A fascinating study that again highlights the central role metabolism plays in activities medicine considers weakly linked or unrelated to metabolism. Namely, the study suggests that the primary trigger of sleep is the accumulation of ROS, which under normal conditions form mostly as a result of excessive fat oxidation, which itself happens mostly under stress. Virtually all ROS is formed as a result of so-called reverse electron flow (REF), which excessive fat oxidation triggers by forming a functional block at electron transport chain (ETC) complex II. ETC II is crucially dependent on the cofactor FAD (synthesized from vitamin B2), and excessive fat oxidation consumes a lot of FAD through the beta-oxidation pathway that precedes entry of fatty acid metabolites into the Krebs cycle. Since high levels of ROS are toxic to cells, it makes perfect sense for organisms to develop an evolutionary conserved (across species and time) mechanism such as sleep that forces the organism to drastically reduced physical\/mental activity, which in turn reduces excessive fat oxidation and thus ROS production. The findings of the study are anecdotally corroborated by multiple reports from people who practice long-distance endurance exercise (which yours truly also used to (ab)use years ago and thus caused severe health disturbances). Namely, they all feel extremely sleepy after a bout of such exercise and often usually sleep for much longer periods of time at night compared to days without such exercise (or less acute stress). Babies are also good example, as they invariably get very sleepy after a stressful or exhausting event, especially if not well-fed prior to the event, thus increasing fatty acid oxidation further. Finally, chemicals that increase electron leakage into the mitochondrial matrix such as 2,4-dinitrophenol (DNP), are also known to cause sleepiness. There is also the co-called “central fatigue” hypothesis, which postulates that fatigue and sleepiness are caused by elevation of brain serotonin and such elevations are known to happen when blood levels of fatty acids are elevated, which results in displacement of tryptophan from albumin and thus increased entry into the brain, leading to increased serotonin synthesis. Interventions that lower fat oxidation and\/or brain serotonin are known to largely prevent the feelings of fatigue and sleepiness, thus corroborating the study findings. Aspirin, which lowers both blood levels of fatty acids as well as plasma serotonin has a known anti-fatigue effect, confirmed in multiple human studies with patients suffering from conditions characterized by debilitating fatigue and daytime sleepiness (e.g. multiple sclerosis, Crohn’s disease, ulcerative colitis, diabetes, cancer, etc).<\/p>\n
https:\/\/www.nature.com\/articles\/s41586-025-09261-y<\/a><\/p>\n https:\/\/www.nature.com\/articles\/s41586-025-09261-y<\/a><\/p>\n https:\/\/www.the-scientist.com\/animals-sleep-because-electrons-leak-73356<\/a><\/p>\n