Predicting and finding geroprotective compounds through modulating conserved longevity–associated aging modules
Currently, no generalizable tools exist for predicting the impact of interventions on aging using gene expression changes. Here, we build a model for predicting potential geroprotectors by deconstructing the aging transcriptome into coexpression modules and identifying those modulated by life span–extending interventions in Caenorhabditis elegans ( C. elegans ). Many of these modules exhibited adaptive changes during aging that are linked to longevity. Using these longevity-associated modules, we predicted and validated 10 compounds (7 previously unreported) that significantly extended life span in C. elegans . RNA sequencing analysis of two top candidates also showed targeted modulation of our longevity-associated modules. We identified conservation of several modules in mice that were also correlated with frailty. Together, our findings demonstrate that beneficial transcriptomic adaptations occur during aging and that targeting longevity-associated modules offers a framework for geroprotector discovery.
Authors
- Brian Keith Kennedy (ORCID: https://orcid.org/0000-0002-5754-1874)
- Esther S.P. Wong (ORCID: https://orcid.org/0000-0003-2421-7346)
- Diogo Barardo (ORCID: https://orcid.org/0000-0001-6177-0728)
- Zhuangli Yee (ORCID: https://orcid.org/0000-0002-0257-5364)
- Weihan Huai
- Sharah Mae Capinpin (ORCID: https://orcid.org/0000-0001-6759-1712)
- Qingyun Wang (ORCID: https://orcid.org/0000-0002-9765-2544)
- Jasinda H. Lee (ORCID: https://orcid.org/0000-0001-7779-8135)
- Shermaine Thein
- Kamil Pabis (ORCID: https://orcid.org/0000-0002-1120-3079)
- Angelica Faye Ga
- Jan Gruber (ORCID: https://orcid.org/0000-0003-3329-3789)
- Zongmin Liu (ORCID: https://orcid.org/0000-0002-5871-5434)
- Jun Tan (ORCID: https://orcid.org/0000-0002-3462-3455)
- Stephen D. Raj (ORCID: https://orcid.org/0000-0003-2927-5000)
- Qing Zhang (ORCID: https://orcid.org/0009-0005-3509-8196)
- Shou-Ping Guan
- Li-Fang Ng (ORCID: https://orcid.org/0000-0002-0792-6864)
- Shivaanisha Raventhiran (ORCID: https://orcid.org/0009-0006-4046-1487)
Institutions
- National University of Singapore (SG)
- Yale-NUS College (SG)
- National University Health System (SG)
Publication Details
- Journal
- Science Advances
- Published
- 2026-09-30
- DOI
- https://doi.org/10.1126/sciadv.aee3657
- Primary Topic
- Genetics, Aging, and Longevity in Model Organisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00