Tier 3 — preclinical

SIRT6, a protein with many faces

Gertler AA, Cohen HY

Biogerontology 2013 Volume 14, issue 6, pages 629–639

Bibliography

DOI: 10.1007/s10522-013-9478-8
PubMed: PMID 24213807
Funding: The research at Cohen's lab is supported by the Israel Science Foundation, Teva Pharmaceutical Industries LTD, I-Core Foundation, Israeli Ministry of Health, and the European Research Council.
Competing interests: Not explicitly declared in the review's acknowledgements section.

Study snapshot

Design	Narrative review synthesising SIRT6 catalytic activities, structure, cellular localisation, transcriptional and post-translational regulation, and roles in DNA repair, metabolism, ageing, and cancer.
Model	Review scope covers in vitro biochemistry, mammalian cell culture, and murine knockout and transgenic studies published up to late 2013, including the Kanfi 2012 male-mouse lifespan finding.
Sample	Not applicable — narrative review.
Intervention	Not applicable — narrative review.
Duration	Not applicable — narrative review.
Endpoints	Not applicable — narrative review synthesising SIRT6 mechanism (deacetylation, mono-ADP-ribosylation, long-chain fatty acyl deacylation), substrates (H3K9, H3K56, PARP1, CtIP, TNF-α, GCN5), phenotypic consequences of SIRT6 gain- and loss-of-function, and implications for age-related disease

What the study showed, in plain terms

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.

Key findings

SIRT6 is now understood as a broader deacylase, not only a deacetylase: its most efficient reported enzymatic activity is removing long-chain fatty acyl groups (myristoyl, palmitoyl) from lysine residues, with the longer the aliphatic tail, the stronger the catalytic efficiency.
SIRT6 crystal structure differs from other sirtuins in two important ways — it lacks the conserved "cofactor binding loop" and instead binds NAD⁺ tightly even without acetylated substrate, and it has a large hydrophobic pocket that accommodates long-chain fatty acyl modifications. These structural features explain both its weak deacetylase activity in older assays and its strong long-chain deacylation activity.
SIRT6 activity is enhanced when SIRT6 is bound to nucleosomes, which the review argues means in vivo activity is likely higher than early biochemical assays with free peptides suggested.
SIRT6 is transcriptionally upregulated by SIRT1–FOXO3a–NRF1 complexes under nutrient stress, by p53 under normal nutrient conditions, and by c-Fos through an AP-1 site in the SIRT6 promoter; it is repressed by microRNA miR-33b.
SIRT6 promotes DNA double-strand break repair through both non-homologous end joining and homologous recombination, deacetylates CtIP at K432/K526/K604 to promote DNA end resection, and mono-ADP-ribosylates PARP1 at K521 to stimulate PARP1's poly-ADP-ribosylase activity at damage sites.
SIRT6 suppresses NF-κB-driven inflammatory and senescence gene expression by deacetylating H3K9 at NF-κB target promoters and destabilising RelA occupancy; haploinsufficiency of RelA extends the lifespan of Sirt6-knockout mice from ~4 weeks to more than 3 months.
SIRT6 represses HIF1α-driven glycolysis; loss of SIRT6 causes a Warburg-like metabolic shift with increased glucose uptake and lactate production, elevated GLUT1/GLUT4, and increased AKT phosphorylation.
Sirt6-transgenic mice overexpressing SIRT6 (Kanfi 2012) show a male-only ~15% median lifespan extension with reduced IGF1 signalling; this was, at time of review, the first mammalian sirtuin shown to extend lifespan.
SIRT6 acts as a tumour suppressor in liver and colon: it co-represses MYC target genes via H3K56 deacetylation and represses survivin via the AP-1/SIRT6 axis; SIRT6-knockout mouse embryonic fibroblasts show enhanced aerobic glycolysis and form tumours when injected into SCID mice.
SIRT6 can also promote survival of already-established cancers by decreasing sensitivity to chemotherapeutics — the review flags this as a caveat to any therapeutic strategy based on broad SIRT6 activation.

What this study can and cannot tell us

This is a narrative review, not a systematic review or meta-analysis. There is no pre-registered search strategy and no formal quality assessment of the primary literature it synthesises.

The review predates almost all human clinical data on SIRT6 activation. In 2013, no clinical trial of a SIRT6 activator had been run, and no natural or pharmacological SIRT6 activator was in widespread use in humans. The review's therapeutic framing is therefore forward-looking rather than evidence-based on human outcomes.

The review acknowledges that SIRT6's roles are context-dependent and sometimes contradictory: SIRT6 is a tumour suppressor in early cancer initiation, but in established tumours it can promote survival and chemotherapy resistance. Any therapeutic strategy based on broad SIRT6 activation would need to reckon with this bidirectional biology, and the review does not resolve when activation would help or harm.

Some of the most consequential findings summarised — the long-chain deacylation activity, the nucleosome-dependent activation, the male-only lifespan effect — were less than a year old at time of writing. As the SIRT6 field has continued to develop, later work has revised or refined several of the mechanistic claims made here, and readers should treat this review as a foundational orientation rather than the current state of the science.