Genetic regulator of lifespan identified

May explain life extension via calorie restriction

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.

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.

Harvard Medical School has more than 5,000 full-time faculty working in eight academic departments based at the School’s Boston quadrangle or in one of 47 academic departments at 17 affiliated teaching hospitals and research institutes. Those HMS affiliated institutions include Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Cambridge Hospital, Center for Blood Research, Children’s Hospital, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children’s Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, VA Boston Healthcare System.

Contact: John Lacey, 617-432-0442, (public_affairs@hms.harvard.edu)
Courtney Humphries, 617-432-0442, (public_affairs@hms.harvard.edu)