Study Finds Clue on How Calorie Restriction Prolongs Life

by VR Sreeraman on Sep 23 2007 12:14 PM

Scientists may now have a new clue about how calorie restriction prolongs life, by finding that certain genes may be the link between calorie restriction and cell survival.

Previous research has linked calorie restriction to longevity, but getting to the core of the molecular machinery that drives this longevity has remained elusive.

Now, researchers from Harvard Medical School, in collaboration with scientists from Cornell Medical School and the National Institutes of Health have discovered two genes in mammalian cells that act as caretakers for cellular longevity. When cells experience certain kinds of stress, such as caloric restriction, these genes rev up and help protect cells from diseases of aging.

"We've reason to believe now that these two genes may be potential drug targets for diseases associated with aging," says David Sinclair, associate professor of pathology at Harvard Medical School and senior author on the paper.

Sinclair says that the genes, which are called SIRT3 and SIRT4 and are members of a larger class of genes called sirtuins, might be targets for drugs to treat age-related diseases in the long run.

In the study, the newly discovered role of SIRT3 and SIRT4 elucidates something scientists have suspected for a long time – mitochondria, a kind of cellular organ that lives in the cytoplasm, are essential for sustaining the health and longevity of a cell.

Sinclair and his collaborators discovered that SIRT3 and SIRT4 play a vital role in a longevity network that maintains the vitality of mitochondria and keeps cells healthy when they would otherwise die.

Sinclair's team studied a complex chemical chain reaction in which these genes push cells to live longer in the face of stress. That stress came in the form of a two-day fast for rats studied by Sinclair and colleagues.

After the rats finished fasting, the researchers studied the rats' livers. They noticed that a protein called NAD+ was present at higher-than-normal levels in the rats' mitochondria.

When cells undergo caloric restriction, signals sent in through the membrane activate a gene called NAMPT. As levels of NAMPT ramp up, a small molecule called NAD begins to build up in the mitochondria. This, in turn, causes the activity of enzymes created by the SIRT3 and SIRT4 genes--enzymes that live in the mitochondria--to increase as well. As a result, the mitochondria grow stronger, energy-output increases, and the cell's aging process slows down significantly.

“We're not sure yet what particular mechanism is activated by these increased levels of NAD, and as a result SIRT3 and SIRT4, but we do see that normal cell-suicide programs are noticeably attenuated. This is the first time ever that SIRT3 and SIRT4 have been linked to cell survival" says Sinclair.

Sinclair and his colleagues have coined a phrase for this observation: the Mitochondrial Oasis Hypothesis.

SIRT3 and SIRT4 may now also be potential drug targets for diseases associated with aging, he says.

"Theoretically, we can envision a small molecule that can increase levels of NAD, or SIRT3 and SIRT4 directly, in the mitochondria. Such a molecule could be used for many age-related diseases,” he says.

The study is published in the September 21 issue of the journal Cell.