Project SIRT6 Activator

SIRT6 Activation to Improve Biological Age Measured by GrimAge in Pre-frail, Middle-aged to Older Men: a Randomized Controlled Trial

The global ageing population is increasingly affected by age-related diseases, which are challenging healthcare systems. Current treatments often extend lifespan without improving healthspan. The geroscience hypothesis suggests that targeting the ageing process could prevent or delay multiple diseases, enhancing healthspan. Fucoidan, a sulfated polysaccharide from brown macroalgae, is a safe dietary supplement with Sirtuin-6 (SIRT6) activating properties, which are linked to longevity. Clinical studies have shown that it reduces inflammatory markers associated with biological aging and frailty and influences DNA methylation in vitro and in vivo; however, its effects on human DNA methylation remain unknown.

Study Overview

• Status: Recruiting
• Conditions: Aging
• Intervention / Treatment: Dietary supplement: Fucoidan; Dietary supplement: Placebo

Detailed Description

Ageing is driven by several interconnected mechanisms, including deoxyribonucleic acid (DNA) damage, mitochondrial dysfunction, depletion of nicotinamide adenine dinucleotide (NAD+) levels, impaired autophagy, stem cell exhaustion, chronic inflammation, loss of protein homeostasis, deregulated nutrient sensing, altered intercellular communication, and microbiome imbalance. Sirtuin 6 (SIRT6) an NAD+ dependent deacetylase and ADP-ribosyl-transferase, has emerged as a pivotal factor in the regulation of several of these mechanisms, including DNA repair, metabolism, and inflammation. Long-lived species have higher SIRT6 activity. Potent and safe SIRT6 activators have the potential to extend human lifespan and healthspan.

Fucoidan, a polymer of L-fucose and L-fucose-4-sulfate derived from brown macroalgae is available as a dietary supplement, safe for human consumption, and rarely causes irritation. Fucoidan exhibits dose-dependent SIRT6-stimulating activity and extends lifespan in model organisms. Inflammation is associated with higher biological age and poor health outcomes, including frailty. In an open-label single-arm clinical study where 400 ml (10mg/ml) fucoidan was administered to 20 cancer patients (mean age 58.9 years) reported a decrease in the interleukin (IL) levels (IL-6, IL-1-beta) and tumour necrosis factor (TNF)-alpha, after 2 weeks compared to baseline levels. In addition, studies found that fucoidan modulates DNA methylation (DNAm) in vitro and in vivo and play a role of inhibiting carcinogenesis. Currently, there is no data about the effect of fucoidan on DNAm in humans.

Therefore, this study will investigate the effects of a SIRT6 activator, compared to a placebo, on DNAm assessed by GrimAge in 60 prefrail, middle-aged to older (50-80 years) healthy males.

The aim is to evaluate the geroprotective effect of a SIRT6 activator and determine whether it can modulate biological pathways of ageing. The investigators hypothesize that supplementation with a SIRT6 activator (2.4 g/day/6 months) will decrease DNAm as assessed by GrimAge in prefrail, middle-aged to older (50-80 years), males and improve biological (inflammatory, glycans) and clinical markers of ageing (frailty, quality of life, sleep, cognitive, body composition, muscular, cardiovascular, and reproductive and skin ageing).

Study objectives: to assess the effect of supplementation with a SIRT6 activator (2.4 g/day/6 months) on biological (epigenetic inflammatory, glycans) and clinical markers of ageing (frailty, quality of life, sleep, cognitive, body composition, muscular, cardiovascular, reproductive and skin ageing) compared to placebo in 60 prefrail, middle-aged to older (50-80 years), males.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Andrea Britta Maier, MD PhD; Phone Number: +65 63793186; Email: a.maier@nus.edu.sg

Study Locations

• Singapore
  • Singapore, Singapore
    • Not yet recruiting
    • NUS Academy for Healthy Longevity, Level 6, MD 11, 10 Medical Dr, Yong Loo Lin School of Medicine, National University of Singapore
    • Contact: Andrea Britta Maier, MD PhD FRACP; Phone Number: 6563793186; Email: a.maier@nus.edu.sg
    • Contact: Hodzic Kuerec Ajla, MD PhD; Phone Number: +65 98376777; Email: ahkuerec@nus.edu.sg
  • Singapore
    • Singapore, Singapore, Singapore, 117597
      • Recruiting
      • Yong Loo Lin School of Medicine, National University of Singapore
      • Contact: Andrea Britta Maier, doctor; Phone Number: (65) 87142729; Email: longevitytrials@nus.edu.sg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. 50-80 years males;
2. Resident of Singapore (citizenship or permanent residency is not required);
3. Prefrail according to Fried frailty phenotype score;
4. English-literate who can understand, read and write in English;
5. Individuals without severe cognitive impairment, as determined by PI judgment;

6. Apparently healthy and non-smokers having not more than 2 of the following conditions. If the conditions are present they have to be stable:

   • Hypertension,
   • Hyperlipidemia,
   • Hyperglycemia,
   • Osteopenia/osteoporosis,
   • Osteoarthritis,
   • COPD,
   • Type 2 diabetes.

Subjects who agree to shave one day before each visit if he has dense facial hairs on their cheeks that could interfere with skin microbiome sampling.

Exclusion Criteria:

1. Pre-existing or history of major cardiovascular disease (e.g., coronary artery disease, heart failure, stroke, peripheral vascular disease);
2. Current cancer or non-stable chronic obstructive pulmonary disease (COPD);
3. Use of anticoagulant medication;
4. Consuming seaweed more than 3 times a week;
5. Having hairiness, moles, tattoos, scars, irritated skin, etc. on the face which could influence the investigation;
6. Having used within the 3 past weeks for more than 3 consecutive days any systemic or topical drugs related to antibiotics or having planned to use these treatments during the study;

7. Having a positive serology for HIV, HEPATITIS B, HEPATITIS C*

   *Subjects will undergo a serology test, which will be conducted at baseline and at the end of the intervention visit. Only for subjects who accepted to undergo skin microbiopsy sampling;

8. Subject with any contra-indication for skin microbiopsies:

   • hypersensitivity or any serious reaction to local anesthesia; (lidocaine/prilocaine), local antibiotics, and antiseptics,
   • with inherited or acquired hemostasis disorders,
   • having had any treatment which may affect the blood coagulation and hemostasis (anti-coagulant medications…),
   • having a history of wound healing defects (hypertrophic scars, keloids…).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SIRT6 activator; Participants in this arm will take 2.4 g/day of Fucoidan (or known as SIRT6 activator) supplement for 6 months	Dietary supplement: Fucoidan; Eligible participants will be randomized to receive SIRT6 Activator (fucoidan) or Placebo for 6 months.
Placebo Comparator: Placebo; Participants in this arm will take 2.4 g/day of placebo for 6 months	Dietary supplement: Placebo; Eligible participants will be randomized to receive SIRT6 Activator (fucoidan) or Placebo for 6 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in blood DNA methylation status, years	DNA methylation aging clock	from baseline to end of intervention (6 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in blood inflammatory markers (pg/mL)	comparison of inflammatory markers: IL-10, IFN-γ，IL-17, TNF-a, IL-6，CXCL9 (pg/mL) at baseline, interim and end-of-trial	from baseline to end of intervention (6 months)
Body Mass Index (BMI) change	comparison of BMI at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Waist-to-hip ratio change	comparison of waist-to-hip ratio at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Body fat mass (kg) change	comparison of body fat mass at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Skeletal muscle mass (kg) change	comparison of skeletal muscle mass at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Percentage body fat (%) change	comparison of percentage body fat at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Systolic blood pressure (mm Hg) change	comparison of systolic blood pressure at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Diastolic blood pressure (mm Hg) change	comparison of diastolic blood pressure at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Pulse rate (BPM) change	comparison of pulse rate at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Skin elasticity (mm/time) change	comparison of skin elasticity measured by he resistance of the skin to the negative pressure (firmness) and its ability to return into its original position (elasticity) displayed as curves (penetration depth in mm/time) at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Skin colour (L* a* b*) change	comparison of skin colour measured using automatic calculation of ITA (Individual Typology Angle) that uses CIE L* a* b* values to classify 6 skin colours from very light to dark at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Skin autofluorescence (au) change	comparison of skin autofluorescence levels calculated by dividing the mean value of the emitted light intensity per nm between 420 and 600 nm by the mean value of the excitation light intensity per nm between 300 and 420 nm, expressed in arbitrary units (AU) at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Skin evaluation: microbiopsies for proteomics		from baseline to end of intervention (6 months)
Complete blood count: lymphocytes_countm, neutrophils_count, monocyte_count, basophil_count, eosinphil_count, WBC_count,PLT_count (*10^9/L)	comparison of blood count at baseline, interim and end-of-trial.	from baseline to end of intervention (6 months)
Change in cognition (Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Test)	comparison of cognition at baseline, interim and end of trial. A RBANS result range from 40-160, the higher scale indicates the better congnition function.	from baseline to end of intervention (6 months)
Change in Physical Activity (Minnesota Leisure Time Activity Questionnaire)	comparison of physical activity at baseline, interim and end of trial. The higher the value (energy expenditure or time), the higher the level of physical activity during leisure time.	from baseline to end of intervention (6 months)
Change in Exhaustion [Center for Epidemiologic Studies Depression Scale (CES-D)]	CES-D scale range from 0-60. The higher the score, the more severe the depressive symptoms. comparison of exhaustion at baseline, interim and end of trial.	from baseline to end of intervention (6 months)
Change in dietary intake (3-day Food Record)	comparison of dietary intake at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Change in quality of life 36-Item Short Form Survey (SF-36)	comparison of quality of life 36-Item Short Form Survey (SF-36) at baseline, interim and end of trial. SF-36_overall range from 0-100, the larger scale indicates the better quality of life.	from baseline to end of intervention (6 months)
Change in Depression, anxiety and/ or stress levels [Depression Anxiety and Stress Scale (21 items) (DASS-21)]	DASS-21 scale ranges from 0-21. The higher the score, the more severe the symptoms in that dimension are. comparison of depression, anxiety and/ or stress levels at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Change in Reproductive health [Androgen Deficiency in Aging Males (ADAM) questionnaire]	Androgen Deficiency in Aging Males (ADAM) questionnaire scale ranges from 0-10. A "Positive" result indicates a high likelihood of androgen deficiency, warranting further clinical evaluation (e.g., testosterone testing). comparison of reproductive health at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Change in sleep quality (modified Pittsburgh Sleep Quality Questionnaire)	modified Pittsburgh Sleep Quality Questionnaire scale ranges from 0-21. Higher total scores indicate worse sleep quality. comparison of sleep quality at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Change in handgrip strength change (kg)	comparison of handgrip strength at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Change in 8-RM leg extension change (kg)	comparison of 8-RM leg extension at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Carotid-femoral Pulse Wave Velocity change	comparison of carotid-femoral pulse wave velocity at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Central Blood pressure change	comparison of central Blood pressure at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Change in blood inflammatory markers:hs-CRP (mg/mL)		basline, 3 months, and 6 months
Change in quality of life: EuroQol-D5-5L (EQ-5D)	A 5-digit code describing a health state. This code is then converted to a single index number using a country-specific value set (a formula based on public preferences). comparison of quality of life of EQ-5D at baseline, interim and end of trial	from baseline to end of intervention (6 months)
Skin micobiopsies for microbiomics.		Time Frame: from baseline to the end of the trial (6 months)
Skin micobiopsies: Transcriptomics		from baseline to the end of ths study (6 months)
skin microbiopsies evaluation: DNA methylation		from baseline to the end of this study (6 months)
Complete blood count: red blood cell_count (*10^12/L)	comparison of blood count at baseline, interim and end-of-trial.	from baseline to end of intervention (6 months)
Complete blood count: Hemoglobulin (*g/L)	comparison of blood count at baseline, interim and end-of-trial.	Time Frame: from baseline to end of intervention (6 months)

Collaborators and Investigators

• Sponsor: National University of Singapore
• Collaborators: University of Rochester; L'Oreal; DoNotAge.org

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2025
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: February 10, 2026
• First Submitted That Met QC Criteria: March 24, 2026
• First Posted (Actual): March 30, 2026

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Aging; Fucoidan; DNA methylation; Geroscience; Healthspan; Epigenetic aging clock; SIRT6 Activator
• Additional Relevant MeSH Terms: fucoidan
• Other Study ID Numbers: NUS-IRB-2024-806

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No