Fasting promotes the expression of SIRT1, an [NAD.sup.+]-dependent protein deacetylase, via activation of PPAR[alpha] in mice

Calorie restriction (CR) extends lifespans in a wide variety of species. CR induces an increase in the [NAD.sup.+]/NADH ratio in cells and results in activation of SIRT1, an [NAD.sup.+]-dependent protein deacetylase that is thought to be a metabolic master switch linked to the modulation of lifespans. CR also affects the expression of peroxisome proliferator-activated receptors (PPARs). The three subtypes, PPAR[alpha], PPAR[gamma], and PPAR[beta]/[delta], are expressed in multiple organs. They regulate different physiological functions such as energy metabolism, insulin action and inflammation, and apparently act as important regulators of longevity and aging. SIRT1 has been reported to repress the PPAR[gamma] by docking with its co-factors and to promote fat mobilization. However, the correlation between SIRT1 and other PPARs is not fully understood. CR initially induces a fasting-like response. In this study, we investigated how SIRT1 and PPAR[alpha] correlate in the fasting-induced anti-aging pathways. A 24-h fasting in mice increased mRNA and protein expression of both SIRT1 and PPAR[alpha] in the livers, where the [NAD.sup.+] levels increased with increasing nicotinamide phosphoribosyltransferase (NAMPT) activity in the [NAD.sup.+] salvage pathway. Treatment of Hepa1-6 cells in a low glucose medium conditions with [NAD.sup.+] or NADH showed that the mRNA expression of both SIRT1 and PPAR[alpha] can be enhanced by addition of [NAD.sup.+], and decreased by increasing NADH levels. The cell experiments using SIRT1 antagonists and a PPAR[alpha] agonist suggested that PPAR[alpha] is a key molecule located upstream from SIRT1, and has a role in regulating SIRT1 gene expression in fasting-induced anti-aging pathways. Keywords SIRT1 * PPAR[alpha] * Calorie restriction * [NAD.sup.+]/NADH