Small Molecule Activators of Sirtuins

In addition to resveratrol and other compounds that activate SIRTl by promoting peptide binding, a different mechanism has been described for isonicotinamide (11), which was shown to activate yeast Sir2 through relief of nicotinamide inhibition [45 ]. 

As discussed previously, nicotinamide is an endogenous sirtuin inhibitor that promotes the chemical reversal of the covalent reaction intermediates and generation of NAD and acetyl lysine, resulting in nicotinamide exchange. Isonicotinmide is competitive with nicotinamide in the exchange reaction thus promoting deacetylation both in vitro and in vivo. 

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Small molecule activators of sirtuins extend Saccharomyces cere-visiae lifespan. Nature 425 191-196. 

Cohen, H.Y., Lamming, D.W., Lavu, S., Wood, J.G. et al. (2003) Small molecule activators of sirtuin expan Saccharomyces cerevisiae lifespan. Nature, 425,191-196. 

Howitz KT, Bitterman KJ, Cohen HM, Lamming DH, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang L-L, Scherer B, Sinclair DA. 2003. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425 191-196. 

Therefore, the search for a stimulator of SIRTl was on. One of the first compounds found that is a natural activator of sirtuins is a small molecule called resveratrol, which is present in red wine and made by many plants when stressed. Feeding resveratrol to yeast, worms, or flies, or placing them on a calorie-restricted diet, extends their life spans about 30%, but only if they possess the SIR2 gene. 

Sinclair, DA. and Guarente, L. (2014) Small-molecule allosteric activators of sirtuins. Annual Review of Pharmacology and Toxicology, 5A, 363 380. 

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