Diet, Exercise, and Prescription Drugs May Lower Epigenetic Age, but Supplement Evidence Remains Mixed

Highlights

• Pharmacological and lifestyle interventions (such as a healthy diet and regular exercise) lowered epigenetic age, whereas supplements showed less consistent results.
• Overall, prescription drugs produced the most notable effects at lowering epigenetic age.

A large new analysis published in Nature Medicine by Yale University researchers has helped sort longevity interventions into groups of those that lower epigenetic age and those that may not. The analysis found that lifestyle interventions (such as a healthy diet and regular exercise) and certain prescription medications were predicted to lower epigenetic age. The data showed that prescription drugs produced the largest average effects in lowering epigenetic age. Meanwhile, results for supplements were mixed.

In their analysis, the Yale researchers pooled data from 51 longevity intervention studies. They applied a panel of 16 epigenetic clocks (clocks that estimate age based on molecular tagging patterns on DNA), together with an additional 94 markers consisting of small chemical units tagged to DNA (called methyl groups). The researchers applied the epigenetic clocks and the 94 methyl group markers across 3,128 DNA methylation samples from the 51 studies.

The most noteworthy aspect of this study is the scale of it; most studies consist of individual trials measuring the effects of single interventions. In contrast, this study utilized 16 epigenetic aging clocks across dozens of studies to compare dietary, prescription drug, and supplementation interventions.

Background Information on Epigenetic Aging Clocks

Epigenetic aging clocks are statistical models that estimate age-related biology from molecular tagging patterns on DNA (the molecular tagging patterns assessed are methyl groups, and their variable patterns are collectively referred to as methylation patterns). In this study, the epigenetic aging clocks analyzed methylation patterns in blood cells from blood samples.

Our methylation patterns tend to change predictably over the lifespan. Importantly, epigenetic aging clocks do not read a person’s DNA sequence; they measure the proportion of methylation at selected DNA sites and combine these values into a score. The resulting score is an estimate of epigenetic age (an age prediction based on methylation patterns).

People who receive an epigenetic age estimate higher than their chronological age (their age based on the number of years they have lived) are predicted to be undergoing accelerated aging. In the same regard, those with an epigenetic age lower than their chronological age are predicted to be undergoing decelerated or a slower pace of aging.

Epigenetic age deviations from someone’s chronological age have consistently predicted the likelihood of illness, injury, or impaired health (a concept known as morbidity) and mortality. Based on epigenetic clocks’ predictions of morbidity and mortality, some scientists have proposed using these clocks as markers to gauge whether an aging intervention is producing a favorable age-related biological change. Nonetheless, it remains uncertain whether epigenetic age estimates indicating reduced epigenetic age (believed to suggest slowed aging) after taking an intervention mean a longer lifespan or a longer duration lived in overall good health.

If lowered epigenetic age from taking an intervention is synonymous with slowed aging, however, this could make evaluating the efficacy of aging interventions much quicker. This is because epigenetic aging tests can produce readings in five to 10 minutes, while it would take decades to test interventions’ effects on human disease, disability, or death (all parameters related to aging).

The Aging Interventions with the Most Notable Effects

The researchers ran statistical analyses on their pooled data to find which aging interventions slow epigenetic aging. They found that two categories of lifestyle interventions do so. The first was a healthy eating pattern, such as a Mediterranean diet, a low-carbohydrate diet, or a low-fat diet. The second lifestyle intervention that slowed epigenetic aging was regular exercise. These findings suggest that people can slow their epigenetic aging through simple lifestyle alterations.

The largest average effects at lowering epigenetic age came from prescription medications. The medications that conferred these effects were metformin (a diabetes medication under investigation as a longevity drug, semaglutide (prescribed for diabetes and weight management), and anti-TNF therapies (used to control inflammation). These medications significantly decreased epigenetic age across all 16 epigenetic clocks used in the study. These findings, suggesting lowered epigenetic aging, may interest researchers looking for ways to slow aging, but should not be interpreted as meaning healthy people should take them to slow aging. Accordingly, some of the studies analyzed involved specific patient populations, so lowered epigenetic aging may, in part, reflect improvements in an underlying disease rather than a direct effect on aging itself.

Mixed Results for Supplements

The research group found that the data for supplements’ effects on epigenetic aging were limited and inconsistent. This does not, however, mean that supplements have no value for some individuals, especially those with specific vitamin or mineral deficiencies. As such, targeting any given deficiency with supplementation may serve to prevent the onset of any age-related diseases associated with that deficiency.

Key Takeaways from the Epigenetic Clock Analysis

As of yet, there is not a single longevity intervention proven to broadly slow aging in humans. The best ways to prevent accelerated aging or possibly slow aging processes remain not smoking, engaging in regular exercise, eating a healthy diet, getting adequate sleep, as well as managing blood pressure, cholesterol levels, and diabetes. Nonetheless, in this analysis from Yale researchers, pharmacological interventions, such as metformin, produced the largest effects in lowering epigenetic age. This raises the question of whether combining pharmacological agents could have additive effects to further lower epigenetic age greater than any agent on its own.

Relatedly, Restorin, a product not included in the supplements tested, contains multiple components targeting different facets of aging. Its components are designed to lower inflammation, improve the function of the cell’s powerhouses (mitochondria), and suppress pathways linked to aging, such as mTOR (a protein that acts as a cellular nutrient and growth sensor). Whether products like Restorin, which combine multiple strategies to promote longevity, lower epigenetic aging remains to be determined in future human trials. However, from a preclinical perspective, SRN-901 (a drug that Restorin is roughly based on) extended the lifespan of aged mice by 33%, a record-setting achievement.

Nonetheless, the question of whether an intervention lowering epigenetic age means that the intervention actually slows aging remains unresolved. The next step for researchers is to establish whether lowering epigenetic age reliably predicts meaningful physiological outcomes, such as preserving physical and cognitive function, lowering disease rates, and extending life lived in good overall health. Until researchers have demonstrated that epigenetic clocks predict these things, a favorable epigenetic aging reading remains a laboratory result for researchers, not a reliable prediction of a longer life.