Aging
Conditions
Keywords
Aging, Geroscience, Fucoidan, SIRT6 Activator, DNA methylation, Healthspan, Epigenetic aging clock
Brief summary
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.
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.
Interventions
DIETARY_SUPPLEMENTFucoidan
Eligible participants will be randomized to receive SIRT6 Activator (fucoidan) or Placebo for 6 months.
DIETARY_SUPPLEMENTPlacebo
Eligible participants will be randomized to receive SIRT6 Activator (fucoidan) or Placebo for 6 months.
Sponsors
National University of Singapore
University of Rochester
L'Oreal
DoNotAge.org
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
50 Years to 80 Years
Healthy volunteers
Yes
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…).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in blood DNA methylation status, years | from baseline to end of intervention (6 months) | DNA methylation aging clock |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in blood inflammatory markers (pg/mL) | from baseline to end of intervention (6 months) | comparison of inflammatory markers: IL-10, IFN-γ，IL-17, TNF-a, IL-6，CXCL9 (pg/mL) at baseline, interim and end-of-trial |
| Body Mass Index (BMI) change | from baseline to end of intervention (6 months) | comparison of BMI at baseline, interim and end of trial |
| Waist-to-hip ratio change | from baseline to end of intervention (6 months) | comparison of waist-to-hip ratio at baseline, interim and end of trial |
| Body fat mass (kg) change | from baseline to end of intervention (6 months) | comparison of body fat mass at baseline, interim and end of trial |
| Skeletal muscle mass (kg) change | from baseline to end of intervention (6 months) | comparison of skeletal muscle mass at baseline, interim and end of trial |
| Percentage body fat (%) change | from baseline to end of intervention (6 months) | comparison of percentage body fat at baseline, interim and end of trial |
| Systolic blood pressure (mm Hg) change | from baseline to end of intervention (6 months) | comparison of systolic blood pressure at baseline, interim and end of trial |
| Diastolic blood pressure (mm Hg) change | from baseline to end of intervention (6 months) | comparison of diastolic blood pressure at baseline, interim and end of trial |
| Pulse rate (BPM) change | from baseline to end of intervention (6 months) | comparison of pulse rate at baseline, interim and end of trial |
| Skin elasticity (mm/time) change | from baseline to end of intervention (6 months) | 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 |
| Skin colour (L* a* b*) change | from baseline to end of intervention (6 months) | 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 |
| Skin autofluorescence (au) change | from baseline to end of intervention (6 months) | 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 |
| 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) | from baseline to end of intervention (6 months) | comparison of blood count at baseline, interim and end-of-trial. |
| Change in cognition (Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Test) | from baseline to end of intervention (6 months) | 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. |
| Change in Physical Activity (Minnesota Leisure Time Activity Questionnaire) | from baseline to end of intervention (6 months) | 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. |
| Change in Exhaustion [Center for Epidemiologic Studies Depression Scale (CES-D)] | from baseline to end of intervention (6 months) | 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. |
| Change in dietary intake (3-day Food Record) | from baseline to end of intervention (6 months) | comparison of dietary intake at baseline, interim and end of trial |
| Change in quality of life 36-Item Short Form Survey (SF-36) | from baseline to end of intervention (6 months) | 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. |
| Change in Depression, anxiety and/ or stress levels [Depression Anxiety and Stress Scale (21 items) (DASS-21)] | from baseline to end of intervention (6 months) | 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 |
| Change in Reproductive health [Androgen Deficiency in Aging Males (ADAM) questionnaire] | from baseline to end of intervention (6 months) | 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 |
| Change in sleep quality (modified Pittsburgh Sleep Quality Questionnaire) | from baseline to end of intervention (6 months) | 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 |
| Change in handgrip strength change (kg) | from baseline to end of intervention (6 months) | comparison of handgrip strength at baseline, interim and end of trial |
| Change in 8-RM leg extension change (kg) | from baseline to end of intervention (6 months) | comparison of 8-RM leg extension at baseline, interim and end of trial |
| Carotid-femoral Pulse Wave Velocity change | from baseline to end of intervention (6 months) | comparison of carotid-femoral pulse wave velocity at baseline, interim and end of trial |
| Central Blood pressure change | from baseline to end of intervention (6 months) | comparison of central Blood pressure at baseline, interim and end of trial |
| 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) | from baseline to end of intervention (6 months) | 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 |
| 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) | from baseline to end of intervention (6 months) | comparison of blood count at baseline, interim and end-of-trial. |
| Complete blood count: Hemoglobulin (*g/L) | Time Frame: from baseline to end of intervention (6 months) | comparison of blood count at baseline, interim and end-of-trial. |
Countries
Singapore
Contacts
CONTACTAndrea Britta Maier, MD PhD
Outcome results
None listed