Autophagy activator AA-20 improves proteostasis and extends <i>Caenorhabditis elegans</i> lifespan
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.
Authors
- José L. Nieto-Torres (ORCID: https://orcid.org/0000-0002-5515-9604)
- Hiroshi Ebata (ORCID: https://orcid.org/0000-0003-2109-159X)
- William C. Hou (ORCID: https://orcid.org/0009-0009-8635-438X)
- Malene Bredahl Hansen (ORCID: https://orcid.org/0000-0003-2006-3503)
- Khalyd J. Clay (ORCID: https://orcid.org/0000-0003-1381-5295)
- Derek Rhoades (ORCID: https://orcid.org/0000-0002-9536-424X)
- Emily P. Bentley
- Shaun H. Y. Lim (ORCID: https://orcid.org/0000-0003-1249-8347)
- Ee Phie Tan (ORCID: https://orcid.org/0000-0003-1352-0366)
- Leonard Yoon (ORCID: https://orcid.org/0000-0002-8663-5757)
- Kristen Johnson (ORCID: https://orcid.org/0000-0003-0788-7217)
- Alan To
- Jin Xu (ORCID: https://orcid.org/0000-0002-5270-0223)
- Sviatlana Zaretski
- Pablo Sanz-Martinez (ORCID: https://orcid.org/0000-0001-8548-8188)
- Jeffery W. Kelly (ORCID: https://orcid.org/0000-0001-8943-3395)
- Alexandra Stolz (ORCID: https://orcid.org/0000-0002-3340-439X)
- Lynée A. Massey (ORCID: https://orcid.org/0000-0002-6908-229X)
- Michael Petrascheck (ORCID: https://orcid.org/0000-0002-1010-145X)
- Saam Doroodian
- Danny Garza
- Lydia Ambaye
- Nora Lyang
Institutions
- Goethe University Frankfurt (DE)
- Scripps Research Institute (US)
- Buck Institute for Research on Aging (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Discovery Institute (US)
- Frankfurt Institute for Advanced Studies (DE)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-08-04
- DOI
- https://doi.org/10.1073/pnas.2423455122
- Citations
- 2
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 2.71
Funders
- American Diabetes Association
- Larry L. Hillblom Foundation
- Ministerio de Ciencia e Innovación
- National Institutes of Health