Nutrition, sirtuins and aging.

Beyond our inherited genetic make-up environmental factors are central for health and disease and finally determine our life span. Amongst the environmental factors nutrition plays a prominent role in affecting a variety of degenerative processes that are linked to aging. The exponential increase of non-insulin-dependent diabetes mellitus in industrialized nations as a consequence of a long-lasting caloric supernutrition is an expression of this environmental challenge that also affects aging processes. The most consistent effects along the environmental factors that slow down aging - from simple organisms to rodents and primates - have been observed for caloric restriction. In the yeast Saccharomyces cerevisiae, the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, sirtuins (silencing information regulators) have been identified to mediate as "molecular sensors" the effects of caloric restriction on aging processes. Sirtuins are NAD(+)-dependent deacetylases that are activated when e.g. cell energy status is low and the NAD(+) over NADH ratio is high. As a consequence transcription rates of a variety of genes including that of the apoptosis inducing p(53) gene are reduced. Moreover, in C. elegans, sirtuins were shown to interact with proteins of the insulin/IGF-1 signaling cascade of which several members are known to extend life span of the nematodes when mutated. Downstream targets of this pathway include genes that encode antioxidative enzymes such as Superoxide dismutase (SOD) whose transcription is activated when receptor activation by insulin/IGF is low or when sirtuins are active and the ability of cells to resist oxidative damage appears to determine their life span. Amongst dietary factors that activate sirtuins are certain polyphenols such as quercetin and resveratrol. Whereas their ability to affect life span has been demonstrated in simple organisms, their efficacy in mammals awaits proof of principle.