Scientists have identified a mechanism that helps aging cells drive the chronic inflammation that is linked to many age-related diseases. The findings help explain how dysfunctional mitochondria work with the cell’s epigenetic machinery to turn on inflammatory genes. Full details are available in a Nature paper titled “Mitochondrial metabolism and epigenetic crosstalk drive SASP” that is available now.
Existing research shows that senescent cells accumulate with age and remain metabolically active even though they no longer divide. As they accumulate, they release a cocktail of inflammatory molecules known as the senescence-associated secretory phenotype, or SASP. This inflammation is thought to contribute to frailty, cardiovascular disease, cancer, neurodegeneration, and other disorders of aging.
In the current study, the scientists focused on switching off this inflammation rather than on getting rid of senescent cells as some other approaches have tried.
The study was done by teams at Mayo Clinic and Sanford Burnham Prebys Medical Discovery Institute and their collaborators elsewhere. It builds on previous work done by João Passos, PhD, a Mayo Clinic researcher and senior author of the study. Passos’ lab previously demonstrated that damaged mitochondria leak mitochondrial DNA and RNA into the cell and this activates immune pathways that trigger inflammation. The current Nature study identifies a second, independent pathway that is equally essential.
“We found that inflammatory signaling alone isn’t enough,” according to Helene Martini, PharmD, PhD, a Mayo Clinic researcher and first author of the study. “The cells also need a metabolic signal from mitochondria that changes how inflammatory genes are turned on.”
Specifically, the scientists discovered that senescent cells increase production of acetyl-CoA. This molecule can be generated from a range of sources in the body, but the data indicate “that in senescent cells, mitochondria constitute a dominant source of acetyl-CoA for chromatin modification.” Once released, acetyl-CoA enables epigenetic modifications that make inflammatory genes more accessible, allowing them to be expressed. Essentially, “we found that dysfunctional mitochondria can promote inflammation by controlling epigenetic switches that turn inflammatory genes on,” Martini said.
In addition, the team identified a promising therapeutic target. They found that blocking a mitochondrial citrate transporter known as SLC25A1 reduced the supply of acetyl-CoA, which “reduces histone acetylation at SASP loci.” In other words, it limited inflammatory gene activation even though the initial immune signals remained present. “These findings position SLC25A1 inhibition as a novel therapeutic target that modulates the inflammatory output of senescent cells through metabolic–epigenetic coupling,” the scientists wrote. “More broadly, they suggest that targeting metabolic inputs into chromatin regulation may represent a tractable strategy to mitigate age-associated inflammation and functional decline.”
