SIRT6, a protein with many faces

This is a review, not a new experiment. It was written in late 2013 to pull together everything the field then understood about SIRT6, from its molecular chemistry up to its role in ageing.

The review covers three enzymatic activities SIRT6 was known to have at the time. First, it removes acetyl groups from specific lysines on histone H3 (K9, K56) and from other proteins. Second, it transfers a mono-ADP-ribose group onto PARP1 and onto itself. Third — a newly reported finding in 2013 — it removes long-chain fatty acyl groups such as myristoyl from proteins like TNF-α, which turned out to be its most efficient enzymatic activity of all. The authors argue that this reclassifies SIRT6 as a broader deacylase, not just a deacetylase.

The pathways SIRT6 sits inside are just as broad. It participates in DNA double-strand break repair through both non-homologous end joining and homologous recombination. It suppresses NF-κB signalling, which controls inflammation and cellular senescence. It represses HIF1α, which shifts cellular metabolism between oxidative respiration and glycolysis. It regulates hepatic gluconeogenesis through GCN5 and PGC-1α. And it acts as a tumour suppressor in liver and colon by co-repressing MYC and survivin, though it can also become important for cancer cell survival once a tumour is established.

The most consequential finding the review integrates is the Kanfi 2012 result that SIRT6 overexpression extends the lifespan of male mice by roughly 15%. Combined with the earlier finding that Sirt6-knockout mice die at about four weeks with a premature-ageing-like phenotype, SIRT6 emerged from this review as the mammalian sirtuin most directly tied to lifespan.

The review's closing argument is that SIRT6 is a plausible therapeutic target for age-related disease, and that developing small-molecule activators — especially ones that exploit the newly discovered long-chain deacylation activity for a better assay — is the practical next step.