A List of Interventions Known to Reduce Epigenetic Age in Humans
Epigenetic control over nuclear DNA structure determines which sequences of DNA are exposed to transcription machinery in the cell nucleus, and thus which genes are expressed. As epigenetic decorations to DNA and its structural helpers are constantly added and removed, structure changes and so does gene expression. Which proteins are produced from their genetic blueprints, and in what amounts, is an important determinant of cell behavior. Epigenetic patterns and the structure of DNA changes with age, and so does gene expression. There are any number of examples of age-related changes in the level of expression of a specific protein that are clearly harmful, as animal studies have shown that health improves when the change is reversed.
If one thinks that aging is essentially epigenetic aging, which many people do judging from the vast funding flowing into the development of partial epigenetic reprogramming therapies intended to reset epigenetic decorations to a youthful pattern, then one should probably be very interested in which other interventions are known to reduce epigenetic age in human trials. People with other opinions on the nature of aging should still find the list interesting. Still, it has to be said that it is far from clear that there is a usefully comprehensive mapping of aging to epigenetic aging, or that even the better epigenetic clocks are actually measuring biological age, or measuring aspects of it in a way that will accurately reflect any given specific change to biochemistry produced by potential treatments for aging. There are clearly mechanisms of aging that cannot be fixed by reprogramming, such as accumulation of metabolic waste that cannot be effectively broken down by even youthful cells, or mutational damage to DNA.
Epigenetic aging clocks estimate age from DNA methylation patterns and have become central tools in longevity research. More recently, next-generation clocks have been developed to better compensate for the known divergence between chronological age and epigenetic age in ways that relate to lifestyle, health, and age-related disease. Although epigenetic clocks represent investigational biomarkers, these newer models are more strongly associated with all-cause mortality risk than first-generation clocks. As such, interventions that modify them are of interest. To test this, we performed a series of systematic searches and identified 41 human studies reporting the effects of interventions on at least one next-generation epigenetic clock.
Our data suggest that a diverse range of pharmaceutical, lifestyle, supplementation, non-pharmaceutical clinical, and psychosocial interventions can decrease epigenetic age, including exercise, a plant-rich diet, the GLP-1 receptor agonist semaglutide, caloric restriction, ketamine, omega-3 fatty acids, a multivitamin-multimineral supplement, umbilical cord plasma, and the cholesterol-lowering drug pitavastatin. Nicotinamide riboside, rapamycin, senolytics, and several other interventions showed no detectable effect, whereas plasmapheresis and other therapeutics accelerated epigenetic aging. We also summarize reported effect sizes and compare next-generation clocks with respect to their frequency of use and responsiveness to intervention.