Resveratrol: candidate for anti-aging pill

References

Animals that eat less live longer. They're healthier, too, and more active. It's not a stretch to say that eating less slows down the aging process.

But eating is such a pleasurable and socially-conditioned part of our lives, that we all have trouble subjecting it to strict controls. Most of us would be very happy to see science develop a pill that offers the benefits of the hungry lifestyle without the hunger.

Scientists refer to the low calorie regimen as "Caloric Restriction", or CR, and the technical name for a chemical that produces the effect of CR in a fully-fed animal is "CR Mimetic".

Resveratrol is the first solid candidate for a CR mimetic. It's still early in the experimental cycle, and data is thin, just because these experiments take time. But results are so positive that scientists and even some medical people are saying it may not be too early to recommend resveratrol as a general anti-aging tonic.

A brief history

The story of resveratrol's discovery begins in the 1990's, when stories first came out about the French paradox: Why is it that with such a rich diet, full of saturated fats, the French have a lower rate of cardiovascular disease than Britain or America? The answer was traced to the French habit of drinking wine with the evening meal, and it was established that something in red wine has a protective effect on the heart.

The first speculation was, maybe it's the alcohol. Could it be that a small amount of alcohol each day protects the arteries? That turned out not to be true. Five years ago, it was discovered that the active agent in red wine providing cardiovascular protection was resveratrol.

It was David Sinclair (now at Harvard) who made the discovery. As a student, he had been working on the mouse gene called SIR2 under the direction of Leonard Guarente at MIT. Yeast cells may seem a funny place to study aging - what does it mean for a single cell to age? - but it turns out that not only do these cells experience aging, but some of the mechanisms of aging in yeast are closely analogous to aging in flies and worms...and you and me. Yeast responds to food scarcity the same way that higher animals do, slowing the pace of aging. And yeast use a hormone very close to insulin in structure to regulate their sugar use, and insulin seems related to the rate of aging in living things from yeast on up.

SIR stands for 'Silent Information Regulator'. The gene contains instructions for a protein that wraps itself around DNA, preventing some areas of the DNA from making their own proteins. Apparently these proteins cause an animal (or a cell) to age, because silencing them has an anti-aging effect. The analog of SIR2 in humans is called SIR-T1, and it also plays a roll in transmitting the signal that tells the cell to slow down the rate of aging in response to food shortage.

In 2002, Sinclair discovered that resveratrol stimulates SIR2 (and SIR-T1) in much the same way that a low-calorie diet does. The race was on to discover the mechanism of action, and to ask whether life can actually be extended with resveratrol. The first animals to be tested were short-lived flies and worms. Resveratrol showed promise, extending life span about 30% in both species.

Animal studies with resveratrol

An enterprising Italian grad student was working with aging in a short-lived species of African fish, and saw an opportunity to try resveratrol for the first time with a vertebrate species. The plan worked swimmingly, and the resveratrol-eaters lived 60% longer than their brother and sister fish.

Mice are short-lived mammals, but an experiment on mouse lifespan still requires 4 years. These experiments are in progress, but early results are already coming out, and they are promising. In an article last fall in the British journal Nature, Dr Sinclair &Co reported that fat mice on resveratrol had metabolic characteristics of thin mice. They were healthier by a broad range of measures, and we might expect that they are aging more slowly as well. Around the same time, a French research group reported that feeding jumbo doses of resveratrol to lab mice gave them phenomenal atheletic endurance - twice that of untreated mice. The boost was traced to a huge increase in the number of mitochondria in muscle cells. Mitochondria are tiny organelles, thousands in a typical cell, which burn sugar to create electrochemical energy, in a form the cell can use.

Resveratrol in humans?

Just this January, an editorial in the Journal of Molecular and Cellular Cardiology recommended that it may not be too early for doctors to recommend resveratrol to their patients as a general preventative. This judgment wasn't based on a thorough knowledge, but a feeling that the potential benefits are so large that they might warrant taking a risk with side effects that have not yet been delineated.

There are no red flags at present, but research is still at such an early stage that it is difficult to know if there will be a serious down side to resveratrol. Rats in a toxicity study experienced kidney damage only after they'd received doses equivalent to half a pound a day in a human scale. The mice in the French experiment were given a human-equivalent dose of about an ounce a day, or several hundred capsules. A colleague of mine, experimenting on himself, reports diarrhea with 3000 mg/day (30 capsules of 100mg each).

Optimal dosage is still a big question mark. Wine varies widely in its resveratrol content, so that it may take anywhere from 2 to 50 glasses of wine to obtain 1 mg of resveratrol. There is a glaring gap between the tiny doses from wine that still seem to provide some benefit and the huge doses - thousands of times bigger when scaled for body weight - that make mice into super athletes. Until some long-term studies have been done in humans, people who experiment on themselves will be flying blind.

The first (expensive) pills sold a few years ago contained 40 mg, but the company has recently announced 100mg capsules at the same price. 250 mg capsules are also available mailorder via the Web. Up until last year there was just one supplier and prices were high; recently several other companies joined the fray, and resveratrol prices have dropped sharply.

But is it natural?

Many WW members eat organic food, pursue a 'natural' lifestyle, and shun pills. I'm sympathetic.

But I also believe that there is one giant limitation to this health strategy, and that is aging. Natural foods are a way to help our bodies do what they were designed by nature to do. But our bodies were never designed to resist aging; in fact, aging is part of nature's developmental program. We are 'designed' to degrade and lose functionality with age. We are programmed to die.

The aging program is flexible in some diabolical ways. We are programmed to age more quickly when life is comfortable, when we are fat and happy and sedentary. Recommended weight on a doctor's chart is unattainable for many of us, and I would argue that truly ideal weight is lower yet.

It is to tap into the flexibility in nature's aging program that I recommend 'unnatural' interventions. Natural foods are for health maintenance; but to combat aging, we require un-natural treatments and supplements.