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Immune system weakening has long been attributed to aging and poor lifestyle choices, but according to an October 2023 study1<\/span><\/sup>\u00a0in Nature Communications, the key reason for this immune system decline is dysfunctional mitochondria, your cells’ powerhouses, particularly the mitochondria found in T cells (a type of immune cell).<\/p>\n When the mitochondria don’t work well, the T cells don\u2019t have the energy required to perform their functions, which leads to a decline in immune system function. This in turn, results in an inability to ward off both acute infections and chronic diseases. As reported by Medical Xpress:2<\/span><\/sup><\/p>\n \u201c… 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 …<\/em><\/p><\/blockquote>\n This research has now shown that the exhaustion process is significantly influenced by … 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.\u201d<\/em><\/p><\/blockquote>\n The good news, which was confirmed by the featured study, is that this decline can be reversed with treatments that target mitochondrial function.<\/p>\n In simple terms, when your body fights an infection, immune cells called CD8+ T cells transform into cytotoxic T lymphocytes (CTLs) to destroy the infected cells. This transformation requires changes in gene expression, cell structure and energy use.<\/p>\n However, in long-lasting infections or cancer, the T cells can become worn out or “exhausted,” losing their effectiveness. This exhaustion is related to energy problems within the cells, particularly in the mitochondria. Researchers are now exploring how fixing these energy problems can rejuvenate exhausted T cells, thereby improving cancer treatments. Bioenergetic researcher Georgi Dinkov comments on these findings:3<\/span><\/sup><\/p>\n \u201cSo far, the decline in immune function seen in aging had been explained with the simplistic \u2018wear and tear\u2019 concept, and when immunodeficiency occurs in younger people it is ascribed either to genetic vulnerability or lifestyle choices such as alcohol\/drug consumption.<\/em><\/p><\/blockquote>\n 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.<\/em><\/p><\/blockquote>\n The study … demonstrates that the direct cause of immune decline is rather simple \u2014 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.<\/em><\/p><\/blockquote>\n 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.<\/em><\/p><\/blockquote>\n The study also demonstrated that such mitochondrial dysfunction is a necessary and sufficient condition for immune decline to occur (aka T-cell \u2018exhaustion\u2019) and that the decline was reversible when mitochondrial function was restored pharmacologically.\u201d<\/em><\/p><\/blockquote>\n So, what is \u201cglycolytic production of energy\u201d and why is it so detrimental? All dietary carbohydrates are digested and broken down into glucose, a type of sugar. Glucose, in turn, can be metabolized (burned) for fuel using two different pathways, as illustrated below.<\/p>\n First, the glucose is metabolized into pyruvate. The pyruvate can then either enter the glycolysis pathway in the cytoplasm of the cell and produce lactate, or it can be converted into acetyl-CoA and shuttled to the mitochondrial electron transport chain.<\/p>\n Cancer cells are notorious for using the glycolysis pathway \u2014 the same pathway glucose goes through when your glucose metabolism is impaired in mitochondria. Basically, this is the pathway your body uses whenever it reaches its limit to how much ATP can be produced in the mitochondria (which is the most efficient and least damaging way to produce energy).<\/p>\n While the glycolysis pathway is wonderful when you need quick fuel, if this is the primary way you burn glucose, then you are in a constant state of activating stress hormones and promoting insulin resistance and diabetes, which in turn creates loads of lactate as a waste product instead of healthy carbon dioxide (CO2<\/sub>) and metabolic water.<\/p>\n Lactate increases reductive stress, which causes reverse electron flow in the mitochondria and increases the ROS to 3% to 4%, which is 30 to 40 times more than when glucose is burned in the mitochondria. This elevated ROS production is what causes T cell damage and death.<\/p>\n What\u2019s more, glycolysis generates only two ATP for every molecule of glucose, which is 95% less energy than would be generated if the glucose was metabolized in your mitochondria.<\/p>\n Now, you\u2019ve probably heard that sugar promotes cancer, because cancer cells preferentially use glycolysis. However, it\u2019s a mistake to think that all glucose uses the glycolysis pathway. As illustrated above, glucose can also be burned in the electron transport chain of the mitochondria, which is the most efficient way to produce energy.<\/p>\n So, when it comes to the \u201csugar fuels cancer\u201d issue, it\u2019s important to make a distinction between the sources of the carbs. While it is technically accurate to call all carbs sugar, there is a radical difference in the source of the carbs \u2014 ripe whole fruits versus starches, for example, and whole fruits versus refined processed sugar (ex: table sugar and high fructose corn syrup).<\/p>\n Refined sugars, as well as many starches, are a common cause of endotoxin production in your gut, which destroys mitochondrial function and results in cancer metabolism, whereas the fructose present in whole foods does not typically result in the production of endotoxin.<\/p>\n This is one of the primary differences between refined sugar and fructose from ripe fruit and helps explain why refined sugars fuel cancer while natural fructose does not. So, to be clear, it\u2019s not sugar that is driving the cancer process per se. It\u2019s really rooted in mitochondrial dysfunction, and fatty acid oxidation (the metabolism of fats instead of glucose) is part of what causes that dysfunction.<\/p>\n For a long time, I believed fats burned \u201ccleaner\u201d than carbs \u2014 that\u2019s one of the \u201cselling points\u201d for keto \u2014 but I\u2019ve since realized we had it backward. Glucose, when burned in the mitochondria, actually burns far cleaner than fat.<\/p>\n So, it\u2019s important to get your macronutrient ratios right, because if the glucose you eat is constantly shuttled into glycolysis, you\u2019re fueling cancer. At the same time, the fat you consume ends up in fat storage rather than being used up for fuel.<\/p>\n Ultimately, you want to burn glucose in your mitochondria, and the way you ensure that is by keeping your dietary fat intake below 35% of your total calories. The reason for this is because when fat intake is too high, glucose gets shuttled into glycolysis. For a more in-depth explanation of this metabolic switch, see \u201cUnderstanding the Randle Cycle<\/a>.\u201d<\/p>\n If you\u2019re insulin resistant, which means you\u2019re metabolically inflexible, that threshold may be closer to 20% or even 10%. So, if you\u2019re insulin resistant, you\u2019ll want to significantly lower your fat intake until your insulin resistance is resolved. Then you can increase it to 30%.<\/p>\n The reason cancer cells use the glycolysis pathway is because they have severely dysfunctional mitochondria. The mitochondria are so damaged, they cannot burn glucose. As a result, the cancer cells must rely on the backup system, glycolysis, to survive. This is what the Warburg Effect is all about.<\/p>\n Likewise, when the mitochondria inside T cells become dysfunctional, the T cells are forced to rely on glycolysis for energy production, which is what causes immune system weakening and failure.<\/p>\n As mentioned in the featured study, T cell exhaustion is a feature of cancer, which makes sense when you consider that it\u2019s all tied to mitochondrial dysfunction. The cancer starts because the mitochondria in cells are severely damaged, and as the disease progresses, the mitochondria in the T cells begin to fail as well.<\/p>\nPoor Mitochondrial Function Can Lead to T Cell Exhaustion<\/h2>\n
<\/div>\n<\/div>\nGlucose Metabolism 101<\/h2>\n
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<\/div>\nThe Downstream Hazards of Glycolysis<\/h2>\n
The Devil\u2019s in the Details<\/h2>\n
You Want to Burn Glucose in Your Mitochondria<\/h2>\n
Dysfunctional T Cells and Cancer Cells Use Glycolysis<\/h2>\n