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Feb. 7, 2005
Enhanced: TARGETED GENES ARE MORE ACTIVE IN FIGHTING AGING
The "guess
your age" booth at a carnival isn't often exactly
right. But it's not usually as off-base as Cynthia Kenyon's
colleagues. A few years ago Kenyon, a molecular geneticist,
had one of her grad students cart a tray of worms around
her lab, asking people how old they thought the worms were.
Most
said about 5 days. What they didn't know was that Kenyon
had tinkered with the worms' genes. The squirmy creatures
had the
perfect health of 5-day-olds, but they were 144 days old — six
times their normal life span.
Over the last decade, Kenyon's
continuing work has shown that "you can make huge changes
in life span so easily" — in worms, at least — by changing
hormone levels and enhancing the effects of fewer than 100
genes.
Some of the target genes produce antioxidants; some make
natural
microbicides; some are involved in transporting fats throughout
the body, and some, called chaperones, "keep the cell components
in good working order," says Kenyon. What they all have in
common is their effect on aging. The more active the genes,
in general, the longer an organism is likely to live.
When
Kenyon's work with worm genes was first published in 1993,
skeptics predicted it wouldn't translate well to humans.
One hundred forty-four days might be ancient for a worm,
but a
far more complex human being can already expect to live about
200 times longer than that. Scientists still don't know exactly
why the life spans are so different, much less what a change
in a worm's life span might mean for a person's. Nonetheless,
much of the cellular machinery in worms closely resembles
that in higher mammals. That finding has opened the door
for a neutraceutical
company, Elixir, which is trying to develop a drug that would
yield the same kind of results as Kenyon's genetic tampering. "I'm
not saying that with a few changes humans could be immortal," she
says. "But it'd be like looking at an 80-year-old and thinking
he was 40." Who could object to that?
Stressed: CHRONIC TENSION MAKES CELLS DETERIORATE FASTER
If
you've ever blamed stress
for new wrinkles or gray hairs, you may have been right. "As
a society, we have a deeply held belief that life stress
causes premature aging, but there's actually been very little
empirical
evidence to show this," says Elisa Epel, assist-ant professor
of psychiatry at the University of California, San Francisco.
Until now. In a UCSF-led study published this past fall in
Proceedings of the National Academy of Sciences, Epel
and her colleagues found that chronic stress — or even the
perception of stress — significantly shortened the length
of telomeres, the tips of chromosomes within cells that can
be used as
a measure of the cells' aging process. The shorter the
telomere, the shorter the cell's life span and the faster
the body's
deterioration. As more cells die, the effects of aging
kick in: muscles weaken, skin wrinkles and eyesight and hearing
worsen.
Epel and her colleagues studied 39 women between
the
ages of 20 and 50 with children suffering from serious
chronic
conditions, like cerebral palsy, and compared them with
19 mothers in the same age group with healthy children. The
longer a woman had been caring for a sick child, the
shorter
her telomeres — and
the greater her oxidative stress (a process that releases
DNA-damaging free radicals).
But what startled researchers
more was that
the most profound differences were tied to the women's
perceptions of how much emotional strain they were under,
regardless
of whether their children were healthy or sick. When
compared with the women with the lowest perceived stress
levels, women
in both groups who described themselves as having the
highest stress levels had telomeres equivalent to someone
10 years
older.
While Epel acknowledges that more studies need
to be
done to confirm her findings, she says the results could
have positive implications. "Now that we think we can
see intracellular damage from stress, people might weigh
the
importance of positive
mental health more heavily," she says, adding that there
is "absolutely" hope
that the DNA damage is reversible. "Lifestyle changes — and
learning to cope well with stress — could potentially
improve your quality of life, your mood and your longevity."
Restricted: A
TOUGH LIMIT ON CALORIE INTAKE MAY SLOW AGING
Leonard
Guarente didn't
come up with the trick of calorie restriction, or strictly
limiting nutrients to achieve longer life. And the
idea sounded crazy back in 1986, when Guarente first proposed
to study
the biology of aging via calorie restriction. Aging
was
seen as
too complex a topic for molecular biologists, and the
effect of calorie restriction on aging, though detailed
in scientific
literature since the 1930s, was even more poorly understood.
Guarente's colleagues called him "bonkers," but he didn't
care: "I
wanted to work on something risky," he says. "Besides,
I had just gotten tenure, and at that point they couldn't
get
rid
of me."
They certainly wouldn't want to now. Guarente
is not the least bit bonkers — and, unbeknown to his
colleagues at the time, he wasn't even the only scientist
thinking
about the
molecular biology of calorie restriction. In the last
decade, researchers have made great strides in understanding
why
a sudden drop in calorie intake can kick up the activity
of a
gene called SIR2 and prolong life in simple organisms.
At the head of the class are Guarente and a Harvard
researcher named
David Sinclair, both of whom are focusing on sirtuins,
the
family of proteins produced by SIR2 or its mammalian
analogue, SIRT1. Guarente's lab has unraveled many
of the basic molecular
processes behind SIR2. For instance, a natural chemical
called NADH can inhibit sirtuins' effects; Guarente's
lab has determined
that yeast with lower NADH levels lives longer. Sinclair's
work has a slightly different focus — resveratrol,
the chemical he has connected to calorie restriction's
effects. (It's
better known as the major reason red wine is touted
as healthful.) Sinclair's work at Harvard has shown
that
heavy doses of
resveratrol
can prolong life span in yeast by 70 percent. Still
another scientist, Marc Tatar, has garnered similar
results in
fruit flies.
The fact that calorie restriction works
isn't all
that surprising from an evolutionary point of view.
In fact, calorie
restriction is an extremely effective strategy for
survival during lean times, when it's an imperative,
not a choice. "Let's
imagine I had a gene that could allow me to suspend
reproduction and slow down aging during a famine," says
Guarente. "When
the famine ends, I'll still be around to reproduce." As
a result, he adds, "every animal we know can do this."
Including
humans, of course. But since few people particularly
want to limit
their calories drastically (least of all Americans),
Guarente is searching for a pill that will have the
same effect. Elixir,
the same company building on Kenyon's work, is also
using Guarente's — which
means, someday, humans may reap the benefits of calorie
restriction without even having to say the word diet.
Sinclair has a
competing company called Sirtris. He expects to get
his drugs into clinics
in just five years. Until then, he'll be drinking one
glass of red wine a day — and toasting to what he hopes
will be a huge success.
Supplemented: TWO
CHEMICALS MADE OLD RATS NEW
Five
years ago Bruce Ames called his son, a computer
executive in New York, with some exciting news. "I told him,
'We're changing old rats to new rats!' " recalls Ames,
a senior scientist at Children's Hospital Oakland Research
Institute
in California.
His son was not impressed. "Let me know when you change
old people to young rats," he said. Such human-to-animal
transformations are still confined to the minds of
sarcastic sons and science-fiction
writers, but researchers are getting closer to replicating
Ames's rat results in humans.
In studies published
in Proceedings of the National Academy of Sciences
in 2002,
Ames and his
colleagues fed older rats two chemicals normally found
in the body's cells
(and also sold as nutritional supplements): acetyl-L-carnitine
and alphalipoic acid. Not only did the rats perform
better on problem-solving and memory tests, but they
moved around
with more ease and energy.
Researchers determined that
the combination of chemicals had improved the function
of mitochondria,
organelles that serve as a cell's main energy source.
Ames formed a company called Juvenon to license the
combination of cell-rejuvenating supplements (also
sold separately
at
several health stores). The company plans to begin
human trials soon
to evaluate the cognitive effects of the dual supplements.
In the meantime, Ames, who chairs Juvenon's scientific
advisory board but gets no proceeds from the company,
is overseeing
lab research on human cells in tissue culture. In one
study, Berkeley researchers found that lipoic acid
protected the
cell from oxidation when iron or hydrogen peroxide
was added.
Now
he hopes to replicate those results in human subjects.
Other studies have already linked unhealthy mitochondria
to Alzheimer's,
Parkinson's, type 2 diabetes and other degenerative
diseases, so reversing or repairing decay in mitochondria
could
help to stave off the age-related diseases. "I'm hoping
we can add a few years to people's lives," says Ames,
who's 76. "I
think we can."
© 2005 Newsweek, Inc.
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