Research Paper Volume 17, Issue 3 pp 757—777
Inhibition of the metalloprotease ADAM19 as a novel senomorphic strategy to ameliorate gut permeability and senescence markers by modulating senescence-associated secretory phenotype (SASP)
- 1 Buck Institute for Research on Aging, Novato, CA 94945, USA
- 2 National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
- 3 Jackson Laboratory, Farmington, CT 06032, USA
- 4 Instituto de Biología Molecular y Celular del Cáncer and Centro de Investigación del Cáncer of Salamanca, University of Salamanca-CSIC, Campus Unamuno s/n, 37007 Salamanca, Spain
- 5 SENS Research Foundation, Mountain View, CA 94041, USA
Received: April 9, 2024 Accepted: March 6, 2025 Published: March 20, 2025
https://doi.org/10.18632/aging.206224How to Cite
Copyright: © 2025 Bar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 (the drosophila orthologue of mammalian ADAM19) as a potential modulator of the senescence-associated secretory phenotype (SASP). Knockdown of meltrin 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.