Incomplete proline catabolism drives premature sperm aging

Infertility is an increasingly common health issue, with rising prevalence in advanced parental age. Environmental stress has established negative effects on reproductive health, however, the impact of altering cellular metabolism and its endogenous reactive oxygen species (ROS) on fertility remains unclear. Here, we demonstrate the loss of proline dehydrogenase, the first committed step in proline catabolism, is relatively benign. In contrast, disruption of alh‐6, which facilitates the second step of proline catabolism by converting 1‐pyrroline‐5‐carboxylate (P5C) to glutamate, results in premature reproductive senescence, specifically in males. The premature reproductive senescence in alh‐6 mutant males is caused by aberrant ROS homeostasis, which can be countered by genetically limiting the first committed step of proline catabolism that functions upstream of ALH‐6 or by pharmacological treatment with antioxidants. Taken together, our work uncovers proline metabolism as a critical component of normal sperm function that can alter the rate of aging in the male reproductive system.