Sirtuins and their role as physiological modulators of metabolism

Abstract

The sirtuins are a family of highly evolutionary conserved NAD+-dependent deacetylases (SIRT1, 2, 3, 5). Certain human sirtuins (SIRT4, 6) have, in addition, an ADP-ribosyltransferase activity. SIRT1 and SIRT2 are located in the nucleus and cytoplasm; SIRT3 exists predominantly in mitochondria, and SIRT6 is located in the nucleus. The mammalian sirtuins have emerged as key metabolic sensors that directly link environmental nutrient signals to metabolic homeostasis. SIRT1 is involved in the regulation of gluconeogenesis and fatty acid oxidation, as well as inhibiting lipogenesis and inflammation in the liver. In addition, they contribute to the mobilization of fat in white adipose tissue, sense nutrient availability in the hypothalamus; regulate insulin secretion in the pancreas; as well as modulating the expression of genes responsible for the activity of the circadian clock in metabolic tissues. Sirtuins are implicated in a variety of cellular functions ranging from gene silencing, through the control of the cell cycle, to energy homeostasis. Caloric restriction, supported by polyphenols, including resveratrol, which is the SIRT1 activator, plays a special role in maintaining energy homeostasis. On a whole body level, the wide range of cellular activities of the sirtuins suggests that they could constitute a therapeutic target to combat obesity and related metabolic diseases. In addition, this work presents the current state of knowledge in the field of sirtuin activity in relation to nutritional status and lifespan.