May 08, 2003
Key Gene For Life Extension By Calorie Restriction Identified

A new study provides evidence that a form of a common vitamin plays a key role in regulating the response of cells to calorie restriction. Calorie restriction is the only reliable way to extend maximal lifespace of a large range of species and a great deal of work is going in to trying to figure out how calorie restriction does that.

Keep in mind while reading this article that nicotinamide is another name for niacinamide and nicotinic acid is another name for niacin. Niacin is the form of vitamin B3 that causes the flushing effect of hot red skin because it causes the release of histamine from mast cells into the bloodstream. Niacin also has a cholesterol lowering effect. Niacinamide is the form of vitamin B3 that people take if they want to avoid the flushing effect but niacinamide does not lower cholesterol.

Also, the NAD mentioned in the article is an acronym for Nicotinamide Adenine Dinucleotide. NAD (sometimes called NADH) is involved in mitochondrial metabolism for breaking down sugars and serves as an energy-carrying molecule. There has been a lot of speculation that calorie restriction may lengthen lifespan in part by causing changes in the regulation of mitochondrial operation that reduce the amount of free radical species generated and therefore reduces the rate of accumulation of damage that leads to old age. However, there has also been speculation that calorie restriction turns on repair systems. In the latter hypothesis calorie restriction makes cells respond as if they are under environmental stress and to take better care of themselves perhaps at the expense of performing at a lower level.

One of the take-home lessons from this article is that large doses of niacinamide taken regularly might either reduce lifespan in general or at least it might block the lfespan-extending effects of calorie restriction.

BOSTON, MA-- Researchers at Harvard Medical School (HMS) have discovered that a gene in yeast is a key regulator of lifespan. The gene, PNC1, is the first that has been shown to respond specifically to environmental factors known to affect lifespan in many organisms. A team led by David Sinclair, assistant professor of pathology at HMS, found that PNC1 is required for the lifespan extension that yeast experience under calorie restriction. A yeast strain with five copies of PNC1 lives 70 percent longer than the wild type strain, the longest lifespan extension yet reported in that organism. Their findings are reported in the May 8 Nature.

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.

An obvious follow-up to this study would be to try giving large doses of nicotinamide to mice on calorie restriction to see if the nicotinamide prevents the metabolic changes that calorie restriction causes. In particular, it would be interesting to look at gene expression changes as measured by gene arrays. Stephen Spindler and his group have already argued for using gene arrays to test for calorie mimetic drugs But they'd also work for testing compounds that blocked the beneficial effects of calorie restriction.

Share |      Randall Parker, 2003 May 08 04:24 PM  Aging Reversal


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