[tt] Physorg: Researchers find connection between caloric restriction and longevity

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Researchers find connection between caloric restriction and longevity
http://www.physorg.com/printnews.php?newsid=109514592

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 lifespan by as much as one-third. But 
getting under the hood of the molecular machinery that drives this 
longevity has remained elusive. Now, reporting in the September 21 issue 
of the journal Cell, 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 gatekeepers 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.

The new genes that Sinclair's group have discovered, in collaboration with 
Anthony Sauve of Cornell Medical School and Rafael de Cabo of NIH, are 
called SIRT3 and SIRT4. They are members of a larger class of genes called 
sirtuins. (Another gene belonging to this family, SIRT1, was shown last 
year to also have a powerful impact on longevity when stimulated by the 
red-wine molecule resveratrol.)

In this paper, the newly discovered role of SIRT3 and SIRT4 drives home 
something scientists have suspected for a long time: mitochondria are 
vital for sustaining the health and longevity of a cell.

Mitochondria, a kind of cellular organ that lives in the cytoplasm, are 
often considered to be the cell's battery packs. When mitochondria 
stability starts to wane, energy is drained out of the cell, and its days 
are numbered. In this paper, 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.

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 amass 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. (Interestingly, this same 
process is also 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," says 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."

In fact, the mitochondria appear to be so essential to the cell's life 
that when all other energy sources inside the cell--including the 
nucleus--are wiped out, yet the mitochondria are kept intact and 
functional, the cell remains alive.

"Mitochondria are the guardians of cell survival," says 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 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. For example, in recent years scientists have become 
increasingly aware of the importance of mitochondrial function in treating 
diseases such as cancer, diabetes, and neurodegeneration.

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

According to Suave of Cornell, "This study also highlights how advanced 
technological methods can help resolve fundamental biological questions in 
ways that were hard to achieve as recently as a few years ago."

Source: Harvard Medical School