While not widely-known, mainstream science now recognizes the role of cellular fragments in triggering chronic inflammation. Namely, due to the structural similarity between mitochondrial DNA/RNA and various species of bacteria and virii, the presence of mitochondrial fragments in the bloodstream triggers a low-grade immune reaction, which has been recognized by medicine in the form of chronic, low-grade inflammation. Said inflammation is present in virtually all people over the age of 50, and is more intense in people with various age-related chronic conditions. That is not surprising, considering that with aging the ratio of catabolic/anticatabolic steroids rises steadily, which leads to increased tissue breakdown and thus increased amounts of mitochondrial (and other cellular) fragments into the blood. However, this mechanistic explanation seems to not capture the entire story. Administration of anticatabolic steroids in doses that restore the catabolic/anticatabolic ratio to youthful levels significantly dampens inflammation, but do not lower it to youthful (low) levels. The study below demonstrates that the missing piece of the puzzle seems to be, once again, oxidative metabolism. Namely, due to declining metabolism, aging cells accumulate the Krebs cycle intermediate (and direct metabolite of pyruvate) known as acetyl-CoA. That acetyl-CoA/CoA ratio, just like the mitochondrial NAD+/NADH ratio, is not just a biomarker of well-functioning oxidative metabolism, but one of the key drivers of the so-called Krebs Cycle. Namely, when a person oxidizes primarily fat (FAO), both of those ratios drop and inhibit the activity of the the rate-limiting enzyme for glucose metabolism – pyruvate dehydrogenase (PDH). In addition, the accumulation of acetyl-CoA and thus higher acetyl-CoA/CoA ratio, combined with a block of Complex II of the electron transport chain (ETC) due to FAD depletion driven by excessive FAO, leads to so-called “reverse electron flow”, which is responsible for 98%-99% of the ROS generation seen in OXPHOS. Thus accumulation of acetyl-CoA and thus higher acetyl-CoA/CoA ratio is both a sign and a cause of inhibited OXPHOS. The study below found that without this acetyl-CoA accumulation, cellular debris alone did not cause an inflammatory reaction. Now, the study itself reduced acetyl-CoA by blocking the transport of citrate into the mitochondria. However, acetyl-CoA accumulation can occur even without a citrate overload. As described above, simply shifting the Randle cycle in favor of FAO can produce sufficiently elevated levels of acetyl-CoA capable of triggering inflammatory reaction. So, to me at least, it seems that the proper way to handle the excess acetyl-CoA is to increase its utilization inside the Krebs cycle, instead of simply blocking its formation. What could lower acetyl-CoA by increasing its utilization? Well, thyroid (T3) is one such substance and niacinamide is another one. The amino acid taurine, in a single dose of 4g, has also been shown in humans to normalize the elevated acetyl-CoA levels, by speeding up its utilization and did so under conditions of metabolic stress, which reliably mimic the conditions seen in aging cells. Simply taking vitamin B5, which is a precursor to CoA, may also lower the acetyl-CoA/CoA ratio and thus dampen inflammation. Once again, we see that something as “simple” as unimpeded electron flow through OXPHOS is not just an issue of generating more “power”, but carries fundamental importance for the systemic health of the organism, and even the aging process itself.
https://www.nature.com/articles/s41586-026-10791-2
https://scitechdaily.com/zombie-cells-reveal-a-surprising-new-driver-of-chronic-inflammation/
“…Researchers have now identified a previously unknown mechanism that helps explain how these aging cells switch inflammatory genes into a highly active state. The findings connect dysfunctional mitochondria — the structures that produce cellular energy — with epigenetic machinery that controls gene activity, revealing a potential new way to reduce harmful inflammation without eliminating the senescent cells themselves. The study, published in Nature, builds on years of research into the senescence-associated secretory phenotype, or SASP, the mixture of inflammatory molecules released by senescent cells. The work was conducted by Mayo Clinic researchers in collaboration with Sanford Burnham Prebys Medical Discovery Institute.”
“…We found that inflammatory signaling alone isn’t enough,” says Helene Martini, Pharm.D., Ph.D., a Mayo Clinic researcher and first author of the study. “The cells also need a metabolic signal from mitochondria that changes how inflammatory genes are turned on.” That second signal involves acetyl-CoA, a molecule produced through mitochondrial metabolism. The researchers found that senescent cells make more acetyl-CoA, which supports epigenetic modifications — chemical changes that influence whether genes are active without changing the underlying DNA sequence. Those modifications make inflammatory genes more accessible to the cellular machinery that reads them, allowing the genes to be expressed more strongly. In this two-part process, leaked mitochondrial DNA and RNA trigger the inflammatory signal, while mitochondrial metabolism supplies the molecular “permission” needed for inflammatory genes to become fully active. “This is a completely new pathway,” says Dr. Martini. “We found that dysfunctional mitochondria can promote inflammation by controlling epigenetic switches that turn inflammatory genes on.””
“…Blocking SLC25A1 reduced the available acetyl-CoA and limited activation of inflammatory genes, even though the original immune signals were still present. The finding identifies a previously unrecognized control point in the inflammatory process and suggests that targeting this pathway could potentially promote healthier aging without requiring senescent cells to be destroyed.”
