The problem this study set out to fix. Epigenetic clocks estimate biological age from DNA methylation patterns in a blood sample, and companies sell them as a way to see whether something you are doing is working. But until now, nobody had checked whether the clocks respond consistently to real interventions across a large number of studies. Lead researcher Raghav Sehgal, an associate research scientist in psychiatry at Yale School of Medicine, put it directly to Yale News: "For the first time we've shown that certain therapies have measurable impacts. This wasn't previously possible, because we didn't have enough data to say these biomarkers are consistently responsive to these interventions."
What they built. The team harmonized 51 longitudinal intervention studies into a single database, TranslAGE, and calculated 16 major epigenetic clocks plus 94 other DNA methylation biomarkers for every study using the same methods. That consistency is the point: individual studies have used different clocks and different analysis choices for years, which made it impossible to compare results across them.
Prescription drugs moved the needle. Interventions already prescribed for metabolic or inflammatory disease produced the strongest, most consistent drops in epigenetic age: metformin, the GLP-1 receptor agonist semaglutide, and anti-TNF anti-inflammatory therapies. These are drugs people take for a diagnosed condition, not something bought off a longevity website.
Diet and exercise held up too. Lifestyle interventions, especially exercise combined with a healthy diet, consistently decreased epigenetic age across studies. Mediterranean-style eating showed up repeatedly. The effect was real but smaller than what the prescription drugs produced.
Supplements mostly did not show up. Over-the-counter longevity supplements, the products marketed hardest at the audience reading this, produced little to no measurable change across the 16 clocks. Newer, second-generation clocks built to predict mortality and pace of aging showed the strongest and most consistent responses overall; older, first-generation clocks were noisier.
A moving clock is not proof of anything by itself. The paper is explicit that responsiveness is not the same as validity: a biomarker changing after treatment does not prove that lifespan or healthspan changed. People with a diagnosed disease also showed larger clock changes than healthy volunteers, which is a reminder that reversing illness can look like reversing aging on a DNA methylation readout without being the same thing.
Semaglutide was one of the interventions with the clearest effect in this study. If you are on a GLP-1 drug, see what to expect from your blood work before and after starting one.