Inhibition of the metalloprotease ADAM19 as a Novel Senomorphic Strategy to Ameliorate gut permeability and senescence markers by modulating senescence-associated secretory phenotype (SASP)

Bar, S.; Hilsabeck, T. A. U.; Pattavina, B.; Dominguez, J. A. L.; Basisty, N.; Bons, J.; Watson, M.; Schilling, B.; Campisi, J.; Kapahi, P.; Sharma, A.

doi:10.1101/2024.12.16.628718

bioRxiv · 10.1101/2024.12.16.628718

Inhibition of the metalloprotease ADAM19 as a Novel Senomorphic Strategy to Ameliorate gut permeability and senescence markers by modulating senescence-associated secretory phenotype (SASP)

Bar, S.·Hilsabeck, T. A. U.·Pattavina, B.·Dominguez, J. A. L.·Basisty, N.·Bons, J.·Watson, M.·Schilling, B.·Campisi, J.·Kapahi, P.·Sharma, A.

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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 {beta} (the drosophila orthologue of mammalian ADAM19) as a potential modulator of the senescence-associated secretory phenotype (SASP). Knockdown of meltrin {beta} resulted in reduced gut permeability, DNA damage, and expression of the senescence marker {beta}-galactosidase (SA-{beta}-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-{beta}-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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Bar, S., Hilsabeck, T. A. U., Pattavina, B., Dominguez, J. A. L., Basisty, N., Bons, J., Watson, M., Schilling, B., Campisi, J., Kapahi, P., Sharma, A.. 2024-12-20. Inhibition of the metalloprotease ADAM19 as a Novel Senomorphic Strategy to Ameliorate gut permeability and senescence markers by modulating senescence-associated secretory phenotype (SASP). https://doi.org/10.1101/2024.12.16.628718

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