Calorie Restriction - Caloric Restriction Mimetics - Sir2/SIRT1 and Resveratrol

Sir2/SIRT1 and Resveratrol

Attempts are being made to develop CR mimetics interventions. Resveratrol has been reported to activate Sir2/SIRT1 and extend the lifespan of yeast, nematode worms, fruit flies, and mice consuming a high caloric diet. Resveratrol does not extend lifespan in normal mice.

The effect of resveratrol on lifespan in C. elegans and Drosophila was re-investigated by D. Gems and L. Partridge. They concluded that previously reported lifespan increases were in fact due to natural variability in C. elegans lifespans. A recent study found resveratrol extends the lifespan of a vertebrate fish by 59%. In the yeast, worm, and fly studies, resveratrol did not extend lifespan if the Sir2 gene was mutated. A 2010 study concluded that SRT1720 and resveratrol are not direct activators of SIRT1.

Matt Kaeberlein and Brian Kennedy at the University of Washington Seattle believe that Sinclair's work on resveratrol is an artifact and that the Sir2 gene has no relevance to CR. They have proposed that the caloric restriction increases lifespan by decreasing the activity of the Target of Rapamycin (TOR) kinase.

Gurarente has recently published that behavior associated with caloric restriction did not occur when Sirt1 knockout mice were put on a calorie restricted diet, the implication being that Sirt1 is necessary for mediating the effects of caloric restriction. However, the same paper also reported that the biochemical parameters thought to mediate the lifespan extending effects of calorie restriction (reduced insulin, IGF-1 and fasting glucose), were no different in normal mice and mice lacking Sirt1. Whether the lifespan-extending effect of CR was still evident in Sirt1 knockout mice was not reported in that study. According to Sinclair's data, Sirtuins (SirT1, Sir2, ...) are behind the putative effect of calorie restriction on longevity, however some research has cast doubt on this. A clinical trial of the resveratrol formulation SRT501 was suspended.

Caloric restriction (CR) extends the life span and prevents aging. It has been found that these effects are modulated by SIRT3, a member of the sirtuins, a class of protein deacetylases. SIRT3 is mitochondrial. SIRT3-knockout mice did not live longer when calorically restricted, but wild type mice did live longer when calorically restricted.