A Direct Link Between Genomic Instability and Inflammation in Senescent Cells
Aging is characterized by constant sterile inflammation, a state that is disruptive to tissue structure and function. A number of forms of molecular damage have been shown via various mechanisms to provoke this inflammation. Mitochondrial dysfunction, for example causes mitochondrial DNA to mislocalize to the cytoplasm, where it triggers an innate immune response that evolved to recognize the presence of bacterial DNA. Mitochondria are the evolved descendants of ancient symbiotic bacteria, and their remnant DNA is close enough to bacterial genomes for this to occur.
In today's open access paper, researchers discuss a different direct link between mutational damage to the genome and inflammation. It nonetheless also involves mitochondria and triggering of the cGAS-STING pathway that recognizes mislocalized DNA fragments. The authors of the paper consider this mechanism in the context of senescent cells, which actively generate inflammatory signaling. Senescent cells are also characterized by DNA damage, and undergo a significant amount of that damage in the process of becoming senescent. Research into the mechanisms driving senescent cell inflammatory signaling may lead to ways to suppress this damaging contribution to the inflammation of aging.
A mitochondria-regulated p53-CCF circuit integrates genome integrity with inflammation
Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Understanding their interrelationship will help unravel new mechanisms and therapeutic targets of aging and age-associated diseases. Here we report a novel mechanism directly linking genomic instability and inflammation in senescent cells, through a mitochondria-regulated molecular circuit that connects the p53 tumor suppressor and cytoplasmic chromatin fragments (CCF), a driver of inflammation through the cGAS-STING pathway.
Activation or inactivation of p53 by genetic and pharmacologic approaches showed that p53 suppresses CCF accumulation and the downstream inflammatory senescence-associated secretory phenotype (SASP), independent of its effects on cell cycle arrest. p53 activation suppressed CCF formation by promoting DNA repair, reflected in maintenance of genomic integrity, particularly in subtelomeric regions, as shown by single cell genome resequencing. Activation of p53 by pharmacological inhibition of MDM2 in old mice decreased features of SASP in liver, indicating a senomorphic role in vivo. Remarkably, mitochondria in senescent cells suppressed p53 activity by promoting CCF formation and thereby restricting ATM-dependent nuclear DNA damage signaling.
This data provides evidence for a mitochondria-regulated p53-CCF circuit in senescent cells that controls DNA repair, genome integrity and inflammatory SASP, and is a potential target for senomorphic healthy aging interventions.