Researchers Discover A New AntiAging Mechanism

By John Wolper
17:30, September 21st 2007
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Researchers Discover A New AntiAging Mechanism

The elixir of life could soon became a scientific reality as the researchers from Harvard Medical School, in collaboration with scientists from Cornell Medical School and the National Institutes of Health reported the discovery of two genes in mammalian cells that act as gatekeepers for cellular longevity.

The fact that the caloric restriction prolongs life has been a scientific fact for almost 70 years, but only now the scientists has started to study the molecular mechanism that links the low-caloric diet to longevity.

In their research, published in the September 21 issue of the journal CelL, the scientists concluded that the caloric restriction is in a fact a stress for the cells to which they respond by activating two protective genes.

The scientific team was lead by David Sinclair, associate professor of pathology at Harvard Medical School and senior author on the paper.

According to their findings the two genes, called 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.

But why is the mitochondria, a kind of cellular organ that lives in the cytoplasm, so important for the cell life?

The mitochondria are considered to be the cell's battery packs and when its stability starts to wane, energy is drained out of the cell, and its days are numbered.

According to Sinclair’s team, when the cells undergo caloric restriction, signals sent in through the membrane activate a gene called NAMPT (nicotinamide phosphoribosyltransferase). 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.

"Mitochondria are the guardians of cell survival," explained 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."

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.

“These two genes, SIRT3 and SIRT4, they make proteins that go into mitochondria. These are little energy packs inside our cells that are very important for staying healthy and youthful and, as we age, we lose them and they get less efficient,” Sinclair said.

According to scientists, the exercises may also boost SIRT 3 levels. "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."

Still the scientist has to determine what is the particular mechanism activated by these increased levels of NAD, and as a result SIRT3 and SIRT4, but they are sure that events leading to cell death are at the very least delayed when there are vast quantities of the enzymes.

In fact, SIRT 3 and SIRT 4 are members of the recently-discovered family of enzymes that promote the body's natural defense against disease. There are seven human sirtuins (SIRT1-7).

Last year, in another study, it was proved that SIRT 1 have a powerful impact on longevity when stimulated by the red-wine molecule resveratrol.

What is more important is that these two genes may be potential drug targets for diseases associated with aging.

"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."

Dave Sinclair is also a co-founder of Sirtris Pharmaceuticals, which is developing drugs that target SIRT genes by miming certain beneficial health effects of calorie restriction, without requiring a change in eating habits.



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