Form and function of actin impacts actin health and aging
Abstract The actin cytoskeleton is a fundamental and highly conserved structure that functions in diverse cellular processes, yet its direct contribution to organismal aging remains unclear. Here, we systematically interrogated how genetic and pharmacologic perturbations of actin structure and function influence lifespan and various hallmarks of aging in Caenorhabditis elegans . Whole-animal and tissue-specific knockdown of actin and key actin-binding proteins (ABPs) - arx-2 (Arp2/3), unc-60 (cofilin), and lev-11 (tropomyosin) - led to premature disruption of filament organization, reduced lifespan, and tissue-specific physiological defects. Bulk and single-nucleus RNA-sequencing revealed that ABP knockdowns elicited a strongly “aged” transcriptome. Actin dysfunction broadly exacerbated many age-associated phenotypes, including mitochondrial dysfunction, lipid dysregulation, loss of proteostasis, impaired autophagy, and intestinal barrier failure. Pharmacological destabilization with Latrunculin A mirrored genetic knockdowns, while mild stabilization with Jasplakinolide modestly extended lifespan, emphasizing that optimal and finely-tuned actin function is critical for healthy aging. Finally, analysis of human genome-wide association data revealed that common ACTB polymorphisms correlate with differences in age-related decline in gait speed, suggesting evolutionary conservation of actin’s role in healthy aging. Taken together, our results provide a comprehensive and publicly accessible resource that maps, for the first time, how actin integrity intersects with diverse aging pathways across tissues and scales. This descriptive framework is intended to enable future mechanistic discovery by offering a deep, unbiased dataset that can be integrated with emerging studies to define how actin dynamics contribute to aging.
Authors
- Toni Castro Torres (ORCID: https://orcid.org/0000-0003-0498-5452)
- Maxim Averbukh (ORCID: https://orcid.org/0000-0002-8516-5714)
- Tyler A. Johnson (ORCID: https://orcid.org/0000-0001-6816-726X)
- M. Nickel (ORCID: https://orcid.org/0000-0003-0419-1329)
- Tripti Nair (ORCID: https://orcid.org/0000-0002-5380-4622)
- Darius Moaddeli
- J. Kim (ORCID: https://orcid.org/0009-0003-6813-2798)
- Naibedya Dutta
- Thalida Em Arpawong (ORCID: https://orcid.org/0000-0001-9671-9535)
- Aeowynn J. Coakley (ORCID: https://orcid.org/0000-0002-9753-2198)
- Shihong Max Gao (ORCID: https://orcid.org/0000-0003-3238-8348)
- Caitlin M. Lange (ORCID: https://orcid.org/0000-0003-4146-5288)
- Ryo Higuchi‐Sanabria (ORCID: https://orcid.org/0000-0001-8936-5812)
- R Barahona
- Shoichiro Ono (ORCID: https://orcid.org/0000-0002-4763-0398)
- Tiffany V. Wang (ORCID: https://orcid.org/0000-0003-2056-4658)
- Navjot Singh (ORCID: https://orcid.org/0000-0003-0409-8482)
- Hunter T. Nelson
- Athena Alcala
- Caroline Kumsta (ORCID: https://orcid.org/0000-0003-3839-4888)
- Maria Oorloff
- Joe A. Gerke
- Sofia F. Odron
- Jacqueline G. Clarke
- Gilberto J. Garcia
- Matthew Vega
- Hemal H. Mehta (ORCID: https://orcid.org/0000-0002-8439-278X)
- Jacob C. Peterson
- Hannah L. Lam-Truong
- Melissa Peruch
- Meng C. Wang
- Khristina E. Young
- Sean P. Curran
- Max A. Thorwald
- Daniella Suh
- Bérénice A. Benayoun
- Cristal M. Hill
- Eileen M. Crimmins
Institutions
- University of Southern California (US)
- Howard Hughes Medical Institute (US)
- Emory University (US)
- Dominican University of California (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Janelia Research Campus (US)
- Discovery Institute (US)
Publication Details
- Journal
- iScience
- Published
- 2026-08-24
- DOI
- https://doi.org/10.1016/j.isci.2026.117256
- Citations
- 1
- Primary Topic
- Genetics, Aging, and Longevity in Model Organisms
- Type
- article
- Field-Weighted Citation Impact
- 3.31
Funders
- Hevolution Foundation
- Howard Hughes Medical Institute
- Simons Foundation
- Larry L. Hillblom Foundation
- Glenn Foundation for Medical Research
- Fondation pour la Recherche Médicale
- National Institutes of Health
- National Institute on Aging
- National Institute of General Medical Sciences