Abstract
Aging is regulated by both genetic and environmental factors, and Caenorhabditis elegans is a key model due to its conserved longevity pathways. The fln-2 gene, encoding an ortholog of human filamin A (FLNa) with up to 27 isoforms, is known to modulate pharyngeal infection and lifespan in C. elegans. Still, its isoform-specific roles and mechanisms have not been fully elucidated. Here, we demonstrate that mutations specifically disrupting the longest fln-2 isoforms (fln-2a/e/s/t/r/u/v/w) extend healthspan, whereas those disrupting all isoforms shorten it. The FLN-2 A/E/S/T/R/U/V/W are enriched in the pharyngeal epical region, and their loss of function results in enhanced pharyngeal grinding efficiency, reduced pharyngeal infections, decreased bacterial colonization in the intestine, and maintenance of intestinal integrity, ultimately extending lifespan. Dietary restriction has been reported to extend lifespan in multiple species, whereas the fln-2 mutations extend lifespan without reducing food intake. These findings demonstrate the molecular mechanism by which specific fln-2 isoforms modulate aging by enhancing pharyngeal function and reducing intestinal bacterial load, providing a new insight into FLNa’s role in aging.
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All data generated or analyzed in this study are included in the article (and its supplementary information files). It can also contact the corresponding author for additional requests.
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Acknowledgements
We thank Xiaochen Wang for kindly supplying the XW16577 and XW20193 strains. Some strains were obtained from the Caenorhabditis Genetics Center (CGC).
Funding
This research was supported by the Ministry of Science and Technology, People’s Republic of China (2021YFA0909300 and 2022YFE0205400), the National Natural Science Foundation of China (32371227, 32370877, 32170828 and 31830042), the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0503203), and the Macau Science and Technology Development Fund (FDCT) (0007/2019/AKP to Yichun Zhu).
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Author contributions include the following: Y.C., Z.S., and Y.Z. conceived and designed the project. Y.C., A.C., Y.R., and X.M. performed the experiments. Z.S., Y.C., and A.C. analyzed the experimental data and interpreted the experimental results. Y.C., Z.S., and Y.Z. wrote the manuscript. B.T. revised the manuscript. All authors have read and agreed to the published version of the manuscript.
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Chang, YH., Chi, AQ., Ren, YC. et al. fln-2 isoform-specifically regulates Caenorhabditis elegans health span by affecting pharyngeal function. Sci Rep (2026). https://doi.org/10.1038/s41598-026-39461-z
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DOI: https://doi.org/10.1038/s41598-026-39461-z
