When the immune system detects an infection or tissue injury, it launches inflammation, a coordinated defense program that recruits immune cells, changes blood flow and activates repair mechanisms. The response is normally temporary, subsiding once the threat has been contained. With age, however, inflammation can become persistent and spread through tissues. Researchers at Sanford Burnham Prebys Medical Discovery Institute, Mayo Clinic and collaborating institutions have now identified a metabolic mechanism that helps sustain this age-associated inflammation. Their findings, published July 29, 2026, in Nature, connect mitochondrial energy production with changes in the way DNA is packaged inside senescent cells. The study also reports that blocking a related metabolic pathway reduced inflammation and improved measures of tissue function and healthspan in aging mice.
The work focuses on senescent cells, sometimes described as “zombie” cells because they stop dividing but do not die. Cell division is essential during development and for repairing damaged tissues, yet cells can permanently exit the cell cycle after experiencing stress, damage or repeated replication. Senescent cells remain metabolically active and continue to communicate with their surroundings. They release a collection of inflammatory proteins, immune-signaling molecules and other factors known as the senescence-associated secretory phenotype, or SASP. As senescent cells accumulate, their secretions can create a chronic inflammatory environment associated with aging, cancer, cardiovascular disease, neurodegeneration and other disorders. Understanding why SASP remains active has therefore become a central goal in efforts to promote healthier aging.
The new study reveals that SASP is driven by the convergence of two mitochondrial pathways. One pathway changes the accessibility of DNA, making inflammatory genes easier for the cell to read. The other activates transcription factors that bind to those exposed genes and stimulate production of inflammatory molecules. “It turns out that there is a convergence of at least two biological pathways related to mitochondria,” said Peter Adams, PhD, a co-corresponding author and the Jeanne and Gary Herberger Leadership Chair in Cancer Research at Sanford Burnham Prebys. Adams is also director and professor in the institute’s Cancer Genome and Epigenetics Program. The findings suggest that senescent cells do not simply become inflammatory because of one isolated defect; instead, their metabolic and immune systems reinforce one another.
Mitochondria are best known as the organelles that generate cellular energy, but they also produce molecules that influence gene regulation. In senescent cells, the researchers found that mitochondria engaged in altered metabolism generated increased amounts of acetyl-CoA. This molecule is a central metabolic intermediate used in energy production and biosynthesis, but it can also affect chromatin, the molecular complex that packages DNA. Acetyl-CoA supplies acetyl groups to histone proteins, which act like spools around which DNA is wound. Histone acetylation generally loosens the interaction between histones and DNA, allowing regions of the genome to become more accessible to the transcriptional machinery. In this case, increased acetyl-CoA helped open chromatin near genes involved in the SASP, creating a genomic environment that favored inflammatory gene expression.
The metabolic signal alone, however, was not sufficient to keep the inflammatory program running. The team found that senescent mitochondria also become damaged and leaky, allowing fragments of mitochondrial DNA and RNA to escape into the cell. Because mitochondria evolved from ancient bacteria, their genetic material can resemble molecular patterns associated with infection. When misplaced mitochondrial nucleic acids enter the cytoplasm, they can activate innate immune sensors and inflammatory signaling pathways. These pathways turn on transcription factors that move toward the newly accessible SASP genes. The result is a two-part mechanism: acetyl-CoA changes the epigenetic landscape, while mitochondrial DNA and RNA activate the immune machinery needed to transcribe the exposed genes.
This interaction helps explain how a cell can remain in a long-lasting inflammatory state even after the original stress that caused senescence has disappeared. Epigenetic changes determine which genes are physically available for use, while immune signals determine whether the cell’s transcriptional machinery is instructed to use them. According to Adams, the researchers wanted to know whether disrupting one part of this partnership could weaken the entire SASP program. Their experiments focused on CTPI-2, a compound that blocks a transport protein involved in supplying a component required for acetyl-CoA production. By limiting this metabolic input, the researchers aimed to prevent inflammatory chromatin regions from remaining open, without directly suppressing every immune signal generated by damaged mitochondria.
In experiments involving mice, CTPI-2 reduced inflammation across multiple tissues and was associated with improved tissue function and healthspan during aging. The treatment did not eliminate the immune signaling caused by mitochondrial leakage. Instead, it interfered with the metabolic component that made SASP genes more accessible. This distinction is important because broad suppression of immune activity can leave older organisms more vulnerable to infections and impair their ability to respond to injury. A strategy that selectively reduces the inflammatory output of senescent cells, while preserving other immune functions, could offer a more precise approach. The researchers emphasize that CTPI-2 remains an experimental tool and that the findings in mice do not establish safety or effectiveness in humans.
The study was led by João Passos, PhD, professor of Physiology at Mayo Clinic, with Hélène Martini, PharmD, PhD, a postdoctoral researcher in the Passos laboratory, serving as first author. The investigators included scientists from Sanford Burnham Prebys, Mayo Clinic, Imperial College London, Albert Einstein College of Medicine and the University of Glasgow. Their results add to a growing body of research showing that metabolism and epigenetic regulation are tightly connected. Nutrient availability, mitochondrial activity and the production of metabolic intermediates can all influence chromatin structure and gene expression. In aging cells, these relationships may become distorted, allowing metabolic changes to amplify inflammatory programs that would normally be temporary or tightly controlled.
The researchers say the findings point toward a new class of potential anti-aging interventions: therapies that target metabolic signals controlling DNA accessibility rather than attempting to remove every senescent cell or block inflammation throughout the body. Such treatments could eventually be combined with senolytic drugs, which are designed to eliminate senescent cells, or with other approaches aimed at improving mitochondrial quality. Much more work is needed to determine whether the same acetyl-CoA-dependent mechanism operates in human tissues, how widely CTPI-2 affects metabolism, and whether long-term treatment produces unwanted effects. For now, the mouse results provide evidence that mitochondrial metabolism and epigenetic control form a crucial molecular bridge between cellular aging and chronic inflammation. The study’s authors argue that disrupting this bridge may help preserve tissue performance and reduce functional decline in later life.
Subject of Research: Animals
Article Title: Mitochondrial metabolism and epigenetic crosstalk drive SASP
News Publication Date: 29-Jul-2026
Web References: Nature article; Peter Adams, PhD; João Passos, PhD
References: Nature; DOI: 10.1038/s41586-026-10791-2
Image Credits: Sanford Burnham Prebys
Keywords: Aging populations, older adults, gerontology, chronic inflammation, inflammatory signaling, mitochondria, mitochondrial function, metabolism, senescence-associated secretory phenotype, acetyl-CoA, epigenetics, healthy aging
