Sirtuin Activators and Weight Loss

Overview

Obesity is a chronic, multifactorial disease associated with a high burden of metabolic, cardiovascular, and psychosocial complications. Despite extensive research, the long-term effectiveness of lifestyle-based weight-management strategies remains limited, and there is a growing interest in molecular pathways that may enhance metabolic flexibility and improve treatment outcomes. Among these pathways, the sirtuin (SIRT) family-particularly SIRT1 and SIRT3-has emerged as a promising target due to its involvement in mitochondrial biogenesis, energy expenditure, oxidative metabolism, and the regulation of insulin sensitivity. Bioactive compounds that activate sirtuins, including nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), resveratrol, and selected polyphenols, have shown metabolic benefits in preclinical models; however, high-quality human trials remain scarce and inconsistent. This project aims to investigate the efficacy of a standardized sirtuin-activator supplement on body-weight reduction, metabolic health, and energy-balance regulation in adults with overweight and obesity. The trial will be a randomized, double-blind, placebo-controlled intervention lasting 24 days. Participants will be assigned to either the sirtuin-activator group or placebo, with both groups receiving standardized dietary plan to ensure consistent caloric intake. The primary outcome will be absolute and relative weight loss, while secondary outcomes will include changes in waist circumference, body-composition parameters, resting metabolic rate, glycemic markers, lipid profiles and physical functioning. A key novelty of this project lies in testing a multi-ingredient formulation designed to synergistically enhance sirtuin signaling, addressing limitations observed in studies using single-compound approaches. By integrating nutritional guidance, rigorous clinical monitoring, and advanced biomarker profiling, this research aims to generate high-quality evidence on whether sirtuin activators can meaningfully augment weight-loss interventions in humans.

1. Background and Rationale Sirtuins (SIRT1-SIRT7) are a family of NAD⁺-dependent enzymes involved in metabolic regulation, mitochondrial biogenesis, oxidative stress response, and inflammation control. Evidence from model organisms demonstrates that sirtuin overexpression can extend lifespan. In mammals, caloric restriction enhances sirtuin synthesis, leading to improved mitochondrial function, reduced oxidative stress, and attenuated inflammation. Collectively, these mechanisms underpin the potential role of sirtuins in promoting metabolic health and preventing non-communicable diseases. Numerous non-nutritive bioactive compounds naturally present in foods activate sirtuin pathways. The most extensively studied is resveratrol, found in grapes and red wine, which has been shown to stimulate SIRT1 and downstream metabolic pathways. Additional sirtuin activators include epigallocatechin gallate (EGCG) from green tea, curcuminoids from turmeric, and quercetin, present in apples, grapes, and onions. Despite their presence in commonly consumed foods, typical dietary intake is low, suggesting that targeted supplementation may be necessary to achieve meaningful physiological effects-particularly in populations at metabolic risk. Overweight and obesity remain major public health challenges worldwide. Excess adiposity is strongly associated with chronic, low-grade inflammation and increased risk of cardiometabolic diseases. While caloric restriction remains a cornerstone of weight reduction, adjunct interventions may enhance metabolic adaptations to energy deficit. SIRT1, for example, has been shown to increase energy expenditure and shift substrate utilization toward enhanced fatty-acid oxidation. Thus, supplementation with sirtuin activators may support weight loss and metabolic improvements when combined with a hypocaloric diet. 2. Study Objective The primary objective of this study is to evaluate the effects of supplementation with sirtuin activators (resveratrol, curcuminoids, EGCG, quercetin) combined with a short-term low-energy diet on: * body weight and body composition, * physical performance, * blood pressure, * biochemical and inflammatory markers in adults with overweight and obesity. 3. Study Design This research will employ a randomized, placebo-controlled, parallel-group design. Participants will be randomly allocated to: * SIRT group: receiving daily supplementation with sirtuin activators in the form of SIRTWAY powdered shakes, * PLA group: receiving visually identical placebo shakes without active compounds. Both groups will follow a structured 24-day low-energy dietary intervention. Study activities will take place between January 2026 and January 2027 at the Department of Human Nutrition and Dietetics, Poznań University of Life Sciences. Assessments will be conducted twice: baseline (Day 0) and post-intervention (Day 25). 4. Participants The study will enroll approximately 45 adults with overweight or obesity. All participants will provide written informed consent. 5. Supplementation Protocol Participants in the SIRT group will receive shakes containing microencapsulated sirtuin activators. The daily dose of active sirtuin activators will be approximately 1280 mg. Placebo shakes will be identical in appearance, taste, and packaging. All components used in the supplements have established safety profiles, including FDA GRAS status where applicable. Adverse effects documented in the literature occur only at doses significantly higher than those used in the present protocol. 6. Dietary Intervention The low-energy diet will consist of three sequential phases: * Phase 1 (Days 1-3): \~1000 kcal/day, 3 shakes + 1 solid meal * Phase 2 (Days 4-10): \~1450 kcal/day, 2 shakes + 2 solid meals * Phase 3 (Days 11-24): \~1600 kcal/day, 2 shakes + 2 solid meals Recipes for home-prepared meals (DASH-based) will be provided in a dedicated e-book. 7. Study Procedures 7.1. Anthropometry and Body Composition Body weight and height measured using a medical-grade RADWAG WPT 60/150 OW scale with stadiometer. Waist and hip circumferences measured with a standardized flexible anthropometric tape.Body composition assessed by air-displacement plethysmography (Bod Pod, Cosmed). All procedures follow validated protocols, with participants measured in a fasted state and wearing swimwear and a swim cap. 7.2. Blood Pressure Resting blood pressure will be taken using the Omron SpotArm i-Q142 device, following 2024 ESH guidelines. Three measurements will be taken; the average of the final two will be recorded. 7.3. Blood Sampling and Biochemistry Venous blood (5 mL) will be drawn twice (Day 0 and Day 25) by licensed medical staff. Serum will be processed, aliquoted, and stored at -80°C. 7.4. Physical Performance Testing Conducted twice (Day 0 and Day 25) by experienced staff. Tests include: Handgrip strength: measured using a Kern MAP 130K1 dynamometer, three trials per hand, averaged. Short Physical Performance Battery (SPPB): assessing lower-limb strength (chair-stand test), static balance, and gait speed over 4 meters. Tests are low-risk; precautionary measures will be taken to minimize falls or discomfort. 7.5. Dietary Assessment Participants will complete 3-day dietary records before intervention. Intake will be analyzed using Dieta 6 software. 8. Safety Considerations All supplements used have established safety thresholds well above the doses administered in the study. Risks related to blood sampling and physical tests are minimal and standard procedures will be followed to prevent adverse events.