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Biochemists calculate the physical limits of reactive oxygen species in cells: they cannot accumulate enough to be the main cause of aging, a role the oxidative stress theory has assigned them for 70 years Redox chemist Christopher Sweitzer of the University of Leicester and co-author Kimya Kaderi calculated how much reactive oxygen species a living cell can produce and retain. Under generous assumptions, the concentration of these molecules does not rise above low micromolar levels — orders of magnitude lower than what the dominant theory predicts. The preprint was posted on October 8, 2026, on Preprints.org and has not yet undergone peer review. Reactive oxygen species (ROS) — byproducts of cellular respiration — have for decades been credited as the primary drivers of aging, cancer, and heart disease. The idea originated from ionizing radiation chemistry: in 1956, gerontologist Denham Harman proposed the free radical theory of aging in the paper “Aging: A Theory Based on Free Radical and Radiation Chemistry” — the title itself revealed its source. The discovery in 1969 of the enzyme superoxide dismutase, which breaks down superoxide, strengthened the idea, although the reaction merely converts one oxidant into another, hydrogen peroxide, without eliminating oxidant chemistry. Sweitzer and Kaderi recalculated the physics from scratch in their preprint. Dissolved oxygen in tissues amounts to units to tens of micromoles per liter — many times less than in a laboratory test tube. Via the mitochondrial respiratory chain, about 0.5% of electron flow leaks into side reactions that produce ROS — even with an exaggerated leak, concentration does not exceed low micromolar values. Hydrogen peroxide is almost instantly scavenged by peroxiredoxin enzymes — among the fastest enzymes in the cell — while glutathione maintains reserves orders of magnitude higher than ROS concentration. When oxygen is scarce, mitochondrial respiration weakens, and the fraction of leaking electrons does not increase — meaning ROS levels are lower precisely where oxygen is least available. Tumors in chronic hypoxia switch to glycolysis — by model, this should reduce mitochondrial ROS, although ROS are considered the engine of their adaptation to hypoxia. The same logic applies to hematopoietic stem cells: in low-oxygen niches of the bone marrow, they suppress mitochondria to maintain quiescence, although decisions to divide or differentiate are linked to ROS. “The resulting model of oxidative stress reflects toxicology logic more than cellular reality — a model built on extreme-condition chemistry and applied to systems where these conditions almost never occur,” the authors write. This aligns with clinical trials: beta-carotene in smokers increased lung cancer incidence by 18%, and the SELECT trial showed vitamin E increased prostate cancer risk by 17%. If ROS were the primary damaging agent, suppressing them should have helped — yet the effect is consistently zero or negative across substances and diseases. Physics permits ROS accumulation in only a few cases: a burst during reperfusion after ischemia, the bactericidal burst of neutrophils, and a lipid peroxidation chain reaction in ferroptosis. Instead, the authors propose that ROS mechanisms be held to the standard of ordinary signaling molecules: demonstrated production, plausible concentration, defined target, and consistency with cellular chemistry. In mice with constitutively active Yamanaka factors — proteins that transiently make mature cells more pliable — the antioxidant N-acetylcysteine in the liver suppressed a proven ROS burst and delayed their death: production, concentration, and target were confirmed experimentally, not theoretically. 🔗 Read original →