A study has discovered a new mitochondrial pathway in senescent cells that alters the way DNA is stored, exposing genes associated with inflammation.
Inflammation is essential for the body to fight infection and repair damage. However, this protective response can become harmful if prolonged, and with age, the body accumulates senescent cells, which can fuel the chronic inflammation associated with many age-related diseases.
Researchers from the Sanford Burnham Prebys Medical Research Institute, the Mayo Clinic, and collaborating institutions have identified a link between mitochondria—the structures that produce cellular energy—and the inflammatory activity of these senescent cells. Their findings, published in the journal Nature, also showed that interfering with part of this process reduces inflammation and improves tissue function and healthspan in aging mice.
This work helps explain how a normally transient immune response can become persistent as cells age, pointing to molecular signals that determine which inflammatory genes become accessible and active.
Normally, many cells divide to maintain growth and replace tissue after injury. However, with age, more cells enter a state of senescence—a condition in which they stop dividing but remain alive and biologically active.
“Senescent cells are not completely inert,” said study co-author Peter Adams of the Sanford Burnham Prebys Institute. “They remain metabolically active and have an inflammatory program that causes them to secrete inflammatory molecules.”
This inflammatory state is known as the senescence-associated secretory phenotype (SASP). It is associated with the persistent inflammation characteristic of aging and numerous chronic diseases.
A research team led by study co-author Professor João Passos from Maio set out to identify the molecular forces governing SASP and determine whether this process can be prevented or reduced.
“It turns out that at least two mitochondria-related biological pathways converge,” said Adams. “One alters the way DNA is stored, promoting the development of SASP-related regions, while the other enhances the expression of SASP genes that are in the public domain.”
The researchers discovered that mitochondria in aging cells behave differently during metabolism. These mitochondria produce increased amounts of acetyl-CoA, a molecule that interacts with histones—spool-like proteins around which DNA is wrapped.
Elevated acetyl-CoA levels weaken this packaging without altering the DNA sequence itself. This makes SASP-related inflammatory genes more accessible for transcription into proteins.
However, increased acetyl-CoA levels alone were not enough to keep aging cells producing inflammatory molecules. A second signal came from damaged mitochondria, which leaked DNA and RNA, activating the immune system. These signals triggered inflammatory transcription factors, which could then act on SASP genes made accessible by excess acetyl-CoA.
“Seeing how these two independent pathways intersect, we wanted to find out whether interrupting one of them could prevent them from cooperating in promoting SASP,” Adams said.
To disrupt the metabolic side of this process, the researchers used a drug called CTPI-2. This compound blocks a transport protein responsible for transporting a component necessary for acetyl-CoA synthesis.
In mice, treatment with CTPI-2 suppressed inflammation in various tissues, while simultaneously improving tissue function and healthspan during aging. Inflammatory immune signals generated by mitochondrial leakage persisted, but restricting metabolic signaling made SASP genes less accessible.
“While immune signaling from damaged mitochondria was still present, disrupting metabolic signaling made SASP genes less accessible and conferred functional benefits,” Adams said. “Using selective inhibitors such as CTPI-2 to reduce acetyl-CoA levels and, consequently, inflammation, is a novel therapeutic strategy worth exploring.”
Furthermore, more broadly, this study suggests that targeting metabolic signals that influence DNA accessibility may represent a new approach to mitigating age-related inflammation and functional decline.
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