Tier 3 — preclinical

SIRT6 activator fucoidan extends healthspan and lifespan in aged wild-type mice

Biashad SA, Hillpot E, Morandini F, Rechsteiner C, Paige V, Tombline G, Lee M, Zheng Z, Liang Y, Martinez J, Sieczkiewicz N, Zhang Z, Volobaev V, Firsanov D, Simon M, Zhang LJ, Robbins PD, Seluanov A, Gorbunova V

bioRxiv (preprint) 2025 Preprint identifier 2025.03.24.645072 (posted 26 March 2025)

Bibliography

DOI: 10.1101/2025.03.24.645072
PubMed: PMID
Funding: Grants from the US National Institute on Aging to A.S. and V.G.
Competing interests: P.D.R. is a cofounder of Itasca Therapeutics. V.G. is a member of Scientific Advisory Boards of GenFlow Bio, DoNotAge, Elysium, Matrix Bio, Faunsome, BellSant, and WndrHlth.

Study snapshot

Design	Interventional in vivo dietary supplementation study in aged wild-type C57BL/6JN mice, with lifespan, frailty, epigenetic-age, plasma cytokine, and multi-omics (RNA-seq, ATAC-seq, MeDIP-seq) endpoints. Complemented by in vitro SIRT6 mono-ADP-ribosylation and deacetylation activity assays with recombinant SIRT6 and multiple fucoidan sources.
Model	Aged C57BL/6JN mice from the NIA colony, treatment initiated at 15 months of age. Additional cohorts: SIRT6-knockout mice (JAX 006050) for causality testing; paraquat oxidative-stress challenge cohort; 1-month tissue-collection cohort. In vitro biochemistry with recombinant human SIRT6 and fucoidan extracts from Fucus vesiculosus, Undaria pinnatifida, Cladosiphon okamuranus, and Macrocystis pyrifera.
Sample	Aging cohort: 44 fucoidan-treated (22 male + 22 female) and 36 control mice. Tissue-collection cohort: 20 mice (5 per sex per diet). Paraquat challenge: 24 mice (6 per group). SIRT6-KO cohort: variable, followed to natural death of pups. In vitro assays: n=3 independent experiments each.
Intervention	Fucoidan (DoNotAge.org-supplied Fucus vesiculosus fucoidan) administered as ~50 mg/day in drinking water plus ~203–253 mg/day mixed into chow, for a total average of ~278 mg/mouse/day. Control diet was matched chow and water without fucoidan. Paraquat oxidative-stress challenge given as 50 mg/kg IP (LD75/15) after 1 month on diet.
Duration	Dietary intervention from 15 months of age through natural death (for lifespan cohort) or 1 month (for tissue-collection cohort). Frailty scored monthly from 19 to 25 months of age. Blood samples collected at 22 and 26 months.
Endpoints	Median and maximum lifespan (both sexes); Frailty score (Whitehead 33-item mouse frailty index) monthly from 19 to 25 months; Blood DNA methylation age (UniversalClock3Blood epigenetic clock); Body mass over time; Plasma cytokine panel (36-plex Luminex); Blood RNA-seq and immune cell composition (mMCP-counter deconvolution); Liver and lung RNA-seq, ATAC-seq, and MeDIP-seq; LINE1 element expression, chromatin accessibility, and methylation state; Tissue H3K9ac levels (surrogate for in vivo SIRT6 deacetylase activity); In vitro SIRT6 mono-ADP-ribosylation and H3K9 deacetylation activities; LINE1 and p21 (CDKN1A) mRNA induction after paraquat oxidative stress; SIRT6-knockout pup lifespan on fucoidan vs control diet

What the study showed, in plain terms

This preprint reports the first direct test of whether oral fucoidan extends lifespan in aged mammals, and whether the benefit depends on SIRT6. Fucoidan is a sulphated polysaccharide from brown seaweed that had previously been shown to activate SIRT6's deacetylation activity in cell-free assays. The team asked two new questions: does fucoidan also activate SIRT6's other catalytic activity — mono-ADP-ribosylation, which is the specific activity elevated in certain human centenarians — and does dietary fucoidan produce measurable longevity or healthspan benefits when started in middle age.

The biochemical answer is yes. Highly purified fucoidan from Fucus vesiculosus was the only tested compound (out of a panel including quercetin, cyanidin, resveratrol, MDL-800, and MDL-801) that increased SIRT6 mono-ADP-ribosylation activity. Fucoidan extracts from Undaria pinnatifida and Cladosiphon okamuranus (mekabu and mozuku seaweeds) also activated the enzyme, though the effect depended on the species and purity — not every brown-algae fucoidan worked. L-fucose, the monosaccharide subunit, had little effect on its own.

The in vivo answer is nuanced and sex-dependent. Starting fucoidan supplementation at 15 months of age (roughly middle-aged mouse) extended median male lifespan by 13% and reduced frailty in both sexes. Female median lifespan increased 3% but the effect did not reach statistical significance. Blood epigenetic-clock age was lower in both sexes at 26 months.

The mechanism the paper connects to fucoidan and SIRT6 is repression of LINE1 transposable elements — mobile DNA sequences that reactivate during ageing and drive chronic inflammation. Fucoidan-treated mouse lungs showed reduced LINE1 expression, reduced chromatin accessibility at LINE1 loci, and increased DNA methylation. Under oxidative stress from paraquat, control-diet mice showed massive LINE1 activation in the lung; fucoidan-treated mice were largely protected. Fucoidan failed to extend lifespan in SIRT6-knockout mice, consistent with the mechanism being SIRT6-mediated.

Key findings

Fucoidan (Fucus vesiculosus, purified) is the only compound in a screen of prior SIRT6 activator candidates (including MDL-800, MDL-801, quercetin, cyanidin, resveratrol, and gal-gal) that stimulated SIRT6 mono-ADP-ribosylation activity in vitro (~4-fold, p = 0.005). Most other tested activators inhibited mono-ADP-ribosylation.
Fucoidan activated SIRT6 mono-ADP-ribosylation with a dose-response saturating around 0.2–0.5 mg/mL. Fucoidan from Undaria pinnatifida and Cladosiphon okamuranus, and DoNotAge-supplied nutritional-grade Fucus vesiculosus fucoidan, all activated the enzyme; a crude Fucus vesiculosus preparation and M. pyrifera fucoidan did not, indicating structural or purity dependence.
L-fucose (the monomeric subunit) had a mild effect on deacetylation and no significant effect on mono-ADP-ribosylation.
Dietary fucoidan (~278 mg/day, started at 15 months of age) extended median male mouse lifespan by 13% (Gehan-Breslow p = 0.009). Female median lifespan increased 3% (p = 0.12, not significant).
Blood UniversalClock3Blood methylation age was lower in fucoidan-treated mice of both sexes at 26 months (Mann-Whitney p = 0.037).
Body mass did not differ between groups, excluding caloric-restriction as the mechanism.
Frailty scores rose more slowly in fucoidan-treated mice of both sexes (linear mixed model p = 0.046 males, p = 0.006 females) across 19–25 months. Improvement was distributed across nearly all major body systems.
SIRT6-knockout mice on fucoidan showed no lifespan benefit (Gehan-Breslow p = 0.87), and fucoidan-treated tissues showed reduced H3K9 acetylation (a SIRT6 deacetylase substrate) in the lungs of males and a downward trend in female lung and liver — supporting SIRT6-mediated mechanism.
Male blood RNA-seq at 22 months showed 2272 downregulated and 926 upregulated genes on fucoidan. Upregulated pathways: RNA modification, B and T cell differentiation, DNA repair, telomere maintenance, histone modification, chromatin organisation. Downregulated: blood coagulation, myeloid differentiation, translation, oxidative stress response, interferon response, and "aging".
Deconvolution of male blood showed higher B and T cell fraction (both p = 0.024) on fucoidan, consistent with reversal of the age-related myeloid bias.
Plasma cytokine panel showed reduced TNFα, IFNα/γ, Ccl2, IL-1β, IL-3, IL-6 in fucoidan-treated males; the opposite trend (mild cytokine elevation) in females, suggesting a sex-dimorphic short-term inflammatory response.
Fucoidan vs Sirt6 overexpression in male liver showed a positive correlation of transcriptional effects (R = 0.35, p < 2.2e−16). Both interventions downregulated acute-phase response genes (Saa1, Saa2, Orm2).
Male lung RNA-seq showed 194 LINE1 families downregulated versus 1 upregulated after fucoidan (binomial p = 8e−57). ATAC-seq and MeDIP-seq confirmed reduced accessibility (p = 3e−34) and increased methylation (p = 2e−42) at LINE1 loci in male lung. Same pattern in female lung.
Paraquat oxidative stress caused massive LINE1 (L1MdA) upregulation in the lungs of control-diet mice; fucoidan pre-treatment significantly reduced this induction (p = 0.014 males, p = 0.022 females). CDKN1A (p21) mRNA induction after paraquat was also reduced by fucoidan pre-treatment.

What this study can and cannot tell us

This is a bioRxiv preprint that has not been peer-reviewed as of population date. Findings are provisional; specific numbers, effect sizes, and interpretations may change in the peer-reviewed version. Reader should treat conclusions as preliminary. The preprint states the manuscript has been submitted to Nature Aging.

Fucoidan is not a defined chemical entity. It is a family of sulphated polysaccharides that vary in composition (fucose/galactose ratio, sulphation pattern, molecular weight, branching) across seaweed species and extraction methods. The paper explicitly shows that different fucoidan sources do not have equivalent SIRT6-activating activity. This limits what "take fucoidan" means as a health recommendation — sourcing and standardisation are decisive.

The male-vs-female discrepancy is substantial. Median lifespan extended 13% in males (significant) versus 3% in females (not significant). Blood transcriptional response was much stronger in males. Female tissues showed some evidence of a mild inflammatory response to short-term fucoidan. The paper attributes the sex difference partly to the anti-inflammatory effect being more pronounced in male liver — but this is speculative and a full mechanism is not established.

The mouse dose of ~278 mg/day for a ~30 g mouse translates to a body-weight equivalent of roughly 9.3 g/kg/day, which is orders of magnitude higher than typical human supplement doses (100–1000 mg/day for a 70 kg adult, or ~1.4–14 mg/kg/day). Direct dose translation is not established; the paper does not attempt human dose modelling.

SIRT6-KO rescue experiments (fucoidan showing no lifespan benefit in SIRT6-KO pups) provide the strongest evidence for SIRT6-mediated mechanism, but as a natural polysaccharide, fucoidan may still have other cellular targets beyond SIRT6 that contribute to the observed effects. The paper acknowledges this explicitly.

Senior author V. Gorbunova is a member of the DoNotAge Scientific Advisory Board and the fucoidan tested in the in vivo cohort was DoNotAge-supplied. This is disclosed but creates a direct commercial relationship between the paper's positive finding and the commercial product.