Metabolic Damage and Premature Thymus Aging Caused by Stromal Catalase Deficiency

T lymphocytes are essential mediators of immunity that are produced by the thymus in proportion to its size. The thymus atrophies rapidly with age, resulting in progressive diminution of new T cell production. This decreased output is compensated by duplication of existing T cells, but it results in gradual dominance by memory T cells and decreased ability to respond to new pathogens or vaccines. Here, we show that accelerated and irreversible thymic atrophy results from stromal deficiency in the reducing enzyme catalase, leading to increased damage by hydrogen peroxide generated by aerobic metabolism. Genetic complementation of catalase in stromal cells diminished atrophy, as did chemical antioxidants, thus providing a mechanistic link between antioxidants, metabolism, and normal immune function. We propose that irreversible thymic atrophy represents a conventional aging process that is accelerated by stromal catalase deficiency in the context of an intensely anabolic (lymphoid) environment. [Display omitted] •The thymus exhibits accelerated atrophy with age due to changes in stromal cells•Global transcriptome analysis reveals that stromal cells are deficient in catalase•Stromal cells showed elevated H2O2 levels and multiple hallmarks of oxidative damage•Genetic or biochemical restoration of antioxidant activity ameliorates thymic atrophy Thymic function is essential for maintenance of immunity but decreases with age. Griffith et al. show that stromal deficiency in catalase leads to mitochondrial dysfunction and DNA damage in stromal cells and that atrophy is ameliorated by genetic complementation of catalase or biochemical antioxidants.