'Longevity' gene, diet linked

Experiments on yeast, worms, and mammals have all revealed that cutting calories extends lifespan, but how is this occurs is largely unknown. Now, two independent studies, one reported in the June 18 Science, from David Sinclair's laboratory at Harvard Medical School, and the other reported in the June 3 Nature, from Leonard Guarente's laboratory at Massachusetts Institute of Technology, have uncovered molecular mechanisms linking aging, diet, and a gene called SIRT1. "People have been studying calorie restriction for 70 years, yet the mechanism is not known," said Sinclair, adding that this new work has finally started to suggest a primary mechanism.In the past, calorie restriction was theorized to be a passive mechanism, whereby fewer calories reduced metabolism and the oxidative stresses that come with it. But the discovery that the protein Sir2—of which SIRT1 is the mammalian orthologue—extends lifespan in yeast and worms, suggested a more regulated mechanism involving Sir2. It was not known if this extended to mammals and SIRT1, and both teams were trying to tackle this question. In the Science study, Sinclair, lead author Haim Cohen, and their colleagues investigated how SIRT1 was involved in calorie restriction in rats, keying on the concept that aging results in cell loss over time. "Caloric restriction and genetic manipulations that extend lifespan typically protect cells from death," Sinclair told The Scientist. Sinclair and colleagues found the SIRT1 expression was higher in 12-month-old rats fed a calorie-restricted diet. This finding also extended to in vitro cell culture, with serum from the calorie-restricted rats inducing SIRT1 expression. The addition of insulin and insulin-like growth factor 1 (two factors known to be involved in extending lifespan) to the calorie-restricted serum blocked the induction of SIRT1. Further investigation revealed that SIRT1 acted on a DNA repair factor Ku70, which was then capable of repressing the apoptosis-inducing protein Bax. This suggested a mechanism in which SIRT1 protected cells from apoptosis. "We propose that one way calorie restriction extends lifespan is by increasing SIRT1 expression, thereby promoting the long-term survival of irreplaceable cells," said Sinclair. "This is great stuff," said Adam Antebi, from Max Planck Institute for Molecular Genetics in Germany. "The discovery that Ku70 is a SIRT1 substrate reveals how SIRT1 could temper apoptosis and promote cell survival," Antebi, who was not involved in the study, told The Scientist.In the Nature study, Leonard Guarente, lead author Frederic Picard, and their colleagues also investigated SIRT1, but from the alternative perspective of fat levels. "Calorie-restricted mice shed their fat, and mice engineered to be lean live longer. This suggested that SIRT1 could be recognizing food scarcity and causing fat shedding," Guarente told The Scientist. Guarente and his colleagues found that SIRT1 indeed promotes fat mobilization. SIRT1 was found to repress the fat-regulating protein PPAR-γ and other genes that drive fat storage following calorie restriction. In addition, the upregulation of SIRT1 in differentiated fats cells caused them to lose fat. "It is a very important finding," said Guarente, that suggests a molecular model where the regulation of fats cells is the first step in translating low calories to long life. Brian Merry, from the University of Liverpool, who was not involved in the study, said that both papers are beginning to extend ideas that originated in yeast with Sir2 and get at the central mechanism of calorie restriction in mammals. This is "very interesting," he said, since "there is an opportunity here to start to bring together the components in the calorie-restricted rodents."Sinclair equated to the findings of the two papers to discovering a 911 emergency system for times when food is scare. "We see SIRT1 as a body defense and survival coordinator. By analogy, Guarente's lab has found the 911 command center, and we've found the roads and emergency vehicles. Both are essential for the 911 system to function," he said.Antebi agreed with the excitement that the results have produced, but also cautioned that "it is still unclear which cellular processes are critical to increase an organism's survival."Still, Sinclair said he hopes this will lead to a "totally new class of drug that stimulates the body's own defenses and combats diseases of aging."

'Longevity' gene, diet linked

SIRT1 may play role in why calorie restriction leads to longer life in rats

Jun 17, 2004

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