A Nature study from Mayo Clinic shows a mitochondrial metabolite unlocks inflammatory genes in senescent cells, and blocking a transporter called SLC25A1 dampened the response.
Chronic, low-grade inflammation is one of the hallmarks of aging. Researchers sometimes call it “inflammaging,” and it is thought to contribute to frailty, cardiovascular disease, cancer, neurodegeneration and a range of other conditions of later life. One major source is senescent cells, aging cells that have stopped dividing but remain metabolically active and release a stream of inflammatory molecules.
Inflammaging can be measured. On average, older adults carry higher blood levels of inflammatory markers such as interleukin-6 and C-reactive protein than younger people, and higher levels are associated with greater risk of disability, chronic disease and death. Unlike the acute inflammation that helps fight an infection or heal a wound, this kind simmers for years without an obvious trigger.
Scientists at Mayo Clinic have now identified a previously unknown mechanism behind that inflammation. Writing in Nature, they report that dysfunctional mitochondria work with the cell’s epigenetic machinery to switch on inflammatory genes, and that blocking a single mitochondrial transporter can turn the response down.
Turning down rather than killing
The mix of molecules senescent cells release is known as the senescence-associated secretory phenotype, or SASP. Much of the effort to target senescence has gone into senolytics, drugs that kill senescent cells outright. The Mayo team took a different approach.
“For years, the field has focused on getting rid of senescent cells,” said senior author João Passos, Ph.D. “Our strategy has been different. Instead of killing the cells, we asked whether we could switch off the inflammation that makes them harmful.”
Drugs that dampen the SASP without destroying the cells are sometimes called senomorphics. They could be useful in tissues where senescent cells also play helpful roles, such as wound healing, or where removing large numbers of cells could cause harm.
An alarm and a permission slip
Earlier work from the Passos lab had shown that damaged mitochondria leak their own DNA and RNA into the main body of the cell. Because mitochondria descend from ancient bacteria, the cell’s immune sensors treat that leaked genetic material as a sign of infection and trigger inflammatory signaling.
The new study shows that this alarm is not enough on its own. “We found that inflammatory signaling alone isn’t enough,” said first author Helene Martini, Pharm.D., Ph.D. “The cells also need a metabolic signal from mitochondria that changes how inflammatory genes are turned on.”
That signal is acetyl-CoA, a small molecule produced through mitochondrial metabolism that sits at the crossroads of energy production and fat synthesis. It is also the raw material cells use to add acetyl groups to histones, the proteins around which DNA is wound. Acetylating histones loosens the packaging and makes nearby genes easier to switch on, one of the main ways cells regulate gene activity without changing the DNA sequence itself.
Senescent cells, the researchers found, ramp up acetyl-CoA production, and the extra supply enables epigenetic changes that open up inflammatory genes. The release puts it this way: leaked mitochondrial DNA and RNA supply the inflammatory “alarm,” while mitochondrial metabolism supplies the “permission” for full gene activation.
“This is a completely new pathway,” Martini said. “We found that dysfunctional mitochondria can promote inflammation by controlling epigenetic switches that turn inflammatory genes on.”
A transporter as a target
The team identified a possible point of intervention: SLC25A1, a protein that transports citrate out of the mitochondria.
Once outside the mitochondria, citrate is split by an enzyme called ATP-citrate lyase to release acetyl-CoA in the cell’s main compartment, where it can reach the nucleus. That makes the citrate transporter a natural chokepoint: limiting it restricts the acetyl-CoA available for modifying histones without directly touching the immune sensors.
Blocking SLC25A1 reduced the supply of acetyl-CoA and limited the activation of inflammatory genes, even though the initial immune alarm signals were still present. In effect, cutting off the permission slip was enough to keep the alarm from producing a full inflammatory response.
The finding links two areas of aging biology that are often studied separately: mitochondrial dysfunction and epigenetic change. Both are listed among the hallmarks of aging that researchers use to organize the field, and the study shows how one can directly drive the other.
A widely cited framework first published in 2013 and updated in 2023 lists a dozen hallmarks of aging, among them mitochondrial dysfunction, epigenetic alterations, cellular senescence and chronic inflammation. Researchers have long suspected these hallmarks are interconnected, and studies like this one begin to map the specific molecular links between them. Inhibitors of the mitochondrial citrate carrier have previously been explored in cancer research, which may give drug developers a starting point.
Early stage
The study is mechanistic and preclinical. The release does not describe the experimental systems in detail, report sample sizes or effect sizes, or discuss limitations, and it refers readers to the paper for the full author list, disclosures and funding. The work was carried out with collaborators at Sanford Burnham Prebys Medical Discovery Institute.
There are also reasons for caution about targeting SLC25A1. Citrate transport and acetyl-CoA are central to normal metabolism, including fat production, and drugs that interfere with them could have wide-ranging effects. Any therapy would need to dampen harmful inflammation without disrupting the essential jobs these pathways do in healthy cells.
Still, the discovery adds a new layer to the understanding of why aging cells become inflammatory and offers a target that does not require killing them. The work is part of Mayo Clinic’s Precure Research initiative, which aims to develop tools for predicting and intercepting disease processes, and appears alongside six other Mayo studies on senescent cells published at the same time.
Notes
- Martini, H., et al. “Mitochondrial metabolism and epigenetic crosstalk drive SASP.” Nature, 29 July 2026. https://www.nature.com/articles/s41586-026-10791-2.
- Mayo Clinic. “Scientists identify new mitochondrial pathway linked to harmful inflammation in aging.” EurekAlert!, 29 July 2026. https://www.eurekalert.org/news-releases/1138097.
Featured image: Transmission electron micrograph of mitochondria in mammalian lung tissue. Credit: Louisa Howard