Autophagy activator AA-20 improves proteostasis and extends <i>Caenorhabditis elegans</i> lifespan.

Abstract

The degradation of cellular components through autophagy is essential for longevity and healthy aging. However, autophagy function decreases with aging, contributing to age-related diseases. In this study, we characterized a small-molecule activator of autophagy called <b>AA-20</b> that enhances autophagy and lipid droplet clearance in human cells and in the nematode <i>Caenorhabditis elegans</i>. <b>AA-20</b> reduces polyglutamine aggregation in an autophagy-dependent manner in both human cells and <i>C. elegans</i>, where it also promotes fitness. Consistently, we found that <b>AA-20</b> extends lifespan in WT <i>C. elegans,</i> but not in autophagy-deficient mutants. Interestingly, our findings suggest that <b>AA-20</b> acts, at least in part, through a mechanism involving the transcription factor EB, but without inhibiting the protein kinase mammalian target of rapamycin complex 1. Collectively, our results identify an autophagy activator <b>AA-20</b>, which may have potential therapeutic implications for aging-related proteinopathies and lipid storage disorders.