A new review published in Frontiers in Genetics on Jun. 16 examines which human interventions can alter next-generation epigenetic aging clocks, while cautioning that changes in these biomarkers do not yet prove true age reversal.
The paper provides a comprehensive list of pharmaceuticals, lifestyle modifications, supplements, and clinical therapeutics reported to reduce estimates from advanced epigenetic clocks. These clocks use DNA methylation data to estimate both chronological and biological age, with next-generation models specifically trained to associate with healthspan, disease risk, mortality risk, and the speed of aging.
According to the review by Adiv Johnson from Tally Health and David Sinclair from Harvard Medical School, 41 human studies were identified reporting the effects of various interventions on at least one next-generation clock. Pharmaceuticals such as emtricitabine-tenofovir-alafenamide (an anti-viral combination), semaglutide (a GLP-1 receptor agonist), ketamine (a psychiatric drug), pitavastatin (a cholesterol-lowering drug), decitabine, bezisterim, metformin, and certain antiretroviral therapies were all found to significantly change at least one clock output in different populations. For example, a 32-week semaglutide treatment reduced several epigenetic aging measures in patients with HIV-related lipohypertrophy.
Lifestyle approaches including plant-rich diets, exercise regimens, calorie restriction programs, omega-3 fatty acid supplementation, and multivitamin-multimineral supplements also showed significant effects on at least one clock measure. Two years of multivitamin-multimineral supplementation or adherence to a plant-rich diet reduced clock-predicted biological age or mortality risk in healthy individuals. Omega-3 supplementation for six weeks reduced harmful age-related changes while increasing protective markers among overweight participants.
Not all tested interventions produced favorable results; some strategies—such as green-based supplements or rapamycin—did not yield significant shifts in clock outputs. The authors highlighted that effect sizes are model-derived estimates rather than direct indicators of overall biological aging or lifespan extension: "these reported effect sizes are model-derived estimates and do not directly translate into changes in whole-body biological aging or expected lifespan," they further noted that these clocks remain investigational biomarkers without validation as clinical surrogate endpoints.
The review concludes by emphasizing the need for further research to understand how these interventions affect DNA methylation status and whether changes correlate with improved health outcomes over time.
