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GENETICS Life Span May Depend on Shifting Toward Survival, Not Putting Brakes on Metabolism Study in Yeast Links Low-level Environmental Stress to Longevity Perhaps our love for food is greater than our lust for life. Why else have few people attempted to pursue the surest way to a longer life span: calorie restriction? Severely cutting calories has been shown to lengthen the lives of organisms from rats to worms to flies to yeast, and even primate studies suggest a strict diet curbs signs of aging and cancer. Since this effect was discovered in 1935, researchers have struggled to explain it. If a mechanism were known, it might reveal a less painful way to lengthen life in humans--we could have our cake and eat it, too. Stress management. Under normal conditions in a yeast cell, the longevity protein Sir2 uses NAD as a cofactor to produce nicotinamide, which then inhibits Sir2 in a negative feedback loop (left). But when the cell is exposed to environmental stresses like calorie restriction, heat shock, or osmotic stress (top), PNC1 gets switched on. The Pnc1 protein converts nicotinamide to nicotinic acid, a molecule that has no effect on Sir2. No longer inhibited by nicotinamide, Sir2 becomes more active, and yeast live longer. A study led by David Sinclair, assistant professor of pathology at HMS, and published in the May 8 Nature finds that a specific gene in yeast regulates the organism's ability to live longer with less sustenance. The gene is also highly responsive to other environmental stresses that have been shown to extend life in yeast. By pinpointing a link between an organism's environment and longevity, the discovery suggests that the prolonged life reached through calorie restriction may be the result of a genetic survival program designed to protect organisms in stressful situations--a program that could, in theory, be manipulated. The Survival Script The study continues a line of longevity research by Sinclair beginning with his discovery while a research fellow at MIT that the loss of the highly repetitive DNA-encoding ribosomes is a major cause of yeast aging. The yeast SIR2 gene, originally discovered by virtue of its role in gene silencing, was found to extend life span in yeast by keeping ribosomal DNA stable. An extra copy of SIR2 allows yeast and C. elegans to live longer, while depriving them of the gene causes them to age prematurely. In contrast to the current model, we show that the life span extension from calorie restriction is the result of an active cellular defense involving the upregulation of a specific gene." --David Sinclair SIR2 is also a requirement for the longer life span that yeast experience under calorie restriction. But the level of Sir2 expressed in the cell does not change with calorie restriction, so researchers have been struggling to find a regulator of Sir2, one that would be affected by calorie restriction. Nixing NAD Some have speculated that the level of NAD, a common metabolite in the cell, acts as a regulatory mechanism for Sir2. Sir2 removes acetyl groups from other proteins and relies on NAD to help it carry out this reaction. However, Sinclair's group believes that the real regulator of Sir2 is one of the products of the reaction between Sir2 and NAD--nicotinamide, a form of vitamin B3. His group has found that nicotinamide acts as an inhibitor of Sir2, shortening the life span of yeast. Furthermore, Sinclair's team discovered that a gene in yeast--PNC1--controls nicotinamide levels by turning nicotinamide into nicotinic acid, a molecule that does not affect life span. "PNC1 gets rid of Sir2 inhibition by nicotinamide," Sinclair said. Without PNC1, calorie-restricted yeast do not live longer. And a yeast strain with five copies of PNC1 lives 70 percent longer than the wild type strain, the longest life span extension yet reported in yeast. Jason Wood, Oliver Medvedik, Rozalyn Anderson, Kevin Bitterman, and David Sinclair (l to r) enabled yeast to live 70 percent longer by giving them extra copies of the gene PNC1. (Photo by Steve Gilbert) Many people assume that calorie restriction works by lowering the rate of metabolism, which might postpone aging processes. The NAD model supports this theory, because NAD levels vary with rates of metabolism in yeast. But the model that Sinclair proposes implies that life span extension is not simply the result of less metabolic wear and tear, but rather the activation of a specific genetic program. "In contrast to the current model, we show that the life span extension from calorie restriction is the result of an active cellular defense involving the upregulation of a specific gene," Sinclair said. He believes that the Pnc1/nicotinamide pathway provides a link between the environment of an organism and its life span. Levels of Pnc1 are highly sensitive to environmental cues like calorie restriction, low salt, and heat. Edward Masoro, professor emeritus at the University of Texas Health Science Center at San Antonio, has championed the notion that calorie restriction is an example of hormesis, a phenomenon in which a low-intensity stress can have a positive effect on an organism. Masoro, who has worked primarily with mammals, said that Sinclair's team "has been able to use yeast to establish rather clearly something I could only hint at in my work with rats." While cautioning that evidence in yeast may not apply to mammals, he said the study provides "the first strong evidence that calorie restriction can have an anti-aging action by a hormetic mechanism." Cynthia Kenyon, the Herbert Boyer distinguished professor of biochemistry and biophysics at the University of California, San Francisco, who studies longevity in C. elegans, said the study shows that longevity from calorie restriction is dependent on the Pnc1/nicotinamide pathway, but that broader interest in this model will hinge on whether the pathway is conserved in different organisms. "People studying other animals will definitely see if there are homologues," she said. In humans, the picture is undoubtedly more complicated; for one, humans have seven SIR genes rather than just SIR2. The nicotinamide pathway is also different in humans, although 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. SIRT1 is known to inhibit the tumor suppressor protein p53, an action that helps cancer cells survive. This raises the concern that any promotion of this pathway might promote cancer even as it switches on a longevity program. But Sinclair notes that calorie-restricted animals have lower, not higher rates of cancer, and that in reality there may be a balance between the two. --Courtney Humphries