Vitamin E supplementation prevents ferroptosis in round spermatids of aged mice

Germ cell depletion in the aged testes has traditionally been attributed to removal by apoptosis. This study aimed to determine whether ferroptosis, an alternative form of cell death driven by iron-dependent lipid peroxidation, also contributes to germ cell loss in the lipid-rich environment of the testis. Here, we demonstrate that pre-meiotic cells are eliminated via apoptosis, whereas post-meiotic round spermatids (RSs) are mainly removed through ferroptosis. Surprisingly, we detected a greater abundance of Y-chromosome-bearing RSs (Y-RSs) than X-carrying RSs (X-RSs) in the aged testis, implying that X-RSs might be more prone to ferroptosis. Young mice fed a vitamin E (VE) deficient diet recapitulated age-related phenotypes, while VE supplementation prevented ferroptosis and promoted the survival of X-RSs in aged mice. Overall, this study reveals that aging causes ferroptosis in RSs, specifically impacting X-RSs, which can be prevented by VE supplementation, effectively reversing age-induced deterioration and contributing to healthy testicular aging.