October
31, 2006
One for the Ages: A Prescription That May
Extend Life
By
MICHAEL MASON
How depressing, how utterly unjust, to be the one in your social
circle who is aging least gracefully.
In a laboratory at the
Yet in the cage next to his, gleefully hooting at strangers, one
of Matthias’s lab mates, Rudy, is the picture of monkey vitality, although he
is slightly older. Thin and feisty, Rudy stops grooming his smooth coat just
long enough to pirouette toward a proffered piece of fruit.
Tempted with the same treat, Matthias rises wearily and extends a frail
hand. “You can really see the difference,” said Dr. Ricki Colman, an associate
scientist at the center who cares for the animals.
What a visitor cannot see may be even more interesting. As a
result of a simple lifestyle intervention, Rudy and primates like him seem
poised to live very long, very vital lives.
This approach, called calorie restriction, involves eating about
30 percent fewer calories than normal while still getting adequate amounts of vitamins, minerals
and other nutrients. Aside from direct genetic manipulation, calorie
restriction is the only strategy known to extend life consistently in a variety
of animal species.
How this drastic diet
affects the body has been the subject of intense research. Recently, the effort
has begun to bear fruit, producing a steady stream of studies indicating that
the rate of aging is plastic, not fixed, and that it can be manipulated.
In the last year, calorie-restricted diets have been shown in
various animals to affect molecular pathways likely to be involved in the
progression of Alzheimer’s disease, diabetes, heart disease,
Parkinson’s disease and cancer. Earlier this
year, researchers studying dietary effects on humans went so far as to claim
that calorie restriction may be more effective than exercise at preventing
age-related diseases.
Monkeys like Rudy seem to be proving the thesis. Recent tests show
that the animals on restricted diets, including Canto and Eeyore, two other
rhesus monkeys at the primate research center, are in indisputably better
health as they near old age than Matthias and other normally fed lab mates like
Owen and Johann. The average lifespan for laboratory monkeys is 27.
The findings cast doubt on long-held scientific and cultural
beliefs regarding the inevitability of the body’s decline. They also suggest
that other interventions, which include new drugs, may retard aging even if the
diet itself should prove ineffective in humans. One leading candidate, a newly
synthesized form of resveratrol — an antioxidant present in large amounts in
red wine — is already being tested in patients. It may eventually be the first
of a new class of anti-aging drugs. Extrapolating from recent animal findings,
Dr. Richard A. Miller, a pathologist at the University of Michigan,
estimated that a pill mimicking the effects of calorie restriction might
increase human life span to about 112 healthy years, with the occasional senior
living until 140, though some experts view that projection as overly
optimistic.
According to a report by the Rand Corporation, such a drug would
be among the most cost-effective breakthroughs possible in medicine, providing
Americans more healthy years at less expense (an estimated $8,800 a year) than
new cancer vaccines or stroke treatments.
“The effects are global, so calorie restriction has the potential
to help us identify anti-aging mechanisms throughout the body,” said Richard
Weindruch, a gerontologist at the University of Wisconsin
who directs research on the monkeys.
Many scientists regard the study of life extension, once just a
reliable plotline in science fiction, as a national priority. The number of
Americans 65 and older will double in the next 25 years to about 72 million,
according to government census data. By then, seniors will account for nearly
20 percent of the population, up from just 12 percent in 2003.
Earlier this year, four prominent gerontologists, among them Dr. Miller, published a paper calling for the government to
spend $3 billion annually in pursuit of a modest goal: delaying the onset of
age-related diseases by seven years.
Doing so, the authors asserted, would lay the foundation for a
healthier and wealthier country, a so-called longevity dividend.
“The demographic wave entering their 60s is enormous, and that is
likely to greatly increase the prevalence of diseases like diabetes and heart
disease,” said Dr. S. Jay Olshansky, an epidemiologist at the University of Illinois
at Chicago, and one of the paper’s authors. “The simplest way to positively
affect them all is to slow down aging.”
Science, of course, is still a long way from doing anything of the
sort. Aging is a complicated phenomenon, the intersection of an array of
biological processes set in motion by genetics,
lifestyle, even evolution itself.
Still, in laboratories around the world, scientists are becoming
adept at breeding animal Methuselahs, extraordinarily long lived and healthy
worms, fish, mice and flies.
In 1935, Dr. Clive McCay, a nutritionist at Cornell University,
discovered that mice that were fed 30 percent fewer calories lived about 40
percent longer than their free-grazing laboratory mates. The dieting mice were
also more physically active and far less prone to the diseases of advanced age.
Dr. McCay’s experiment has been successfully duplicated in a
variety of species. In almost every instance, the subjects on low-calorie diets
have proven to be not just longer lived, but also more resistant to age-related
ailments.
“In mice, calorie restriction doesn’t just extend life span,” said
Leonard P. Guarente, professor of biology at the Massachusetts
Institute of Technology. “It mitigates many diseases of aging: cancer,
cardiovascular disease, neurodegenerative disease. The gain is just enormous.”
For years, scientists financed by the National Institute on Aging
have closely monitored rhesus monkeys on restricted and normal-calorie diets.
At the
Those on normal diets, like Matthias, are beginning to show signs
of advancing age similar to those seen in humans. Three of them, for instance,
have developed diabetes, and a fourth has died of the disease. Five have died
of cancer.
But Rudy and his colleagues on low-calorie meal plans are faring
better. None have diabetes, and only three have died of cancer. It is too early
to know if they will outlive their lab mates, but the dieters here and at the
other labs also have lower blood pressure
and lower blood levels of certain dangerous fats, glucose and insulin.
“The preliminary indicators are that we’re looking at a robust
life extension in the restricted animals,” Dr. Weindruch said.
Despite widespread scientific enthusiasm, the evidence that
calorie restriction works in humans is indirect at best. The practice was
popularized in diet books by Dr. Roy Walford, a legendary pathologist at the University of
California,
Largely as a result of his advocacy, several thousand people are
now on calorie-restricted diets in the
Mike Linksvayer, a 36-year-old chief technology officer at a
Mr. Linksvayer, 6 feet tall and 135 pounds, estimated that he gets
by on about 2,000 to 2,100 calories a day, a low number for men of his age and
activity level, and his blood pressure is a remarkably low 112 over 63. He said
he has never been in better health.
“I don’t really get sick,” he said. “Mostly I do the diet to be
healthier, but if it helps me live longer, hey, I’ll take that, too.”
Researchers at Washington University in
In previous studies, people in calorie-restricted groups were
shown to have lower levels of LDL, the so-called bad cholesterol, and
triglycerides. They also showed higher levels of HDL, the so-called good
cholesterol, virtually no arterial blockage and, like Mr. Linksvayer,
remarkably low blood pressure.
“Calorie restriction has a powerful, protective effect against
diseases associated with aging,” said Dr. John O. Holloszy, a
Researchers at Louisiana State University reported in April in The
Journal of the American Medical
Association that patients on an experimental low-calorie diet had lower
insulin levels and body temperatures, both possible markers of longevity, and
fewer signs of the chromosomal damage typically associated with aging.
These studies and others have led many scientists to believe they
have stumbled onto a central determinant of natural life span. Animals on
restricted diets seem particularly resistant to environmental stresses like
oxidation and heat, perhaps even radiation. “It is
a very deep, very important function,” Dr. Miller said. Experts theorize that
limited access to energy alarms the body, so to speak, activating a cascade of
biochemical signals that tell each cell to direct energy away from reproductive
functions, toward repair and maintenance. The calorie-restricted organism is
stronger, according to this hypothesis, because individual cells are more
efficiently repairing mutations, using energy, defending themselves and mopping
up harmful byproducts like free radicals.
“The stressed cell is really pulling out all the stops” to
preserve itself, said Dr. Cynthia Kenyon, a molecular biologist at the
But many experts are unsettled by the prospect, however unlikely,
of Americans adopting a draconian diet in hopes of living longer. Even the
current epidemiological data, they note, do not consistently show that those
who are thinnest live longest. After analyzing decades of national mortality
statistics, federal researchers reported last year that exceptional thinness, a
logical consequence of calorie restriction, was associated with an increased
risk of death. This controversial study did not attempt to assess the number of
calories the subjects had been consuming, or the quality of their diets, which
may have had an effect on mortality rates.
Despite the initially promising results from studies of primates,
some scientists doubt that calorie restriction can ever work effectively in
humans. A mathematical model published last year by researchers at
“Calorie restriction is doomed to fail, and will make people
miserable in the process of attempting it,” said Dr. Jay Phelan, an
evolutionary biologist at the
Mice who must scratch for food for a couple of years would be
analogous, in terms of natural selection, to humans who must survive 20-year
famines, Dr. Phelan said. But nature seldom demands that humans endure such
conditions.
Besides, he added, there is virtually no chance Americans will
adopt such a severe menu plan in great numbers.
“Have you ever tried to go without food for a day?” Dr. Phelan
asked. “I did it once, because I was curious about what the mice in my lab
experienced, and I couldn’t even function at the end of the day.”
Even researchers who believe calorie restriction can extend life
in humans concede that few Americans are likely to stick to such a restrained
diet over a long period. The aging of the body is the aging of its cells,
researchers like to say. While cell death is hardwired into every organism’s
DNA, much of the infirmity that comes with advancing years is from an
accumulation of molecular insults that, experts contend, may to some degree be
prevented, even reversed.
“The goal is not just to make people live longer,” said Dr. David
A. Sinclair, a molecular biologist at Harvard. “It’s to see eventually that an
80-year-old feels like a 50-year-old does today.”
In a series of studies, Dr. Kenyon, of the
Insulin is necessary for the body to transport glucose into cells
to fuel their operations. Dr. Kenyon and other researchers suggest that worm
cells with mutated receptors may be “tricked” into sensing that nutrients are
not available, even when they are. With its maintenance machinery thereby
turned on high, each worm cell lives far longer — and so does the worm.
Many experts are now convinced that the energy-signaling pathways
that employ insulin and IGF-1 are very involved in fixing an organism’s life
span. Some researchers have even described Type 2 diabetes, which is marked by
insensitivity to the hormone insulin, as simply an accelerated form of aging.
In yeast, scientists have discovered a gene similar to daf-2
called SIR2, that also helps to coordinate the cell’s
defensive response once activated by calorie restriction or another external
stressor. The genes encode proteins called sirtuins, which are found in both
plants and animals.
A mammalian version of the SIR2 gene, called SIRT1, has been shown
to regulate a number of processes necessary for long-term survival in
calorie-restricted mice.
Scientists are now trying to develop synthetic compounds that
affect the genes daf-2 and SIRT1.
Several candidate drugs designed to prevent age-related diseases,
particularly diabetes, are on the drawing boards at biotech companies. Sirtris
Pharmaceuticals, in
While an anti-aging pill may be the next big blockbuster, some
ethicists believe that the all-out determination to extend life span is veined
with arrogance. As appointments with death are postponed, says Dr. Leon R.
Kass, former chairman of the President’s Council on Bioethics, human lives may
become less engaging, less meaningful, even less
beautiful.
“Mortality makes life matter,” Dr. Kass recently wrote.
“Immortality is a kind of oblivion — like death itself.”
That man’s time on this planet is limited, and rightfully so, is a
cultural belief deeply held by many. But whether an increasing life span
affords greater opportunity to find meaning or distracts from the pursuit, the
prospect has become too great a temptation to ignore — least of all, for
scientists.
“It’s a just big waste of talent and wisdom to have people die in their 60s and 70s,” said Dr. Sinclair of
Harvard.