As our bodies grow, cells proliferate to form tissues, and cells frequently have to be repaired or replaced throughout life. But the genome can also become less stable over time, or may pick up mutations that can lead to disease; these and other processes can cause cells to enter a state in which they stop dividing, known as senescence. Senescent cells become more common as we age. There also tends to be more inflammation as we age, but the link between increasing instability in the genome and inflammation is not well understood. Now scientists have reported a direct connection between DNA instability and inflammation in senescent cells. The findings have been reported in Nature Communications.
"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," noted senior study author Peter Adams, Ph.D., director and professor of the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys.
Senescent cells secreting these inflammatory molecules are said to have the senescence-associated secretory phenotype (SASP). When there are high levels of these inflammatory secretions, it my lead to a form of chronic inflammation known as inflammaging, which has been previously associated with many age-related diseases.
In this study, the researchers generated senescent human cells by irradiating them. Bits of damaged DNA, called cytoplasmic chromatin fragments (CCF) can be released into cellular cytoplasm from the nucleus. CCF can lead to SASP. When the irradiated cells were analyzed, the scientists determined that a crucial DNA repair protein called p53 can reduce CCF, and SASP.
In aged mice in which p53 was activated, there were still the same high levels of senescent cells that are typical of aged mice. But less CCF accumulated, so biomarkers of age-related SASP were reduced, which may also reduce inflammaing.
Mitochondria can help influence the SASP-suppressing action of p53. Mitochondria were found to be dysfunctional in senescent cells, and these stressed powerhouses can lead to the formation of CCF. When the damaged mitochondria in senescent cells were removed, CCF formation was suppressed, and p53 was activated.
"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 first study author Karl Miller, Ph.D., staff scientist in the Adams lab at Sanford Burnham Prebys. "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."
Sources: Sanford Burnham Prebys, Nature Communications
