Gene That Extends Lifespan In Yeast Points To Paradigm Shift In Longevity Research; May Explain Life Extension Via Calorie Restriction

The PNC1 protein regulates nicotinamide, a form of vitamin B3. Sinclair's group previously found that nicotinamide acts as an inhibitor of Sir2, the founding member of a family of proteins that control cell survival and lifespan. Sir2 extends lifespan in yeast by keeping ribosomal DNA stable. PNC1 converts nicotinamide into nicotinic acid, a molecule that does not affect lifespan. In doing so, it keeps nicotinamide from inhibiting Sir2, allowing the yeast to live longer.

The finding implies that lifespan is not simply dependent on accumulated wear and tear or metabolism, as some researchers have suggested, but is at least partly controlled by an active genetic program in cells--one that could theoretically be boosted. "In contrast to the current model, we show that the lifespan extension from calorie restriction is the result of an active cellular defense involving the upregulation of a specific gene," Sinclair said.

For decades researchers have known that severe calorie restriction extends the lives of many organisms like yeast, fruit flies, worms, and rats, and it also slows the aging process and prevents cancer in rats. But why less food seems to help organisms live longer has been puzzling. While Sir2 is a necessary part of the equation, calorie restriction does not affect Sir2 levels, indicating that Sir2 must be regulated by another protein that does respond to calorie restriction.

Some researchers have speculated that NAD, a cofactor of Sir2 and a common metabolite in the cell, acts as a regulatory mechanism. Because NAD levels vary with rates of metabolism in yeast, this model suggests that calorie restriction might lengthen lifespan by lowering metabolism. However, Sinclair's group showed that the effect of PNC1 was independent of NAD availability. They believe that the real regulator of Sir2 is nicotinamide, which is one of the products of the reaction between Sir2 and NAD.

PNC1 levels are highly sensitive to environmental cues like calorie restriction, low salt, and heat that are known to make yeast live longer. Sinclair's team believes that the PNC1/nicotinamide pathway provides a genetic link between the environment of an organism and its lifespan, allowing an organism to actively change its survival strategies according to the level of environmental stress it senses.

In humans, the picture is undoubtedly more complicated; for one, humans have seven Sir genes, not just Sir2. The nicotinamide pathway is also different in humans, but Sinclair's group has shown that nicotinamide inhibits human SIRT1, a homologue of Sir2. His group is now investigating human genes that may play the same role as PNC1.

One of the immediate implications of the work is that it emphasizes the functional difference between nicotinamide and nicotinic acid. Nicotinic acid (niacin) is a known anticholesterol treatment, while nicotinamide (or niacinimide) is sometimes touted for anti-aging abilities and is in clinical trials as a therapy for diabetes and cancer. However, the two substances are sometimes sold interchangeably as supplements under the name vitamin B3. "Our study raises the concern of taking high doses of nicotinamide," Sinclair said, because nicotinamide puts a damper on Sir2's actions in the cell.

This research was supported by grants from the National Institute on Aging and the Harvard-Armenise Foundation. Fellowships were supported by the Ellison Medical Research Foundation, John Taplan Posdoctoral Fellowship Program, National Science Foundation Scholarship Program, and the American Federation of Aging Research.

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