Impact of diet and lifestyle interventions on core molecular longevity pathways and the human healthspan: a mechanistic review

Aging is a complex, multifactorial biological process and the primary risk factor for chronic disease.While genetic factors play a role, environmental interventionsspecifically diet and lifestyle-profoundly impact the rate and quality of human aging.This mechanistic narrative review integrates recent advances, focusing on the dynamic modulation and synergistic interactions between interventions and core longevity pathways.We examine how caloric restriction (CR), intermittent fasting (IF), and macronutrient ratios-especially protein restriction (PR)-affect key molecular pathways, including the sirtuin, AMP-activated protein kinase (AMPK), and Mechanistic Target of Rapamycin (mTOR) pathways.We also show how this work relates to human clinical work and how it affects new biomarkers, such as the epigenetic clock, as well as the gut microbiome's impact on long-term diet-related outcomes.We also have an interactive model that illustrates how physical activity and diet interact along these pathways, highlighting mechanisms such as hormesis and interorgan communication.Understanding these linked processes will be essential to devising personalized longevity approaches to lengthen human healthspan and reverse age-related decline.