Sirtuin (NAD+-dependent deacetylase) (SIRT)

Sirtuins (SIRT1-7) are a conserved family of NAD+-dependent deacylases that serve as critical metabolic sensors, linking cellular energy status to gene expression and protein function. They regulate diverse biological processes including mitochondrial biogenesis, DNA repair, and inflammation by removing acetyl groups from target proteins such as PGC-1alpha and p53 (Haigis and Sinclair, 2010). Since sirtuin activity is strictly limited by the availability of NAD+, increasing intracellular NAD+ levels has emerged as a primary therapeutic strategy to enhance sirtuin function. This approach avoids the need for direct small-molecule binding to the enzyme itself, which has proven challenging for some sirtuin isoforms (Imai and Guarente, 2014). Indirect activation is typically achieved via NAD+ precursors like nicotinamide riboside or by inhibiting NAD+-consuming enzymes such as CD38 and PARP1 (Cantó et al., 2015). These strategies are currently being investigated for their potential to treat age-related metabolic decline, neurodegenerative diseases, and cardiovascular conditions. By restoring NAD+ levels, these therapies aim to rejuvenate sirtuin-mediated pathways that typically decline with age (Rajman et al., 2018). Overall, sirtuins represent a central node in the regulation of longevity and metabolic health, making them high-value targets for indirect pharmacological intervention.

Other names

Silent information regulatorNAD-dependent protein deacetylaseClass III histone deacetylaseSIR2-like protein

Elevation of intracellular NAD+ levels increases the availability of the essential co-substrate for sirtuin enzymes, thereby enhancing their catalytic activity in deacetylation and ADP-ribosylation reactions (Cantó et al., 2015; Imai and Guarente, 2014).