans. Hypertension, as doctors call it, was once thought to be a normal part

of aging. But researchers now know that high

blood pressure is dangerous at any age.

When we talk about blood pressure, what we’re

actually referring to is the pressure within the aorta

and the large arteries that connect to it. Blood

pressure is measured in millimeters of mercury

(mmHg) and recorded as two numbers. Systolic

blood pressure (the top number in a blood pressure

reading) is the maximum pressure that occurs in

the blood vessels when the heart contracts. As the

heart relaxes between beats, the pressure dissipates. This low pressure is measured as diastolic

(the bottom number) blood pressure.

Systolic blood pressure is largely determined by

the stiffness of the arteries and the amount of

blood pumped through them during a heart beat.

Many doctors once believed that as we got older

our bodies needed increased systolic blood pressure to push blood through stiffened arteries. But

researchers now know that this increase is not

normal, and that high blood pressure at any age

significantly increases the risk of heart attack,

strokes, and kidney failure. 

Today, most experts recommend that blood pressure not exceed 120/80 mmHg. Smoking, high

cholesterol, and diabetes can elevate the risk of

developing high blood pressure. Check your blood

pressure regularly. If it is elevated, talk with your

doctor. Exercise, dietary changes and, in some

cases, medication can make a difference. •

High blood pressure is more common with age.

Getting your blood pressure checked regularly is one

of the best ways to detect this condition. Regular

aerobic exercise can help keep it within the normal

range.

The Nitty Gritty of High Blood Pressure

39
ARTERIAL LUMEN

NITRIC OXIDE

SMOOTH 

MUSCLE CELLS

ENDOTHELIAL CELLS

RED BLOOD CELLS

ADVENTITIA

outer layer of 

blood vessel

MEDIA

middle layer of blood

vessel containing 

smooth muscle cells

INTIMA

innermost layer of blood vessel

lined with endothelial cells that

release nitric oxide

40

Much of angiotensin II’s damage is done in partnership with an enzyme called NADPH oxidase,

the primary source of free radicals in the arteries.

After angiotensin II activates it, NADPH oxidase

causes an increase in production of superoxide, a

free radical. Superoxide binds with nitric oxide to

create an even more potent free radical called peroxynitrite. Peroxynitrite then binds to proteins

and nitrites, harming them. Like other free radical

processes, this chain of events steals bioavailable

nitric oxide away from endothelial cells, leaving

them more vulnerable to damage. But the impact

of angiotensin II isn’t limited to the intima. It also

has an important role in age-associated alterations

of the media, the middle layer of the arterial wall.

But they do know that endothelial cells depend 

on nitric oxide to help subdue the production of

oxygen free radicals. Nitric oxide molecules can

eradicate some of these free radicals, but in the

process they also destroy themselves. This leaves

less nitric oxide available to help endothelial cells

keep arteries in tiptop shape.

Angiotensin II, a growth factor involved in this

process, is more prevalent in aging arteries. In

addition to increasing free radical production,

angiotensin II decreases nitric oxide production

and stimulates blood vessel inflammation. It also

can cause vessels to tighten and raise blood pressure, forcing the heart to work harder.

Production of Nitric Oxide (NO) in Arteries
41

In addition to depleting nitric oxide, free radicals

can damage the membranes and DNA of

endothelial cells in the intima and smooth muscle

cells in the media. Free radical damage is one of

many things that can induce some of these cells to

stop functioning, shrink, and ultimately die in a

process known as apoptosis. Apoptosis may contribute to the decline in cardiovascular health as

we age. Free radicals also can oxidize proteins,

altering their structure and function. As a result,

these proteins can’t work properly, and this can

trigger a cascade of cellular alterations that promote stiffening and thickening of arterial walls

and contribute to atherosclerotic plaque build up.

Stuck in the Middle with You

With age, some smooth muscle cells in the media

die causing the remaining ones to work harder

and grow larger. Over time, other alterations cause

Young Artery

Old Artery

Arterial

Lumen

Adventitia

Media

Intima

Arteries: Young and Old

some smooth muscle cells to stop contracting as

usual. Instead, these cells begin producing excessive amounts of proteins and other matrix substances, creating an imbalance of elastin and 

collagen in the media. As the amount of collagen

increases in the blood vessel wall, it tends to bind

to glucose molecules, forming crosslinks known

as advanced glycation end products (AGES). This

process, which has been compared to what 

happens as turkey is roasted in an oven, is slow

and complex. But as more AGES form, the collagen strands in the media turn brown, become

crosslinked, and become less supple. Age takes its

toll on elastin, too. It becomes overloaded with

calcium, stretches out, and eventually ruptures,

further eroding an artery’s flexibility.

Scientists studying this process are particularly

intrigued by matrix metalloprotease-2 (MMP2), an

enzyme activated by angiotensin II as well as many

Biochemical changes can lead to structural

breakdowns in the aging arterial wall
42

other signals. Although many of its functions are

unclear, studies in rodents, monkeys, and humans

suggest MMP2 helps break down key components

of the basement membrane, the barrier that separates the intima from the media in artery walls.

MMP2, in conjunction with angiotensin II, also

activates other growth factors, such as transforming growth factor, which might stimulate collagen

and cell growth, the development of fibrous tissue,

and contribute to thickening of the intima. In

addition, this combination of MMP2 and

angiotensin II activates PDGF-B, a growth factor,

which acts as an attractant that lures smooth muscle cells to migrate from the media to the intima.

But in smaller blood vessels, the activity of PDGFB and other growth factors, such as vascular

endothelial growth factor (VEGF), tend to decline

with age. These growth factors play an important

role in a process called angiogenesis that leads to

the development of new small blood vessels. In

some cases, angiogenesis can stimulate the growth

of new collateral small vessels around narrow

spots or blockages in the arteries that threaten to

reduce blood flow to the heart. As we age, however, this process switches off. Enzymes that break

down collagen also seem to be involved in this

process and are less active as we get older. Scientists

are still unraveling why this happens, but as ageassociated changes and damage accumulate in

endothelial cells, they secrete less of the critical

growth factors needed for angiogenesis.

Angiogenesis also depends, in part, on the availability of nitric oxide, which declines with age. In

addition, there appears to be an age-associated

decrease in the number of endothelial progenitor

cells. These adult stem cells are produced in the

bone marrow and circulate in the bloodstream.

Under certain circumstances, endothelial progenitor cells can differentiate into endothelial cells,

which are needed to form new blood vessels or

repair damaged ones. In essence, progenitor cells

are the “mothers” of “daughter” endothelial cells.

As the number of progenitor cells declines, angiogenesis is less likely to occur. Researchers are investigating ways, such as gene and cell therapy, to

reactivate angiogenesis in older people who have

cardiovascular disease. But scientists have much to

learn about the safety and efficacy of these techniques. (See Can Gene Therapy Be Used to Treat

Heart Problems? page 43)

From Balloon to Bicycle Tire

Scientists are still piecing together how, or even if,

many of these various processes interact. But they

do know that, as the result of these and other ageassociated changes in large arteries, the endothelial

barrier in the intima becomes more porous. Some

of the signals these cells transmit to the smooth

muscle cells in the media become garbled. In turn,

these smooth muscle cells can mistakenly perceive

that an injury has occurred. They move into the

intima, multiply, and produce collagen and other

molecules. In reaction, the endothelial cells produce substances that send signals to circulating

blood cells to help out in the repair process.

Unfortunately, in their effort to help, blood cells

stick to endothelial cells instead of flowing

smoothly through the blood vessel. The net impact

of these interactions is that the intimal-media layer

...angiogenesis can stimulate the growth of new collateral small vessels around narrow

spots or blockages in the arteries that threaten to reduce blood flow to the heart.

Scientists are still unraveling why this happens, but as age-associated changes and 

damage accumulate in endothelial cells, they secrete less of the critical growth factors

needed for angiogenesis. 
I

n the future an experimental technique, called

gene therapy, may allow doctors to treat heart

disease and other cardiovascular disorders by

inserting a gene into a patient’s cells instead of

using drugs or surgery. Investigators are testing

several approaches to gene therapy including:

• Replacing a mutated gene that causes 

disease with a healthy copy of the gene

• Inactivating or “knocking out” a mutated 

gene that is functioning improperly, or

• Introducing a new gene into the body to 

help fight a disease.

The NIH has been on the cutting edge of this

research. More than a decade ago, for instance,

cardiovascular investigators began experimenting

with ways to increase the supply of certain growth

factors through gene therapy. If more growth factors could be produced, scientists theorized they

might stimulate angiogenesis—the growth of new

small blood vessels called capillaries. 

Knowing the genes that code for the growth factors,

the investigators found ways to add copies of

these genes to heart muscle. To get genes to the

myocytes, they engineered molecular delivery

trucks called vectors for the genes. These vectors,

made from inactivated adenoviruses—the same

viral culprits that cause the common cold—were

injected into rats. Scientists hoped the vectors

would unload their DNA cargo, which then would

begin producing the proteins needed to induce

capillary growth. And in this experiment, that’s

exactly what happened. One of the vectors worked.

More recently, scientists successfully used gene

therapy in older rats to increase the activity of the

gene that produces calcium pump proteins on

sarcoplasmic reticulum, the cellular storage bin

for calcium. This therapy significantly improved

heart muscle contraction in these rodents. In

another animal study, researchers at The Johns

Hopkins School of Medicine in Baltimore used

gene therapy to convert a small region of guinea

pig heart muscle tissue into specialized pace

making cells. Potentially, this technique could

one day lead to the development of genetically

engineered, biological pacemakers to replace

implantable electronic devices. However, scientists must overcome many technical challenges

before gene therapy will be a practical approach

to treating disease. •

Can Gene Therapy be Used

to Treat Heart Problems?

The NIH has been on the cutting edge of this research. More than a decade ago, for

instance, cardiovascular investigators began experimenting with ways to increase the

supply of certain growth factors through gene therapy.

Every day, your body’s cells depend on genes, coded

segments of DNA (below), to tell them how to

work. Gene therapy is an exciting area of scientific

research that one day could help treat inherited

and acquired diseases, including cardiovascular

disorders.

43
44

Blood often tells the story of our lives. Tests thatmeasure blood cholesterol levels and other cardiovascular risk factors have become a routine part

of health screenings. And in the future, doctors may

check yet another blood test—one that measures

inflammation—that may help them better assess

the risk of disease in the aging heart and arteries.

The test measures levels of C-reactive protein

(CRP), a substance produced in the liver, which is

often elevated in people

who have rheumatoid arthritis and other diseases that

cause chronic inflammation. Several studies have

indicated that increased

blood levels of CRP in otherwise healthy people are

associated with an increased

risk of heart attack, stroke,

and other cardiovascular

problems. 

Scientists are still investigating whether CRP is

merely an indicator of

inflammation or if it has an

active role in this process.

In any case, cardiovascular

risk factors such as excessive weight, diabetes, and a sedentary lifestyle are

associated with high CRP blood levels. Healthy people with CRP levels less than 1 milligram per liter

of blood are considered at the lowest risk of a cardiovascular event in the next 10 years. Depending

on medical history and other factors, a person at

intermediate risk—1 to 3 milligrams of CRP per

liter of blood—could have up to a 20 percent risk

of having a heart attack in the next decade. Those

with CRP levels of 3 milligrams or more per liter

have the highest risk.

However, researchers stress that inflammation is

just one of many factors that could increase your

risk of cardiovascular disease as you get older. To

date no evidence has

emerged to suggest that

treating people for elevated

CRP alone improves survival

or reduces cardiovascular

complications. For now,

detection and treatment of

more well-established risk

factors, such as high blood

pressure and high blood cholesterol, remains a greater

priority.

But some treatments for

these other risk factors

could help lower CRP. The

same lifestyle changes, for

instance, that help lower

cholesterol—regular exercise, a healthy diet, weight

loss, and quitting smoking—can also help reduce

inflammation. Aspirin and other drugs, including

cholesterol-lowering medications such as statins,

can decrease CRP levels as well. •

New Blood Test May Help Doctors Detect

Emerging Heart Disease

...some treatments for these other risk factors could help lower CRP. The same

lifestyle changes, for instance, that help lower cholesterol—regular exercise, a healthy

diet, weight loss, and quitting smoking—can also help reduce inflammation. 

Some studies have linked high-levels of

C-reactive protein, above, to cardiovascular

disease. In the future, a blood test for this

substance might help doctors better evaluate a person’s risk of heart attack or stroke.
45

thickens, contributes to arterial stiffness, and creates a fertile environment for the development of

atherosclerosis in aging arteries.

The cumulative effect of all these age-related changes

can be boiled down to this: the ability of larger

blood vessels to expand and contract diminishes,

the lumen enlarges, and the arterial walls thicken.

The result is “hardened”or stiffened arteries that set

the stage for the onset of high blood pressure, elevated pulse wave velocity, atherosclerosis, and other

precursors of cardiovascular disease. The more

severe the effects of aging are on the blood vessels,

the easier it is for atherosclerosis, hypertension, and

other processes to do damage and, in turn, have an

effect on the rate of aging in the vessels. Smoking,

lack of exercise, a poor diet, and obesity also can

exacerbate these effects.

It’s this cycle, with age as the principal instigator,

which gradually helps change youthful and

healthy blood vessels into old and potentially diseased ones. In a sense, this progression transforms

a young person’s arteries, which are like soft latex

balloons, into the equivalent of rigid, bulky bicycle

tires in later life.

However, arterial stiffness and intimal-medial

thickening occur at varying rates in different people.

Studies suggest that the rate of both of these agerelated changes predict stroke, heart disease, and

other cardiovascular problems. For example, in one

large study that followed healthy volunteers who

had no previous symptoms of heart disease, those

who had the greatest amount of intimal-media

thickening were four times more likely to develop

cardiovascular conditions over the next 7 years

compared to those with the least arterial thickening.

Similarly, studies have shown that healthy people

with the stiffest blood vessels were three times

more apt to develop high blood pressure over a 

5-year span than those with more pliable vessels.

In yet another large-scale study, involving 3,075

healthy older people, those who had the highest

pulse wave velocity (PWV)—a measure of arterial

stiffness—were three times more likely to die of

cardiovascular disease than those who had the

lowest PWVs.

“Clearly, many people of middle and advanced

age whom we once thought of as healthy actually

aren’t,” Dr. Lakatta says. “It is becoming more

apparent that changes in the aging circulatory system, even among those who don’t have outward

symptoms, precede and predict a higher risk of

developing cardiovascular diseases. The greater

these changes are, the greater is the risk for getting

these diseases.”

Keeping Your Arteries Healthy

The well-being of your arteries depends on a

healthy endothelium, the inner lining of your

blood vessels.

“Endothelial cells are the prima donnas within the

blood vessels. They control almost every activity

that occurs in the vessels, and they’re fundamentally altered with age,” Dr. Lakatta says. “People

who maintain a healthy endothelium as they get

older and those who make an effort to do things

that promote the repair of injured endothelium

can reduce the risk of heart attacks and strokes

caused by atherosclerosis or hypertension.”

“Endothelial cells are the prima donnas within the blood vessels. They control almost

every activity that occurs in the vessels, and they’re fundamentally altered with age,” 

Dr. Lakatta says. “People who maintain a healthy endothelium as they get older and those

who make an effort to do things that promote the repair of injured endothelium can

reduce the risk of heart attacks and strokes caused by atherosclerosis or hypertension.”
46

and heart rate. Free radicals in smoke slash the

amount of nitric oxide available in the blood

stream. Nitric oxide, as you may recall, is a signaling

molecule that helps keep arteries pliable. Because

nicotine causes narrowing of blood vessels, less

oxygen is transported to the heart. If you smoke,

blood platelets become stickier and are more apt to

form clots in your arteries.

As we mentioned earlier, high blood pressure—

hypertension—causes blood vessels to thicken,

diminishes production of nitric oxide, promotes

blood clotting, and contributes to the development of atherosclerotic plaques in the arteries.

Blood pressure is considered high when systolic

pressure exceeds 140 mmHg and when diastolic

blood pressure is higher than 90mmHg.

Excessive weight increases the risk of high blood

pressure and can increase the likelihood that you’ll

have high blood triglycerides and low HDL cholesterol, Dr. Lakatta says. Being overweight can

also increase the probability you’ll develop insulin

resistance, a precursor of diabetes. (See Metabolic

Syndrome Accelerates Aging of Arteries, page 48)

Diabetes, a disease in which the body does not

produce or properly use insulin, becomes more

common as we age. In fact, nearly half of all cases

are diagnosed after age 55. Atherosclerosis develops

earlier and is more aggressive in people who have

diabetes. In part, this occurs because diabetes

causes the endothelium to produce excessive

amounts of superoxide anion, a free radical that

destroys nitric oxide. People age 65 and older who

have diabetes are nearly four times more likely than

those who don’t to develop peripheral vascular

disease, a condition that clogs the arteries that

Although scientists still have much to learn about

the endothelium and what can be done to keep it

healthy, a number of studies suggest that certain

modifiable risk factors can have an important

impact on the cardiovascular system. For instance,

regular moderate exercise,such as running,walking,

or swimming can reduce body fat, increase lean

muscle mass, decrease blood pressure, increase

HDL cholesterol (the “good” cholesterol) levels,

and lessen the extent of arterial stiffening. All of

these exercise-induced changes can have a positive

influence on endothelial cells. (See Exercise: Your

Heart’s Best Friend, page 47)

In addition, scientists have long known that tobacco

smoke contains numerous toxic compounds, such

as carbon monoxide, that promote endothelial cell

damage. Smoking also increases blood pressure

Endothelial cells, such as this one, produce substances that regulate the structure and function of

the arterial wall. Endothelial cells may play a critical role in the aging of arteries and the onset of

high blood pressure and atherosclerosis.

...moderate exercise, such as running, walking, or swimming can reduce body fat, increase

lean muscle mass, decrease blood pressure, and increase HDL cholesterol levels. All of

these exercise-induced changes can have a positive influence on endothelial cells.
47

I

n one of her better-known gags, comic Ellen

DeGeneres quips, “My grandmother started

walking five miles a day when she was 60. Now

she’s 97 years old and we don’t know where the

heck she is.”

Funny, yes. But regular physical exercise is no

joke. In fact, it may be the most important thing

a person can do to fend off heart disease, stroke,

and other age-associated diseases. Emerging scientific evidence suggests that people

who exercise regularly not only

live longer, they live better.

Scientists have long known that

regular exercise causes certain

changes in the hearts of

younger people: Resting heart

rate is lower, heart mass is

higher, and stroke volume is

higher than in their sedentary

counterparts. These differences

make the heart a better pump.

Evidence now suggests these

changes occur even when exercise training begins later in life, at age 60 or 70,

for instance. In other words, you don’t lose the

ability to become better physically conditioned.

In addition, several studies have shown that exercise not only helps reduce debilitating symptoms

such as breathlessness and fatigue in people who

have heart failure, it also prolongs life.

Exercise training may be effective because it

appears to improve the function of virtually every 

Exercise: Your Heart’s Best Friend

cell in the cardiovascular system. Animal studies, for instance, suggest that regular aerobic

workouts help heart muscle cells remove calcium from their inner fluid at a faster rate after a

contraction. This improved calcium cycling allows

the heart to relax more and fill with more blood

between beats.

Exercise also improves blood vessel elasticity and

endothelial function, in part, by

blocking the production of damaging free radicals and maintaining the production of nitric

oxide, an important signaling

molecule that helps protect the

inner layer of the arteries.

Together, these changes can

slow the progression of atherosclerosis and other age-related

cardiovascular conditions.

Endurance exercises such as

brisk walking increase your

stamina and improve the health

of your heart, lungs, and circulatory system. But other exercises are equally important to maintaining health

and self-reliance as you get older. Strength exercises, for instance, 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. •

This free booklet is available in both

English and Spanish from the NIA.

The booklet is also available online

at www.niapublications.org/

exercisebook/index.asp.

For more information contact:

NIA Information Center 

P.O. Box 8057 

Gaithersburg, MD 20898-8057

1-(800)-222-2225 

1-(800)-222-4225 TTY

www.niapublications.org
Many older Americans have high blood pressure or high blood sugar or just a bit too

much fat on the belly. While each of these conditions alone is bad enough, having all of these

conditions at once—a cluster called metabolic

syndrome—magnifies the risk of developing

heart disease and stroke. And NIA scientists

may have discovered a reason why: Metabolic

syndrome appears to

accelerate stiffening

and thickening of the

arteries.

Metabolic syndrome—

also known as syndrome

X or insulin resistance

syndrome—may affect

as many as 47 million

Americans, according to

the Centers for Disease

Control and Prevention

(CDC). After age 50, a person has a better than

one in three chance of developing this group of

medical conditions characterized by insulin

resistance and the presence of obesity, abdominal

fat, high blood sugar and triglycerides, low HDL

(good) blood cholesterol, and high blood pressure.

To determine the effects of metabolic syndrome

on aging arteries, NIA researchers studied 471

participants—average age 59—in the Baltimore

Longitudinal Study of Aging (BLSA). None of

these participants had any detectable signs of

cardiovascular disease when initially examined.

But those who had three or more conditions

associated with metabolic syndrome developed

stiffer and thicker arteries at earlier ages than

those who didn’t have the syndrome. 

“It’s as if the metabolic syndrome makes your

blood vessels older,” says Angelo Scuteri, MD,

PhD, an investigator at the NIA’s Laboratory of

Cardiovascular Science. “If you have metabolic

syndrome, when you are 40 your arteries look like

they are 55 or 60.”

As this work moves forward, scientists hope they

can determine how metabolic syndrome promotes

accelerated aging in the arteries and perhaps discover ways to prevent or treat it. •

Metabolic Syndrome Accelerates 

Aging of Arteries

Age

Arterial Stiffness

with

Metabolic

Syndrome

without

Metabolic

Syndrome

Metabolic Syndrome 

Increases Arterial Stiffness

35 50 65 80

Age-effect p<0.0001, MS effect p<0.01, Interaction n.s.

Arterial stiffness, a risk factor for age-related cardiovascular diseases, increases more rapidly in older

Angelo Scuteri people who have metabolic syndrome.

MD, PhD

48
Based on the best available scientific evidence, the American Heart Association (AHA)

recommends a diet that includes a variety of fruits, vegetables, and grains, while limiting

consumption of saturated fat and sodium. 

49

arteries, dietary experts say. Fruits and vegetables

also contain plenty of soluble fiber, a substance

that has been shown to reduce blood cholesterol

levels, which is healthy for the endothelium.

Breads, cereals, and other grain foods, which provide complex carbohydrates, vitamins, minerals,

and fiber, are associated with a decreased risk of

cardiovascular disease, according to the AHA

Dietary Guidelines. However, some studies suggest

carry blood to the legs or arms. And, cardiovascular

diseases and stroke are leading causes of diabetesrelated deaths. If you suspect you have or are at

risk for diabetes, check with your doctor.

Symptoms include increased thirst, increased

hunger, fatigue, increased urination—especially at

night, unexplained weight loss, blurred vision,

and slow healing of wounds and sores.

Researchers have also found that stress reduction

techniques, such as taking a walk, practicing yoga,

or deep breathing are important to cardiovascular

health. Emotional stress triggers the release of

adrenaline from the adrenal gland and noradrenaline from the nerve endings in your heart and

blood vessels. These hormones make the heart

beat faster and adversely affect blood vessels. Under

stress, an older person’s blood pressure rises more

rapidly and stays higher longer than a younger person’s because the older person’s blood vessels are

stiffer and have lost much of their elasticity.

Healthy Foods, Healthy Arteries:

Is There a Connection?

What you eat can help keep your heart and arteries

healthy—or lead to excessive weight, high blood

pressure, and high blood cholesterol—three key

factors that increase the risk of developing cardiovascular disease, according to the National Heart,

Lung, and Blood Institute. Based on the best available scientific evidence, the American Heart

Association (AHA) recommends a diet that includes

a variety of fruits, vegetables, and grains, while

limiting consumption of saturated fat and sodium.

Fruits and vegetables have lots of antioxidants

such as vitamin C and vitamin A that neutralize

free radicals and may prevent oxidation in the

Fruits and vegetables are key components of a

heart-healthy diet. These food contain compounds

that can help subdue free radicals, prevent oxidation in the arteries, and lower blood cholesterol

levels, all of which are important for maintaining

a thriving endothelium.
50

eating less sugar, breads, and other simple and

complex carbohydrates can lower blood insulin

levels and decrease body fat and weight—three

factors that are linked to an increased risk of heart

disease and stroke. In recent years, a number of

dietary recommendations based on these findings

have become popular and are currently catching

the public’s awareness. While contentious, these

are important issues and long-term studies are

required to determine the risks and benefits of

such diets, Dr. Lakatta says.

Saturated fats are usually solid at room temperature. These fats are primarily found in animal

foods like meat, poultry, and dairy products like

butter. Saturated fats tend to raise levels of “bad”

low-density lipoprotein (LDL) and increase the

risk of atherosclerosis. In fact, within 2 hours of

eating a high saturated fat meal, endothelial cells

don’t work as well. Such meals can cause a temporary 50 percent dip in endothelial function, even

in healthy young people who have no risk factors

for atherosclerosis, Dr. Lakatta says.

In addition to saturated fats, some scientists are

concerned about trans-fatty acids—unsaturated

fats that have been artificially solidified by food

manufacturers in a process called hydrogenation

to make products like margarine and vegetable

shortenings.These scientists suspect that trans-fatty

acids, which are often described as hydrogenated

or partially hydrogenated fats on many food

labels, are more damaging to the heart and arteries than saturated fats.

But researchers have found other types of fats

may be beneficial. Monounsaturated fats, found

mainly in plant foods such as peanuts and olives,

help lower LDL cholesterol. Like polyunsaturated

fats, monounsaturated fats are usually liquid at

room temperature. Polyunsaturated fats, found in

fish, nuts, and dark leafy vegetables, have been

getting a lot of attention from scientists in the

past few years. They’ve concluded that one type of

polyunsaturated fat—omega-3 fatty acid—found

in fish may promote several things that improve

endothelial function, including increasing nitric

oxide production, slashing the production of free

radicals and other substances that cause inflammation, and boosting HDL cholesterol levels. Fish

Blood cholesterol, shown here in a crystallized

image, is one of many modifiable risk factors that

contribute to the onset of atherosclerosis and cardiovascular disease in later life. Dietary changes

and regular exercise can help keep blood cholesterol levels under control.

Control over the condition of our arteries may also lie in how much salt we consume.

In cultures where little sodium (in the form of salt) is consumed, blood pressures do

not rise with age. 
51

such as salmon, herring, and mackerel are good

sources of omega-3s.

Control over the condition of our arteries may

also lie in how much salt we consume. In cultures

where little sodium (in the form of salt) is consumed, blood pressures do not rise with age.

Cultural differences have also been found in arterial

stiffness. One study compared rural and urban

populations in China. The urban population consumed much higher levels of sodium than the

rural groups. And they had stiffer arteries. Other

researchers found that sodium appears to accelerate

age-associated stiffening of arteries. In particular,

sodium promotes thickening of aging arterial

walls, reduces the amount of nitric oxide available

to endothelial cells, and promotes the formation

of oxygen free radicals. But shifting to a low sodium diet, research suggests, can begin to diminish

arterial stiffness in as little as 2 weeks.

Most of the sodium in your diet comes from

processed foods. The remaining is added at the

table and while cooking. Scientists who study this

issue suggest limiting the amount of sodium that

you consume from all these sources to no more

than 1,500 milligrams (mg) each day (an average American adult consumes about 3,300 milligrams daily). They recommend reading food

labels carefully and buying foods that say “reduced

sodium,” “low in sodium,” “sodium free,” or “no

salt added.” Some dietitians suggest seasoning

foods with herbs and spices like oregano, onion

powder, or garlic instead of sodium.

Scientists suspect the more lifestyle changes,

including diet and exercise, you can incorporate

into your life, the better off your arteries will be,

because these interventions work independently

as well as in unison to promote the vitality of

endothelial cells and contribute to reducing the

risk of cardiovascular disease.

Scientists suggest that you consume no more than

1,500 milligrams (mg) of sodium each day (an

average American adult consumes about 3,300

milligrams daily).

53

they’ve also learned that preventive measures,

such as getting regular exercise, eating a healthy

diet, and not using tobacco, can have a profound

impact on the aging cardiovascular system.

In the future, interventions to slow accelerated

aging of the heart and arteries in apparently

healthy young and middle-age people could prevent or delay the onset of heart disease, stroke,

and other cardiovascular disorders in later life,

Dr. Lakatta says.

These interventions

may take many

forms. For instance,

the more we understand about the

changes that take

place in cells and

molecules during

aging, the closer we

get to the possibility

of designing drugs

targeted to those changes. Gene therapies can also

target specific cellular changes and could potentially be a way to intervene in the aging process.

Achieving these goals will likely require considerable effort and as much, or perhaps even more,

ingenuity and innovation in the coming years as

has been shown in the past. NIA investigators and

others are already taking steps to meet these challenges. They still have many questions to answer

and mysteries to solve. But as this work progresses

and scientists unravel more of the aging heart’s

secrets, the hope of forestalling cardiovascular 

disease and improving the quality of life for older

people may come closer to reality.

WHAT LIES Ahead

In 1903, Dutch physiologist Willem Einthoven,

MD, PhD invented the electrocardiograph, a

machine that measures the minute electrical currents generated by the heart. Initially, it was a

cumbersome and costly device, taking five technicians to operate. During the procedure, patients

had to place both hands and both feet in buckets

of water. But as a result of this advance cardiologists

began, for the first time, to fully understand the

electrical processes involved in generating the heart

beat. With this knowledge, they were able to more

precisely diagnosis certain cardiovascular problems.

A little more than a century later, scientific ingenuity has led to the development of many other

advances. Scientists, for instance, have developed

magnetic resonance imaging and other noninvasive

ways to study the aging heart. Researchers have

discovered a host of innovative drug treatments to

help the ailing heart and arteries work better. And

cardiologists and surgeons have successfully pioneered the use of cardiac catheterization, cardiovascular stents, implantable pacemakers, bypass

surgery, and heart transplants.

No doubt about it, doctors know more about the

heart and how to keep it healthy than at any other

time in history. In just the past 30 years, gerontologists have revolutionized ideas about what happens in the older heart. They’ve learned, for

instance, that age-related changes in the structure

and function of the heart occur in virtually every

person. Mounting evidence suggests that some of

these changes, previously thought to be a part of

normal aging, precede and predict the onset of

cardiovascular diseases, even among those who do

not yet have signs or symptoms of disease. But

He is the best physician who is the most ingenious inspirer of hope.

SAMUEL TAYLOR COLERIDGE, ENGLISH POET AND PHILOSOPHER, 1772-1834

Willem Einthoven, MD, PhD,

Dutch physiologist 
54

ACTION POTENTIAL – An abrupt, transient

change in the electrical charge along a heart muscle cell membrane; the first of several steps leading

to the cell’s contraction.

ADVENTITIA – The outermost layer of arterial

wall; it is composed of connective tissue.

AFTERLOAD – The mechanical load encountered

by the heart following the onset of contraction;

the forces that resist the flow of blood from the

heart. The afterload may increase with age due to

increasingly stiff arteries and an increased tone of

the smaller arteries.

ANGIOTENSIN – A chemical that constricts

blood vessels, which raises blood pressure.

AORTA – The largest artery in the body. It conducts blood away from the heart, then branches

into many smaller arteries that take blood to the

rest of the body. The diameter of the aorta

enlarges with age and its walls become stiffer.

ARTERIES – Blood vessels that carry blood away

from the heart to all parts of the body. Some

enlarge with age and become thicker and stiffer.

Arterial walls consist of three layers: the intima,

media, and adventitia.

ARTERIOLES – The very small arteries that take

blood from the arteries to the capillaries.

ATHEROSCLEROSIS – A condition of the arteries in which the interior of the artery wall is made

thick and irregular by deposits of fatty substances

and invasive cells from the blood and arterial wall

and matrix substances synthesized by the cells.

ATRIOVENTRICULAR NODE – A group of special conduction fibers at the base of the wall

between the right atrium and ventricle. They relay

the electrical impulses to the ventricle to initiate

contraction. These electrical impulses originate in

the heart’s pacemaker, the sinoatrial node within

the right atrium.

ATRIUM – One of the two upper chambers of the

heart. The right atrium receives blood depleted of

oxygen from the veins; the left atrium receives

blood with fresh oxygen from the lungs. The left

atrial cavity enlarges with age.

AUTONOMIC NERVOUS SYSTEM – That part

of the nervous system that controls involuntary

muscles, such as the heart. It uses chemicals, such

as catecholamines, to send messages from the

brain to the heart. With age, the body’s response to

cathecholamines withers.

BARORECEPTOR RESPONSE – The body’s

response to pressure sensitive nerves in the carotid

artery that help regulate heart rate and arterial

pressure; the response grows weaker with age.

BLOOD PRESSURE – The force that flowing blood

exerts against artery walls. Systolic blood pressure

occurs when the heart contracts and pumps blood

into the aorta. Diastolic blood pressure occurs when

the aortic valve closes and the heart relaxes and refills

with blood.

CALCIUM PUMP PROTEINS – Proteins on the

sarcoplasmic reticulum that remove calcium from

the cell cytosol after a contraction. The number of

these pump proteins declines with age.

CALCIUM TRANSIENT – The transient increase

in calcium in the cytosol following excitation,

which causes a contraction. It grows longer with age.

CAPILLARIES – The smallest blood vessels that

take blood from the arterioles to cells in the body.

CARDIAC CYCLE – The cycle of synchronized

activities that occurs during one heart beat.

CARDIAC OUTPUT – The amount of blood a

heart pumps each minute. It is calculated by multiplying heart rate by stroke volume.

CARDIOVASCULAR – Of or pertaining to the

heart and blood vessels.

GLOSSARY
55

CHEMOKINES – A type of cytokine that carries

messages between cells. In a sense, they tell cells

where to go. If chemokines are increased in a particular tissue, such as an artery, the cell with the

receptor, or partner, for that particular molecule is

attracted to move into that tissue.

CHOLESTEROL – A waxy, fat-like substance

present in cell walls or membranes everywhere in

the body, including the heart. Excess cholesterol is

deposited in arteries, including the coronary

arteries, where it contributes to the narrowing and

blockages that cause the signs and symptoms of

heart disease. Cholesterol is carried in small packages called low density (LDL) and high density

(HDL) lipoproteins.

CONTRACTILE (MYOFILAMENT) PROTEINS –

Proteins in myocytes that change their configuration in order to bring about a shortening or contraction of the cell. This may change with age.

CONTRACTILE STATE – The ability of the heart

muscle cells to contract, also referred to as contractility.

CORONARY HEART DISEASE – Also called

coronary artery disease ischemic heart disease. A

narrowing of the coronary arteries due mostly to

atherosclerosis resulting in a decreased flow of

blood to the heart muscle and thus lower levels of

oxygen reaching the heart.

CORONARY FLOW – The flow of blood through

the coronary arteries that nourish the heart muscle.

CYTOKINE – 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.

CYTOSOL – The fluid inside heart and blood

vessel cells.

DIASTOLE – The period during a heart beat

when the chambers are filling with blood and the

heart muscle is relaxed.

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 of molecules in the

nucleus of each cell that carries the genetic information necessary for all cellular functions, including the building of proteins.

ECHOCARDIOGRAM (ECG OR EKG) – A visual

record of the heart’s electrical activity.

EJECTION FRACTION – The fraction of end

diastolic volume pumped out with each beat.

ELECTROCARDIOGRAPHY – A method of

graphically recording the structure and movement of the heart by the echo caused by beams of

ultrasonic waves.

END DIASTOLIC VOLUME – The volume of

blood in the left ventricle at the end of diastole,

just before the next beat.

ENDOTHELIUM – The smooth inner lining of

many body structures, including the heart and

blood vessels. Endothelial cells are a primary component of the intima.

END SYSTOLIC VOLUME – The volume of

blood left in the heart at the end of the heartbeat.

ENZYME – A protein that promotes a specific

biochemical reaction in the body without itself

being permanently changed or destroyed.

Enzymes may have an important role in the ageassociated changes in structure and function that

occur in the heart and arteries.

FRANK-STARLING LAW OF THE HEART – 

A phenomenon in which the more the heart muscle is stretched the more vigorously it contracts.
56

FREE RADICALS – Molecules with unpaired

electrons that react readily with other molecules.

Free radicals can damage myocytes as well as the

membranes and DNA of endothelial cells in the

intima and smooth muscle cells in the media. This

damage can promote stiffening and thickening of

arterial walls. Free radicals also can contribute to

atherosclerotic plaque build up.

GENE – A segment of DNA that codes for a specific protein or other molecule. Each gene contains a specific sequence of chemicals. The

sequence is referred to as a “code” because it specifies the order of amino acids (chemical building

blocks of proteins) in the end product.

GENE EXPRESSION – The process by which the

information contained in genes is transcribed and

translated into proteins. Age-related changes in

gene expression may account for some changes in

heart and artery function.

HEART ATTACK – The death of a portion of

heart muscle, resulting when an obstruction in

one of the coronary arteries prevents an adequate

oxygen supply to that muscle. Heart attacks may

be referred to in terms of obstruction (coronary

thrombosis) or in terms of the damage done

(myocardial infarction).

HEART FAILURE – A condition in which the

heart is unable to pump the amount of blood

needed by the body. Heart failure can develop

from many heart and circulatory disorders, such

as high blood pressure heart attack. It often leads

to congestion in the body tissues, with fluid accumulating in the abdomen and legs and/or in the

lungs. This condition is often called congestive

heart failure.

HEART RATE – The number of beats per minute.

HIGH BLOOD PRESSURE – An unstable or persistent elevation of blood pressure above the normal range. Blood pressure often increases with age.

High blood pressure increases the risk of heart disease and stroke; also known as hypertension.

HIGH DENSITY LIPOPROTEINS (HDL) – The

"good" cholesterol. HDL carries cholesterol in the

blood from other parts of the body back to the

liver, which leads to its removal from the body.

HDL helps keep cholesterol from building up in

the walls of the arteries.

HYPERTROPHY – Enlarge or enlargement. The

myocytes that make up the walls of the heart

hypertrophy with age.

ISCHEMIA – Decreased blood supply to the heart

muscle.

INTIMA – The innermost layer of arterial wall

closest to the blood. It is composed of a single

layer of specialized cells, called endothelial cells,

which sit atop the sub-endothelial space and a

wall called the basement membrane.

LOW DENSITY LIPOPROTEIN (LDL) – The

“bad” cholesterol. High LDL cholesterol leads to a

build up of cholesterol in arteries. The higher the

LDL level in your blood, the greater chance you

have for getting coronary heart disease.

LUMEN – The tube-like opening in arteries and

other vessels that blood flows through on its journey throughout the body.

MAXIMUM HEART RATE – The number of beats

per minute during rigorous exercise. It declines by

about 25 to 30 percent between the ages 20 and

80, regardless of physical fitness status. Scientists

estimate maximum heart rate by subtracting your

age from 220.
57

MAXIMUM OXYGEN CONSUMPTION – The

amount of oxygen used by the body at peak exercise capacity. Also known as VO2 max, it is considered the best measure of cardiorespiratory physical fitness. Women tend to have less lean muscle

mass than men, and it is lean muscle mass that

needs the most oxygen. When studies compare

oxygen consumption based on the amount of lean

muscle rather than overall body size, the gender

differences disappear. Women, in other words, use

the same amount of oxygen as men.

MEDIA – The middle layer of the arterial wall. It

is composed of smooth muscle cells surrounded

by a network of fibers primarily made of two proteins, collagen, and elastin. The elastin forms concentric rings within the vessel wall.

MITRAL VALVE – The valve between the left atrium and ventricle. It closes more slowly with age

because the rate of blood flow into the left ventricle that pushes it closed decreases with age.

MYOCARDIUM – The heart muscle.

MYOCYTE – A heart muscle cell. Myocytes decline

in number but grow larger with age.

NONINVASIVE TECHNIQUES – Medical procedures that do not require needle puncture, surgery, or entering the artery.

ORGANELLE – A structure inside a cell, such as

the sarcoplasmic reticulum.

OXYGEN CONSUMPTION – The amount of oxygen the entire body uses in a certain time period.

It is calculated by taking the amount of oxygen in

the arteries and subtracting the amount left in the

veins after the body’s cells have taken out oxygen.

The result is then multiplied by cardiac output.

PRELOAD –The amount of blood in the left ventricle before contraction.

PROTEINS – Molecules composed of amino

acids arranged in a specific order. Certain proteins, such as the calcium pump protein and the

contractile protein myosin, appear to change with

age which may account for some alterations in the

function of the aging heart.

SARCOPLASMIC RETICULUM – A structure or

organelle inside a myocyte. Its function is to store

and release calcium for use during a contraction

and to remove calcium after calcium transient

causes a contraction. It removes calcium more

slowly with age.

SINOATRIAL NODE – The heart’s pacemaker. A

group of specialized cells in the right atrium wall

that give rise to the electrical impulses that initiate

contractions.

STROKE VOLUME – The amount of blood

pumped with each heart beat.

SYSTOLE – The period during a heart beat when

the heart muscle contracts and blood is pumped out.

VEINS – The blood vessels that return blood to the

heart after the body’s cells have extracted oxygen.

VENTRICLE – A chamber of the heart that

pumps blood out. The right ventricle pumps

blood to the lungs where it picks up oxygen; the

left ventricle pumps blood into the aorta, which

distributes it to the rest of the body.
58

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64

Writer

Doug Dollemore

Office of Communications 

and Public Liaison

National Institute on Aging 

National Institutes of Health

Design

Megan Riordan, Designer

John Vance, Managing Art Director

Levine & Associates, Inc.

Washington, DC

Photography/Illustrations

Cover — illustration, Levine &

Associates, photos courtesy of Getty

Images, Inc.

Page 2 — Three generations, illustration,

Levine & Associates, photo courtesy of

Getty Images, Inc.

Page 5 — “Anatomy of the Heart”

illustration, Levine & Associates

Page 7 — Heart woodcut, courtesy 

of the National Library of Medicine,

National Institutes of Health; MRI image,

courtesy of Dynamic Graphics, Inc.

Page 8 — John Bicknell, illustration,

Levine & Associates, photo courtesy of

Doug Dollemore 

Page 9 — John Bicknell photo,

courtesy of Doug Dollemore

Page 10 — Edward Lakatta photo,

courtesy of Edward Lakatta

Page 11 — “Heart Dynamics”

illustration, Levine & Associates

Page 12 — Gary Gerstenblith photo,

courtesy of Gary Gerstenblith

Page 12-13 — “In a Heart Beat”

illustrations, Levine & Associates

Page 14 — PET/CT scan images of

resting and stressed heart, courtesy 

of Swiss National Science Foundation,

University Hospital, Zurich

Page 15 — “The Heart: Young and Old”

illustration, Levine & Associates

Page 17 — Water aerobics photos, courtesy of the National Institute on Aging,

National Institutes of Health 

Page 18 — “When the Brain Talks to the

Heart” illustration, Levine & Associates

Page 20 — Scientist at microscope,

illustration, Levine & Associates,

photo courtesy of Getty Images, Inc.

Page 21 — Myocyte, courtesy 

of Edward Lakatta

Page 22 — Calcium release in myocyte

images, courtesy of the James Hogg

iCAPTURE Centre for Cardiovascular

and Pulmonary Research, University of

British Columbia

Page 23 — “How a Myocyte Contracts”

illustration, Levine & Associates

Page 27 — “Contractile Proteins”

illustration, Levine & Associates

Page 28 — “Opposing Pressures”

illustration, Levine & Associates

Page 29 — Christiaan Leewenburgh

photo, courtesy of Christiaan

Leewenburgh

Page 30 — Piero Anversa photo,

courtesy of Piero Anversa

Page 31 — Stem cell, courtesy 

of Piero Anversa

Page 32 — Happy couple, illustration,

Levine & Associates, photo courtesy 

of Getty Images, Inc.

Page 33 — Heart blood vessel photo,

courtesy of the James Hogg iCAPTURE

Centre for Cardiovascular and

Pulmonary Research, University of

British Columbia

Page 35 — Inflammation in the atherosclerosis process illustrations, courtesy

of the Massachusetts Medical Society,

The New England Journal of Medicine

Page 36 — “Age and Arteries”

illustration, Levine & Associates

Page 37 — Magnified arterial wall 

section, courtesy of the University of

Western Australia

Page 39 — Man getting blood pressure

checked, courtesy of the National

Institute on Aging, National Institutes

of Health

Page 40 — “Production of Nitric

Oxide” illustration, Levine & Associates

Page 41 — “Young and Old Arteries”

illustration, Levine & Associates

Page 43 — DNA, courtesy of Getty

Images, Inc.

Page 44 — C-reactive protein structure,

adapted from original by Paul Ridker,

Harvard University Medical School,

Pathology Department

Page 46 — Endothelial cell, courtesy 

of Molecular Expressions: http://www.

microscopy.fsu.edu, Florida State

University

Page 47 — Exercise, courtesy 

of the National Institute on Aging,

National Institutes of Health

Page 48 — Metabolic syndrome graph,

Levine & Associates; Angelo Scuteri

photo, courtesy of Angelo Scuteri

Page 49 — Man in kitchen, courtesy 

of Dynamic Graphics, Inc.

Page 50 — Crystallized cholesterol under

the microscope, courtesy of Molecular

Expressions: http://www.microscopy.

fsu.edu, Florida State University

Page 51 — Nutrition label, courtesy 

of Getty Images, Inc.

Page 52 — Heart researchers, illustration, Levine & Associates, photos 

courtesy of Getty Images, Inc.

Page 53 — Willem Einthoven and early

electrocardiograph, circa 1907, courtesy

of the Heart Rhythm Foundation

Thanks to David Burton and Nancy Clark, JBS, Inc.

Special thanks to Edward G. Lakatta, M.D., chief of the Laboratory of Cardiovascular Science at the National

Institute on Aging and to Jerome Fleg, M.D., medical officer at the National Heart, Lung and Blood Institute.

Acknowledgements
Of the heart. This moves of itself and does not stop unless forever.

LEONARDO DA VINCI, 1510
NATIONAL INSTITUTES OF HEALTH NATIONAL INSTITUTE ON AGING

Office of Communications and Public Liaison

Building 31; Room 5C27

Bethesda, MD 20892-2292

301-496-1752

www.nia.nih.gov

NIH PUBLICATION NO. 05-3738 • APRIL 2005