One highly studied mechanism implicated in the clinical benefits of calorie restriction involves sirtuins, a large and diverse family of enzymes that regulate gene expression. The first sirtuin, silent information regulator 2 (Sir2), was described in yeast. Sir2 is a class III histone deacetylase that uses the cofactor nicotinamide adenine dinucleotide (NAD+) in a catalytic reaction that releases nicotinamide (a feedback inhibitor) and O-acetyl ADP ribose (Imai et al. 2000; Marmorstein 2004; Sauve et al. 2006). It has been reported that increased Sir2 activity lengthens life span, and that calorie restriction increases Sir2 levels and does not promote longevity in SIR2 knockouts (Kaeberlein et al. 1999; Lin et al. 2000, 2004; Tissenbaum and Guarente 2001; Rogina and Helfand 2004). In mammals, calorie restriction increases the expression of Sirt1, the Sir2 mammalian ortholog, in various tissues, including brain. Resveratrol, a natural Sirt1 activator found in red wine, lengthens the life span of mice and prevents the age-related deterioration of their motor function (Cohen et al. 2004; Baur et al. 2006). Additionally, resveratrol stimulates AMP kinase activity in neurons (Dasgupta & Milbrandt, 2007), and more importantly, protects against kainic acid-induced seizures and oxidative stress in rats (Gupta et al., 2002).
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