Beyond glucose: How early lifestyle intervention rewires the long-term trajectory of multimorbidity and healthy aging

Intensive lifestyle intervention and metformin are established strategies for preventing type 2 diabetes, yet their comparative effects on long-term multimorbidity remain uncertain. This commentary synthesizes evidence from landmark prevention trials and the recent 21-year follow-up of the US Diabetes Prevention Program to evaluate how early interventions shape chronic disease accumulation. Intensive lifestyle modification consistently reduces long-term multimorbidity risk, whereas metformin shows no significant benefit compared with placebo despite similar efficacy in delaying diabetes. Mechanistically, lifestyle acts as a form of systemic biological reprogramming, simultaneously modulating inflammation, mitochondrial function, and gut microbiome composition to create a broad shield against multisystem aging. In contrast, metformin primarily targets hepatic glucose metabolism, pathways insufficient to counteract the diverse hallmarks driving multimorbidity. Current evidence is limited by homogeneous populations, self-reported behavioral data, and incomplete characterization of molecular mediators linking early lifestyle changes to decades-later outcomes. Future priorities include integrated trials that combine lifestyle with next-generation metabolic therapies, such as GLP-1 receptor agonists; multi-omics profiling to elucidate mechanisms; and broader inclusion of diverse demographic groups. For individuals with prediabetes, current data support prolonged lifestyle intervention as the foundational strategy for preserving healthspan rather than merely preventing hyperglycemia. Clinicians should prioritize sustained behavioral programmes and explore synergistic combinations with emerging pharmacotherapies to optimize healthy aging