Sirtuins, aging, and metabolism

Sirtuins are nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylases that link protein acetylation, metabo-lism, aging, and diseases of aging. Sirtuins were initially found to slow aging in lower organisms and more recently shown to mediate many effects of calorie restriction on metabolism and longevity in mammals. This chapter focuses on two key mam-malian sirtuins, SIRT1 (which resides mainly in the nucleus) and SIRT3 (which is mitochondrial). I discuss the many protein substrates of these sirtuins and how they determine the metabolic strategy most efficacious under scarce or abundant food supplies. I also discuss the logic by which sirtuins link protein acetylation and metabolism. Finally, I discuss emerging data showing protection by sirtuins against most of the common diseases of aging. It is possible that sirtuins will be novel targets to combat these diseases pharmacologically. Sirtuins are NAD-dependent protein deacetylases that are homologous to yeast Sir2p, one of the genes involved in silencing in that organism (Klar et al. 1979). Interest in sirtuins grew when Sir2p was shown to slow aging in yeast mother cells (Kaeberlein et al. 1999). Subsequent studies showed similar effects on aging in Caenorhabdi-tis elegans and Drosophila (Tissenbaum and Guarent