1,25-Dihydroxyvitamin D deficiency accelerates male reproductive senescence in aging mice and 1,25(OH)D alleviates oxidative stress via NF-κB/SOD.

1,25(OH)D has been demonstrated to exert direct actions on male reproductive system in humans or in animals. With age, renal synthesis of 1,25(OH)D declines significantly, and vitamin D supplementation has been found to alleviate the manifestations of male reproductive aging. Therefore, the relationship between 1,25(OH)D and male reproductive aging needs further study. To determine whether 1,25(OH)D deficiency accelerates male reproductive senescence in aging mice, wild-type and male mice fed a rescue diet after weaning, and the reproductive phenotypes were evaluated at 12-18 mo of age. We demonstrated that 1,25(OH)D deficiency accelerated male reproductive senescence, representing lower fertility efficiency and gonadal hormone levels, reducing cell proliferation, and increasing cell apoptosis, cellular senescence, and the senescence-associated secretory phenotype (SASP). We confirmed that the increased oxidative stress and DNA damage detected in mice resulted in accelerated reproductive senescence in reproductive system, since exogenous antioxidant pyrroloquinoline quinone (PQQ) supplementation could largely rescue reproductive aging phenotype. We further validated the antioxidant effect of 1,25(OH)D in aging wild-type mice and senescent Leydig cells by treated 18-mo-old wild-type male mice or TM3 cells with 1,25(OH)D or vehicle. We assessed the differential gene expression between grouped senescent TM3 cells using RNA-Seq and verified 1,25(OH)D exerted an antioxidant role by acting NF-κB/SOD. This study suggests that 1,25(OH)D deficiency accelerates male reproductive senescence in aging mice by increasing oxidative stress and 1,25(OH)D plays a role in alleviating oxidative stress via NF-κB/SOD signaling pathway. Based on this studies, we propose that 1,25(OH)D can delay male reproductive aging, and we also propose that 1,25(OH)D regulates NF-κB to exert antioxidant effect. Therefore, by targeting a fundamental aging mechanism, 1,25(OH)D may be an effective agent in maintaining fertility and postponing male reproductive senescence.