Epigenetic Age Acceleration and Cardiometabolic Biomarkers in Response to Weight‐Loss Dietary Interventions Among Obese Individuals: The <scp>MACRO</scp> Trial

Epigenetic clocks have emerged as promising biomarkers of aging, but their responsiveness to lifestyle interventions and relevance for short-term changes in cardiometabolic health remain uncertain. In this study, we examined the associations between three epigenetic aging measures (DunedinPACE, PCPhenoAge acceleration, and PCGrimAge acceleration) and a broad panel of cardiometabolic biomarkers in 144 obese participants from the MACRO trial, a 12-month weight-loss dietary intervention comparing low-carbohydrate and low-fat diets. At pre-intervention baseline, DunedinPACE was significantly associated with several cardiometabolic biomarkers (FDR [false discovery rate] < 0.05), including insulin, homeostatic model assessment for insulin resistance (HOMA-IR), total cholesterol, high-density lipoprotein cholesterol, C-reactive protein, adiponectin, and ghrelin. These associations were substantially attenuated following the intervention, with only CRP and adiponectin remaining significant. Changes in epigenetic aging measures were not significantly associated with changes in biomarkers, nor did they mediate the effects of weight loss. Our findings highlight DunedinPACE as a sensitive biomarker of cardiometabolic health in adults with obesity but raise questions about the utility of epigenetic clocks as causal targets in short-term lifestyle interventions. While caloric restriction may attenuate some phenotypic manifestations of biological aging, short-term changes in epigenetic aging measures may not fully reflect underlying cardiometabolic changes. These results underscore the need for caution in interpreting epigenetic aging as a modifiable intervention target.