17. Small molecule SIRT1 activators for the treatment of aging and age-related diseases

Basil P. Hubbard, Trends Pharmacol Sci. 2014 Mar; 35(3):146-54.

Recent studies in mice have identified single molecules that can delay multiple diseases of aging and extend lifespan. In theory, such molecules could prevent dozens of diseases simultaneously, potentially extending healthy years of life. In this review, we discuss recent advances, controversies, opportunities, and challenges surrounding the development of SIRT1 activators, mole-cules with the potential to delay aging and age-related diseases. Sirtuins comprise a family of NAD+-dependent deacylases that are central to the body’s response to diet and exercise. New studies indicate that both natural and synthetic sirtuin activating compounds (STACs) work via a common allosteric mechanism to stimulate sirtuin activity, thereby conferring broad health benefits in rodents, primates, and possibly humans. The fact that two-thirds of people in the USA who consume multiple dietary supplements consume resveratrol, a SIRT1 activator, underscores the importance of understanding the biochemical mechanism, physiological effects, and safety of STACs. The quest to delay aging History and myth abound with discoveries of potions that impart longer life. Only recently, however, has our level of knowledge reached a point where a ‘panacea’ –a medicine that prevents and treats multiple age-related diseases – is scientifically possible. This optimism is afforded by the relatively recent discovery of genes and small molecules that can extend lifespan in yeast, worms, flies, and mice [1– 5]. There are at least three main pathways that control lifespan in mammals: insulin/insulin-like growth factor 1 (IGF-1), tuberous sclerosis complex (TSC)/mammalian tar-get of rapamycin (mTOR), and the sirtuins[3,6,7]. These pathways are believed to control the response to adversity and cellular stress, such as DNA damage, hypoxia, or a reduced supply of resources from the environment. Molecules that modulate each of these pathways are known and have been shown in animals to prevent a diverse set of age-related diseases, including cancer, cardiovascular disease, osteoporosis, and type 2 diabetes [2,3,6–8]. Whether drugs can be made to safely modulate these pathways and retard aging in humans is not yet known, but we appear to be closer than ever. In this review, we focus on pharmacolo-gical activation of a key sirtuin, SIRT1, an area of research that has undergone considerable progress recently, with paradigms challenged and key questions being resolved.