A study found a new mitochondrial pathway in senescent cells that alters how DNA is stored, exposing genes linked to inflammation.
Inflammation is essential when the body needs to fight an infection or repair an injury. But the same protective response can become harmful when it persists, and with age, the body accumulates senescent cells that can fuel chronic inflammation associated with many age-related diseases.
Researchers at Sanford Burnham Prebys Medical Discovery Institute, Mayo Clinic, and collaborating institutions have now identified a connection between mitochondria, the structures that produce cellular energy, and the inflammatory activity of these aging cells. Their findings, published in Nature, also showed that interfering with part of this process reduced inflammation and improved tissue function and healthspan in aging mice.
The work helps explain how a normally temporary immune response can become sustained as cells age, pointing to molecular signals that determine which inflammatory genes become accessible and active.
Senescent cells sustain inflammation with age
Many cells normally divide to support growth and replace tissue after injury. As people age, however, increasing numbers of cells enter senescence, a state in which they stop dividing but remain alive and biologically active.
“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.”
This inflammatory state is known as the senescence-associated secretory phenotype (SASP). It has been linked to persistent inflammation associated with aging and to numerous chronic diseases.
A research team led by the laboratory of senior and co-corresponding author João Passos, PhD, a professor of Physiology at Mayo Clinic, set out to identify the molecular forces driving SASP and determine whether the process could be prevented or reduced.
Two mitochondrial signals expose inflammatory genes
“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.”
The researchers found that mitochondria in senescent cells behave differently while carrying out metabolism. These mitochondria produce increased amounts of acetyl-CoA, a molecule that interacts with histones, the spool-like proteins around which DNA is wrapped.
Higher acetyl-CoA levels loosen this packaging without changing the DNA sequence itself. That makes inflammatory genes associated with SASP more accessible so they can be transcribed into proteins.
But increased acetyl-CoA alone was not enough to keep senescent cells producing inflammatory molecules. A second signal came from damaged mitochondria, which leaked DNA and RNA that activated the immune system. Those signals switched on inflammatory transcription factors that could then target the SASP genes made accessible by excess 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.
Blocking one pathway reduced inflammation in mice
To disrupt the metabolic side of this process, the researchers used a drug called CTPI-2. The compound blocks a transport protein responsible for carrying a component needed to make acetyl-CoA.
In mice, treatment with CTPI-2 suppressed inflammation across multiple tissues while improving tissue function and healthspan during aging. The inflammatory immune signals generated by leaking mitochondria remained, but limiting the metabolic signal made SASP genes less accessible.
“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.”
Reference: “Mitochondrial metabolism and epigenetic crosstalk drive SASP” by Hélène Martini, Jodie Birch, Francisco D. M. Marques, Stella Victorelli, Anthony B. Lagnado, Nicholas Pirius, Ana Catarina Franco, Gung Lee, Yeaeun Han, Jennifer L. Rowsey, Wazim Mohammed Ismail, Amelia Mazzone, Tianna M. Espe, Taro Hitosugi, Ya Li, Alexander M. Washington, Aaron Havas, Rabi Murad, Xue Lei, Rebecca A. Porritt, Oliver D. K. Maddocks, Jair Machado Espindola-Netto, Dominik Saul, Sundeep Khosla, Diana Jurk, Enis Kostallari, Alexandre Gaspar-Maia, Peter D. Adams and João F. Passos, 29 July 2026, Nature.
DOI: 10.1038/s41586-026-10791-2
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.
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