Autophagy activator AA-20 improves proteostasis and extends Caenorhabditis elegans lifespan
- Ee Phie Tan
- Nora Lyang
- Saam Doroodian
- Pablo Sanz-Martinez
- Jin Xu
- Sviatlana Zaretski
- José L. Nieto-Torres
- Hiroshi Ebata
- Shaun H. Y. Lim
- William C. Hou
- Khalyd J. Clay
- Leonard Yoon
- Lynée A. Massey
- Derek Rhoades
- Danny Garza
- Kristen A. Johnson
- Alan To
- Lydia Ambaye
- Emily P. Bentley
- Michael Petrascheck
- Alexandra Stolz
- Jeffery W. Kelly
- Malene Hansen
2025-08-04
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 AA-20 that enhances autophagy and lipid droplet clearance in human cells and in the nematode Caenorhabditis elegans . AA-20 reduces polyglutamine aggregation in an autophagy-dependent manner in both human cells and C. elegans , where it also promotes fitness. Consistently, we found that AA-20 extends lifespan in WT C. elegans, but not in autophagy-deficient mutants. Interestingly, our findings suggest that AA-20 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 AA-20 , which may have potential therapeutic implications for aging-related proteinopathies and lipid storage disorders.