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ADP-ribosyltransferase pathway

Deacylase pathway

1.

Unknown pathway

1. Brain-specific Sirt1-overexpressing (BRASTO) transgenic mice show a lifespan extension of 16% for females and 9% for males. (Satoh 2013)

Sirtuins

Sirtuins are a class of proteins that possess both mono-ADP-ribosyltransferase and deacylase activity in various organisms. Sirtuins can promote longevity in yeast, worms, and flies. SIRT1 decreases in mice SCN with age. Mammalian SIRT6 declines with age, increases longevity when upregulated in mice, and accelerates aging when downregulated in mice. SIRT6 promotes DNA repair and protects the brain from the accumulation of toxic proteins. The histone deacetylase 

Papers

SIRT6 is a DNA double-strand break sensor

2020 - Lior Onn. SIRT6 directly recognizes DNA damage through a tunnel-like structure that has high affinity for DSBs. SIRT6 relocates to sites of damage independently of previously known signaling and recruits the proteins of the homologous recombination and non-homologous end joining pathways. 

 

SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species 

2019 - Xiao Tian, Vera Gorbunova. Using a panel of 18 rodent species with diverse lifespans, this study shows that more robust DSB repair, but not NER, coevolves with longevity. It further shows that the capacity of the SIRT6 protein to promote DSB repair accounts for a major part of the variation in DSB repair efficacy between short- and long-lived species. 

 

Neuroprotective Functions for the Histone Deacetylase SIRT6

2017 - Shai Kaluski. Mechanistically, SIRT6 regulates Tau protein stability and phosphorylation through increased activation of the kinase GSK3α/β. SIRT6 mRNA and protein levels are reduced in patients with Alzheimer's disease.