Autophagy decline during ageing: Molecular regulation, tissue specificity, and therapeutic potential.

During ageing, cell regulation has declined, as indicated by the buildup of damaged organelles and macromolecules and impaired proteostasis. Autophagy is a lysosome-based cell self-digestion mechanism that removes "cellular waste," which includes damaged organelles and abnormally altered proteins or protein aggregates. Thus, autophagy is a mechanism that is effective in maintaining normal cellular functioning via regulating the quality of proteins and organelles. However, ageing tissues and several age-related disorders have been demonstrated to have dysfunctional autophagy, resulting in the pathogenesis of cardiovascular, neurodegenerative, metabolic, muscular, and ocular disorders. Molecularly, dysregulation of nutrient-sensing pathways such as AMPK and mTOR, impaired transcriptional control by TFEB and FOXO, and reduced lysosomal competence contribute to the reduction of autophagy. Moreover, in several preclinical studies, pharmacological agents restore autophagic flux via inhibition of mTOR, activation of AMPK, and polyphenols, caloric restriction, and exercise (lifestyle interventions), show an effective role in the treatment of several disorders related to ageing. Furthermore, substantial pre-clinical data indicate the current knowledge about the molecular regulation of autophagy, its tissue-specific decline during ageing, and therapeutic strategies to restore autophagy to treat age-related disorders. Additionally, there is no clinical data available in order to confirm the safety and efficacy of their treatment, so a deeper study of autophagic modulation could serve as a basis for therapeutic interventions that encourage healthy ageing and delay age-related disorders in clinical models as well. Conclusively, according to several preclinical data, therapeutic measures show an effective role in treating several age-related disorders via targeting the autophagy pathway.