Transcriptional Dysregulation of Autophagy in Aging and Potential Interventions: Insights Into TFEB and FOXOs

Autophagy is a highly conserved cellular degradation and recycling process essential for maintaining cellular homeostasis. However, autophagic activity declines with age, contributing to the accumulation of damaged organelles and protein aggregates. The decline in autophagic activity is considered a primary hallmark of aging, as it contributes to cellular dysfunction and the onset of age-associated diseases, including neurodegenerative disorders and metabolic dysfunction. Sustaining autophagy with age requires transcriptional regulation, which may become impaired with age. In this review, we summarize current understanding of transcriptional regulation of autophagy during aging, with a specific focus on transcription factor EB (TFEB) and forkhead box O (FOXO) transcription factors. We integrate mechanistic insights from both mammalian systems and model organisms to highlight how their regulatory activity declines with age through changes in expression, post-translational modifications, nuclear transport, and transcriptional efficiency. We further explore pharmacological and lifestyle interventions aimed at restoring autophagic function to mitigate cellular decline. Given the pivotal role of autophagy in promoting cellular resilience and disease prevention, targeting autophagy-regulating transcription factors holds promise as a therapeutic strategy to counteract age-related functional decline and extend healthspan.