SIRT6 in DNA Repair, Metabolism, and Ageing

This is the review that put SIRT6 on the map for the ageing biology field. Two years earlier, the Alt lab at Harvard had shown that mice lacking SIRT6 develop a rapid-ageing syndrome and die at about four weeks old. This 2008 paper asked why. It laid out three parallel arguments — genomic stability, insulin signalling, and sirtuin biology — and used the SIRT6 data to weave them together.

On the genomic stability side, the review argues that SIRT6-null cells fail specifically at base excision repair — the pathway that fixes single-base DNA damage from oxidation, alkylation, and deamination. This connects SIRT6 loss to the same class of ageing phenotype seen in humans with rare progeroid syndromes like Cockayne syndrome and Werner syndrome.

On the metabolism side, the review shows how SIRT6 knockout produces hyperactive insulin/IGF1-like signalling. Because reduced insulin signalling is one of the most conserved pro-longevity interventions in worms, flies, and mice, hyperactive IIS in SIRT6-null mice is a mechanistic explanation for the accelerated-ageing phenotype.

On the sirtuin biology side, the review places SIRT6 in the context of all seven mammalian sirtuins, arguing that different family members do different jobs but share the underlying property of being NAD+-dependent nutrient sensors. The paper is the reason later reviews describe SIRT6 as a "longevity enzyme". Not because Lombard and colleagues had proof of that in humans — nobody did — but because they made a coherent theoretical case that every subsequent review has built on.