Aging Therapeutics: Sirtuin-Activating Compounds (STACs)

Sirtuin 1 docking with substrate NAD+

Dr. Richard Miller, MD/PhD, Professor at the University of Michigan, on aging:

“It seems reasonable to suppose that the discovery of a technique that can, in a laboratory animal, diminish to near zero the incidence of neoplasia, cardiovascular illnesses, and diabetic changes would prompt a substantial public commitment to working out the mechanism of the intervention and developing analogues that work well in humans.
Reasonable but wrong: such an intervention has been clearly established for decades, and yet its investigation receives such a small proportion of governmental research funding that it cannot be seen in a pie chart.”

Sirtuins are genes implicated in wide range of processes impacting aging including genomic stability, apoptosis, metabolism, ROS mitigation, stress tolerance, inflammation, and chromatin organization.

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 highly promising targets in cancer research. Sirtuins alsomediate some of the benefits of dietary restriction.

Caloric Restriction Slows Aging

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 intracellular 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). Evolutionarily, the organism may want to outlive periods of famine in order to reproduce during a time of plenty. So cells become more resillient.

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).

Pterostilbene, a more potent analogue of resveratrol.

Sirtuin activating compounds (resveratrol, pterostilbene) may be a promising drug class. Glaxo spent $720M 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.

Learn more about STACs and Sirtuins:

Sinclair, D and Guarente, L. 2014. Small Molecule Allosteric Activators of Sirtuins.

Guarente, L. 2011. Sirtuins, Aging, and Medicine. NEJM.

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