Study finds new mitochondrial pathway in senescent cells that changes how DNA is stored to expose inflammatory genes
When our immune system detects a pathogen or injury, it sets off biological alarm bells. This alert brings in a variety of immune and other cells to deal with the threat and heal any harm done.
This rapid response to danger—called inflammation—is critical for our health, but it should only last as long as needed to stop infections and heal our wounds. As we grow older, however, we accumulate a type of cell that promotes chronic inflammation—and which has been linked to many age-related diseases.
Scientists at Sanford Burnham Prebys Medical Discovery Institute, Mayo Clinic and their international collaborators published findings July 29, 2026, in Nature revealing a new connection between energy-producing mitochondria and this sustained inflammation. They also found that blocking a related gene reduced inflammation and promoted healthier aging in mice.
Normally, some cells in our body are able to divide. This ability underpins our growth into adults and ability to recover after injury. As we age, more of our cells are prone to becoming zombie-like senescent cells that are no longer dividing to make new cells.
“Senescent cells are not completely inert,” said co-corresponding author Peter Adams, PhD, the Jeanne and Gary Herberger Leadership Chair in Cancer Research at Sanford Burnham Prebys. Adams also is director of and professor in the Cancer Genome and Epigenetics Program.
“They remain metabolically active and have an inflammatory program causing them to secrete inflammatory molecules.”
Cells “running” this inflammatory program are considered to exhibit the senescence-associated secretory phenotype (SASP) that is linked to age-related pervasive inflammation and many chronic diseases.
Led by the lab of senior and co-corresponding author João Passos, PhD, a professor of Physiology at Mayo Clinic, the research team searched for molecular drivers of SASP with the goal of finding a way to prevent it or reduce it.
“It turns out that there is a convergence of at least two biological pathways related to mitochondria,” said Adams. “One alters how DNA is stored to promote areas related to SASP, and the other boosts the expression of the exposed SASP genes.”
While senescent cells remain metabolically active, the mitochondria in charge of their energy production are unusual. The scientists discovered a new quirk in which senescent mitochondria conducting metabolism also produce more acetyl-CoA. This molecule interacts with spool-like histone proteins that hold DNA like a thread. Without changing the DNA, acetyl-CoA loosens its histone spool and opens up inflammatory genes for transcription into proteins.
Peter Adams, PhD, is the Jeanne and Gary Herberger Leadership Chair in Cancer Research at Sanford Burnham Prebys. Adams also is director of and professor in the Cancer Genome and Epigenetics Program. Image credit: Sanford Burnham Prebys.
On its own, this metabolic signal sent through acetyl-CoA is not enough to make senescent cells continuously spill out inflammatory molecules. The other requirement is an uptick in immune signals caused by DNA and RNA seeping out of damaged mitochondria and triggering the immune system. These signals activate inflammatory transcription factors that home in on the SASP genes exposed by overabundant acetyl-CoA.
“After seeing how these two independent pathways intersect, we wanted to see if interrupting one could prevent their partnership in promoting SASP,” said Adams.
The research team turned to a drug called CTPI-2. It blocks the activity of a transport protein that carries a component required to produce acetyl-CoA. When tested in mice, CTPI-2 suppressed inflammation across tissues as well as improved tissue function and healthspan during aging.
“Even though the immune signaling from leaky mitochondria was still present, disrupting the metabolic signal made SASP genes less accessible and produced functional benefits,” said Adams. “Using selective inhibitors such as CTPI-2 to reduce acetyl-CoA and, in turn, inflammation is a novel therapeutic strategy that should be explored.
Also, more broadly, this research shows that targeting metabolic signals that influence DNA accessibility may represent a new approach for mitigating age-associated inflammation and functional decline.”
Hélène Martini, PharmD, PhD, a postdoctoral researcher in the Passos lab at Mayo Clinic, is first author of the publication.
Additional authors include:
- Aaron Havas, Rabi Murad, Xue Lei and Rebecca A. Porritt at Sanford Burnham Prebys
- Anthony B. Lagnado, Nicholas Pirius, Ana Catarina Franco, Gung Lee, Yeaeun Han, Jennifer L. Rowsey, Stella Victorelli, Wazim Mohammed Ismail, Amelia Mazzone, Tianna M. Espe, Taro Hitosugi, Ya Li, Alexander M. Washington, Jair Machado Espindola-Netto, Dominik Saul, Sundeep Khosla, Diana Jurk, Enis Kostallari and Alexandre Gaspar-Maia at Mayo Clinic
- Jodie Birch at Imperial College London
- Francisco D. M. Marques at Albert Einstein College of Medicine
- Oliver D. K. Maddocks at the University of Glasgow
The study was supported by the National Institutes of Health, National Institute on Aging, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Department of Defense Ovarian Cancer Research Program, Hevolution Foundation, The Glenn Foundation for Medical Research, Cancer Research UK and Robert and Arlene Kogod Center on Aging.
The study’s DOI is 10.1038/s41586-026-10791-2.