Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Abstract

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.

Aging by epigenetics—A consequence of chromatin damage?

“…Chemopreventative strategies may also counter age-associated diseases other than cancer. Remarkably, addition of a SirT1 activator, resveratrol, to the diet of mice fed a high fat diet prolongs the healthy lifespan of those mice [114,115], apparently mimicking the well-established contribution of dietary caloric restriction to longevity [116]. Although there are questions as to whether resveratrol extends lifespan through SirT1 and whether SirT1 acts through chromatin [117,118], these studies demonstrate the potential of chemopreventative strategies to combat aging.…”

The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster

“…These individuals are more susceptible to type 2 diabetes, cardiovascular disease, stroke, and a host of other age-related diseases. Studies in mice and humans have shown that resveratrol can lower glucose levels and may be an effective intervention for the treatment of type 2 diabetes, a disease that is prevalent in both aging and obesity Milne et al 2007;Szkudelska and Szkudelski 2010). Resveratrol has also been shown to reduce oxidative damage in human cells and animal models (Szkudelska and Szkudelski 2010;Baur 2010;Frankel et al 2011).…”

Androgen depletion in humans leads to cavernous tissue reorganization and upregulation of Sirt1–eNOS axis

“…Several studies point to Sirt1 as a chief regulator of NO synthesis in endothelium (Milne et al 2007;Pillarisetti 2008;Potente et al 2007) employing an Akt-mediated pathway of eNOS phosphorylation (Lovren et al 2009) or promoting eNOS catalytic activity through deacetylation of lysines 496 and 506 (Mattagajasingh et al 2007). As NO itself appears to reciprocally activate Sirt1 expression and activity (Ota et al 2007), then Sirt1-eNOS axis emerges as a decisive regulatory mechanism in CC endothelium.…”