SIRT6 (sirtuin 6; HGNC:14934, NCBI Gene ID 51548) is a human locus mapped to chromosome band 19p13.3 that encodes nuclear chromatin-bound NAD+-dependent deacetylase, long-chain deacylase & mono-ADP-ribosyltransferase Sirtuin 6 (355 aa; EC 2.3.1.286). SIRT6 acts in H3K9ac/H3K56ac/H3K18ac telomeric & LINE-1 retrotransposon silencing, PARP1/SNF2H DSB repair & HIF1A/MYC/PCSK9 repression, together with SIRT1 (Nuclear Sirtuin 1 Paralog Gene), SIRT7 (Nucleolar Sirtuin 7 Paralog Gene), and PARP1 (Mono-ADP-Ribosylated at Lys521 by SIRT6 at DNA Breaks). Encodes the chromatin-bound sirtuin 6 that deacetylates histone H3 (H3K9ac, H3K56ac), promotes DNA double-strand break repair, silences LINE-1 retrotransposons, and extends mammalian lifespan.
Genomic Organization & Cytogenetic Locus: 8-exon gene at chromosome 19p13.3 encoding a 355-amino-acid nuclear enzyme that lacks the conserved cofactor-binding loop helix bundle of other sirtuins, enabling SIRT6 to bind NAD+ in the absence of acetylated substrate, accomodate long-chain myristoyl acyl groups (such as on TNF-alpha), and have its histone deacetylase activity stimulated >30-fold by nucleosome binding and free long-chain polyunsaturated/monounsaturated fatty acids (such as oleic acid).
Cellular & Tissue Expression Profile: Constitutively localized to nuclear euchromatin, pericentric heterochromatin, and telomeres across all human tissues.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Executes three foundational anti-aging functions on chromatin: (1) arrives within <5 seconds at DNA double-strand breaks to mono-ADP-ribosylate PARP1 at Lys521 and recruit the chromatin remodeler SNF2H (SMARCA5) and WRN helicase, driving homologous recombination and non-homologous end joining (comparative biology across 18 rodent species demonstrated that species maximum lifespan—including the 32-year-lived naked mole-rat—correlates directly with SIRT6 DSB repair efficiency); (2) deacetylates Histone H3 at Lys9 (H3K9ac) and Lys56 (H3K56ac) at telomeres and co-represses HIF1A (glycolysis), MYC (ribosome biogenesis), NF-kappaB (inflammation), and FOXO3-recruited PCSK9 (lowering LDL-cholesterol); and (3) mono-ADP-ribosylates KAP1 (TRIM28) to package parasitic LINE-1 retrotransposons into silent heterochromatin and prevent sterile cGAS-STING interferon inflammation.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Homozygous Sirt6 loss in mice causes lethal hypoglycemia and premature progeroid degeneration within 4 weeks (and homozygous inactivating p.Asp63His in humans is perinatally lethal with severe brain and cardiac defects), whereas transgenic whole-body overexpression of Sirt6 extends median and maximal lifespan in both male and female mice by 15–30% while suppressing hepatic gluconeogenesis and cancer; furthermore, Sequencing of Ashkenazi Jewish centenarians identified a rare hypermorphic allele (centSIRT6: p.Asn308Lys / p.Ala313Ser) that doubles mono-ADP-ribosylation activity, enhances DNA repair and LINE-1 silencing, and selectively kills cancer cells.
Therapeutic & Clinical Pharmacology: Allosterically activated up to 35-fold by fucoidan oligosaccharides from brown algae and synthetic pyrroloquinoxaline/quinazolinone activators (MDL-800, MDL-811, UBCS039) under investigation for MASH, glioblastoma, and healthy longevity.