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Only recently have human aging studies entered the realm of serious science.
The National Institute on Aging was formed just 20 years ago. Models for
studying human aging were rare until recently.
"In the animal world, aging is almost nonexistent," says Jan Vijg,
director of the molecular genetics section of Beth Israel Hospital's gerontology
division, in Boston. "Most animals die of infectious diseases or accidents
or are killed long before they become adults, let alone get a chance to
age."
This is not to say that animals do not have long lifespans: some tortoises
may live 150 years. Consider the saga of Scottish ornithologist George Dunnet
and the fulmar, told in two photographs. In the first, taken by a shoreline
in 1950, Dunnet is in the act of tagging a young adult female bird. Dunnet
looks fit, in his twenties or thirties, and sports a full head of dark,
wavy hair. The second picture, taken in 1992, shows an older, sagging Dunnet,
with thinning grey hair, while the fulmar looks almost identical to its
1950 picture.
Why not study these long-lived animals to further understand human aging?
Because, although they can rack up years, in an important physiological
sense they are not aging. There's nothing to distinguish the fulmar from
its younger fellows but a 42-year-old leg band. Females of this species,
and some others, remain fertile at a point in their lifespans long after
humans would have undergone menopause. By the same token, there are species
that age very quickly after reproduction. For example, take the rapid physical
deterioration that occurs in sockeye salmon as they make their way upstream
to spawn. One sees bone deformity, muscle weakness, reduced immunity, and
finally an exhausted death. A decline that takes decades in humans is compressed
into days. Extrapolations from these species to ours would be fraught with
misgivings.
"Rodent aging is well characterized," says Beth Israel gerontology
division chief Jeanne Y. Wei, M.D., "and there are transgenic mouse
models that can give valuable insights. But there are many ways in which
we can never extrapolate from the rodent to the human. Unfortunately, it's
extremely difficult to do longitudinal aging studies in humans.
"There are all kinds of obstacles," Wei continues. "One of
the problems of studying the elderly is that the techniques change over
time. For instance, blood glucose measurement techniques have changed significantly
over the past few years. Means of data analysis change. People and groups
change. There are mass lifestyle changes, such as the recent focus on exercise,
or the exodus from farming communities. Something can be added to the drinking
water, like fluoride, that has the potential to skew your sample enormously.
Or people may change their dietary habits in very subtle ways.
"Another confounding aspect of studying aging is that you're usually
studying only survivors; you're finding out a lot about the diseases that
certain subjects have died from and others have managed to survive or avoid.
For example, you may see a drop in cholesterol at a certain age. That drop
could be due to changes in measurement technique, which have changed over
the last few years, or to dietary intake, which has also changed drastically
due to improved awareness of the importance of diet, or it could be simply
that most of the study subjects with high cholesterol have died by this
age. And none of this would really tell us anything about aging."
Wei is director of Harvard's division on aging, a consortium that brings
together researchers and clinicians throughout the University's affiliates.
The division was born in 1979 out of a collaboration between doctors Jack
Rowe and Richard Besdine. Rowe, a Beth Israel nephrologist who had trained
at the National Institute on Aging, believed that geriatricians needed to
begin working with subspecialists from all disciplines to answer basic questions
about aging: how it affects functioning of major systems and what implications
it has for disease prevention and treatment.
Besdine, who came from the Hebrew Rehabilitation Center for Aged, promoted
research into so-called "geriatric syndromes": falls, incontinence,
and dehydration, to list just a few. Researchers who trained under Besdine
have gone to extraordinary lengths to investigate the multiple causes of
these syndromes and develop imaginative treatments (see "Make Me Dry,"
page 58).
"Aging is so complex that we probably can't study it with the same
methodological techniques we have used for other diseases," concedes
Wei. "We need new methods, new paradigms, a new way of looking at things
to find out what happens to people as they get older."
Oscar Wilde's dying words in a cheap, poorly appointed Paris hotel were
supposed to have been, "Either this wallpaper goes or I do." Wilde's
nonchalance is not widely shared; intrinsic to the way we think about life
is that it is worth holding on to at all costs, to the point that we refuse
to acknowledge death. Why else would so many people put off for so long
important decisions about health-care proxies, do-not-resuscitate instructions,
inheritance and funeral plans?
Our genes point to a different set of priorities. Their only goal and measure
of success is reproduction. If you die without reproducing, your individualized
collection of genes dies, too. Any genetic features interfering with reproduction
are automatically unlikely to survive in future generations, while genes
that abet mating are preserved. But so are the genes that undoubtedly play
a role in all the chronic diseases of aging-Alzheimer's disease, heart disease,
diabetes, osteoporosis, cancer, and others.
"Aging occurs after you've had your children," Jan Vijg says.
"Consequently, there is no selection for successful aging genes.Genes
with negative effects in old age have a tendency to stick, because they've
been passed along before they've had the chance to affect reproduction."
Many experts on aging agree that genes determine who ages successfully.
That's too bad, because when it comes to aging, genes can be notoriously
bad decision-makers. For example, Vijg says, choices our genes made millenia
ago made us reliant on oxygen. A highly reactive element, oxygen bonds to
almost anything in the environment, including important biomolecules like
DNA. This reactivity renders oxygen highly toxic; the element deactivates
enzymes, contorts protein, and compromises the DNA sequence perhaps as often
as 100,000 times a day in each human body.
Long ago in our evolution, however, genes were selected that acknowledged
that the competitive advantage of metabolizing oxygen, which can produce
lots of energy quickly, was worth the long-term risk of chronic oxygen toxicity.
Animals developed highly specialized red blood cells for transporting oxygen
safely through the bloodstream in ways that temporarily prevent it from
reacting with other molecules.
Just the fact that we breathe oxygen is evidence of our genes' ambivalence
toward longevity. Oxygen's toxicity seldom becomes an issue until we age.
Vijg thinks that oxidative damage may be one of the major causes of the
aging process, and went to the trouble of developing a complicated mouse
model to look further into the question. The model enabled him to measure
for the first time the "mutation load" that accumulates in specific
tissues-heart or liver, for instance-as mice age or develop tumors.
Vijg was surprised to find that there were widespread mutations in adult
mouse brain and liver. Because both these tissues have stopped growing in
the adult mouse, they should have been less vulnerable to mutations. Presumably,
the majority of the mutations could have been caused by oxidative damage.
"It's quite possible that the major defense mechanism against this
type of damage is simply cell death," Vijg says. "Now we need
to find out how frequent these mutations are. Are they mutations or deletions?
Could it be that these are just background mutations in an aging genome?
Although this is still a rough methodology, it may enable us to look for
ways to improve the DNA defense system."
