Sex matters in macroautophagy: Sex-driven differences in autophagic function in aging and aging related-diseases

Autophagy is a fundamental cellular process essential for maintaining homeostasis, particularly in the context of aging and age-related diseases. Increasing evidence highlights biological sex as a critical modulator of autophagy, influencing its basal activity, regulatory pathways, and responsiveness to stress. Distinct autophagic profiles in males and females (across tissues, species and developmental stages) may underlie sex-specific vulnerabilities and divergent disease trajectories. These differences are evident in conditions such as neurodegeneration, cardiovascular disease, cancer, sarcopenia or chronic inflammation, all of which are commonly associated with aging. Indeed, aging is a major risk factor for the onset and progression of these pathologies. Importantly, sex-dependent variations in autophagy might also impact the efficacy and safety of therapeutic interventions, challenging the validity of uniform treatment strategies. Despite growing recognition of these disparities, significant knowledge gaps remain. This review summarizes current understanding of sex-related differences in autophagy, focusing on genetic and hormonal influences across the lifespan. The evidence supports the need for future research to systematically incorporate sex as a biological variable in experimental design and data analysis, utilize dynamic assessments of autophagy flux and investigate the interplay among genetic, hormonal, epigenetic, and post-translational regulatory mechanisms. Developing preclinical models that reflect human diversity-including genetic heterogeneity and relevant hormonal states-is imperative. Embracing the complexity of sex-dependent autophagy regulation is essential for translating mechanistic insights into effective, personalized interventions that improve health outcomes for both women and men.