Sirtuin 6 (SIRT6) centenarian variant (centSIRT6)

Sirtuin 6 (SIRT6) is a nuclear enzyme belonging to the sirtuin family of NAD+-dependent protein deacetylases, functioning as a histone deacetylase, deacylase, and mono-ADP-ribosyltransferase [1, 13]. The 'centenarian variant' (centSIRT6) refers to a specific genetic allele, notably the N308K/A313S double mutant, which is significantly enriched in human centenarians and associated with exceptional longevity [1, 3]. This variant exhibits a unique functional profile, showing reduced deacetylase activity but markedly enhanced mono-ADP-ribosyltransferase activity and a stronger interaction with the nuclear scaffold protein Lamin A/C [4, 6]. These alterations lead to improved DNA double-strand break repair, more effective silencing of LINE1 retrotransposons, and increased resistance to oxidative stress [1, 17]. As a therapeutic target, SIRT6 is highly relevant for treating age-related pathologies, including metabolic syndrome, cardiovascular diseases, and neurodegeneration [11, 14, 18]. It also acts as a potent tumor suppressor in many contexts by regulating glycolysis and maintaining genomic integrity, although its role can be complex in certain cancers [8, 16]. Drug development efforts are currently focused on identifying small-molecule activators, such as MDL-800 and various polyphenols, that can mimic the beneficial effects of the centenarian variant [9, 12, 15]. These modulators typically bind to an allosteric acyl channel pocket to enhance SIRT6's catalytic efficiency, offering a promising strategy for extending healthspan and treating chronic diseases [12, 19].

Other names

SIRT6 N308K/A313ScentSIRT6Sirtuin 6 longevity variantHuman SIRT6 centenarian allele

SIRT6 activators typically bind to an allosteric acyl channel pocket to enhance the enzyme's catalytic activities, specifically deacetylation and mono-ADP-ribosylation, thereby promoting DNA repair and metabolic homeostasis.