For nearly 70 years scientists have known that caloric restriction prolongs life. In everything from yeast to primates, a significant decrease in calories can extend life span by as much as one third. But definitively fingering the mechanisms that drive this longevity has remained elusive.
Reporting in the Sept. 21 Cell, researchers from HMS, in collaboration with scientists from Cornell Medical School and the National Institutes of Health, have discovered two genes in mammalian cells that apparently act as gatekeepers of cellular longevity. When cells experience certain kinds of stress, such as caloric restriction, these genes rev up a defense, which protects the cells against the deleterious effects of aging like insulin resistance, muscle wasting, and neurodegeneration.
“We’ve reason to believe now that these two genes may be potential drug targets for diseases associated with aging,” said David Sinclair, HMS associate professor of pathology and senior author on the paper.
The genes whose role Sinclair and his colleagues illuminated are members of the sirtuin family of deacetylases, SIRT3 and SIRT4. (Last year, the Sinclair lab showed that another sirtuin gene, SIRT1, has a powerful impact on longevity when stimulated by resveratrol, a compound found in red wine.) The action of the two protein products confirms what scientists have suspected for a long time: mitochondria are vital for sustaining the health and longevity of a cell. Since mitochondria are a cell’s power generators, if their stability starts to wane, energy declines, and the cell’s days are numbered. In this paper, Sinclair and his collaborators discovered that SIRT3 and SIRT4 play a vital role in a network that maintains the vitality of mitochondria and keeps cells healthy.
When cells undergo caloric restriction, signals sent in through the membrane activate the gene NAMPT. As levels of the NAMPT protein ramp up, the small molecule NAD begins to amass in the mitochondria. This buildup increases the activity of mitochondrial enzymes created by SIRT3 and SIRT4. As a result, the mitochondria grow stronger, energy output increases, and the cell’s aging process significantly slows down. (Interestingly, this same process also is activated by exercise.)
“We’re not sure yet what particular mechanism is activated by these increased levels of NAD, and as a result, SIRT3 and SIRT4,” said Sinclair, “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.
“Mitochondria are the guardians of cell survival,” adds Sinclair. “If we can keep boosting levels of NAD in the mitochondria, which in turn stimulates buckets more of SIRT3 and SIRT4, then for a period of time the cell really needs nothing else.” Sinclair and his colleagues refer to this observation as the mitochondrial oasis.
In recent years, scientists have become increasingly aware of the importance of mitochondrial function in treating disorders associated with aging such as cancer, diabetes, and neurodegenerative diseases. SIRT3 and SIRT4 may now potentially be drug targets in new therapeutic approaches. “Theoretically, we can envision a small molecule that can increase levels of NAD, or SIRT3 and SIRT4 directly, in the mitochondria,” said Sinclair. “Such a molecule could be used for many age-related diseases.” (For a video interview with Sinclair, see The Biology of Aging.)
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