Sirtuins

Sirtuins (SIRTs) are NAD+-dependent histone deacetylases, and seven mammalian homologs of yeast Sir2, named SIRT1 to SIRT7, have been identified. ^[1] SIRT1 and SIRT2 are distributed in the nucleus and cytoplasm, SIRT3, SIRT4 and SIRT5 are localized in the mitochondria, and SIRT6 and SIRT7 are distributed in the nucleus. ^[2] Sirtuins catalyze the deacetylation of various substrate proteins, thereby modulating numerous biological processes including transcription, DNA repair and genome stability, metabolism, and signal transduction. ^[2]

As NAD+-consuming enzymes, sirtuins couple the cellular NAD+/NADH ratio to their deacetylase activity, so their function reflects the metabolic and energy state of the cell. ^[3] SIRT1 deacetylates a variety of proteins including histones and non-histone proteins, and alterations to SIRT1 expression and activity have been linked to inflammatory diseases. ^[3] Two metabolic sensors, AMP-activated protein kinase (AMPK) and SIRT1, directly affect PGC-1alpha activity through phosphorylation and deacetylation respectively, acting as an orchestrated network that controls cellular energy expenditure and mitochondrial biogenesis. ^[4] Three mitochondrial sirtuins, SIRT3, SIRT4 and SIRT5, act as metabolic sensors that modulate the activity of metabolic enzymes via protein deacetylation or mono-ADP-ribosylation in response to nutritional status. ^[5]

Sirtuins are highly conserved across species from yeasts to primates and play a crucial role in linking aging and disease, participating in nearly all key physiological and pathological processes from development to stress response and aging. ^[6] The expression of SIRT1 is diminished with aging in mice, whereas increased expression of SIRT1 is sufficient to extend lifespan in yeast, Caenorhabditis elegans and mice. ^[7] Of the seven mammalian isotypes, SIRT1 and SIRT6 are well recognized for regulating signaling pathways related to aging, counteracting mechanisms such as DNA damage, chronic inflammation and metabolic dysfunction. ^[8] NAD+ levels decline during ageing in multiple model organisms including rodents and humans, and this decline limits the activity of NAD+-dependent enzymes such as the sirtuins. ^[9]

Because sirtuin modulation could have beneficial effects on several human diseases, there is growing interest in discovering small molecules that modify their activity, and either activation or inhibition may be desirable depending on the pathological condition and target tissue. ^{[10] [11]} Resveratrol has been described as the most potent natural compound able to activate SIRT1, mimicking the positive effect of calorie restriction, though it has low bioavailability and interacts with multiple molecular targets. ^[12] The notion of SIRT1's regulation of PGC-1alpha activity and its role in mitochondrial biogenesis has been controversial. ^[13] Because many age-associated functional defects tracking with the age-related NAD+ decline can be ameliorated by restoring NAD+ levels, the combination of sirtuin activation and NAD+ intermediate supplementation has been proposed as a potential anti-aging intervention. ^[14]