Caloric Restriction Comes in a Pill

Scientists have provided the strongest evidence yet that the anti-aging benefits of calorically restricted diets can be duplicated -- minus the near-starvation -- by a pill.

In a study published today in Cell Metabolism, mice given resveratrol -- the first of an eagerly-anticipated class of longevity drugs -- enjoyed dramatically improved health, even when they started taking the drug late in life.

Resveratrol didn't extend the lives of normal mice, but it did protect them from the ravages of time. The rodents had stronger hearts, clearer eyes, more limber muscles and firmer bones. Closer analysis revealed the same cell-level changes produced by caloric restriction, an extreme form of dieting that consistently lengthens the lives of lab animals but is impractical, if not dangerous, for people.

"For the first time, we can mimic caloric restriction in an otherwise healthy animal," said study co-author David Sinclair, a Harvard University biologist and co-founder of Sirtris Pharmaceuticals. "That's been the goal of the field for decades. We didn't know it was possible to let an animal eat whatever it wants, but still get the benefits. We now have evidence."

Sinclair discovered several years ago that resveratrol activates the SIRT1 enzyme, one of an enzyme family known as sirtuins. Caloric restriction also activates sirtuins, which regulate cell function and rejuvenate mitochondria, the cellular components that convert glucose to chemical energy.

In 2006, Sinclair and National Institute on Aging gerontologist Rafael de Cabo, also a co-author of the Cell Metabolism study, used resveratrol to improve the health and extend the lives of obese mice on high-calorie diets. The latest study involved both obese and normal mice, fed standard, low- and high-calorie fare.

Regardless of mouse weight and diet, resveratrol worked wonders. At two years of age, or the mouse equivalent of senescence, the mice were more coordinated than their non-dosed counterparts. Their bones were thicker and stronger, their eyes free of cataracts, their hearts beating strong. At the cellular level, tissues displayed gene-level changes almost identical to those produced by caloric restriction.

The mitochondria of resveratrol-taking mice also proved healthy. Mitochondrial degeneration has been implicated in a variety of diseases, leading some researchers to believe that heart disease, cancer and dementia -- all the so-called diseases of aging -- have a common root.

"The mice had tremendous health benefits from taking resveratrol," said de Cabo. "If any of those parameters translate to humans, it will be tremendous."

When Sinclair and de Cabo's mice started taking resveratrol they were one year old, roughly equivalent to 35 human years. The success suggests that the drug's benefits could be enjoyed by people who begin taking it during adulthood.

The researchers are currently testing whether starting a resveratrol regimen earlier will provide the life extension seen in calorically restricted animals, but de Cabo is not especially concerned with the outcome.

"Would you rather live to be 122 and be wheelchair-bound for the last 50 years of your life, or live to 90 and be fully active?" he said.

Both de Caba and Sinclair caution that mouse results won't necessarily translate to human success. There is, however, reason for guarded optimism: mice are notoriously imperfect modelers of human neurological disorders, but fare much better as models of our metabolism -- the very metrics that de Caba and Sinclair analyzed.

Resveratrol has also proved non-toxic in mice, and human use has not revealed any glaring side effects.

"It has been used for many years," said University of Southern California gerontologist Valter Longo, "and as far as I know has not been yet been associated with any toxicity." Longo was not involved in the study.

Sirtris Pharmaceuticals has already started clinical trials of resveratrol and a more-refined sirtuin activator. In June they were purchased for $720 million by Glaxo Smith Kline, signaling the seriousness with which academics and the pharmaceutical industry views the field.

"You've got to take aging research seriously if a company is willing to put down three-quarters of a billion dollars on it," said Sinclair.

"One never knows," he continued. "But we're getting closer to knowing whether in our lifetime we'll be able to find drugs that treat diseases by targeting aging."

Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span [Cell Metabolism]

RESOURCE/SOURCE: http://blog.wired.com/wiredscience/2008/07/caloric-restric.html on Thursday July 3, 2008.