Sirtuin activators.

BACKGROUND: Sirtuin 1-7 (SIRT1-7) are deacetylases that are dependent on NAD(+) for their activity. SIRT1 down-regulates p53 activity, increasing lifespan, cell survival, and neuroprotection; it also deacetylates peroxisome proliferator-activated receptor-gamma and its coactivator 1alpha, promoting fat mobilization, increasing mitochondrial size and number, and positively regulating insulin secretion. Sirtuins link nutrient availability and energy metabolism. Calorie restriction, which increases lifespan and is beneficial in age-related disorders, activates sirtuin. Major efforts are thus focused to developing sirtuin activators.
OBJECTIVE: After discussing the potential involvement of sirtuins in pathophysiological processes, this review looks at new, synthetic sirtuin activators.
CONCLUSIONS: To date, resveratrol is the most potent natural compound able to activate SIRT1, mimicking the positive effect of calorie restriction. Resveratrol might help in the treatment or prevention of obesity and in preventing the aging-related decline in heart function and neuronal loss. As resveratrol has low bioavailability and interacts with multiple molecular targets, the development of new molecules with better bioavailability and targeting sirtuin at lower concentrations is a promising field of the medicinal chemistry. New SIRT1 activators that are up to 1000 times more effective than resveratrol have recently been identified. These improve the response to insulin and increase the number and activity of mitochondria in obese mice. Human trials with a formulation of resveratrol with improved bioavailability and with a synthetic SIRT1 activator are in progress.