Tier 3 — preclinical

Fucoidans are senotherapeutics that enhance SIRT6-dependent DNA repair

Robbins PD, Zhang L, Elsallabi O, Soto-Palma C, Bartz J, Salekeen R, Nunes A, Xu W, Lee K, Hughes B, Zhang B, Mohamed A, McGowan SJ, Angelini L, O'Kelly R, Biashad SA, Hillpot E, Morandini F, Seluanov A, Gorbunova V, Dong X, Niedernhofer LJ

Research Square (preprint, not peer-reviewed) 2025 Preprint, rs.3.rs-6613032/v1

Bibliography

DOI: 10.21203/rs.3.rs-6613032/v1
PubMed: PMID 40502774
PubMed Central: PMC12155233
Funding: Funding for this research was provided by NIH grants R01 AG069819 (PDR), P01 AG043376 (PDR, LJN), U19 AG056278 (PDR, LJN, VG), RO1 AG063543 (LJN), P01 AG062413 (LJN, PDR), U54 AG079754 (LJN, PDR), U54 AG076041 (LJN, PDR) and T32AG029796 (CSP). P01 AG047200 (AS, VG), P01 AG051449 (AS, VG), R01 AG027237 (VG), R37 AG046320 (AS).
Competing interests: LJN and PDR are co-founders of Itasca Therapeutics and LJZ, LJN, and PDR have filed multiple patents on senotherapeutics. VG is a member of Scientific Advisory Boards of GenFlow Bio, DoNotAge, Elysium, Matrix Bio, Faunsome, BellSant, and WndrHlth.

Study snapshot

Design	Preclinical mechanistic study: phenotypic senescent cell library screen (12 fucoidan variants), in vivo dosing in two mouse aging models, bulk RNA-seq of treated senescent cells, and SIRT6-dependent mechanism validation via siRNA knockdown and knockout MEFs.
Model	In vitro: Ercc1-/- and wild-type mouse embryonic fibroblasts, human IMR90 fibroblasts, human umbilical vein endothelial cells (HUVECs), HCA2 human fibroblast NHEJ-GFP reporter cells, SIRT6+/+ and SIRT6-/- MEF NHEJ reporter cells. In vivo: 32-month-old female wild-type C57BL/6 mice (naturally aged) and Ercc1-/Δ progeroid mice (male and female).
Sample	Naturally aged mice: n=6 per group (vehicle, Fucoidan-FV, Fucoidan-MP). Ercc1-/Δ progeroid mice: n=8 per group. In vitro experiments: n=2-3 biological replicates depending on assay.
Intervention	Fucoidan-FV (Fucus vesiculosus, Sigma F8190): 1 g/kg/day oral gavage (naturally aged mice) or 0.5% in chow ad libitum (progeroid mice). Fucoidan-MP (Macrocystis pyrifera, Sigma F8065): 500 mg/kg/day oral gavage in naturally aged mice.
Duration	Naturally aged mice: 5 consecutive daily doses, tissues collected 2 days after last dose. Progeroid mice: 6 weeks continuous dietary exposure starting at 10 weeks of age.
Endpoints	SA-β-gal (C12FDG) positive cell reduction and selectivity index vs non-senescent cells; Tissue mRNA expression of senescence markers (p16, p21) and SASP factors (Tnfa, Il6, Il1b, Mcp1, Cxcl1) by RT-qPCR; Composite aging symptom score (progeroid mice: tremor, kyphosis, dystonia, ataxia, gait, hindlimb paralysis, grip strength); p21+ γδ T cell frequency in spleen; SIRT6 deacetylation activity (fluorometric assay) and mono-ADP-ribosylation activity (fluorescein-NAD+ gel assay); NHEJ-mediated DNA repair efficiency (GFP reporter after I-SceI-induced double-strand breaks); γH2AX foci as marker of DNA damage; Transcriptomic changes by bulk RNA-seq (DEGs, GSEA, interaction network analysis)

What the study showed, in plain terms

Cells that have stopped dividing but refuse to die — called senescent cells — accumulate in tissues as we age. They pump out inflammatory signals that damage nearby healthy tissue and drive age-related conditions like arthritis, kidney decline, and cardiovascular disease. Compounds that either selectively kill these cells (senolytics) or quiet their inflammatory output (senomorphics) are among the most actively pursued anti-aging interventions.

This study screened a library of fucoidans — sulphated sugar chains extracted from brown seaweed — to see whether any behaved as senotherapeutics. One in particular, fucoidan from the seaweed Fucus vesiculosus (called Fucoidan-FV), stood out. In cell culture it reduced senescence markers without killing cells. In 32-month-old naturally aged mice given oral doses for five days, it lowered senescence and inflammatory markers in the kidney and lung. In progeroid mice — a strain that ages roughly six times faster than normal — six weeks of Fucoidan-FV in chow reduced age-related symptoms and tissue senescence.

The mechanism appears to run through SIRT6, an enzyme that helps repair DNA damage and regulates inflammation. Fucoidan-FV boosted two of SIRT6's enzymatic activities, particularly its mono-ADP-ribosylation function, and improved non-homologous end joining — a key pathway for repairing DNA double-strand breaks. Crucially, when the researchers knocked out SIRT6, most of fucoidan's benefit disappeared, confirming that its senotherapeutic effect runs at least partly through SIRT6 activation. A second fucoidan variant from Macrocystis pyrifera instead acted as a senolytic, killing senescent cells rather than quieting them — showing that fucoidans from different seaweed species can have distinct biological effects.

Key findings

Of 12 fucoidan variants screened, Fucoidan-FV (from Fucus vesiculosus) had the strongest senomorphic activity with EC50 of 55.89 μg/mL in senescent Ercc1-/- MEFs and selectivity index >16.1 versus non-senescent cells.
Fucoidan-MP (from Macrocystis pyrifera) had a distinct senolytic profile with EC50 5.087 μg/mL and selectivity index >176.9, selectively killing senescent cells rather than quieting them.
In 32-month-old naturally aged wild-type mice, Fucoidan-FV (1 g/kg/day oral gavage × 5 days) significantly reduced kidney mRNA expression of p16, p21, Tnfa, Il6, Il1b, Mcp1, and Cxcl1, and reduced p21+ senescent γδ T cells in spleen.
In Ercc1-/Δ progeroid mice, six weeks of Fucoidan-FV (0.5% in chow) significantly reduced composite aging symptom scores at weeks 11-12 and reduced senescence and SASP marker expression across kidney, lung, quadriceps, liver, and brain tissue.
Fucoidan-FV increased SIRT6 deacetylation activity and, to a greater extent, SIRT6 mono-ADP-ribosylation activity in cell-free assays.
Fucoidan-FV increased NHEJ-mediated DNA repair efficiency in a dose-dependent manner, up to approximately 270% of baseline at 900 μg/mL in human fibroblast NHEJ reporter cells.
The DNA repair enhancement was abolished by SIRT6 siRNA knockdown, and Fucoidan-FV failed to reduce γH2AX foci in SIRT6 knockout MEFs — confirming SIRT6-dependence of the DNA repair effect.
The senomorphic effect of Fucoidan-FV was significantly diminished (though not fully abolished) in SIRT6 knockout senescent MEFs, indicating the senomorphic activity is partly SIRT6-dependent.
Bulk RNA-seq of Fucoidan-FV-treated senescent MEFs showed downregulation of SASP factors and Wnt signalling and ECM remodelling pathways, alongside upregulation of DNA repair genes (ERCC1, RPA1, RFC5, MCM6, AURKA, PLK3) and cell cycle progression pathways.

What this study can and cannot tell us

This is a Research Square preprint that has not undergone peer review. The Research Square banner explicitly states findings should not be considered conclusive or used to inform clinical practice until peer-reviewed publication.
All in vivo evidence comes from mice (naturally aged C57BL/6 and Ercc1-/Δ progeroid). No human clinical data are presented, and the accelerated aging model does not fully recapitulate normal human aging.
The naturally aged mouse dosing regimen was short (5 daily doses); long-term safety and efficacy of chronic administration in aged wild-type mice are addressed in the accompanying Biashad et al preprint rather than in this paper.
The molecular mechanism by which fucoidan — a large sulphated polysaccharide unlikely to enter cell nuclei — activates nuclear SIRT6 remains unresolved. The authors speculate that gut microbial metabolites or breakdown products may be the active species, but these putative active fragments have not been identified.
SIRT6-dependent effects were only partial, particularly at high fucoidan concentrations, indicating additional unidentified mechanisms contribute. Fucoidan is known to bind TLR4 among other targets.
Fucoidan preparations vary substantially in molecular weight, sulphation degree, and sugar composition depending on seaweed species, geography, harvest season, and extraction method. Effects observed with one Sigma-Aldrich Fucus vesiculosus preparation may not generalise to other commercial fucoidan products, including branded supplements sold to consumers.
Senior author Vera Gorbunova serves on the Scientific Advisory Board of DoNotAge (among other longevity supplement companies). Two other authors are co-founders of Itasca Therapeutics and hold senotherapeutic patents. These competing interests are disclosed in the paper's declaration of interests and are relevant when interpreting any commercial application of these findings.