Tier 3 — preclinical

The Identification of a SIRT6 Activator from Brown Algae Fucus distichus

Rahnasto-Rilla MK, McLoughlin P, Kulikowicz T, Doyle M, Bohr VA, Lahtela-Kakkonen M, Ferrucci L, Hayes M, Moaddel R
Marine Drugs 2017 Volume 15, issue 6, article 190

Bibliography

DOI
10.3390/md15060190
PubMed
PMID 28635654
PubMed Central
PMC5484140
Funding
Intramural Research Program of the National Institute on Aging, NIH (Bohr, Ferrucci, Moaddel). No commercial industry funding declared.
Competing interests
The authors declare no conflict of interest.

Study snapshot

DesignIn vitro biochemistry — accelerated solvent extraction of brown macroalgae, activity screening on purified SIRT6 using a synthetic H3K9-acetylated peptide substrate, mass-spectrometry identification of the active fraction, dose-response characterisation.
ModelPurified recombinant human SIRT6 protein; synthetic H3K9-acetylated peptide substrate; five brown macroalgae species — Fucus distichus, Fucus vesiculosus, Cystoseira tamariscifolia, Cystoseira nodicaulis, Alaria esculenta.
SampleTriplicate biochemistry assays; five extract species tested; eight sub-fractions of the F. distichus extract characterised.
InterventionApplication of brown-algae fraction extracts (0.5 mg/mL, 1.0 mg/mL) and purified fucoidan (25, 50, 100 μg/mL) to purified SIRT6 in H3K9 deacetylation reactions; specificity testing against SIRT1, SIRT2, SIRT3 in parallel.
DurationNot applicable — single-time-point in vitro biochemistry.
EndpointsRate of H3K9 deacetylation by purified SIRT6 with vs. without extract or purified fucoidan; Fold-activation of SIRT6 deacetylase activity vs. baseline; Sirtuin specificity — SIRT1, SIRT2, SIRT3 as controls; Structural characterisation of active fucoidan fraction by mass spectrometry

What the study showed, in plain terms

This is the paper that started the fucoidan-SIRT6 story. A collaboration between the US National Institute on Aging, an Irish food research centre, and a Finnish university, published in 2017, asked a specific question: are there natural compounds in brown seaweed that activate SIRT6?

The team screened five species of brown macroalgae — bladderwrack (Fucus distichus and Fucus vesiculosus), two species of Cystoseira, and Alaria esculenta — for activity on purified SIRT6 in a test tube. Three of the five significantly increased SIRT6's ability to remove acetyl tags from histone H3 at lysine 9 — the enzyme's best-characterised job.

The most potent was Fucus distichus. The team then fractionated the F. distichus extract and used mass spectrometry to identify the specific active compound. It was fucoidan — a sulfated polysaccharide made of L-fucose sugar units chemically decorated with sulfate groups. Purified fucoidan at 100 μg/mL boosted SIRT6 deacetylase activity roughly 355-fold above baseline.

Critically, the activation was SIRT6-specific. When the same fucoidan was tested against SIRT1, SIRT2, and SIRT3, no significant activation was seen. This is the specificity finding that makes fucoidan interesting as a targeted SIRT6 activator — it's not just a general sirtuin booster.

Everything the field has done on fucoidan-SIRT6 since — including the 2025 mouse lifespan and senotherapeutic papers — traces back to this observation.

Key findings

  • Screened five brown macroalgae species and identified three (F. distichus, F. vesiculosus, Cystoseira nodicaulis) as significant activators of SIRT6-mediated H3K9 deacetylation in a purified in vitro assay.
  • Fucus distichus extract was the most potent. Mass-spectrometry fractionation identified fucoidan as the specific active molecule responsible for the SIRT6 activation.
  • Purified fucoidan enhanced SIRT6 deacetylase activity approximately 355-fold at 100 μg/mL — a strikingly large effect size compared to typical enzyme activators.
  • The activation was SIRT6-specific — no significant enhancement of SIRT1, SIRT2, or SIRT3 deacetylase activity was observed with the same fucoidan.
  • Structural analysis showed the active F. distichus fucoidan was built up mainly of the repeating "A" unit type of sulfated fucose polymers, structurally distinct from the "B" unit type dominant in F. vesiculosus fucoidan.
  • The paper explicitly proposed fucoidan as a candidate natural product for the prevention of age-associated diseases and metabolic syndrome disorders through targeted SIRT6 activation.

What this study can and cannot tell us

This is entirely an in vitro biochemistry paper — purified SIRT6 protein and a synthetic H3K9-acetylated peptide substrate in a test tube. No cellular experiments, no animal experiments, and no test of whether ingested fucoidan reaches SIRT6 inside a living cell at a bioactive concentration. The 355-fold activation number is meaningful for pharmacology, but it does not translate directly to a whole-organism effect.

Fucoidan is a large sulfated polysaccharide with typical molecular weights in the 20–200 kDa range. Oral bioavailability of intact fucoidan is limited by molecular size, and the fraction that reaches systemic circulation intact — and then the nucleus of a target cell where SIRT6 resides — is a separate question from what fucoidan does to purified SIRT6 in a tube. This paper does not address it.

The activation was tested only on SIRT6 deacetylase activity. The subsequent mono-ADP-ribosylation arm of SIRT6, later shown by Biashad 2025 and Robbins 2025 to be functionally distinct and centenarian-relevant, was not tested in 2017.

Only F. distichus fucoidan was characterised in detail. The paper flagged that structural differences between F. distichus and F. vesiculosus fucoidans exist ("A" vs "B" repeating units), foreshadowing the species-specificity finding that would become important in the 2025 preprints. But it did not systematically map structure-activity relationships across fucoidan sources — that came later.

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Reviewed by , Medical Advisory Board · Last verified against PubMed on 10 August 2026