Calorie restriction anti-aging may operate via mitochondria

Mitochondria play an unexpectedly important role in cell survival in the face of stress, according to a paper in this week’s Cell.
The authors suggest that this cell stress response may provide clues about how calorie restriction extends lifespan in mammals. This research also confirms one of the seven parts of the SENS strategy for life extension.

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Sinclair, working with colleagues at his company, at Cornell University in New York and the U.S. National Institutes of Health, identified the actions of two more sirtuin genes called SIRT3 and SIRT4. They found the enzymes controlled by these genes help preserve the mitochondria — little organs inside of cells that provide their energy.

Researchers report in the journal Cell that the phenomenon is likely linked to two enzymes—SIRT3 and SIRT4—in mitochondria (the cell’s powerhouse that, among other tasks, converts nutrients to energy). They found that a cascade of reactions triggered by lower caloric intake raises the levels of these enzymes, leading to an increase in the strength and efficiency of the cellular batteries. By invigorating the mitochondria, SIRT3 and SIRT4 extend the life of cells, by preventing flagging mitochondria from developing tiny holes (or pores) in their membranes that allow proteins that trigger apoptosis, or cell death, to seep out into the rest of the cell.

“We didn’t expect that the most important part of this pathway was in the mitochondria,” says David Sinclair, an assistant professor of pathology at Harvard Medical School and a study co-author. “We think that we’ve possibly found regulators of aging.”

“As long as the mitochondria are physiologically active, the cell can otherwise be depleted of energy, but it stays alive,” Sinclair said.

“I think SIRT3 is the next most interesting sirtuin from a drug development standpoint,” Sinclair says. “It does protect cells, but there’s growing evidence that it may mediate the benefits of exercise as well.”

Sinclair’s lab is now working on developing what he calls a possible “supermouse” with elevated levels of NAMPT to see if it lives longer and is more disease-resistant than normal mice.

Sinclair is eager to see the results of his experiments with the supermouse. “Depending on how this mouse turns out,” he says, “we may put NAMPT on the list of drug targets, as well.”

The recent SENS3 (on using engineering approaches to life extension) conference discussed several methods to repair and preserve mitochondria Mitochondrial damage is one of seven kinds of damage resulting from aging which if the damage was prevented or greatly reduced or repaired could result in lifespans increasing by several decades. This study also provides more evidence that the SENS approach is likely to succeed because one of the seven causes of damage identified by SENS has been separately confirmed as having an antiaging effect when modified.

Sirtris Pharmaceuticals shares rose 11% after release of the study results

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