bioRxiv : the preprint server for biologyDec 4, 2023

How p53 controls DNA protection and inflammation linked to cell aging

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 5, 2026

Abstract

A novel mechanism linking genomic instability and inflammation in senescent cells involves a mitochondria-regulated circuit driven by p53.

Genomic instability and inflammation are key characteristics of aging.
p53 activation reduces the accumulation of cytoplasmic chromatin fragments (CCF) and the associated inflammatory response without impacting cell cycle arrest.
Enhanced DNA repair activity from p53 activation helps maintain genomic integrity, especially in subtelomeric regions.
Pharmacological activation of p53 in aged mice reversed markers of aging and inflammation, including changes in liver monocytes and macrophages.
Mitochondria in senescent cells may inhibit p53 function by promoting CCF formation, leading to reduced DNA damage signaling.

Simplified

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 driven by p53 and cytoplasmic chromatin fragments (CCF). We show, through activation or inactivation of p53 by genetic and pharmacologic approaches, that p53 suppresses CCF accumulation and the downstream inflammatory senescence-associated secretory phenotype (SASP), without affecting cell cycle arrest. p53 activation suppressed CCF formation by promoting DNA repair, and this is reflected in maintenance of genomic integrity, particularly in subtelomeric regions, as shown by single cell genome resequencing. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reversed signatures of aging, including age- and senescence-associated transcriptomic signatures of inflammation and age-associated accumulation of monocytes and macrophages in liver. Remarkably, mitochondria in senescent cells suppressed p53 activity by promoting CCF formation and thereby restricting ATM-dependent nuclear DNA damage signaling. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation. This pathway is immunomodulatory in mice and a potential target for healthy aging interventions by small molecules already shown to activate p53.

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How p53 controls DNA protection and inflammation linked to cell aging

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