With the delay of parenthood becoming more common, the age at which men father children is on the rise. While the effects of advanced maternal age have been well documented, only recently have studies started to focus on the impact of advanced paternal age (APA) in the context of male reproduction. As men age, the antioxidant defense system gradually becomes less efficient and elevated levels of reactive oxygen species (ROS) accumulate in spermatozoa; this can impair their functional and structural integrity. In this review, we present an overview of how oxidative stress is implicated in male reproductive aging by providing a summary of the sources and roles of ROS, the theories of aging, and the current animal and human studies that demonstrate the impacts of APA on the male germ line, the health of progeny and fertility, and how treatment with antioxidants may reverse these effects.

The efficiency of antioxidant defense system decreases with aging, thus resulting in high levels of reactive oxygen species (ROS) and DNA damage in spermatozoa. This damage can lead to genetic disorders in the offspring. There are limited studies investigating the effects of the total loss of antioxidants, such as superoxide dismutase-1 (SOD1), in male germ cells as they progress through spermatogenesis. In this study, we evaluated the effects of aging and removing SOD1 (in male germ cells of SOD1-null (Sod1−/−) mice) in order to determine the potential mechanism(s) of DNA damage in these cells. Immunohistochemical analysis showed an increase in lipid peroxidation and DNA damage in the germ cells of aged wild-type (WT) and Sod1−/− mice of all age. Immunostaining of OGG1, a marker of base excision repair (BER), increased in aged WT and young Sod1−/− mice. In contrast, immunostaining intensity of LIGIV and RAD51, markers of non-homologous end-joining (NHEJ) and homologous recombination (HR), respectively, decreased in aged and Sod1−/− mice. Gene expression analysis showed similar results with altered mRNA expression of these key DNA repair transcripts in pachytene spermatocytes and round spermatids of aged and Sod1−/− mice. Our study indicates that DNA repair pathway markers of BER, NHEJ, and HR are differentially regulated as a function of aging and oxidative stress in spermatocytes and spermatids, and aging enhances the repair response to increased oxidative DNA damage, whereas impairments in other DNA repair mechanisms may contribute to the increase in DNA damage caused by aging and the loss of SOD1.