Project SIRT6 Activator

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

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

• Pre-existing or history of major cardiovascular disease (e.g., coronary artery disease, heart failure, stroke, peripheral vascular disease);
• Current cancer or non-stable chronic obstructive pulmonary disease (COPD);
• Use of anticoagulant medication;
• Consuming seaweed more than 3 times a week;
• Having hairiness, moles, tattoos, scars, irritated skin, etc. on the face which could influence the investigation;
• 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;
• 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;

• 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…).