One for the Ages: A Prescription That May Extend Life

[Guest guest]

A motivational piece on CR from the NY Times:

http://snipurl.com/10w8w

- Diane

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One for the Ages: A Prescription That May Extend Life

by Jeff /University of Wisconsin-Madison

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 time's 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

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.

A. , 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

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.

, 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 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.

" 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, Los Angeles, who spent much of the

last 30 years of his life following a calorie-restricted regimen. He

died of Lou Gehrig's 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 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 entrée). 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.

" 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 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.

" Calorie restriction has a powerful, protective effect against

diseases associated with aging, " said Dr. O. Holloszy, a

Washington University professor of medicine. " We don't know how long

each individual will end up living, but they certainly have a longer

life expectancy than average. "

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. 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. Kenyon, a molecular biologist at the

University of California, San Francisco. " This system could have

evolved as a way of letting animals take a timeout from reproduction

when times are harsh. "

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.

" 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 University of California, Los Angeles, and a

co-author of the paper. " We do see benefits, but not an increase in

life span. "

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. 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 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 " 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 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 cell's 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 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.