Immunodeficiency driven by mitochondrial dysfunction, can be reversed
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This is study that has very wide applicability since the immune system plays a role not only in acute issues such as COVID-19, but also in chronic conditions such as HIV/AIDS, and even cancer. So far, the decline in immune function seen in aging had been explain with the simplistic “wear and tear” concept, and when immunodeficiency occurs in younger people it is ascribed either to genetic vulnerability or lifestyle choices such as alcohol/drug consumption. In other words, to this day medicine does not seem to have a good grip on why immune function fails in aging and disease, and what (if anything) can be done to prevent that. The study below demonstrates that the direct cause of immune decline is rather simple – decline in mitochondrial function (OXPHOS). When T-cells (immune cells produced by the thymus) have dysfunctional mitochondria, they have to rely exclusively on glycolysis for energy production. Glycolytic production of energy is insufficient to support proper T-cell differentiation and activity, and in fact can lead to T-cell damage or even death due to the high amount of reactive oxygen species (ROS) produced when glycolysis is the main mode of energy production. The study also demonstrated that such mitochondrial dysfunction is a necessary and sufficient condition for immune decline to occur (aka T-cell “exhaustion”) and that the decline was reversible when mitochondrial function was restored pharmacologically. A corollary of such findings is that anything that suppresses oxidative metabolism directly causes immune decline (and ultimately failure). Chronic stress is one such example of a “metabolic inhibitor” and the well-known, but not-fully-explained, role of cortisol as immunosuppressant is now elucidated considering cortisol is a potent suppressor of mitochondrial biogenesis and function. In terms of remedies, aspirin, niacinamide, vitamin D, thyroid, progesterone, quinones, etc would probably be the most directly accessible and helpful remedies for restoring/improving mitochondrial function.
https://dx.doi.org/10.1038/s41467-023-42634-3
https://medicalxpress.com/news/2023-11-dysfunction-mitochondria-exhaustion-cells.html
“…In the immune system, chronic infections and the defense against tumors often lead to the phenomenon of T cell exhaustion: In this process, the T lymphocytes gradually lose their function, which impairs their responses against cancer and infections. The molecular mechanisms that control this loss of function have not been fully unraveled. This research has now shown that the exhaustion process is significantly influenced by the “powerhouses of the cells,” the mitochondria. When mitochondrial respiration fails, a cascade of reactions is triggered, culminating in the genetic and metabolic reprogramming of T cells, a process that drives their functional exhaustion. But this “burnout” of the T cells can be counteracted—pharmacological or genetic optimization of cellular metabolism increases the longevity and functionality of T cells. This can be achieved, for example, by overexpressing a mitochondrial phosphate transporter that drives the production of the energy-providing molecule adenosine-triphosphate.”
“…”It was commonly assumed that the observed alterations in the mitochondrial (energy) metabolism were a consequence of T-cell exhaustion,” says Vaeth. To demonstrate that mitochondrial dysfunction is the actual cause of T cell exhaustion, his research group developed a new genetic model. It switches off the mitochondrial phosphate transporter (Slc25A3) and paralyses mitochondrial respiration in T cells. As a result, the T cells are forced to switch to alternative metabolic pathways, mainly aerobic glycolysis, to meet their bioenergetic demand in the form of adenosine triphosphate. However, this metabolic adaptation causes an increased production of reactive oxygen species in the T cells. Elevated levels of oxygen radicals prevent the degradation of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α). The accumulation of HIF-1α protein causes a genetic and metabolic reprogramming of the T cells, accelerating their exhaustion. “This HIF-1α-dependent control of T-cell exhaustion was previously unknown. It represents a critical regulatory circuit between mitochondrial respiration and T cell function, serving as a ‘metabolic checkpoint’ in the process of T-cell exhaustion,” explains Vaeth.”
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@haidut Fasting must do a doozy on those thymic T-cells. Thanks for the post.
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Very interesting, I’ve had issues with runaway inflammation for years, but it’s only been in the last few as I incorporated Peat’s ideas that I’ve been able to sense it. Recently I’ve had tons of success with aspirin and b vitamins, but on occasion, (for reasons I’m still not sure on) I will get a big inflammatory response the entire length of my alimentary canal. I can literally see the inflammation of my gums when this happens.
Recently on a whim I tried some Panquinone, and the inflammation abated immediately. I checked the old thread on Panquinone for information about it being an anti-inflammatory, but there was no such mention. Sure enough, today I come across this information, and I have my answer!
Many thanks for your work Haidut!