Nicotinamide adenine dinucleotide (NAD) is a ubiquitous biological molecule that participates in many metabolic reactions. Recent studies show that NAD also plays important roles in transcriptional regulation, longevity, calorie-restriction-mediated life-span extension and age-associated diseases. It has been shown that NAD affects longevity and transcriptional silencing through the regulation of the Sir2p family, which are NAD-dependent deacetylases. Many human diseases are associated with changes in NAD level and/or the NAD : NADH ratio, raising the possibility that the Sir2p family might play a role in these diseases.