Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases

Abstract

Since the discovery of NAD-dependent deacetylase activity of the silent information regulator-2 (SIR2) family ('sirtuins'), many exciting connections between protein deacetylation and energy metabolism have been revealed. The importance of sirtuins in the regulation of many fundamental biological responses to various nutritional and environmental stimuli has been firmly established. Sirtuins have also emerged as critical regulators for aging and longevity in model organisms. Their absolute requirement of NAD has revived an enthusiasm in the study of mammalian biosynthesis of NAD. Sirtuin-targeted pharmaceutical and nutriceutical interventions against age-associated diseases are also on the horizon. This review summarizes the recent progress in sirtuin research (particularly in mammalian sirtuin biology) and re-evaluates the connection between sirtuins, metabolism, and age-associated diseases (e.g., type-2 diabetes) to set a basis for the next ten years of sirtuin research.

Figure 1

The tissue-specific metabolic functions of SIRT1 in the regulation of insulin sensitivity and secretion. SIRT1 plays a critical role in maintaining a delicate balance between insulin sensitivity and secretion in major metabolic tissues, such as liver, skeletal muscle, white adipose tissue (WAT), and pancreatic β cells. In the liver, SIRT1 regulates glucose production through PGC-1α, FOXO1, CRTC2, and STAT3 and appears to repress insulin sensitivity. SIRT1 also regulates LXRα and PPARα for cholesterol and fatty acid metabolism. In skeletal muscle, SIRT1 improves insulin sensitivity by increasing fatty acid oxidation through PGC-1α and repressing the expression of PTB1B. In WAT, SIRT1 promotes fatty acid mobilization by repressing PPARγ function and also regulates the production/secretion of adiponectin and FGF21 through FOXO1 and/or PPARγ. In pancreatic β cells, SIRT1 promotes glucose-stimulated insulin secretion and likely contributes to β cell adaptation in response to insulin resistance.

Figure 2

The role of SIRT1 in the induction of age-associated physiological changes. A variety of environmental and nutritional perturbations likely induce DNA damage and a reduction in NAD biosynthesis over time, resulting in the redistribution of SIRT1 and the reduction in SIRT1 activity in many different tissues. These events might affect SIRT1- mediated biological processes in tissues, causing the reduction in physiological robustness and aging.

Figure 3

SIRT1 as a molecular target for pharmaceutical and nutriceutical anti-aging interventions. Small molecule SIRT1-activating compounds (STACs) and the enhancement of NAD biosynthesis could mimic metabolic responses to caloric restriction (CR) through SIRT1 activation, leading to a possible extension of health span in mammals.