Sirtuin-activating Compounds (STACs)


Sirtuins are NAD+ dependent histone deacetylases. That is, they remove acetyl groups from the proteins around which DNA is wrapped, regulating (typically silencing) the expression of certain genes. Sirtuins are implicated in wide range of processes impacting aging including genomic stability, apoptosis, metabolism, ROS mitigation, stress tolerance, inflammation, and chromatin organization.

Sirtuins mediate some of the benefits of dietary restriction.

When an organism is deprived of food, nicotinamide adenine dinucleotide (NAD+) levels rise relative to NADH. Higher NAD+ activates sirtuins, which silence genes at the chromatin level and deacetylate proteins involved in signaling.

In many organisms, caloric restriction without malnutrition results in prolonged lifespan, healthspan and other salutary metabolic effects (including autophagy, reduced inflammation and oxidative stress mitigation).

Mammals possess seven sirtuins (SIRT1-7), which share a 275 residue catalytic core (containing a Rossman fold and zinc finger domain). They are localized to the nucleus (SIRT6 and SIRT7), mitochondria (SIRT3, 4, and 5), and traverse the cytosol and nucleus (SIRT1 and SIRT2).

Sirtuin activating compounds (resveratrol, pterostilbene) may be a promising drug class. Glaxo spent over $700M to acquire Sirtis in 2007, a company led by David Sinclair at Harvard. Though this deal remains controversial, and GSK has wound down the Sirtris research, there is little doubt that STACs like pterostilbene (a more potent, lipid soluble analogue of resveratrol) offer therapeutic value with low toxicity.

Pterostilbene — more potent than resveratrol.

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