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.

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.

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…).