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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?
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Normal
Aging
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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.
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The Immune
System
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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 (see Hormones and Research on
Aging). 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.
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Caloric
Restriction
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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.
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Behavioral
Factors
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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.
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Physiologic
Clues: Selected Readings
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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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