Links Between Autophagy and Healthy Aging

• Autophagy is a molecular hallmark of aging, and generally declines over time. • Many longevity interventions induce autophagy to extend lifespan and improve healthspan. • Lifestyle factors, such as diet, exercise, sleep, and temperature modulation, all affect autophagy. • Identification of autophagy modulators holds promise to improve healthspan. Several if not all manifestations of aging can be postponed by a healthy lifestyle involving a balanced diet coupled with regular exercise and sufficient sleep. Similarly, various genetic and pharmacological longevity interventions can exert beneficial effects across species in a conserved manner, extending both lifespan and healthspan. While all these interventions—ranging from genetic perturbations to pharmacological supplementation to lifestyle changes—affect diverse biological processes, a common candidate mechanism underpinning at least some of their benefits is autophagy, a cellular recycling process essential for maintaining cellular homeostasis. In this review, we summarize how autophagy is affected by various pharmacological and lifestyle factors, with a focus on studies in which autophagy has been shown to play a causal role in promoting healthy aging. Specifically, we review the molecular mechanisms through which pharmacological agents, dietary restriction, exercise, sleep adjustments, as well as temperature modulation affect autophagy to extend lifespan and often also healthspan in model organisms and humans. Still, major gaps remain in human research due to limited assays to monitor autophagy and the scarcity of longitudinal studies linking autophagy dynamics to health outcomes. Closing this gap is a key challenge in converting discoveries from model organisms into interventions that consistently enhance healthy aging in humans. By summarizing current findings and highlighting remaining uncertainties, this review aims to provide a roadmap for translating insights on autophagy from model organisms into strategies to promote healthy aging in humans.