The rise in life expectancy has significantly increased the occurrence of age-related chronic diseases, leading to escalating expenses for both society and individuals. Among the main factors influencing health and lifespan, lifestyle takes a forefront position. Specifically, nutrition, mental activity, and physical exercise influence the molecular and functional mechanisms that contribute to the prevention of major age-related diseases. Gaining deeper insights into the mechanisms that drive the positive effects of healthy lifestyles is valuable for creating interventions to prevent or postpone the development of chronic degenerative diseases. This review summarizes the main mechanisms that underlie the positive effect of lifestyle factors in counteracting the major age-related diseases involving brain health, musculoskeletal function, cancer, frailty, and cardiovascular diseases, among others. This knowledge will help to identify high-risk populations for targeted intervention trials and discover new biomarkers associated with healthy aging.