Necroptosis promotes the Aging of the Male Reproductive System in Mice

Necroptosis is a form of programmed necrotic cell death in mammals that is mediated by a pair of kinases, RIP1 and RIP3, as well as the RIP3 substrate MLKL. We report here that male reproductive organs of both RIP3-and MLKL-knockout mice retain \"youthful\" morphology and function into advanced age, while those of age-matched wild type mice deteriorate. The RIP3 phosphorylation of MLKL, the activation marker of necroptosis, is detected in spermatogonial stem cells in the testes of old but not in young wild type mice. When the testes of young wild type mice are given a local necroptotic stimulus, their reproductive organs showed accelerated aging. Feeding of wild type mice with an RIP1 inhibitor prior to the normal onset of age-related changes in their reproductive organs blocked the appearance of signs of aging. Thus, necroptosis in testes promotes the aging-associated deterioration of the male reproductive system in mice.