The role of NAD+ dependent histone deacetylases (sirtuins) in ageing

Histone deacetylases (HDACs) are enzymes that are able to deacetylate lysine side chains in histones and certain non-histone proteins which leads to altered states of conformation and activity for the proteins in question. Three classes of histone deacetylases have been recognized in humans. Class I and II are zinc-dependent amidohydrolases and eleven subtypes have been discovered (HDAC1-11). Class III enzymes depend in their catalysis on NAD(+) and subsequently, O-acetyl ADP ribose and nicotinamide are formed as a consequence of the acetyl transfer. Due to the homology to the yeast histone deacetylase Sir2p the NAD(+)-dependent deacetylases are also termed sirtuins and seven members (Sirt1-7) are known in humans. Sirtuins are found from bacteria to eukaryotes and altogether about 60 isoforms have been characterized in different organisms. Sirtuins have been implicated in the regulation of molecular mechanisms of aging. The overexpression of sirtuin enzymatic activity leads to an increase of lifespan in Saccharomyces cerevisiae and Caenorhabditis elegans that can also be reached by calorie restriction. Sirtuins have been proposed to act as sensors for glucose uptake that respond to the levels of NAD(+) but more complex ways of action have been suggested as well. This article will present the members of the human sirtuin family with their respective functions and review the existing druglike inhibitors and activators of sirtuin activity.