In humans and other multicellular organisms, cells multiply. This defining feature allows embryos to grow into adulthood, and enables the healing of the many bumps, bruises and scrapes along the way.
Certain factors can cause cells to abandon this characteristic and enter a zombie-like state known as senescence where they persist but no longer divide to make new cells. Our bodies can remove these senescent cells that tend to pile up as we age. The older we get, however, the less efficient our immune systems become at doing so.
“In addition to no longer growing and proliferating, the other hallmark of senescent cells is that they have this inflammatory program causing them to secrete inflammatory molecules,” said Peter Adams, Ph.D., director and professor of the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys and senior and co-corresponding author of the study.
Cells “running” this inflammatory program are considered to exhibit the senescence-associated secretory phenotype (SASP). Too many cells with SASP secreting inflammatory molecules can contribute to chronic inflammation in the body. This pervasive inflammation—called “inflammaging”—has been linked to many age-related diseases.
Scientists at Sanford Burnham Prebys and collaborators across the country published findings in Nature Communications showing that the mitochondria powering our cells also control the ability of a DNA repair protein to suppress SASP, which may reduce or delay inflammaging.
The research team turned human cells senescent by exposing them to radiation and then used those cells to demonstrate that DNA fixer tumor protein p53 suppressed SASP and one of its triggering events, the formation of cytoplasmic chromatin fragments (CCF).
These fragments are bits of damaged DNA that have been spewed from the cells’ nuclei into the gel-like cytoplasm that occupies the space in the cell between the outer membrane and central nucleus. The presence of DNA where it does not belong can trigger the immune system and contribute to SASP.
The scientists validated their findings in mice by treating them with a drug developed by cancer researchers to activate p53 as a way of suppressing tumors. In aged mice, the drug did not reduce the number of senescent cells but instead reversed the cellular signature that marks age-associated SASP, potentially stopping the inflammatory pollution that can lead to inflammaging.
In addition, the investigators discovered that senescent cells suffer from dysfunction in the mitochondria, serving as cells’ primary source of energy. Stressed mitochondria can cause senescent cells to form CCF and dampen the expression of the gene carrying the blueprint for p53.
“Altogether, we’ve identified a cellular circuit capable of promoting DNA repair and genome integrity while suppressing the dangerous inflammatory feature of senescent cells that contribute to age-related diseases,” said Karl Miller, Ph.D., staff scientist in the Adams lab at Sanford Burnham Prebys and lead and co-corresponding author of the study.
“We also have shown that this pathway can be modified by existing drugs in cultured cells and mice, so it may be possible to one day design a treatment that targets p53 to promote healthier aging.”
More information: Karl N. Miller et al, p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells, Nature Communications (2025). DOI: 10.1038/s41467-025-57229-3
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