Biochemists calculated the physical limits of reactive oxygen species in cells: concentrations are too low to make them the main cause of aging, a role the oxidative stress theory has assigned them for 70 years

Biochemists calculated the physical limits of reactive oxygen species in cells: concentrations are too low to make them the main cause of aging, a role the oxidative stress theory has assigned them for 70 years

Redox chemist Christopher Switzer of the University of Leicester and coauthor Kimya Kaderi calculated how much reactive oxygen species a living cell can produce and retain. Even with generous assumptions, concentrations remain in the low micromolar range, orders of magnitude below those assumed by the prevailing theory. Their preprint was posted on Preprints.org on 8 October 2026 and has yet to undergo peer review.

Reactive oxygen species (АФК) are byproducts of cellular respiration that have been described for decades as a primary driver of aging, cancer, and heart disease. The idea originated in the chemistry of ionizing radiation. In 1956, gerontologist Denham Harman proposed the free radical theory of aging in his paper “Aging: A Theory Based on Free Radical and Radiation Chemistry,” whose title explicitly identified its basis. The 1969 discovery of superoxide dismutase, an enzyme that breaks down superoxide, strengthened the idea, although the reaction converts one oxidant into another, hydrogen peroxide, leaving oxidant chemistry in place.

Switzer and Kaderi revisited the physical calculations in their preprint. Dissolved oxygen concentrations in tissues range from single digits to tens of micromoles per liter, several times lower than in a laboratory test tube. About 0,5% of the electron flow through the mitochondrial respiratory chain leaks into side reactions that generate АФК. Even when the assumed leakage is inflated, concentrations remain in the low micromolar range. Peroxiredoxins, among the fastest enzymes in the cell, break down hydrogen peroxide almost immediately, while glutathione provides a reserve at concentrations orders of magnitude higher than those of АФК.

When oxygen is scarce, mitochondrial respiration slows and the fraction of electrons that leak does not increase. АФК production therefore falls precisely where oxygen is least available. Chronically hypoxic tumors switch to glycolysis, which the model predicts should reduce mitochondrial АФК production, although АФК are considered a driver of tumor adaptation to hypoxia. The same reasoning applies to blood stem cells: in oxygen-poor regions of the bone marrow, they suppress mitochondrial activity to remain quiescent, although АФК have been linked to their decision to divide or differentiate.

“The resulting model of oxidative stress reflects the logic of toxicology more than the reality of the cell: it is built on the chemistry of extreme conditions and applied to systems in which those conditions almost never occur,” the authors write.

This is consistent with clinical trial results: beta-carotene increased lung cancer incidence among smokers by 18%, while vitamin E increased prostate cancer risk by 17% in the SELECT trial. If АФК were the primary agents of damage, suppressing them should help. Across different compounds and diseases, however, the effects have consistently been absent or harmful.

The physical constraints allow АФК to accumulate in several circumstances: the burst when blood flow returns after ischemia, the bactericidal burst in neutrophils, and the chain reaction of lipid oxidation during ferroptosis. The authors propose assessing АФК mechanisms by the same criteria used for other signaling molecules: demonstrated production, a plausible concentration, a defined target, and compatibility with cellular chemistry. In mice with continuously active Yamanaka factors, proteins that briefly make mature cells more flexible, the antioxidant N-acetylcysteine in the liver suppressed a demonstrated surge in АФК and delayed the animals’ deaths. Production, concentration, and target were established experimentally, providing direct support beyond the theory.