Physiologic
Clues
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IN
SEARCH OF
THE SECRETS OF AGING
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Research
on the physiology of aging is puzzling out the characteristics
of normal aging -- aging in the absence of disease. Studies
are also looking at behavioral factors, such as diet and
exercise, and at what happens in key organ systems as
people age.
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We don't know
very much about the man who lived to 120 years of age, but we
can assume that he escaped the diseases that kill many people
in their 70s and 80s. In fact, escape from disease is the most
common reason that all of us can now expect to live longer than
our grandparents.
Chronic diseases
and disability were once thought inseparable from old age. This
view is changing rapidly as one disease after another joins
the ranks of those that can be prevented or at least controlled,
often through changes in lifestyle.
We now know,
for example, that most people can avoid lung disease by not
smoking. And heart disease and stroke rates have fallen at the
same time that Americans have lowered their fat consumption,
begun to exercise more, and quit smoking.
If chronic disease
is not intrinsic to the aging process, as many gerontologists
now believe, then what is? What are the universal or "normal"
aging processes?
Normal
Aging
Many of the answers
to this question are coming from the Baltimore Longitudinal Study
of Aging (BLSA). In this long-term study, begun in 1958, researchers
are studying the aging process in more than 1,000 people from
age 20 to age 90 and beyond.
They have found
that variations in human development increase as people age
and that organ systems within a single individual can change
at different rates. This suggests that genetic, lifestyle, and
disease processes all affect the rate of aging and that several
distinct processes are involved.
More information
on normal aging comes from NIA's Biomarkers of Aging project.
Begun in 1987, this 10-year effort is singling out key biological
signs that characterize the aging process. The project is based
on the idea that biomarkers are a better measure of an organism's
aging status than chronological age itself. Once the biomarkers
have been identified, it will be easier to study normal aging,
diseases, and anti-aging interventions.
Researchers
investigating the physiology of aging have focused on two organ
systems in particular that seem to serve as pacemakers of declining
functions. One of these, the endocrine system, is discussed
on pages 19-21. The other is the immune system.
The
Immune System
When Sherechiyo
Izumi contracted pneumonia and died at the age of 120, it was
his immune system that failed. One of the many bacteria or viruses
that cause pneumonia broke through the elaborate, natural defenses
that protect humans from infection. Scientists have long known
that these defenses decline with age; now, some of the underlying
mechanisms are coming to light.
A multiplicity
of cells, substances, and organs make up the immune system.
The thymus, spleen, tonsils, bone marrow, and lymphatic system,
for example, produce, store, and transport a host of cells and
substances -- B-lymphocytes and T-lymphocytes, antibodies, interleukins,
and interferon, to name a few. Several are of special interest
to gerontologists. These include the white blood cells or lymphocytes,
which fight invading bacteria and other foreign cells.
Lymphocytes
fall into two major classes: B-cells and T-cells. B-cells mature
in the bone marrow, and one of their functions is to secrete
antibodies in response to infectious agents or antigens. T-cells
develop in the thymus, which shrinks in size as people age;
they are divided into cytotoxic T-cells and helper T-cells.
Cytotoxic T-cells attack infected or damaged cells directly.
Helper T-cells produce powerful chemicals, lymphokines, that
mobilize other immune system substances and cells.
T-cells and
their lymphokine products have intrigued gerontologists ever
since it was learned that T-cells -- or more precisely the functioning
population of T-cells -- declines with age. While the number
of T-cells remains about the same, the proportion of them that
proliferate and function declines. Studies have also shown that
in older people, T-cells destroyed by trauma, such as burns,
take longer to renew than they do in younger people.
Most research
on the aging immune system now centers on these cells. One group
of T-cell products, interleukins, occurs at different
levels as people age. The interleukins -- there are about a
dozen identified so far -- serve as messengers, relaying signals
that regulate the immune response. Some, like interleukin-6,
rise with age, leading to speculation that they interfere in
some way with the immune response. Others, like interleukin-2,
which stimulates T-cell proliferation, tend to fall with age.
Gerontologists
continue to study the interleukins, not only for clues to the
mechanisms of aging, but also for their potential in primary
care. Findings to date suggest that tests for interleukins,
though not yet available, may someday help in the detection
and treatment of immune problems.
Another focus
of research is the interaction of hormones and the immune system.
DHEA, for example, has been shown to revive immune responses
in aging animals. Reducing estrogen levels depresses IL-2 levels.
And two pituitary hormones, prolactin and growth hormone, may
also be linked to the immune response. Pituitary tumor cells,
implanted in aged rats, have induced the thymus to grow to its
youthful size and increased the proportion of helper T-cells
and other immune system cells.
While both the
immune and the endocrine systems are undoubtedly involved in
aging, researchers continue to search for the mechanisms to
explain their effects. One approach to studying aging, caloric
restriction, is expected to yield some clues.
Caloric
Restriction
In a laboratory
at the University of California at Los Angeles, thousands of
mice are living to the advanced ages of 30 and 40 months or
more -- far beyond their normal life spans. The fundamental
reasons are not yet understood. It may have something to do
with DNA repair rates, or free radical levels, or hormonal balance,
or cell senescence, or all of these plus other mechanisms.
What is known
is that the mice live on restricted diets. Fed 30 to 60 percent
fewer calories than normal (but all the necessary nutrients),
the mice survive months longer than mice on a normal feeding
schedule.
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What
is Normal Aging?
Individuals
age at extremely different rates. In fact even within
one person, organs and organ systems show different rates
of decline. However, some generalities can be made, based
on data from the Baltimore Longitudinal Study of Aging.
It is important to remember that these statements do not
apply to all people.
Heart.
It grows slightly larger with age. Maximal oxygen consumption
during exercise declines in men by about 10 percent with
each decade of adult life and in women, by about 7.5 percent.
However, cardiac output stays nearly the same as the heart
pumps more efficiently.
Lungs.
Maximum breathing (vital) capacity may decline by about
40 percent between the ages of 20 and 70.
Brain.
With age, the brain loses some cells (neurons) and others
become damaged. However, it adapts by increasing the number
of connections between cells -- synapses -- and by regrowing
the branch-like extensions, dendrites and axons, that
carry messages in the brain.
Kidneys.
They gradually become less efficient at extracting wastes
from the blood. Bladder capacity declines. Urinary incontinence,
which may occur after tissues atrophy, can often be managed
through exercise and behavioral techniques.
Body
Fat. The body does not lose fat with age but redistributes
it from just under the skin to deeper parts of the body.
Women are more likely to store it in the lower body --
hips and thighs -- men in the abdominal area.
Muscles.
Without exercise, estimated muscle mass declines 22 percent
for women and 23 percent for men between the ages of 30
and 70. Exercise can prevent this loss.
Sight.
Difficulty focusing close up may begin in the 40s; the
ability to distinguish fine details may begin to decline
in the 70s. From 50 on, there is increased susceptibility
to glare, greater difficulty in seeing at low levels of
illumination, and more difficulty in detecting moving
targets.
Hearing.
It becomes more difficult to hear higher frequencies with
age. Hearing declines more quickly in men than in women.
Personality.
After about age 30, personality is stable. Sudden changes
in personality sometimes suggest disease processes.
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The findings
in this UCLA laboratory, headed by Roy Walford, are not isolated
ones. In studies in other laboratories, again and again, undernutrition
has increased the life
Undernutrition
without malnutrition extends life spans in laboratory
animals.
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spans of nearly every
animal species studied -- protozoa, fruit flies, mice, rats, and
other laboratory animals. Now researchers are investigating whether
and how caloric restriction will affect aging in primates, human's
closest relatives in the animal kingdom.
Particularly
intriguing to many gerontologists are findings that animals
on restricted diets have reduced rates of disease. In one of
the largest studies to date, Roderick Bronson at Tufts University
found that caloric restriction not only extended life span in
mice, but also
prevented or slowed down development
of every disease and all types of tumors. These results, described as
stunning by gerontologists, have raised hope that further study of caloric
restriction will help uncover the mechanisms responsible for disease in
old age.
However, whether
or not caloric restriction would have the same effect in humans
remains a major question. Studies with monkeys are underway
at the National Institute on Aging, where rhesus and squirrel
monkeys are growing up on a calorically restricted diet. At
the University of Wisconsin, preliminary results in Richard
Weindruch's laboratory show some promising early signs of improved
health in aged monkeys kept on restricted diets.
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The
Next Step:
Caloric Restriction in Primates
At the
NIH Animal Center in Poolesville, Maryland, about 75
rhesus and squirrel monkeys are on diets; they eat 30
percent less than they would normally but get all the
necessary nutrients. Another 75 monkeys, the control
group, are eating as much as they want or ad libitum.
The differences between the two groups, as they reach
maturity and begin to age, are expected to provide insights
into how caloric restriction influences life span.
The
monkeys that arrived at the Poolesville laboratory in
1987 have responded to caloric restriction as expected;
their maturation, measured by factors such as skeletal
development and onset of puberty, has been delayed by
about a year or year and a half. This is comparable
to the delays in maturation seen in calorically restricted
rodents.
As the
monkeys grow into young adulthood and beyond, George
Ruth and his colleagues at the NIA's Gerontology Research
Center in Baltimore, where the project is coordinated,
will be monitoring dozens of signs of aging, ranging
from immune response to activity level to anti-oxidant
levels to fingernail growth. The measurements will be
compared with those of the monkeys in the control group
and should provide leads to some of the anti-aging mechanisms
at work in caloric restriction.
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On a practical
level, though, most gerontologists don't expect caloric restriction
ever to become a widespread means of extending the human life
span. What they hope to learn from studies of caloric restriction,
once its mechanisms are understood, is how to improve health
and prevent or postpone the diseases of advancing age.
Speculation
about how caloric restriction works covers a broad field, reflecting
the wide range of effects it has in laboratory animals. Because
cutting down on calories slows metabolism, and free radicals
are by-products of metabolism, caloric restriction may reduce
free-radical damage. And because caloric restriction lowers
body temperature slightly, cells may sustain less genetic damage
and repair it more readily than at normal body temperature.
In addition, scientists speculate that caloric restriction preserves
the capacity of cells to proliferate, that it moderates the
decline in growth hormone, and that it keeps the immune system
functioning at youthful levels.
In fact its
effects are so pervasive that some scientists postulate the
existence of a single, master gene whose expression is influenced
by caloric restriction and which in turn modifies all aging
processes. Whether or not this proves correct, continued work
with caloric restriction is expected to uncover much more about
the mechanisms of aging.
Behavioral
Factors
Salads in fast-food
restaurants and low-fat labels in supermarkets signal a transformation
in Americans' eating habits that is reflected in mortality rates.
Deaths from heart disease have declined 45 percent in the United
States since 1950, partly due to the switch to lower-fat, lower-cholesterol
diets, and to other behavioral factors, like smoking cessation
and exercise.
Diet and exercise,
in particular, are thought to have a major impact on a constellation
of changes that are common with advancing age. These include
higher levels of fats or lipids in the blood, changing levels
of blood sugar and insulin, a tendency toward obesity, and increased
central body fat -- that which settles around the waist and
abdomen. So common are these among older people that they have
been given a name -- syndrome x -- and their relationship to
heart and other cardiovascular diseases is the focus of many
studies.
Syndrome x may
be preventable through low-fat and low-cholesterol diets, but
these are not the only aspects of nutrition that may influence
life expectancy. Gerontologists have been scrutinizing a wide
range of nutrients with an eye toward their role in aging processes.
Calcium and vitamin D, for example, help reduce the thinning
of bones that accompanies aging in almost everyone but particularly
in older women, many of whom are at high risk for osteoporosis.
Another nutrient, vitamin E, may be critical to the immune system,
while beta carotene, vitamin C, and vitamin E appear to fight
oxidative damage.
Startling to
many experts is the finding that most older people are not getting
the recommended daily allowances (RDAs) of some nutrients. The
Baltimore Longitudinal Study on Aging found deficiencies among
elderly people in calcium, zinc, iron, magnesium, vitamins B6,
B12, D, and E, and folic acid, a finding confirmed at the USDA
Human Nutrition Research Center on Aging. Nutritionists point
out that precisely what the RDAs should be for older people
is not clear.
Researchers
are also studying exercise as a behavioral factor that may have
an impact on how long we live -- or at least on how healthy
we are in old age. One landmark study at Tufts has shown that
exercise can strengthen muscles, improve mobility, and reduce
frailty even among 90-year-olds.
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Exercise
at 90: It Works.
Exercise
is a powerful health promoter at any time of life. Even
80- and 90-year-olds can benefit, according to a study
by Maria Fiatarone of the USDA Human Nutrition Center
on Aging at Tufts University. Here is how Fiatarone
described her findings to the House Select Committee
on Aging in February 1991:
"Starting
with a small group of ten 90-year-old residents of the
Hebrew Rehabilitation Center for Aged in Massachusetts,
we demonstrated that the muscle weakness and atrophy
of aging were in fact not at all immutable. These residents
increased their leg muscle strength by 174 percent and
their muscle size by 9 percent after only 8 weeks of
weight-lifting exercise. More importantly, as we have
expanded this research to a much larger group of volunteers
through the support of grants from the National Institute
on Aging and others, it is clear that such training
can improve walking speeds, mobility, independence in
daily activities, and reduce dependence on canes, walkers,
and wheelchairs in some individuals. At a cellular level,
we now have preliminary evidence that this increased
muscle function is accompanied by the actual growth
of new muscle fibers, a finding never before demonstrated
after strength training."
Rose
Karsh, a participant in the study, described it from
her point of view:
"When
I finished the study I was able to life 50 pounds with
each leg which surprised me very much at my age. After
the test was over I was able to walk around the center
without any assistance, and it made me feel very proud
that I could do that. It made me feel younger and gayer.
I use my cane to protect myself from falling only when
I walk outside. I don't have to use a walker."
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Exercises that
put weight on bones, such as jogging, walking, and weight-lifting,
have been shown to strengthen them. Researchers, as a result,
are exploring the potential of exercise to reduce the risk of
osteoporosis. This condition, with its fragile, easily broken
bones, is a major cause of fractures among older people, frequently
results in disability, and eventually leads to institutionalization
for many.
Physiologic
Clues: Selected Readings
Adler, W., Song,
L, Chopra, R.K., Winchurch, R.A., Waggie,K.S., Nagel, J.E.,
"The Immune Deficiency of Aging," in Powers, D., Morley, J.,
Coe, R., eds., Aging, Immunity, and Infection, New York:
Springer, 1993.
Fiatarone, M.A.,
Marks, E.C., et al., "High-IntensityStrength Training in Nonagenarians,"
Journals of the American Medical Association 263:3029-3034,
1990.
National Institute
on Aging. Research on Older Women:Highlights from the Baltimore
Longitudinal Study of Aging, Bethesda, MD: National Institutes
of Health, 1991.
Shock, N.W.,
Greulich, R.G., Andres, R.A., Arenberg, D.,Costa, P.T., Lakatta,
E.G., Tobin, J.P., Normal Human Aging: The Baltimore Longitudinal
Study of Aging, Washington, DC: U.S. Government Printing
Office, 1984.
Warner, H.R.,
and Kim, S.K., "Dietary Factors Modulating theRate of Aging,"
in Goldberg, I., ed., Functional Foods, New York: Van
Nostrand Reinhold, 1993.
Weindruch, R.,
and Walford, R.L., The Retardation of Agingand Disease by
Dietary Restriction, Springfield, IL: Charles C. Thomas,
1988.
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