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The fountain of youth - well, not quite yet
(February 2007)

Life expectancy at birth in the United States is about 77 years (a bit more for women, a bit less for men).  If diseases affecting older people (heart disease, stroke, cancer, diabetes) can be either prevented or successfully treated, our life expectancy could increase to 90 or 95 years.  If we can modify the aging process itself, life expectancy at birth could reach an average 110 to 120, or more, years.  Scientists have been studying the aging process and have made breathtaking progress.  The potential to extend life spans to 110 to 120 or more years is no longer science fiction.  For about a century, it has been known that reducing the caloric intake of many species by 30 to 40 percent (but avoiding malnutrition) is associated with a marked increase in life spans (from 30 percent to more than 200 percent).  Recently, it has been shown that caloric restriction works, in part, by stimulating certain genes, especially a group called sirtuitins.  The prolongation of life spans probably relates to the stimulated genes producing proteins that increase the capacity to cope with a variety of stresses.  That has led to a flurry of activity to find substances that mimic the effects of caloric restriction and stimulate the sirtuitin genes.  A group led by Dr David Sinclair of Harvard Medical School tested a large number of substances and found one called resveratrol which is found in red wine and grape skins to be particularly potent in its ability to stimulate these genes, especially one called SIR-2.  First, they showed that resveratrol extended the life span of earthworms and fruit flies.  Now, in a landmark study published in the journal Nature, the same group of Harvard investigators, in collaboration with multiple other investigators, shows that resveratrol can prolong life in overweight mice.

Middle-aged mice were kept on a standard mouse diet or were fed a high fat, high caloric diet.  Half of the high fat, high calorie diet group were given a huge dose of resveratrol daily, the equivalent of drinking several hundred bottles of red wine each day.  The high caloric-high fat mice got fat and died early, but those high calorie mice given resveratrol were less likely to die; indeed, their death curves were about the same as mice on the standard diet.  In addition to the 31 percent reduced risk of death, the high-calorie resveratrol-treated mice showed better motor skills, showed no liver infiltration by fat, and had less diabetic characteristics.  In general, except for a continuing elevation of blood cholesterol levels, the resveratrol reversed the deleterious effects of the high fat- high caloric diet so, even though fat, they resembled the standard diet mice.

The investigators concluded “the ability of resveratrol to prevent the deleterious effects of excess caloric intake and modulate known longevity pathways suggests that resveratrol and molecules with similar properties might be valuable tools in the search for key regulators of energy balance, health, and longevity”.

Commentary: This is an extraordinary study with gargantuan implications.  The authors talk about reversing undesirable physiologic effects induced by chronic diseases or abnormalities, including obesity and diabetes, but that is not really where they are going.  This is all about reversing or preventing the aging process itself, as well as the diseases that accompany it.  Several points deserve emphasis:

- The dose of resveratrol was huge (22 milligrams per kilogram).  High calorie-high fat diet mice were also given 5 milligrams per kilogram, still a huge amount, but the results were not reported here - it is likely the findings were considerably less dramatic.

- The results reported here have nothing to do with human red wine consumption.  A person could be besotted with red wine 24 hours a day every day and not come anywhere remotely close to the dosage used or, for that matter, to the 5 milligram per kilogram dose administered, but not reported.

- Not all the obesity-related abnormalities were reversed, in particular the blood cholesterol levels.

- One hallmark of increased longevity accompanying caloric restriction is a low level of a hormone called insulin-like growth factor one (IgF1).  That was indeed lowered somewhat compared to the high calorie-high fat diet group, but the levels were not a lot lower and were still much higher than the levels in the standard diet mice.

The investigators are now studying resveratrol in standard diet, non-obese mice.  Those results will tell us a great deal about its ability to prevent diseases of aging and increase longevity.

Baur, J.A., et al.  Resveratrol improves health and survival of mice on a high calorie diet.  Nature.  Published online November 1, 2006.

It is well to remember that, in this study, resveratrol reversed the shorter life span of obese mice; this was not a study of increased life span in normal diet mice.  The study does advance the scientific determination to find drugs that increase life span, first in mice and rats, then in monkeys and finally in humans.  We are not there yet by a long shot, but the progress, as exemplified by this report, is extraordinary.  Other compounds, like resveratrol, or derived from it, will be investigated based on their ability to stimulate genes of the sirtuitin group (particularly SIR-2).  This field will explode in the coming years.

Dr Sinclair is a hyper-enthusiast and a superb investigator, but, is, in the judgement of this reviewer, behaving a bit irresponsibly.  According to newspaper reports, he says he and half his laboratory are not waiting for the evidence, but are now taking 5 milligrams per kilogram a day of reservatrol.  He did not identify his source, but it may well be from his own for profit company.  That is a very big dose of a drug never tested in humans whose safety profile is not known.  Just because it does some interesting things in mice does not mean similar benefits will be found in humans and there could be adverse effects at small doses, let alone the huge doses he and his colleagues are supposedly taking.

There is already a book published that extols resveratrol as virtually the fountain of youth.  It, or any drug with similar actions, could be, could extend life spans by decades, and could also reduce the burden of some chronic diseases.  But, we need multiple careful studies moving from mice (where we are now) up the species chain to primates (monkeys) and finally to humans.

Dr Sinclair’s good work is leading the field; his unbridled and wild enthusiasm will surely unleash a resveratrol and resveratrol-like drugs entrepreneurial juggernaught that will make a lot of money for a lot of manufacturers and sellers.  For the public, there are four possible outcomes:

1.         No benefit, no harm.
2.         Benefits in either disease prevention or longevity.
3.         Both benefits and harms.
4.         No benefit, only harms.

Of course, there is one guaranteed outcome: the users will part with considerable money.

That is why drug discovery and testing for efficacy and safety must be carried out with deliberation and care - and why the public must be patient.  Assuming the newspaper reports are accurate, Dr Sinclair is undercutting his marvelous scientific studies with his not so marvelous proselytizing.  That is unfortunate.

There is one other point.  The science of modification of the aging process is moving so rapidly that we had better start to think about the societal consequences of extraordinary life spans (see Archives, two articles under Essays).