SIRT6 is one of seven mammalian sirtuins — NAD+-dependent enzymes involved in DNA repair, chromatin regulation, metabolism and cellular stress responses. The SIRT6Activator evidence base now spans foundational molecular biology, animal longevity studies, natural and synthetic activator pharmacology, human aging-association studies, fucoidan research and direct clinical testing of synthetic SIRT6 activation. For supplement-specific translation, fucoidan remains the key clinical bridge: the 2026 peer-reviewed NUS PROMETHEUS protocol uses DoNotAge.org SIRT6Activator® at 2.4 g/day as one component of a multimodal precision-geromedicine program, while the randomized Project SIRT6 Activator trial (NCT07500649) is testing 2.4 g/day fucoidan against placebo. Separately, the synthetic SIRT6 activator forvisirvat (SP-624) has progressed through published Phase 1 human safety/pharmacokinetic studies and a 319-person Phase 2 depression trial. These drug studies establish direct human SIRT6-activator translation, but they do not prove anti-aging efficacy or validate fucoidan as equivalent to forvisirvat.
Large human oral-exposure study showing measurable post-ingestion fucoidan in urine. Useful for bioavailability plausibility, but the Cladosiphon okamuranus material differs structurally from Fucus-derived SIRT6Activator and the study did not measure SIRT6.
Peer-reviewed mechanistic Alzheimer-model study with neuronal/cell work and systemic pharmacological SIRT6 activation in APP/PS1 mice showing both pathology and cognition outcomes.
Peer-reviewed preclinical cancer study combining clinical-database associations with lung-cancer cell experiments and A549 xenografts.
Peer-reviewed preclinical oncology study spanning zebrafish genetics, cell models and mouse xenografts, including MDL-800 pharmacology.
Foundational cancer-mechanism study spanning cells, conditional mouse genetics and human tumor-expression data; not evidence that a SIRT6 activator prevents or treats human cancer.
Peer-reviewed mechanistic HCC study with cell, animal and human-tissue components defining a tumor-suppressive AMPK-mTOR-TFEB-autophagy pathway.
Important countervailing preclinical cancer evidence showing context-dependent pro-tumor effects after SIRT6 activation; directly relevant to safety framing.
Sourcedoi:10.1186/s12935-025-04125-xPMID 41530841PMC12809971
Peer-reviewed translational cancer study integrating human tumor datasets/specimens, cell systems and multiple mouse models to establish a context-specific oncogenic role for SIRT6.
Current peer-reviewed review focused specifically on the dual tumor-suppressive and tumor-promoting roles of SIRT6 and the need for context-specific therapeutic targeting.
Peer-reviewed cancer-genetics and mechanistic study characterizing naturally occurring patient-derived SIRT6 mutations and their effects on stability, catalytic activity and tumor-suppressive function.
Peer-reviewed cell and xenograft study directly testing the selective SIRT6 activator MDL-800 in two squamous-cell carcinoma models.
Comprehensive narrative review synthesising preclinical mechanism and translational data on the mammalian sirtuin family in cardiovascular physiology and pathology. Not a systematic review; not a primary human dataset.
Peer-reviewed mouse and macrophage mechanistic study identifying a SIRT6-TLR4 deacetylation pathway in atherosclerosis.
Peer-reviewed mechanistic cardiac study using mouse pressure-overload models, AAV cardiomyocyte targeting and cellular rescue experiments.
Peer-reviewed aged-mouse and cardiomyocyte study linking SIRT6 to mitochondrial fusion and cardiac aging.
Peer-reviewed mechanistic vascular study combining diabetic atherosclerosis models with endothelial-cell-specific Sirt6 loss and molecular analysis of ZEB1/claudin-1 barrier regulation.
Preclinical mechanistic study combining in vitro senescent cell screens with in vivo mouse work in naturally aged and progeroid models; findings remain preliminary as the paper is a Research Square preprint that has not undergone peer review.
Sourcedoi:10.21203/rs.3.rs-6613032/v1PMID 40502774PMC12155233
Landmark preclinical genetic knockout study establishing the mammalian SIRT6 phenotype in cells and mice; foundational loss-of-function evidence with no human data.
Mechanistic cell-based study across human fibroblasts, osteosarcoma cells, and mouse embryonic fibroblasts with in vitro biochemistry. Translational relevance to Werner syndrome premature ageing, but no direct human clinical evidence.
Cross-species comparative biology with cell-based DNA repair assays, biochemical characterisation of SIRT6 mutants, and Drosophila lifespan validation. Preclinical scope only, but strong causal inference through amino acid swap experiments.
Preclinical mechanistic study using human U2OS and HeLa cell lines with purified recombinant SIRT6 protein. Combines live imaging of GFP-tagged proteins after UV laser-induced damage, in vitro DNA-binding assays, LacO tethering assays, and site-directed mutagenesis of the predicted DNA-binding tunnel. Foundational mechanism paper — first to demonstrate direct DNA-binding by any sirtuin — but entirely cell-culture and biochemical, no human or animal data.
Preclinical mechanistic study combining human diploid fibroblast reporter assays for DNA repair, phospho-specific antibody validation, in vitro kinase reactions, and confocal laser irradiation microscopy in U2OS cells and mouse embryonic fibroblasts. Establishes the JNK-SIRT6-PARP1 signalling axis with strong biochemical and cellular evidence. No in vivo animal or human clinical data.
Sourcedoi:10.1016/j.celrep.2016.08.006PMID 27568560PMC5089070
Peer-reviewed human-cell aging study using fibroblasts from 19 donors and mechanistic SIRT6/PARP1 experiments to connect SIRT6 decline with reduced base-excision repair.
Foundational mechanistic study connecting SIRT6 to LINE1 repression and age-related loss of retrotransposon silencing.
Peer-reviewed aging study using aged mice, intestinal epithelial-specific Sirt6 deletion and three-dimensional intestinal organoids with mechanistic rescue experiments.
Preclinical multi-omic study in transgenic SIRT6-overexpressing mice and AAV-mediated hepatic SIRT6 overexpression in aged wild-type mice, using ATAC-seq, whole-genome methylation, RNA-seq and ChIP-seq to assess reversal of age-associated chromatin changes.
Sourcedoi:10.1038/s41467-026-73115-yPMID 42135312PMC13376905
Direct randomized placebo-controlled human Phase 1 evidence for an orally active synthetic SIRT6 activator. It establishes early safety/PK, not anti-aging efficacy.
Large randomized double-blind placebo-controlled Phase 2 human study of a direct oral SIRT6 activator. The primary depression efficacy endpoint was negative overall.
Sourcedoi:10.1080/03007995.2025.2574465PMID 41099447 Trial registry
Human cross-sectional molecular-aging study directly measuring SIRT6-related expression and epigenetic regulators in healthy young, middle-aged and long-lived adults.
Sourcedoi:10.1080/15592294.2020.1780081PMID 32573339PMC7678931
Human cross-sectional biomarker study in healthy adults directly measuring serum SIRT6 and telomerase; useful association evidence but not proof of causality.
Large human cross-sectional study linking serum SIRT6 with frailty phenotype; clinically relevant association but not evidence that SIRT6 activation prevents or reverses frailty.
Peer-reviewed human clinical-trial protocol with named SIRT6Activator exposure and extensive phenotyping, but it is a single-arm multimodal study and this paper reports the design rather than efficacy results.
Sourcedoi:10.1007/s11357-026-02394-6PMID 42393428 Trial registry
Double-blind randomized placebo-controlled human trial using Fucus vesiculosus extract containing 85% fucoidan. Highly relevant to same-species human tolerability, but it did not test SIRT6 activation and did not outperform placebo on the primary osteoarthritis symptom outcome.
Randomized double-blind placebo-controlled human pilot showing repeated high-dose fucoidan exposure and selected immune effects. It used Cladosiphon fucoidan, so it cannot be treated as direct SIRT6Activator evidence.
Randomized double-blind placebo-controlled human trial in older adults providing useful immune-response and tolerability evidence for orally administered seaweed fucoidan, but not a direct SIRT6 study.
Foundational mechanistic SIRT6 study linking H3K9 deacetylation at NF-kappaB target genes to inflammatory gene regulation and the premature-aging phenotype of SIRT6 deficiency; preclinical rather than human intervention evidence.
Peer-reviewed mechanistic asthma study using myeloid-specific Sirt6 deletion and pharmacological inhibition, providing strong evidence that SIRT6 can be pro-inflammatory in a cell-specific context.
Mechanistic mouse aging study showing an inflammatory pathway downstream of LINE1 derepression; highly relevant to inflammaging but not human intervention evidence.
Peer-reviewed mechanistic cell and animal study using both SIRT6 activation and inhibition to test causality in the LINE1-cGAS-STING pathway.
Preclinical whole-organism intervention study across two independent transgenic mouse lines. Direct lifespan endpoint in mammals, but not human evidence.
Peer-reviewed comparative and mechanistic study spanning mammalian species, biochemical analyses and human fibroblast mutagenesis; strong mechanistic longevity evidence but not an intervention trial.
Preclinical mouse genetics study directly testing SIRT6 Ser10 phosphorylation, DNA repair, LINE1 repression and lifespan. Mechanistically important but not peer reviewed as of the audit date and not a human intervention.
Peer-reviewed mouse aging and lifespan study with hepatocyte-specific SIRT6 loss in both sexes plus pharmacological rescue with MDL-800 in aged female mice.
Preclinical mouse mechanism study with supporting cell-culture experiments. Establishes a novel one-carbon/transsulfuration mechanism for SIRT6-mediated healthy longevity in aged livers, but the entire dataset is animal and in vitro — no human evidence.
Randomized double-blind placebo-controlled human trial with inflammatory, metabolic and microbiome outcomes. Relevant to human fucoidan physiology, but the source/formulation was not the DoNotAge SIRT6Activator product and SIRT6 was not measured.
Foundational mechanistic metabolic study in cells and SIRT6-deficient mice; highly relevant to glucose biology but not direct human intervention evidence.
Recent mechanistic SIRT6-activator study with hepatocyte and mouse steatosis experiments plus contextual human NAFLD transcriptomic analysis; not a human treatment trial.
Peer-reviewed cell-type-specific obesity study with mouse genetics, adoptive transfer, single-cell RNA sequencing and human obesity-associated expression observations.
Peer-reviewed mechanistic hepatocyte study directly testing SIRT6 activation and inhibition in sterol-dependent cholesterol feedback regulation.
Mechanistic skeletal-muscle study in a muscle-specific SIRT6 knockout model; directly relevant to exercise/metabolism but preclinical.
Strong mechanistic exercise/muscle study with human exercise-associated expression data plus mouse genetic and activator experiments; intervention efficacy remains preclinical.
Small randomized double-blind placebo-controlled human exercise trial using a defined Undaria pinnatifida/Fucus vesiculosus fucoidan blend. Directly useful for muscle/functional human translation, though sample size is very small and it does not test SIRT6.
Sourcedoi:10.1038/s41598-025-24066-9PMID 41249370PMC12624114 Trial registry
Biochemical and cell-based screening study of natural flavonoids as SIRT6 modulators; important for natural-activator claims but not human supplementation evidence.
Mechanistic preclinical study combining brain-specific conditional knockout mouse, cellular CRISPR and shRNA models, and human Alzheimer's disease tissue analysis; published in a peer-reviewed journal.
Sourcedoi:10.1016/j.celrep.2017.03.008PMID 28355558PMC5389893
Preclinical multi-omics study in brain-specific SIRT6-knockout mice with functional validation in human neuroblastoma cells and cross-reference against published human brain aging and neurodegenerative disease datasets. Strong mechanistic depth, but the human comparison is transcriptomic overlap rather than clinical intervention.
Current peer-reviewed review of sirtuin isoforms and small-molecule modulation in Alzheimer disease; useful contextual evidence but not SIRT6-specific clinical efficacy proof.
Peer-reviewed rat pharmacology study using two SIRT6 activators and pathway inhibition to test a SIRT6-Nrf2-NLRP3 mechanism in neuropathic pain.
Narrative review synthesising preclinical mechanistic and animal-model data on SIRT6's roles in the retina and retinal pigment epithelium, including SIRT6's regulation of glucose metabolism, oxidative stress defence, autophagy and epigenetic state in ocular tissues.
Sourcedoi:10.3389/fcell.2023.1244765PMID 38016059PMC10646311
Peer-reviewed pharmacology study using MDL-800, SIRT6 knockdown, cell fibrosis/inflammation systems and a bleomycin mouse model with lung-function and survival endpoints.
Peer-reviewed mechanistic study integrating human and mouse single-cell lung data with macrophage senescence and fibrosis experiments, showing a context in which SIRT6-mediated deacetylation contributes to pathology.
Peer-reviewed translational study combining human DKD spatial profiling with cell-specific genetic and pharmacological SIRT6 experiments in mice.
Current peer-reviewed review synthesizing SIRT6 biology across acute kidney injury, diabetic kidney disease, hypertensive nephropathy, renal fibrosis and renal-cell carcinoma, with emphasis on cell-type specificity and therapeutic modulators.
Peer-reviewed mechanistic study identifying lamin A as an endogenous SIRT6 activator and linking that activation to DNA-damage recruitment and repair signaling.
Peer-reviewed structural/biochemical study combining molecular-dynamics simulations with purified-enzyme assays to define N-terminal-domain control of SIRT6 catalysis.
Landmark biochemical and structural drug-discovery study identifying the first synthetic SIRT6 activators and their binding pocket.
Landmark preclinical pharmacology paper identifying MDL-800 as a selective cellular SIRT6 allosteric activator.
Current medicinal-chemistry and preclinical pharmacology paper defining forvisirvat's discovery, selectivity, binding site, brain penetration and antidepressant-like activity.
Current biochemical medicinal-chemistry work extending the griseofulvin/forvisirvat SIRT6 activator scaffold; no in-vivo human outcomes.
Sourcedoi:10.1021/acsmedchemlett.5c00690PMID 41847663PMC12989997
Current peer-reviewed review synthesizing the medicinal chemistry, structure-activity relationships, activators, inhibitors and translational challenges of SIRT6 modulation; valuable for current pharmacology framing but not primary efficacy evidence.
Peer-reviewed biochemical and computational study directly testing ursolic-acid binding, kinetics and structural effects on purified human SIRT6; mechanistically useful but not cellular, animal or clinical efficacy evidence.
Small single-blind human pilot directly relevant to the frequently cited anticoagulant concern with oral fucoidan. It found strong in-vitro anticoagulant activity but no obvious clinically important oral anticoagulant effect with the formulation and duration tested.
Preclinical whole-organism study in two mouse cohorts (male and female inbred C57BL/6JOlaHsd) with lifespan endpoint, in vivo multi-omics, and 13C isotope tracing. Robust mechanism, but no human data.
Mechanistic in vitro and cell-culture study establishing SIRT6–PARP1 interaction and identifying PARP1 K521 as the mono-ADP-ribosylation site. Foundational mechanism, no whole-organism efficacy data.
Ex vivo human primary chondrocyte study across three age groups with pharmacological SIRT6 modulation, complemented by aged murine chondrocyte data. Human tissue is authentic but not a randomised human trial; results are chondrocyte-level, not clinical.
Preclinical whole-organism study with lifespan and frailty endpoints in inbred male and female C57BL/6JN mice, supported by in vitro biochemistry and multi-omics tissue analysis. Not peer-reviewed at time of population.
Comprehensive narrative review of SIRT6 in vitro biochemistry, mammalian cell biology, and murine genetic models. No systematic-review methodology and no human clinical trial data available at time of writing, but the field's foundational synthesis for the SIRT6 mechanism-to-lifespan story.
Human genetic association study combined with extensive in vitro biochemistry and human cell-line characterisation of the centenarian SIRT6 variant; the genetic enrichment was not statistically significant due to cohort size, and there is no human clinical or lifespan outcome data.
Comprehensive narrative review synthesising mouse knockout, mouse overexpression, primate, cell-biological, and biochemical evidence on SIRT6, with limited human observational data (polymorphism association studies) and no human clinical trial data.
Comprehensive narrative review synthesising in vitro, animal, and clinical evidence on SIRT6's three enzymatic activities and their roles across ageing, immunity, and cancer. Not primary data, but the reference synthesis for SIRT6's context-dependent (dual) role in cancer across 12+ tumour types.
Human case-control genetic association study, single site, moderate sample size (503 total). Reported longevity association at the allele-frequency level but the adjusted multinomial logistic regression found no independent effect of the SIRT6 rs350846 genotype after controlling for BMI, blood pressure, and HDL cholesterol. Best treated as hypothesis-generating for the SIRT6-human-longevity link, not confirmatory.
SourcePMID 28032059PMC5182250
Comprehensive narrative review synthesising the SIRT6 literature two years after the founding Mostoslavsky 2006 knockout paper. Not primary data. The framing citation for how the field integrated DNA repair, metabolism, and ageing under a single SIRT6 umbrella — cited repeatedly by every subsequent SIRT6 review through 2025.
Sourcedoi:10.1111/j.1365-2796.2007.01902.xPMID 18226091PMC2486832
Comprehensive open-access narrative review synthesising the SIRT6 mechanism and disease literature. Not primary data. Notable as the most recent (October 2025) broad synthesis published in a well-cited pharmacology journal, and useful for its dedicated section on small-molecule SIRT6 activators and inhibitors currently in preclinical and early clinical development.
Preclinical in vitro biochemistry paper. Systematic screen of five brown macroalgae extracts for SIRT6 modulator activity, followed by mass-spectrometry identification of the active compound and dose-response characterisation on purified SIRT6. Foundational — established fucoidan as a natural SIRT6 activator — but entirely in vitro, no cellular or animal validation in this paper. Cellular and animal follow-ups came in later work by other groups.
In vitro proteomics and cell-culture mechanistic study using HEK293 and CEMT human cell lines. Defines the SIRT6 interactome and phosphorylation landscape but does not test physiological, animal, or clinical outcomes.
Comprehensive narrative review synthesising in vitro biochemistry, structural biology, cellular studies in mouse and human cell lines, and murine genetic models across all published SIRT6 literature through mid-2020. The field's most cited mechanistic reference for SIRT6 catalysis and small-molecule modulator development. Not a systematic review and not primary data.
Purely in silico molecular dynamics simulation study. Provides high-resolution mechanistic insight into SIRT6-substrate-activator interactions but does not include any in vitro biochemistry, cellular experiments, or animal data.
Preclinical mechanistic study combining in vitro biochemistry, isoform-specific activity assays, and X-ray crystallography of SIRT6/quercetin and SIRT2/quercetin complexes. No human data.
Preclinical mechanistic study combining activity-based small-molecule screening, structure-activity chemistry, steady-state and pre-steady-state kinetics, and mutagenesis of recombinant SIRT6. No human data.
Narrative review synthesising preclinical mechanistic and cell biology evidence for SIRT6 function across four domains (heterochromatin, stem cells, cancer, metabolism). Not primary data.
Preclinical structural and biochemical study combining X-ray crystallography of three SIRT6 complexes with quantitative deacetylation kinetics and ligand binding measurements. No cellular or in vivo data.
Preclinical in vitro enzymology characterising Sirtuin deacylation across a panel of 13 acyl-lysine modifications and demonstrating direct SIRT6 activation by biologically relevant free fatty acids. No cellular or in vivo data.
Preclinical multi-omics study in two human melanoma cell lines with CRISPR/Cas9 or shRNA-mediated SIRT6 knockdown. Bulk RNA-seq and label-free proteomics with Ingenuity Pathway Analysis. No animal or human clinical data.
Preclinical in vitro study across multiple human tumour cell lines using the synthetic SIRT6 activator UBCS039, with catalytic-dead SIRT6 H133Y control and antioxidant and autophagy-inhibitor rescue experiments. No animal or human data.
Preclinical mechanistic study combining bioinformatics, in vitro cell biology, biochemical interaction mapping, and mouse subcutaneous xenograft validation. Human colorectal cancer tissues used only for expression correlation, not clinical outcome data.
Peer-reviewed translational preclinical study using UVA-exposed human dermal fibroblasts plus UV-irradiated mouse skin with SIRT6 activator and inhibitor experiments.
