How Aging Cells Learn to Stay Inflamed

Key takeaways

• Researchers identified how aging "senescent" cells use two connected mitochondrial signals to keep sending out inflammatory messages long after they should have stopped.
• One signal makes inflammatory genes easier to access, while a second, separate mitochondrial signal switches those exposed genes on.
• Blocking just the first signal with a compound called CTPI-2 reduced inflammation across multiple tissues in mice and supported healthier aging, even though the second signal was still present.
• The bigger picture: mitochondrial metabolism itself may be a workable dial for turning down the low-grade inflammation that tends to build with age.

As cells age, a growing number of them stop dividing but don't actually die off. Instead, they enter a lingering, "zombie-like" state called senescence, staying metabolically active and continuing to send out inflammatory signals long after their original job is done. This pattern, known as the senescence-associated secretory phenotype, or SASP, has been linked to the broader inflammation that tends to accumulate with age.

Researchers at Sanford Burnham Prebys, Mayo Clinic, and collaborating institutions wanted to understand exactly what keeps these cells switched on, and whether that process could be interrupted.

Two mitochondrial signals, one inflammatory result

The team traced the behavior back to mitochondria, the cell's energy-producing structures. In senescent cells, mitochondria produced elevated amounts of a molecule called acetyl-CoA, which loosens the way DNA is packaged around structural proteins called histones. That loosening doesn't change the genetic code, but it makes inflammatory genes more physically accessible.

On its own, though, that wasn't enough to explain the constant stream of inflammatory signals. A second mitochondrial process was also at play: damaged mitochondria leaked genetic material into parts of the cell where it doesn't belong, and the immune system interpreted that misplaced material as a danger signal. That signal activated the switches needed to turn on the inflammatory genes that had already been made accessible by the first process.

What happened when researchers intervened

To see whether disrupting this partnership mattered, researchers tested a compound called CTPI-2, which blocks a transport protein involved in producing acetyl-CoA. In mice, the treatment lowered inflammation across several tissues and improved tissue function during aging.

What made this especially interesting is that the second signal, the leaking genetic material, was still present the whole time. By interrupting just the first signal and making inflammatory genes harder to access, researchers still achieved meaningful functional benefits. The two processes needed each other to fully activate inflammation, so weakening one link was enough to blunt the outcome.

A longevity lens: taming inflammation at the source

Chronic, low-grade inflammation is one of the more consistent threads running through aging research, showing up across nearly every tissue and system in the body over time. What this study adds is a specific, targetable mechanism behind part of that process, rooted in cell metabolism rather than the immune system alone.

That distinction matters. It suggests there may be multiple entry points for addressing age-related inflammation, not just calming immune signaling directly, but also adjusting the metabolic conditions that make inflammatory genes accessible in the first place.

The takeaway

This work was done in mice, and translating it into human strategies will take considerably more research. But the finding reframes inflammation and aging as a metabolic story as much as an immune one, tracing a clear, mechanistic path from mitochondrial function to gene accessibility to a lasting inflammatory state. That kind of specificity is exactly what makes a target worth pursuing further.

References:

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, João F. Passos. Mitochondrial metabolism and epigenetic crosstalk drive SASP. Nature, 2026; 656 (8129): 980 DOI: 10.1038/s41586-026-10791-2