ArticleThe EMBO journal2022
A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A.
Erratum issuedOpen access · bronzeAbstract read
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Article in The EMBO journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 41 papers.
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41 citing papers in PubMed, 59 citations in OpenAlex.
- The Hallmarks of Aging: From Molecular Mechanisms to Clinical Translation.International journal of molecular sciences · 2026Review
- Emerging roles of SIRT6 and its modulators in kidney diseases.Cell death discovery · 2026Review
- Cellular Senescence and Aging: Mechanisms, Disease Convergence, and Therapeutic Frontiers.MedComm · 2026Review
- Centenarian SIRT6 variants elevate SIRT6 protein and enhance cellular senescence resistance.Research square · 2026Article
- DREAM repressive activity links somatic mutation, lifespan and disease.Nature aging · 2026Article
- Beyond deacetylation: crosstalk mechanisms and context-dependent regulation of sirtuin non-classical enzymatic functions in disease.Molecular medicine (Cambridge, Mass.) · 2026Review
- Versatile and sensitive detection of mono- and poly(ADP-ribosyl)ation reveals XRCC1-dependent remodelling of PARP1 signalling.Nature communications · 2026Article
- Article
- Rare longevity-associated variants, including a reduced-function mutation in cGAS, identified in multigenerational long-lived families.bioRxiv : the preprint server for biology · 2025Article
- SIRT6 in Cancer: Mechanistic Insights into Its Dual Roles in Cancer Biology and Implications for Precision Therapeutic Development.Biomolecules · 2025Review
- Sirt6 prevents the age-related decline of HProceedings of the National Academy of Sciences of the United States of America · 2025Article
- POLR3A mutations cause nucleolus abnormalities and aberrant telomerase RNA metabolism in induced pluripotent stem cells from Wiedemann-Rautenstrauch premature aging syndrome patient.Biogerontology · 2025Article
- Article
- Targeting DNA damage in ageing: towards supercharging DNA repair.Nature reviews. Drug discovery · 2025Review
- The DREAM complex links somatic mutation, lifespan, and disease.bioRxiv : the preprint server for biology · 2025Article
- Review
- Senotherapy for chronic lung disease.Pharmacological reviews · 2025Review
- Fucoidans are senotherapeutics that enhance SIRT6-dependent DNA repair.Research square · 2025Article
- Sirt6 deficiency promotes senescence and age-associated intervertebral disc degeneration in mice.Bone research · 2025Article
- Review
Corrections and comments
- Erratum issued
Authors and funding
32 authors at 7 institutions in 2 countries.
Matthew Simon *Department of Biology, University of Rochester, Rochester, NY, USA.ORCID 0000-0002-4395-0917
Jiping Yang *Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA.ORCID 0000-0001-6332-8693
Jonathan GigasDepartment of Biology, University of Rochester, Rochester, NY, USA.
Eric J EarleyBiostatistics and Epidemiology, RTI International, Durham, NC, USA.ORCID 0000-0001-6576-1319
Eric HillpotDepartment of Biology, University of Rochester, Rochester, NY, USA.
Lei ZhangDepartment of Biochemistry, Molecular Biology and Biophysics and Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.
Maria ZagorulyaDepartment of Biology, University of Rochester, Rochester, NY, USA.
Greg TomblineDepartment of Biology, University of Rochester, Rochester, NY, USA.
Michael GilbertDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Samantha L YuenDepartment of Biochemistry, Molecular Biology and Biophysics and Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.
Alexis PopeDepartment of Obstetrics and Gynecology, Columbia University, New York, NY, USA.
Michael Van MeterDepartment of Biology, University of Rochester, Rochester, NY, USA.
Stephan EmmrichDepartment of Biology, University of Rochester, Rochester, NY, USA.ORCID 0000-0002-0537-4242
Denis FirsanovDepartment of Biology, University of Rochester, Rochester, NY, USA.
Advait AthreyaDepartment of Biology, University of Rochester, Rochester, NY, USA.ORCID 0000-0001-7931-3568
Seyed Ali BiashadDepartment of Biology, University of Rochester, Rochester, NY, USA.ORCID 0000-0001-9591-7687
Jeehae HanDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
Seungjin RyuDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.ORCID 0000-0001-6353-8789
Archana TareDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
Yizhou ZhuDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.ORCID 0000-0002-0234-4603
Adam HudginsDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.ORCID 0000-0002-2737-6839
Gil AtzmonDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
Nir BarzilaiDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
Aaron WolfeIchor Therapeutics, Lafayette, NY, USA.ORCID 0000-0001-5287-8710
Kelsey MoodyIchor Therapeutics, Lafayette, NY, USA.
Benjamin A GarciaDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
David D ThomasDepartment of Biochemistry, Molecular Biology and Biophysics and Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.ORCID 0000-0002-8822-2040
Paul D RobbinsDepartment of Biochemistry, Molecular Biology and Biophysics and Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.
Jan VijgDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.ORCID 0000-0002-8457-9595
Andrei SeluanovDepartment of Biology, University of Rochester, Rochester, NY, USA.ORCID 0000-0003-3400-538X
Yousin SuhDepartment of Obstetrics and Gynecology, Columbia University, New York, NY, USA.ORCID 0000-0002-6014-3084
Vera GorbunovaDepartment of Biology, University of Rochester, Rochester, NY, USA.ORCID 0000-0001-8979-0333
University of Rochester · USAlbert Einstein College of Medicine · USUniversity of Minnesota · USColumbia University · USIo Therapeutics (United States) · USUniversity of Pennsylvania · USRTI International · US
Funding
THE IMPACT OF CELLULAR DEFENSE ON THE ROLE OF Ku80 IN GENOME MAINTENANCE AND LONGP01AG017242 · NIA · UNIVERSITY OF TEXAS HLTH SCI CTR SAN ANT · PI VIJG, JAN · 1999 to 2023
$46.1MThe role of hyaluronan in longevity and cancer resistance of longest-lived rodentP01AG047200 · NIA · UNIVERSITY OF ROCHESTER · PI Andrei Seluanov · 2014 to 2026
$36.9MSomatic Activation of Retrotransposition: A New Molecular Mechanism of Aging?P01AG051449 · NIA · BROWN UNIVERSITY · PI John M Sedivy · 2016 to 2026
$30.4MValidation and characterization of the identified variants associated with human longevity in mouse modelsU19AG056278 · NIA · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI NIR J BARZILAI, Paul D. Robbins · 2017 to 2026
$24.5MShared Resources Core 2: Quantitative Proteomics CoreP01CA196539 · NCI · ROCKEFELLER UNIVERSITY · PI MUIR, TOM · 2015 to 2024
$17.6MIdentifying protective omics profiles in centenarians and translating these into preventive and therapeutic strategiesUH3AG064704 · NIA · BOSTON UNIVERSITY MEDICAL CAMPUS · PI PERLS, THOMAS T, SEBASTIANI, PAOLA · 2022 to 2025
$14.7MData Analysis CoreU54AG076040 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI CHRISTIANO, ANGELA M, MENON, VILAS · 2021 to 2025
$13.1MEinstein's Nathan Shock Center of Excellence in Basic Biology of AgingP30AG038072 · NIA · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI HUFFMAN, DEREK MAJOR · 2010 to 2024
$10.8MIdentifying protective omics profiles in centenarians and translating these into preventive and therapeutic strategiesUH2AG064704 · NIA · BOSTON UNIVERSITY MEDICAL CAMPUS · PI PERLS, THOMAS T, SEBASTIANI, PAOLA · 2019 to 2021
$9.4MCombinatorial Actions of Genetic Variants and Gender Bias of Alzherimer's DiseaseR01AG057706 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GAGE, FRED H, GLASS, CHRISTOPHER K · 2017 to 2021
$8.1MResilience to Alzheimer's disease in humans with exceptional longevityR01AG057909 · NIA · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI BARZILAI, NIR J, ZHANG, ZHENGDONG · 2017 to 2021
$6.2MThe role of SIRT6 posttranslational modifications in aging and genome stability. Supplement: Testing SIRT6 activators as potential Alzheimer's disease therapy.R01AG027237 · NIA · UNIVERSITY OF ROCHESTER · PI Vera Gorbunova · 2006 to 2026
$6.2MNCI NIH HHS P01 CA196539NIAID NIH HHS R01 AI118891NIA NIH HHS P01 AG017242NIA NIH HHS P01 AG047200NIA NIH HHS P01 AG051449NIA NIH HHS P30 AG038072NIA NIH HHS R01 AG027237NIA NIH HHS R01 AG046320NIA NIH HHS R01 AG055501NIA NIH HHS R01 AG057433NIA NIH HHS R01 AG057706NIA NIH HHS R01 AG057909NIA NIH HHS R01 AG061521NIA NIH HHS R37 AG046320NIA NIH HHS RF1 AG057341NIA NIH HHS U19 AG056278NIA NIH HHS U54 AG076040NIA NIH HHS UH2 AG064704NIA NIH HHS UH2 AG064706NIA NIH HHS UH3 AG064704NIA NIH HHS UH3 AG064706
Abstract
Sirtuin 6 (SIRT6) is a deacylase and mono-ADP ribosyl transferase (mADPr) enzyme involved in multiple cellular pathways implicated in aging and metabolism regulation. Targeted sequencing of SIRT6 locus in a population of 450 Ashkenazi Jewish (AJ) centenarians and 550 AJ individuals without a family history of exceptional longevity identified enrichment of a SIRT6 allele containing two linked substitutions (N308K/A313S) in centenarians compared with AJ control individuals. Characterization of this SIRT6 allele (centSIRT6) demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double-strand break repair, and more robustly kill cancer cells compared with wild-type SIRT6. Surprisingly, centSIRT6 displayed weaker deacetylase activity, but stronger mADPr activity, over a range of NAD
Indexed as
Lamin Type ASirtuinsAged, 80 and overAllelesCentenariansGenomic InstabilityHumansLamin Type ASIRT6 protein, humanSirtuinscentenarianslaminlongevitySIRT6
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