Researchers from Sanford Burnham Prebys Medical Discovery Institute, Mayo Clinic and collaborating institutions found that malfunctioning mitochondria in ageing cells can help activate inflammatory genes and keep the immune system in a prolonged state of alert. The findings were published in the journal Nature.
As people age, some cells enter a state called senescence. These cells stop dividing but remain alive and metabolically active.
They can release inflammatory molecules through a process known as the senescence-associated secretory phenotype, or SASP.
This activity has been linked to age-related inflammation and several chronic diseases.
The researchers found that mitochondria, which produce much of the energy cells need, play an important role in this process.
In senescent cells, mitochondria produce increased amounts of acetyl-CoA, a molecule involved in metabolism.
Acetyl-CoA can interact with histones, proteins that help package DNA. This interaction makes some parts of DNA more accessible, including genes involved in the inflammatory SASP response.
However, researchers found that this metabolic change alone was not enough to fully activate the inflammatory genes.
A second mitochondrial process was also involved. Damaged mitochondria can release DNA and RNA into parts of the cell where they normally should not be.
The immune system can interpret this misplaced genetic material as a danger signal, triggering an inflammatory response.
The researchers found that the two processes work together.
One makes inflammatory genes easier to access, while the other provides the immune signal needed to activate them.
To determine whether this process could be interrupted, the team tested a drug called CTPI-2 in mice.
The drug blocks a transport protein involved in producing acetyl-CoA.
The treatment reduced inflammation in several tissues and improved tissue function and healthspan in ageing mice.
Although the immune signals caused by mitochondrial DNA and RNA leakage remained, reducing the metabolic signal made the inflammatory genes less accessible and weakened their effects.
Peter Adams, a co-corresponding author from Sanford Burnham Prebys, said the findings suggest that targeting metabolic signals that influence DNA accessibility could represent a new approach to addressing age-related inflammation and functional decline.
However, the findings are still at the research stage. Further studies will be needed to determine whether targeting this pathway can be safely and effectively used to treat age-related inflammation in humans.
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