SIRT6

SIRT6 (Sirtuin 6), a NAD+-dependent histone deacetylase and ADP-ribosyltransferase, regulates genomic stability, DNA repair, metabolic homeostasis, and inflammation. Also termed Sir2-like 6 or SIR2L6, it primarily deacetylates H3K9ac and H3K56ac, modulating chromatin structure and gene silencing. Mechanistically, SIRT6 coordinates stress responses by interacting with transcription factors (NF-κB, HIF1α) and DNA repair machinery (PARP1, BRCA1). It suppresses glycolysis while promoting mitochondrial respiration via PI3K/AKT and AMPK pathways, and its deficiency accelerates aging phenotypes. SIRT6 dysfunction correlates with carcinogenesis, metabolic syndrome, neurodegenerative disorders (Alzheimer's), and cardiovascular diseases. Pharmaceutical efforts focus on developing activators (e.g., MDL-800) to enhance its enzymatic activity, with preclinical studies showing lifespan extension and metabolic improvements. Challenges remain in achieving tissue-specific targeting and minimizing off-target effects.