"Our data show that ADAM19 may be important in mitigating the inflammatory response to intestinal damage and cellular senescence."
BUFFALO, NY — April 29, 2025 — A new research paper was published in Aging (Aging-US) Volume 17, Issue 3 , on March 20, 2025, titled " Inhibition of the metalloprotease ADAM19 as a novel senomorphic strategy to ameliorate gut permeability and senescence markers by modulating senescence-associated secretory phenotype (SASP) ."
Researchers, led by first author Sudipta Bar and corresponding authors Amit Sharma and Pankaj Kapahi from the Buck Institute for Research on Aging , have found that the enzyme ADAM19 plays an important role in regulating aging in cells and inflammation in the gut. Their study shows that blocking ADAM19 reduced gut damage and inflammation in fruit flies, mice, and human cells. This discovery points to a new possible way to treat gut disorders related to aging by reducing the harmful signals from senescent (aging) cells.
As individuals age, DNA damage can lead to the accumulation of senescent cells, contributing to tissue damage. These are cells that stop dividing and release harmful inflammatory substances called the senescence-associated secretory phenotype (SASP). In this study, researchers used fruit flies to search for genes involved in radiation-related gut damage. They identified a gene called meltrin, which is similar to human ADAM19. When meltrin was turned off, the flies had less gut leakage, less inflammation, and fewer signs of cellular aging.
"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)."
To test if these results applied beyond flies, the team inhibited ADAM19 in mice using a drug called batimastat. Mice treated with the drug after chemotherapy exposure had stronger gut barriers and lower levels of inflammatory markers. The findings extended to human cell cultures, where ADAM19 inhibition reduced signs of cellular aging, including the expression of SASP proteins and β-galactosidase, a classic aging marker.
Importantly, this approach does not kill aging cells like many 'senolytic' therapies but instead reduces the harmful substances they release, making it a potential "senomorphic" strategy. The study also showed that ADAM19 helps release certain SASP proteins by cutting them at the cell surface, suggesting a direct role in regulating inflammatory signals.
Through proteomic analysis, the team identified 12 SASP proteins that were significantly reduced when ADAM19 was blocked. Many of these proteins are linked to inflammation, immune response, and tissue remodeling in diseases such as inflammatory bowel disease and Crohn's disease. This connection underlines the relevance of the findings for treating chronic gut disorders in aging populations.
By targeting ADAM19, researchers may have found a new way to protect gut health and lower inflammation caused by aging cells. This study offers a promising path for creating treatments that maintain healthy tissues without having to destroy aging cells, which could benefit people with gut damage related to aging or medical treatments.
Read the full paper: DOI: https://doi.org/10.18632/aging.206224
