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Researchers Pinpoint Link Between Caloric Restriction and Longevity

When under stress, two genes within mitochondria guard against cell death

THURSDAY, Sept. 20 (HealthDay News) -- Harvard researchers report they have uncovered a molecular clue that seems to explain why cutting calories might lengthen your life.

It turns out that mitochondria guard against cell death, and two specific genes within the mitochondria actually carry out that task, the scientists say. Mitochondria are compartments within a cell that are dedicated to energy production, and their loss is thought to be a major cause of aging.

The research also identifies two potential drug targets that could be exploited to slow down the aging process, said lead researcher David Sinclair, director of the Paul F. Glenn Laboratories for Aging Research at Harvard Medical School.

Sinclair and his colleagues found that, when either rat or human cells were deprived of nutrients (as in a caloric-restriction diet), the overall cellular concentration of a compound known as NAD dropped precipitously -- but not within mitochondria. Indeed, following any kind of cellular stress, mitochondrial NAD concentration actually increased.

Sinclair's team found that mitochondria can synthesize their own NAD to withstand stress, thereby helping the cells stay alive long enough to repair themselves.

Two members of a family of genes called sirtuins were required for this effect to occur, the authors found. Those proteins, SIRT3 and SIRT4, both reside within the mitochondria, and they need NAD to do their jobs.

"We were able to mimic calorie restriction in a dish," said Sinclair, "and that's important, because for decades, people knew calorie restriction made the cells less prone to death, but not how it worked, and we tracked it down to the mitochondria and to SIRT3 and SIRT4."

The findings were published in the Sept. 21 issue of Cell.

"This is really a great paper, and it basically provides very new knowledge about how NAD biosynthesis is regulated in our cells," said Dr. Shin-ichiro Imai, an assistant professor of molecular biology and pharmacology at the Washington University School of Medicine, in St. Louis.

The mammalian sirtuin family contains seven members, one of which, SIRT1, had previously been implicated in mammalian aging. "What we publish now is there are two more [sirtuins] that could lead to important drugs," Sinclair said.

"What's exciting is these genes make proteins that reside in mitochondria, and we discovered that if those genes keep mitochondria active, that's the gatekeeper of cell health," he added. "The cell can be essentially dead, but if the mitochondria and the sirtuins are active, the cells will live."

This suggests that if SIRT3 and SIRT4 could be chemically activated, it might be possible to achieve the benefits of caloric restriction without the diet. That could slow the progress of diseases based on cell death, such as Alzheimer's, cancer and diabetes, he said, and possibly extend life span as a result.

Sinclair said he is now looking for compounds that could activate SIRT3, and, as co-founder of Sirtris Pharmaceuticals, a drug development company that focuses on sirtuins, he is in a position to do so.

Imai was guarded on the question of whether pharmacologic activation of sirtuins is necessarily a good idea -- cell death is nature's way of eliminating severely damaged, and potentially cancerous, cells, after all.

"In general, there are benefits to increasing cell survival, but still we don't know precise details to this decision-making process," he explained. "So, I am very cautious about this. However, scientifically, I think this discovery is great, because it gives hope to us to develop a drug via the sirtuins."

Sirtris already has one sirtuin-activating compound in clinical trials. The company recently announced it was initiating early clinical trials of SRT501, a SIRT1 activator based on resveratrol, a compound found in red wine.

"This paper indicates that several other sirtuins, SIRT3 and SIRT4, also play an important role in sensing the energy environment and linking calorie restriction to beneficial effects on health," said Sirtris Chief Executive Officer Christoph Westphal.

"We have continued to develop new drugs to target SIRT1, but we also think SIRT3 and SIRT4 are going to be very promising drug targets," he added.

More information

For more on calorie restriction, visit the Calorie Restriction Society.

SOURCES: David Sinclair, Ph.D., director, Paul F. Glenn Laboratories for Aging Research, Harvard Medical School, Boston; Christoph Westphal, M.D., Ph.D., CEO and vice chairman, Sirtris Pharmaceuticals, Cambridge, Mass.; Shin-ichiro Imai, M.D., Ph.D., assistant professor, Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis; Sept. 21, 2007, Cell

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