Tier 4 — mechanistic

SIRT6: novel mechanisms and links to aging and disease

Luisa Tasselli, Wei Zheng, Katrin F. Chua
Trends in Endocrinology & Metabolism 2017 Volume 28, issue 3, pages 168–185

Bibliography

PubMed
PMID 27836583
PubMed Central
PMC5326594
DOI
10.1016/j.tem.2016.10.002
Funding
NIH-supported author manuscript (PMCID: PMC5326594); specific grant numbers are not listed in the accessible manuscript record.
Competing interests
Not stated in the manuscript text

Study snapshot

DesignNarrative review; not a systematic review or meta-analysis.
ModelReview scope covers mouse SIRT6 knockout and overexpression models; human embryonic and adult (haematopoietic, mesenchymal) stem cells; human tumour tissue and cell lines; human patient samples for HGPS.
SampleNot applicable to a narrative review.
InterventionNot applicable. Review covers SIRT6 genetic manipulation across the cited primary literature.
DurationNot applicable.
EndpointsNot applicable. Review focus: SIRT6 substrates and enzymatic activities; heterochromatin silencing at telomeres, LINE-1 elements, and pericentric repeats; stem cell homeostasis; tumour suppression and cancer progression; glucose and lipid homeostasis; circadian regulation.

What the study showed, in plain terms

This is a comprehensive review, not a new experiment. The authors — a Stanford group led by Katrin Chua that has published extensively on SIRT6 — catalogued what was known as of late 2016 about how SIRT6 protects against ageing-related diseases and mapped the molecular activities responsible.

SIRT6 is presented as a chromatin-regulating enzyme with three distinct catalytic activities: removing acetyl groups from specific sites on histone H3 (H3K9, H3K56, H3K18), attaching ADP-ribose to other proteins, and removing long-chain fatty acids from lysine residues. The review argues that different activities dominate in different biological contexts, and that separation-of-function mutations in SIRT6 will be essential for working out which activity drives each physiological effect.

Four areas of SIRT6 biology are covered in detail. First, SIRT6 silences repetitive parts of the genome (telomeres, LINE-1 retrotransposons, pericentric satellite repeats) that become unstable with age. Second, SIRT6 is required for proper differentiation of embryonic stem cells and for long-term self-renewal of adult haematopoietic and mesenchymal stem cells. Third, SIRT6 is a tumour suppressor in many cancers by restraining the Warburg glycolytic shift, but its role can flip in some tumour types where it is upregulated. Fourth, SIRT6 sits at a control point for glucose and lipid metabolism, repressing glycolytic and lipogenic gene expression and coordinating circadian rhythms in the liver.

The review closes by highlighting SIRT6 activation as a promising therapeutic strategy for age-related metabolic and degenerative diseases, while cautioning that context-dependent effects (particularly in cancer) will complicate drug development.

Key findings

  • SIRT6-deficient mice show shortened lifespan and phenotypes resembling accelerated ageing; SIRT6-overexpressing mice show subtle male-specific lifespan extension and protection against diet-induced metabolic pathology.
  • SIRT6 is a highly selective histone deacetylase for H3K9ac, H3K56ac, and H3K18ac on nucleosomes; activity on peptides is orders of magnitude weaker, indicating that physiological chromatin context is required for efficient catalysis.
  • SIRT6 silences LINE-1 retrotransposons through mono-ADP-ribosylation of the heterochromatin factor KAP1; loss of SIRT6 with age or DNA damage permits LINE-1 transposition and genomic instability.
  • SIRT6 maintains pericentric heterochromatin by deacetylating H3K18; loss produces mitotic errors and cellular senescence — a mechanism potentially relevant to Hutchinson-Gilford Progeria Syndrome, in which mutant Lamin A fails to activate SIRT6.
  • SIRT6 represses pluripotency genes (Oct4, Sox2, Nanog) in embryonic stem cells and Wnt-pathway targets in haematopoietic stem cells; SIRT6 loss impairs stem cell differentiation, self-renewal, and reprogramming to iPSCs.
  • SIRT6 acts as a tumour suppressor by co-repressing HIF-1α glycolytic targets (blocking the Warburg effect), c-Myc ribosome-biogenesis targets, and in pancreatic cancer by silencing the oncofetal protein Lin28b.
  • In some cancers (multiple myeloma, hepatocellular carcinoma, skin, prostate) SIRT6 is upregulated and may promote tumour cell survival, chronic inflammation, or drug resistance — indicating that SIRT6 has context-dependent roles in cancer biology.
  • Liver-specific SIRT6 knockout causes fatty liver through enhanced glycolysis and triglyceride synthesis; SIRT6 represses SREBP1/2, PCSK9, and hepatic gluconeogenesis via FoxO1 and PGC-1α pathways.
  • SIRT6 coordinates the hepatic circadian transcriptome through timed chromatin recruitment of CLOCK:BMAL1 and SREBP1 to lipid-metabolism genes; loss disrupts circadian oscillation of lipid metabolites.

What this study can and cannot tell us

This is a narrative review, not a systematic review or meta-analysis. The authors did not use pre-registered search strategies or formal quality assessment tools. Conclusions should be read as informed synthesis, not statistical summary.

Coverage is weighted toward mechanism and cell biology. Direct clinical evidence for SIRT6 modulation in human disease is limited to observational associations (tumour tissue expression, HGPS cell studies) — no human trials of SIRT6-activating interventions are discussed.

Two of the three authors work in the Chua laboratory, which has authored many of the primary studies cited (particularly on H3K18 pericentric deacetylation and stem cell biology). This is normal for a specialist review but the framing naturally emphasises the authors' own body of work.

Published in November 2016 with a knowledge cutoff of roughly mid-2016. Substantial subsequent findings — including detailed mechanisms of small-molecule SIRT6 activation, the Klein et al. 2020 conformational-change model, the You et al. 2019 quercetin structural work, and the identification of MDL-800-class activators — post-date this review and are not covered.

Editorial review

Reviewed by the Biohack Blueprint research team

Last verified

Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology