SIRT6 activator fucoidan extends healthspan and lifespan in aged wild-type mice
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Abstract
SIRT6 is a protein deacylase, deacetylase, and mono-ADP-ribosylase (mADPr) regulating biological pathways important for longevity including DNA repair and silencing of LINE1 retrotransposons. SIRT6 knockout mice die by 30 days of age, whereas SIRT6 overexpression increases lifespan in male mice. Finding safe pharmacological activators of SIRT6 would have clinical benefits. Fucoidan, a polysaccharide purified from brown seaweed, has been identified as an activator of SIRT6 deacetylation activity. Here, we show that fucoidan also activates SIRT6 mADPr activity, which was shown to be elevated in certain human centenarians. Administering fucoidan to aged mice led to a significant increase in median lifespan in male mice. Both male and female mice demonstrated a marked reduction in frailty and epigenetic age. Fucoidan-treated mice showed repression of LINE1 elements suggesting that the beneficial effects of fucoidan are mediated, at least in part, by SIRT6. As brown seaweed rich in fucoidan is a popular food item in South Korea and Japan, countries with the highest life expectancy, we propose that fucoidan supplementation should be explored as a safe strategy for activating SIRT6 and improving human healthspan and lifespan.
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Review coordinated by Life Science Editors Foundation Reviewed by: Dr. Angela Andersen, Life Science Editors Foundation & Life Science Editors. Potential Conflicts of Interest: None.
PUNCHLINE: Fucoidan, a dietary polysaccharide derived from brown seaweed, is identified as a dual-function activator of SIRT6, enhancing both deacetylase and mono-ADP-ribosylation (mADPr) activity. In aged mice, fucoidan supplementation extends lifespan in males, reduces frailty in both sexes, and restores youthful chromatin and immune profiles through SIRT6-dependent mechanisms—highlighting its potential as a natural longevity therapeutic.
BACKGROUND: SIRT6 is a chromatin-associated enzyme that safeguards genomic integrity, represses retrotransposons like LINE1, and modulates inflammation and metabolism—functions tightly linked to aging. While …
Review coordinated by Life Science Editors Foundation Reviewed by: Dr. Angela Andersen, Life Science Editors Foundation & Life Science Editors. Potential Conflicts of Interest: None.
PUNCHLINE: Fucoidan, a dietary polysaccharide derived from brown seaweed, is identified as a dual-function activator of SIRT6, enhancing both deacetylase and mono-ADP-ribosylation (mADPr) activity. In aged mice, fucoidan supplementation extends lifespan in males, reduces frailty in both sexes, and restores youthful chromatin and immune profiles through SIRT6-dependent mechanisms—highlighting its potential as a natural longevity therapeutic.
BACKGROUND: SIRT6 is a chromatin-associated enzyme that safeguards genomic integrity, represses retrotransposons like LINE1, and modulates inflammation and metabolism—functions tightly linked to aging. While overexpression of SIRT6 extends lifespan in mice, loss-of-function causes rapid aging and early death. Safe, pharmacologically tractable SIRT6 activators have been limited, and none have been shown to activate both major SIRT6 enzymatic functions. Fucoidan, a sulfated polysaccharide from brown algae consumed widely in high-longevity populations like Japan and South Korea, was previously shown to enhance SIRT6 deacetylase activity in vitro. This study explores its in vivo efficacy, enzymatic specificity, and potential to slow aging through chromatin and immune system rejuvenation.
QUESTION ADDRESSED:
Can a safe, natural compound be used to activate SIRT6 in vivo and, through this activation, extend lifespan and healthspan?
SUMMARY: The authors demonstrate that fucoidan robustly activates SIRT6 enzymatic functions, uniquely enhancing both deacetylation and mono-ADP-ribosylation (mADPr) activity—the latter previously associated with enhanced longevity in human centenarians. In aged wild-type mice, midlife fucoidan supplementation significantly extends lifespan in males and slows frailty progression in both sexes without affecting body weight. Fucoidan reduces epigenetic age, suppresses LINE1 retrotransposons, and restores immune homeostasis via increased lymphoid cell fractions and reduced inflammatory cytokines—effects absent in SIRT6 knockout mice. Multi-omic profiling reveals transcriptional and epigenetic changes resembling SIRT6 overexpression and opposing aging trajectories, particularly in male tissues.
KEY RESULTS
Fucoidan is a rare natural compound that activates both of SIRT6’s key enzymatic activities—unlike other known activators.
Figure 1 + Figure S1A–B: Fucoidan is a dual-function activator of SIRT6
In vitro assays demonstrated that fucoidan robustly stimulates SIRT6 deacetylase and mono-ADP-ribosylation (mADPr) activity.
Among various small molecules tested, only fucoidan enhanced both functions—L-fucose (its monomer) was ineffective.
F. vesiculosus extract showed the strongest activation, with effects saturating between 0.2–0.5 mg/mL.
Other known SIRT6 deacetylase activators (e.g., MDL-800) either had no effect or inhibited mADPr activity, underscoring fucoidan’s unique dual role.
Midlife fucoidan treatment increases lifespan in male mice and slows frailty in both sexes without affecting body weight.
Figure 2A–D + Figure S1A–B + Figure S2A–B: Fucoidan extends male lifespan and reduces frailty in both sexes
Male mice showed a 13% increase in median lifespan (p = 0.009); the effect in females was not significant.
Monthly frailty scoring revealed slower frailty progression in both males (p = 0.046) and females (p = 0.006), with improvements seen across multiple organ systems.
Epigenetic clock analysis at 26 months confirmed reduced biological age in treated mice (p = 0.037).
Body mass was unaffected, ruling out calorie restriction as a confounding factor.
No benefit was observed in SIRT6 knockout mice (Figure S2A), confirming the effects are SIRT6-dependent.
H3K9 acetylation, a SIRT6 target, was reduced in treated lung and liver tissues (Figure S2B).
Fucoidan reprograms the immune landscape in aging males, increasing lymphoid cell fractions and suppressing pro-inflammatory cytokines.
Figure 3A–E + Figure S3A–D: Fucoidan modulates immune composition and suppresses inflammation—especially in males
In 22-month-old male mice, blood RNA-seq showed 2,272 genes downregulated and 926 upregulated; females showed no significant changes.
Downregulated pathways included interferon signaling, myeloid activation, and coagulation, while upregulated genes promoted B and T cell differentiation and RNA processing.
Plasma cytokines (TNFα, IL-6, IL-1β, IFNγ) were significantly lower in treated males, but increased slightly in females, suggesting a sex-specific immune modulation.
Immune cell deconvolution showed increased lymphoid and decreased myeloid populations in males—indicating reversal of the age-related myeloid skew.
In male tissues, fucoidan induces gene expression programs that mirror SIRT6 overexpression and oppose aging trajectories.
Figure 4A–F + Figure S4A–B + Figure S5A–D: Fucoidan mimics SIRT6 overexpression and counteracts aging-related gene expression in males
In male lungs, fucoidan’s transcriptomic effects were negatively correlated with aging signatures from Tabula Muris Senis, particularly in protein folding genes.
In male livers, gene expression changes were positively correlated with those from SIRT6 overexpression studies.
Key inflammatory genes like Saa1/2 and Orm2 were strongly downregulated, matching systemic reductions in inflammatory cytokines.
In female tissues, fucoidan either mimicked aging or had minimal effects, reinforcing the male-specific efficacy of the intervention.
Fucoidan represses transposable elements and protects against oxidative stress through enhanced LINE1 silencing and reduced p21 expression.
Figure 5A–C + Figure S5E: Fucoidan suppresses LINE1 transposons and protects against genotoxic stress
In lungs, multi-omic profiling (RNA-seq, ATAC-seq, MeDIP-seq) showed widespread LINE1 repression at the transcriptional, chromatin accessibility, and methylation levels.
In livers, the pattern was less consistent across data types.
In a paraquat-induced oxidative stress model, fucoidan-fed mice showed blunted LINE1 reactivation and reduced expression of p21 (CDKN1a)—a marker of DNA damage response—highlighting improved stress resilience via chromatin stabilization.
STRENGTHS:
First study to demonstrate dual enzymatic activation of SIRT6 by a natural compound.
Shows lifespan and healthspan extension in aged animals with midlife intervention.
Integrates multi-omics, chromatin biology, inflammation, and organismal physiology.
Robust sex-specific analysis, revealing differential molecular and systemic responses.
Confirms SIRT6 dependency using knockout models and known substrates.
FUTURE WORK:
What are the minimal active structures in fucoidan responsible for SIRT6 activation?
Can SIRT6-mediated chromatin remodeling by fucoidan reverse age-related disease phenotypes?
Could selective derivatives be developed to target specific SIRT6 activities?
Would clinical trials in elderly humans show benefits in frailty, LINE1 expression, or epigenetic aging?
How do sex hormones or metabolic differences modulate the fucoidan response?
FINAL TAKEAWAY: This study establishes fucoidan as a natural and potent dual-activator of SIRT6 that enhances chromatin stability, represses transposable elements, and improves aging phenotypes in vivo. The work elegantly links SIRT6 enzymatic activity to systemic aging outcomes and opens the door to dietary or pharmacological interventions that target aging at the level of chromatin organization and genome defense. Fucoidan’s strong safety profile and traditional dietary use suggest rapid translational potential in human aging research.
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