Harvard researchers find longevity, restricted diet link

4 min read

Enzymes rev up cellular power pack

Researchers believe they’ve found the cellular link between extremely restricted diets and dramatically lengthened lifespan and hope to use the knowledge to develop new treatments for age-related diseases.

The research, conducted by scientists at Harvard Medical School, Cornell University Medical School, and the National Institutes of Health, illuminates for the first time the cellular processes triggered by extremely low-calorie diets.

Scientists have known for about 70 years that extremely restricted diets — where caloric intake is 30 percent to 40 percent below normal — can extend lifespan by as much as a third. In addition, those years are healthier and relatively free of common age-related debilities such as cancer, heart problems, and type 2 diabetes.

The longer, healthier lives have been seen in a host of animals maintained on a very low-calorie diet, including mice, rats, and monkeys. What scientists haven’t been able to figure out, until now, is why eating a lot less makes one live a lot longer.

The answer, it turns out, lies in tiny bodies inside each cell that act as cellular battery packs. As one ages, cells lose these battery packs — called mitochondria — and slow down. Extremely restricted diets, it turns out, revs them back up again.

“For decades we have understood that mitochondria are the power packs of cells,” said Harvard Medical School Associate Professor of Pathology David Sinclair, the study’s senior author. “[This research] shows that they are the gatekeepers of our health.”

The research, published in the Sept. 21 issue of the journal Cell, shows that calorie restriction sparks a chain reaction within cells that creates two enzymes called SIRT3 and SIRT4. The enzymes cross into mitochondria, making them grow stronger and increase energy output.

Understanding the cellular processes involved not only advances knowledge about the body, it also provides an opportunity to create drugs to mimic the natural compounds at work, Sinclair said.

The most likely drug target in this case is a small molecule called NAD that triggers the production of SIRT3 and SIRT4, Sinclair said. If a synthetic molecule that mimics NAD’s effects can be made, it may be possible to re-create the longevity of an extremely low-calorie diet without the need to subsist for years on 30 percent to 40 percent less food.

“What we’re working toward is a drug that gives the benefit of exercise and diet without having to exercise and diet,” Sinclair said.

This is not the first step Sinclair has taken toward that goal. In 2003, he isolated the compound in red wine, called resveratrol, that gives the drink beneficial health effects. His research on resveratrol showed that it, too, had dramatic effects on lifespan, lengthening it for yeast, worms, and fruit flies.

A drug based on his red wine findings has been developed by Sirtris, a Cambridge-based company that Sinclair helped found. Aimed at treating type 2 diabetes, the drug is in clinical trials, though it probably won’t be available for public use until 2012. Drugs that might come out of his SIRT3 and SIRT4 discovery would not be available for years after that.

Despite the likely time lag between discovery and usable drugs, Sinclair said he was excited by the findings. Now that they’ve found other potential drug targets, they may one day be able to combine molecules mimicking both the effects of red wine and a reduced-calorie diet in a single pill, providing a drug with multiple health effects.

“We don’t know if we’re five years away or 50, but we’ve never been this potentially close [to a drug treating the maladies of old age],” Sinclair said.

Sinclair’s future research will continue to focus on the family of genes that create both the red wine molecule and SIRT3 and SIRT4. Researchers have identified seven different genes — called sirtuins — in the family so far, Sinclair said.

“We’re working on all seven, trying to understand whether they play roles in diseases and aging,” Sinclair said. “What I’m excited about is that the potential payoff is so big. We may see this in my lifetime.”