Inhibition of the metalloprotease ADAM19 as a novel senomorphic strategy to ameliorate gut permeability and senescence markers by modulating senescence-associated secretory phenotype (SASP)
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Abstract
Accumulation of DNA damage can accelerate aging through cellular senescence. Previously, we established a Drosophila model to investigate the effects of radiation-induced DNA damage on the intestine. In this model, we examined irradiation-responsive senescence in the fly intestine. Through an unbiased genome-wide association study (GWAS) utilizing 156 strains from the Drosophila Genetic Reference Panel (DGRP), we identified meltrin β (the drosophila orthologue of mammalian ADAM19) as a potential modulator of the senescence-associated secretory phenotype (SASP). Knockdown of meltrin β resulted in reduced gut permeability, DNA damage, and expression of the senescence marker β-galactosidase (SA-β-gal) in the fly gut following irradiation. Additionally, inhibition of ADAM19 in mice using batimastat-94 reduced gut permeability and inflammation in the gut. Our findings extend to human primary fibroblasts, where ADAM19 knockdown or pharmacological inhibition decreased expression of specific SASP factors and SA-β-gal. Furthermore, proteomics analysis of the secretory factor of senescent cells revealed a significant decrease in SASP factors associated with the ADAM19 cleavage site. These data suggest that ADAM19 inhibition could represent a novel senomorphic strategy.
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- Authors
- Bar, S., Hilsabeck, T. A. U., Pattavina, B., López-Domínguez, J. A., Basisty, N., Bons, J., Watson, M., Schilling, B., Campisi, J., Kapahi, P., & Sharma, A.
- Affiliations
- Buck Institute for Research on Aging (US)
- Buck Institute for Research on Aging, Novato, CA 94945, USA
- National Institutes of Health (US)
- Corresponding author
- Sharma, Amit
- ORCID
- Venue
- Aging
- Publisher
- Impact Journals, LLC
- Published
- 2025-03-20
- Volume
- 17
- Issue
- 3
- Pages
- 757-777
- ISSN
- 1945-4589 (ISSN-L)
- PMC
- PMC11984429
- OpenAlex
- W4408658383
- Cited by
- 3
- References
- 78
- Citations by year
- 2026: 3
- FWCI
- 1.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Aging (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion, cc-by)
- Funders
- Larry L. Hillblom Foundation (2019-A-026-FEL)
- SENS Research Foundation
- Buck Institute for Research on Aging
- National Institutes of Health (1s10od016281-01)
- National Institute on Aging (R01AG038688, R21AG054121, R01AG045835, U01AG060906, P01AG017242)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- ADAM19, metalloprotease inhibition, senescence, intestinal permeability, senescence-associated secretory phenotype, intestinal barrier
- MeSH terms
- Senescence-Associated Secretory Phenotype, Aging, Animals, DNA Damage, Humans, Permeability, Cellular Senescence, Drosophila Proteins, Mice, ADAM Proteins, Genome-Wide Association Study
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