sirtuin

Sirtuins are a family of enzymes that regulate cellular processes through NAD+-dependent deacetylation and, in some cases, mono-ADP-ribosylation. They were first identified as Silent Information Regulator 2 (SIR2) in yeast, and are evolutionarily conserved across organisms. In mammals there are seven members, SIRT1 through SIRT7, each with distinct subcellular localizations and functions.

Sirtuin enzymatic activity requires nicotinamide adenine dinucleotide (NAD+), linking their function to the cell’s metabolic state. Deacetylation of lysine residues on histone and non-histone proteins consumes NAD+ and produces nicotinamide and O-acetyl-ADP-ribose. Localizations vary by member: SIRT1 mainly nuclear and cytosolic; SIRT2 cytosolic; SIRT3-5 mitochondrial; SIRT6 nuclear; SIRT7 nucleolar. Some sirtuins can also act as mono-ADP-ribosyltransferases.

Sirtuins regulate transcription, mitochondrial biogenesis, DNA repair, metabolism, and stress responses. Notable targets include transcription factors and coactivators such as p53, FOXO, NF-κB, and PGC-1alpha. Through these interactions, sirtuins influence aging-related processes, caloric restriction responses, and metabolic homeostasis. Evidence for lifespan extension in model organisms is robust in yeast and some animal models, but extrapolation to humans remains uncertain.

In research and medicine, sirtuins are explored as potential therapeutic targets for metabolic disorders, neurodegenerative diseases, and cancer. Activators such as resveratrol and synthetic compounds have been studied, but clinical efficacy remains debated. Inhibitors and genetic models help elucidate function. Overall, sirtuins are integral to coordinating energy status with cellular fate decisions, but their roles in human aging require further study.