'Zombie' Cells Drive Chronic Inflammation Through a Mitochondrial Switch, Study Finds

As people age, senescent "zombie" cells accumulate in the body: they have stopped dividing but remain metabolically active, releasing inflammatory molecules that contribute to persistent inflammation linked to frailty, cardiovascular disease, cancer and neurodegeneration. Researchers at the Mayo Clinic, working with the Sanford Burnham Prebys Medical Discovery Institute, have identified a previously unknown mechanism that helps explain how these aging cells switch their inflammatory genes into a highly active state, according to a study published in Nature.

Earlier research from the laboratory of senior author Joao Passos had shown that damaged mitochondria - the structures that produce cellular energy - leak mitochondrial DNA and RNA into the cell, activating immune pathways that promote inflammation. The new study shows this inflammatory alarm is only part of the process. "We found that inflammatory signaling alone isn't enough," said first author Helene Martini. "The cells also need a metabolic signal from mitochondria that changes how inflammatory genes are turned on."

That second signal involves acetyl-CoA, a molecule produced through mitochondrial metabolism. Senescent cells make more acetyl-CoA, which supports epigenetic modifications - chemical changes that influence whether genes are active without altering the underlying DNA sequence - making inflammatory genes more accessible to the cellular machinery that reads them.

The researchers also identified a possible point for intervention: SLC25A1, a mitochondrial transporter involved in supplying the acetyl-CoA needed for these epigenetic changes. Blocking SLC25A1 reduced available acetyl-CoA and limited activation of inflammatory genes, even though the original immune signals were still present.

"For years, the field has focused on getting rid of senescent cells," said Passos. "Our strategy has been different. Instead of killing the cells, we asked whether we could switch off the inflammation that makes them harmful."