A Novel Caloric Restriction-Like Mimetic Affects Longevity in Yeast by Reprogramming Core Metabolic Pathways

Glucose limitation is a simple intervention that extends yeast replicative lifespan (RLS) via the same pathway(s) thought to mediate the benefits of caloric restriction (CR) in mammals. Here we report on “C1”, a small molecule that mimics key aspects of CR. C1 was identified in a high throughput screen for drug-like molecules that reverse the RLS shortening effect of the sirtuin inhibitor and NAD+ precursor nicotinamide. C1 reduces the cellular dependence on glycolysis and the pentose phosphate pathway, even in the presence of glucose, and compensates by elevating fatty acid -oxidation to maintain acetyl-CoA levels. C1 acts either downstream of Sir2 or in an independent CR pathway. In this regard, chemical-genetic interactions indicate that C1 influences Tor2 signaling via effects on phosphoinositide pools. Key activities of C1 extend to mammals. C1 stimulates -oxidation in mammalian cells, and in mice, reduces levels of triacylglycerides and cholesterol in livers of lean and obese mice. C1 confers oxidative resistance to diamide in both yeast and mammalian cells. In conclusion, C1 induces global changes in metabolism in yeast and mammalian cells that mimic aspects of CR. Future work will be aimed at identifying the cellular target of C1

Effects of an Unusual Poison Identify a Lifespan Role for Topoisomerase 2 in Saccharomyces Cerevisiae

A progressive loss of genome maintenance has been implicated as both a cause and consequence of aging. Here we present evidence supporting the hypothesis that an age-associated decay in genome maintenance promotes aging in Saccharomyces cerevisiae (yeast) due to an inability to sense or repair DNA damage by topoisomerase 2 (yTop2). We describe the characterization of LS1, identified in a high throughput screen for small molecules that shorten the replicative lifespan of yeast. LS1 accelerates aging without affecting proliferative growth or viability. Genetic and biochemical criteria reveal LS1 to be a weak Top2 poison. Top2 poisons induce the accumulation of covalent Top2-linked DNA double strand breaks that, if left unrepaired, lead to genome instability and death. LS1 is toxic to cells deficient in homologous recombination, suggesting that the damage it induces is normally mitigated by genome maintenance systems. The essential roles of yTop2 in proliferating cells may come with a fitness trade-off in older cells that are less able to sense or repair yTop2-mediated DNA damage. Consistent with this idea, cells live longer when yTop2 expression levels are reduced. These results identify intrinsic yTop2-mediated DNA damage as a potentially manageable cause of aging

A Novel Caloric Restriction-Like Mimetic Affects Longevity in Yeast by Reprogramming Core Metabolic Pathways

Glucose limitation is a simple intervention that extends yeast replicative lifespan (RLS) via the same pathway(s) thought to mediate the benefits of caloric restriction (CR) in mammals. Here we report on “C1”, a small molecule that mimics key aspects of CR. C1 was identified in a high throughput screen for drug-like molecules that reverse the RLS shortening effect of the sirtuin inhibitor and NAD+ precursor nicotinamide. C1 reduces the cellular dependence on glycolysis and the pentose phosphate pathway, even in the presence of glucose, and compensates by elevating fatty acid -oxidation to maintain acetyl-CoA levels. C1 acts either downstream of Sir2 or in an independent CR pathway. In this regard, chemical-genetic interactions indicate that C1 influences Tor2 signaling via effects on phosphoinositide pools. Key activities of C1 extend to mammals. C1 stimulates -oxidation in mammalian cells, and in mice, reduces levels of triacylglycerides and cholesterol in livers of lean and obese mice. C1 confers oxidative resistance to diamide in both yeast and mammalian cells. In conclusion, C1 induces global changes in metabolism in yeast and mammalian cells that mimic aspects of CR. Future work will be aimed at identifying the cellular target of C1

Effects of an Unusual Poison Identify a Lifespan Role for Topoisomerase 2 in Saccharomyces Cerevisiae

A progressive loss of genome maintenance has been implicated as both a cause and consequence of aging. Here we present evidence supporting the hypothesis that an age-associated decay in genome maintenance promotes aging in Saccharomyces cerevisiae (yeast) due to an inability to sense or repair DNA damage by topoisomerase 2 (yTop2). We describe the characterization of LS1, identified in a high throughput screen for small molecules that shorten the replicative lifespan of yeast. LS1 accelerates aging without affecting proliferative growth or viability. Genetic and biochemical criteria reveal LS1 to be a weak Top2 poison. Top2 poisons induce the accumulation of covalent Top2-linked DNA double strand breaks that, if left unrepaired, lead to genome instability and death. LS1 is toxic to cells deficient in homologous recombination, suggesting that the damage it induces is normally mitigated by genome maintenance systems. The essential roles of yTop2 in proliferating cells may come with a fitness trade-off in older cells that are less able to sense or repair yTop2-mediated DNA damage. Consistent with this idea, cells live longer when yTop2 expression levels are reduced. These results identify intrinsic yTop2-mediated DNA damage as a potentially manageable cause of aging