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

Abstract

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, molecules 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.

Keywords: STAC; aging; allosteric activator; cancer; cardiovascular disease; chromatin; deacetylase; diabetes; inflammation; sirtuin.

Figure 1. Sirtuin activating compounds (STACs) that extend lifespan and/or healthspan

The quest to find molecules that slow aging has rapidly advanced in recent years. Small molecule SIRT1 activators include (A) First generation molecules such as resveratrol and like polyphenols [5], (B) second generation STACs such as the imidazothiazoles [8], and (C) third generation STACs such as benzimidazoles and urea-based scaffolds [38, 39].

Figure 2. Proposed mechanism for allosteric SIRT1 activation by STACs

SIRT1 deacetylates target proteins (yellow) using NAD⁺ as a cosubstrate to generate a deacetylated product, O-acetyl-ADP ribose (OAcADPR) and nicotinamide (NAM). Biochemical and structural data favor a mechanism of direct “assisted allosteric activation” by STACs that is mediated by an N-terminal activation domain. Mutation of a conserved glutamate to lysine or alanine (E230K/A) in a structured N–terminal domain blocks activation by resveratrol and 117 synthetic STACs, arguing for a common mechanism of activation [39]. Fluorophores that were initially thought to be a requisite for activation in vitro are now known to mimic natural hydrophobic amino acids adjacent to the acetylated lysine (denoted by a Y in substrate). Binding of substrates with hydrophobic motifs near the acetyl site induce a conformational change upon binding, forming a specific exosite that allows activators to bind in a productive manner and in turn stabilize the docked substrate. Positive charges C-terminal to E230K interact with the negative charge of E230 to assist with the enzyme-STAC-substrate complex. Whether or not peptide K_m corresponds to K_d is not yet known.

Figure 3. Outline of STAC effects on aging and age-related diseases

Resveratrol – yellow peg, SRT1720 – green peg, SRT2104 and the related brain-penetrant molecule SRT3025 – red peg. Age-related diseases on the right panel that are ameliorated by STACs are indicated with colored peg. Asterisks denote studies in progress.