Mike
Linksvayer, 36, on a low-calorie diet for six years, is 6 feet and 135 pounds,
and his blood pressure is 112 over 63.
Canto, left,
a rhesus monkey, is aging fairly well at 25 on a calorie restriction diet.
Owen, though only a year older than Canto, is frail and moves slowly. He eats a
normal diet.
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 Wisconsin National Primate
Research Center, Matthias is learning about timeÕs caprice the hard way. At 28,
getting on for a rhesus monkey, Matthias is losing his hair, lugging a paunch
and getting a face full of wrinkles.
Yet in the cage next to his, gleefully hooting at
strangers, one of MatthiasÕs 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. ÒYou can really see the difference,Ó 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 AlzheimerÕs disease, diabetes, heart disease, ParkinsonÕs 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 bodyÕs 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.
ÒThe effects are global, so calorie restriction has
the potential to help us identify anti-aging mechanisms throughout the body,Ó
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.
ÒThe demographic wave entering their 60s is
enormous, and that is likely to greatly increase the prevalence of diseases like
diabetes and heart disease,Ó said Dr. S. Jay Olshansky, an epidemiologist at
the University of Illinois at Chicago, and one of
the paperÕs authors. ÒThe simplest way to positively affect them all is to slow
down aging.Ó
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. McCayÕs 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.
ÒIn mice, calorie restriction doesnÕt just extend
life span,Ó said Leonard P. Guarente, professor of biology at the Massachusetts Institute of Technology. ÒIt
mitigates many diseases of aging: cancer, cardiovascular disease,
neurodegenerative disease. The gain is just enormous.Ó
For years, scientists financed by the National
Institute on Aging have closely monitored rhesus monkeys on restricted and
normal-calorie diets. At the University of Wisconsin, where 50 animals survive
from the original group of 76, the differences are just now becoming apparent
in the older animals.
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.
ÒThe preliminary indicators are that weÕre looking
at a robust life extension in the restricted animals,Ó 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, Los Angeles, who
spent much of the last 30 years of his life following a calorie-restricted
regimen. He died of Lou GehrigÕs disease in 2004 at 79.
Largely as a result of his advocacy, several
thousand people are now on calorie-restricted diets in the United States, says
Brian M. Delaney, president of the Calorie Restriction Society.
Mike Linksvayer, a 36-year-old chief technology
officer at a San Francisco nonprofit group, embarked on just such a diet six
years ago. On an average day, he eats an apple or some cereal for breakfast,
followed by a small vegan dish at lunch. Dinner is whatever his wife has cooked,
excluding bread, rice, sugar and whatever else Mr. Linksvayer deems unhealthy
(this often includes the entrŽe). On weekends, he occasionally fasts.
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.
ÒI donÕt really get sick,Ó he said. ÒMostly I do
the diet to be healthier, but if it helps me live longer, hey, IÕll take that,
too.Ó
Researchers at Washington University in St. Louis have been
tracking the health of small groups of calorie-restricted dieters. Earlier this
year, they reported that the dieters had better-functioning hearts and fewer
signs of inflammation, which is a precursor to clogged arteries, than similar
subjects on regular diets.
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.
ÒCalorie restriction has a powerful, protective
effect against diseases associated with aging,Ó said Dr. John O. Holloszy, a
Washington University professor of medicine. ÒWe donÕt know how long each
individual will end up living, but they certainly have a longer life expectancy
than average.Ó
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. ÒIt is a very deep, very important
function,Ó 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.
ÒThe stressed cell is really pulling out all the
stopsÓ to preserve itself, said Dr. Cynthia Kenyon, a molecular biologist at
the University of California, San Francisco. ÒThis system could have evolved as
a way of letting animals take a timeout from reproduction when times are
harsh.Ó
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 University of California, Los Angeles, and University of California, Irvine,
predicted that the maximum life span gain from calorie restriction for humans
would be just 7 percent. A more likely figure, the authors said, was 2 percent.
ÒCalorie restriction is doomed to fail, and will
make people miserable in the process of attempting it,Ó said Dr. Jay Phelan, an
evolutionary biologist at the University of California, Los Angeles, and a
co-author of the paper. ÒWe do see benefits, but not an increase in life span.Ó
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.
ÒHave you ever tried to go without food for a day?Ó
Dr. Phelan asked. ÒI did it once, because I was curious about what the mice in
my lab experienced, and I couldnÕt even function at the end of the day.Ó
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
organismÕs 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.
ÒThe goal is not just to make people live longer,Ó
said Dr. David A. Sinclair, a molecular biologist at Harvard. ÒItÕs to see
eventually that an 80-year-old feels like a 50-year-old does today.Ó
In a series of studies, Dr. Kenyon, of the
University of California, San Francisco, has created mutant roundworms that
live six times longer than normal, largely because of a mutation in a single
gene called daf-2. The gene encodes a receptor on the surface of cells similar
to a receptor in humans that responds to two important hormones, insulin and the insulin-like growth
factor 1 or IGF-1.
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 ÒtrickedÓ 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 organismÕs 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 cellÕs 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 Boston, already has begun
testing a new drug in patients with Type 2 diabetes that acts on SIRT1 to
improve the functioning of mitochondria, the cellÕs energy factories.
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 PresidentÕs Council on Bioethics,
human lives may become less engaging, less meaningful, even less beautiful.
ÒMortality makes life matter,Ó Dr. Kass recently
wrote. ÒImmortality is a kind of oblivion — like death itself.Ó
That manÕs 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.
ÒItÕs a just big waste of talent and wisdom to have people die in their 60s and 70s,Ó said Dr. Sinclair of Harvard.