The PEX5 Redox-Logistics Hypothesis of Aging: PEX5-Cys11 Recycling, Catalase Import, and SIRT3 as Components of a Testable Model of Cellular Aging

This hypothesis article proposes a testable redox-logistics model of cellular aging centered on the peroxisomal import receptor PEX5. The model integrates established observations concerning redox-sensitive monoubiquitination of PEX5-Cys11, age-associated accumulation of PEX5 at peroxisomal membranes in replicatively aging human fibroblasts, impaired catalase import, and cellular redox homeostasis. The central hypothesis is that chronic redox deterioration may impair efficient PEX5-Cys11-dependent receptor recycling, producing prolonged PEX5 membrane retention and altered peroxisomal matrix-protein import. Changes in catalase localization and hydrogen-peroxide homeostasis could then further disturb cellular redox conditions, potentially establishing a self-reinforcing redox-logistics failure. SIRT3 is proposed as a testable upstream modifier of this threshold through its effects on mitochondrial and cellular redox state. No direct SIRT3–PEX5 regulatory relationship or familial SIRT3 segregation with cardiovascular longevity is assumed to have been established. Instead, the article defines prospective genetic and cellular experiments capable of supporting, modifying, or falsifying these proposed connections. The article explicitly distinguishes previously established experimental observations from the novel mechanistic hypotheses and predictions introduced here. Preprint. This manuscript has not undergone peer review.