From semaglutide and omega-3s to plant-rich diets and statins, a new review maps which human interventions shift next-generation epigenetic aging clocks, while cautioning that clock changes do not yet prove age reversal.
Study: Turning back time: a comprehensive list of interventions that decrease next-generation epigenetic aging clocks in humans. Image Credit: Lightspring / Shutterstock
A new paper published in the journal Frontiers in Genetics provides a comprehensive list of interventions reported to reduce estimates of next-generation epigenetic aging clocks in humans.
Background
Epigenetic aging clocks are powerful machine learning methods that use DNA methylation information to estimate chronological and clock-predicted biological age, as well as to assess how anti-aging and disease-preventive interventions affect epigenetic aging markers.
The first-generation epigenetic clocks were built and trained exclusively to predict a person’s chronological age, which reflects the exact amount of time a person has spent on earth since birth. Next-generation clocks, on the other hand, have been explicitly trained to associate with healthspan, lifestyle, disease, mortality risk, and the speed of the aging process, thereby making them more strongly associated with biological age-related outcomes than earlier clocks.
However, these clocks remain investigational biomarkers and are not yet validated clinical surrogate endpoints. Changes in clock outputs do not necessarily prove improved clinical outcomes or true whole-body age reversal.
Given the growing interest in the responsiveness of next-generation clocks to anti-aging interventions, Adiv Johnson from Tally Health and David Sinclair from Harvard Medical School performed a series of systematic searches and identified 41 human studies reporting the effects of interventions on at least one next-generation epigenetic clock. Their primary aim was to highlight performance differences in terms of responsiveness.
Interventional Studies Involving Next-Generation Epigenetic Aging Clocks
The analysis of studies using different pharmaceuticals, including emtricitabine-tenofovir-alafenamide, semaglutide, ketamine, pitavastatin, decitabine, bezisterim, metformin, antiretroviral therapy, and related nucleos(t)ide reverse transcriptase inhibitor regimens, revealed significant changes in at least one next-generation epigenetic aging clock.
A 12-week treatment with emtricitabine-tenofovir-alafenamide (anti-viral combination medication) was found to reduce several epigenetic clock outputs in healthy individuals without HIV, although it also reduced AdaptAge, a clock intended to capture beneficial adaptive changes.
A 32-week semaglutide (Glucagon-Like Peptide-1">GLP-1 receptor agonist) treatment was found to reduce a range of next-generation epigenetic aging clocks predicting clock-estimated biological age and aging speed in patients with HIV-related lipohypertrophy.
A reduction in OMICmAge was observed following 2-3 weeks of ketamine infusions (psychiatric drug) in patients with major depressive disorder or post-traumatic stress disorder, while other initially significant clock changes did not remain significant after correction. After two years of pitavastatin (cholesterol-lowering drug) treatment in patients with HIV infection, DunedinPACE was significantly reduced.
Lifestyle and Supplementation Findings
The analysis of studies using different lifestyle interventions or supplements, including a plant-rich diet, exercise, calorie restriction, omega-3 fatty acids, and multivitamin-multimineral supplements, revealed significant changes in at least one next-generation epigenetic aging clock.
Two years of multivitamin-multimineral supplementation was found to reduce two PC-based epigenetic clock measures reflecting clock-predicted biological age and mortality risk in healthy individuals. Similarly, a 6-week supplementation with omega-3 fatty acids was found to reduce epigenetic clocks reflecting harmful age-related changes and increase epigenetic clocks reflecting protective, adaptive changes in overweight individuals.
A similar reduction in epigenetic clock-predicted biological age and mortality risk was observed in healthy individuals receiving a plant-rich diet, but not in the physical activity arm alone. In non-obese individuals, a 2-year calorie restriction was found to reduce epigenetic clock-predicted biological aging speed.
Not all lifestyle or supplementation approaches produced favorable clock changes. One study found that supplementation, combined with encouragement to walk and practice mindfulness, increased DunedinPACE after 1 year.
Non-Pharmaceutical Therapeutics and Psychosocial Findings
Three significant non-pharmaceutical clinical therapeutics were identified, including plasmapheresis, umbilical cord plasma concentrate, and kidney transplantation or dialysis. Among these therapeutics, plasmapheresis (the removal of plasma) was found to increase selected epigenetic-age and aging-speed clock outputs in healthy individuals. In contrast, both kidney transplantation and umbilical cord plasma therapy reduced selected epigenetic aging measures in patients with chronic kidney disease and healthy individuals, respectively.
Among psychosocial interventions, a 20-week internet-based training program for parent-child interaction was found to reduce biological aging speed in young individuals with developmental delay.
Non-Significant Findings
This category included the highest number of studies and interventions. Among different interventions that failed to significantly alter epigenetic aging, metformin produced mixed results. While a 6-month metformin treatment failed to improve epigenetic aging clocks in overweight or obese breast cancer survivors, a 24-week treatment with this anti-diabetic drug significantly reduced PC DNAm PhenoAge and PC GrimAge in individuals with virologically suppressed HIV and normal glucose.
Other interventions that produced non-significant outcomes included green-based supplements, rapamycin, home-based exercise, some antiretroviral therapy strategies, a relationship education program, folic acid, and nicotinamide riboside, among others.
Magnitude of Interventional Outcomes
Among the interventions analyzed, the greatest impact was observed with emtricitabine-tenofovir-alafenamide, which reduced DNAm PhenoAge by more than 6 years. Other notable interventions with significant clock-reducing effects were omega-3 fatty acids, semaglutide, bezisterim, and kidney transplantation, with semaglutide also showing a second large effect on Systems Age.
Among interventions that reduced the speed of biological aging, the greatest impact was observed with semaglutide, followed by emtricitabine-tenofovir-alafenamide, an internet-based training program for parent-child interaction, pitavastatin, protein-energy supplementation, caloric restriction, and omega-3 fatty acids.
The authors emphasized that these reported effect sizes are model-derived estimates and do not directly translate into changes in whole-body biological aging or expected lifespan.
Take-Home Message
This systematic search-based review highlights the reported responsiveness of well-established interventions in slowing down next-generation epigenetic aging clocks that estimate physiological conditions of cells and tissues (clock-predicted biological age) based on chemical modification of DNA (methylation status).
Future studies are needed to decode how these interventions modulate DNA methylation status to accelerate or decelerate epigenetic age estimates. Further validation against age-related health outcomes will also be needed before these clocks can be used as clinical surrogate endpoints. Interpretability of the findings is particularly valuable in a clinical context. Recent advances in artificial intelligence have led to the development of more interpretable epigenetic clocks.
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