Sirtuin 1 and oxidative stress

Abstract

Sirtuin 1 (SIRT1) is a NAD+-dependent histone/protein deacetylase that regulates a variety of cellular functions such as genome maintenance, longevity, and metabolism. This chapter focuses on the functions of SIRT1 in the context of oxidative stress. SIRT1 stimulates mitochondrial biogenesis, reduces superoxide generation from the respiratory chain, and enhances manganese superoxide dismutase (SOD2) expression in mitochondria, resulting in increased mitochondrial superoxide dismutation. By elevating cellular levels of tetrahydrobiopterin, SIRT1 prevents superoxide production from the uncoupled endothelial nitric oxide synthase. In addition, SIRT1 accelerates the detoxification of reactive oxygen species by upregulating cellular antioxidant enzymes, including SOD1, catalase, glutathione peroxidase 1, and thioredoxin-1. On the other hand, oxidative stress modulates SIRT1 expression and activity. Whereas the upregulation of SIRT1 expression has been reported in several pathological situations, chronic stress conditions are likely to downregulate SIRT1 levels. Furthermore, oxidative stress promotes posttranslational modifications and the degradation of SIRT1 and reduces the cellular concentration of NAD+. Thus, a successful pharmacological approach should not only overcome the pathological downregulation of SIRT1 expression but also improve NAD+ availability and SIRT1 activity.