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Life Extension: Longevity Gene Activated by Diet Restriction

‘Longevity’ gene, diet linked SIRT1 may play role in why calorie restriction leads to longer life in rats

By David Secko, The Scientist, 18 Jun 2004

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 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.

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