Male aging in germ cells: What are we inheriting?

Aging is a significant risk factor for male fertility and can lead to severe developmental disorders in offspring. It disrupts testicular function and spermatogenesis, resulting in sperm abnormalities and DNA fragmentation. Male aging alters the genome and epigenome of germ cells due to persistent oxidative stress caused by the cumulative effects of environmental factors over a lifetime. At the molecular level, DNA damage occurs and is poorly repaired due to impaired DNA repair pathways, leading to unrepaired lesions and de novo mutations. Aging also creates distinct epigenetic landscapes that modify gene expression in germ cells, affect the DNA damage response, and generate de novo DNA and epigenetic mutations that are transmitted to the sperm and inherited by the offspring. This review discusses current knowledge on the age-associated effects on male germ cells and the genomic and epigenomic mechanisms contributing to altered male reproductive health and outcomes in progeny. We propose a male reproductive aging threshold, where cumulative exposure to risk factors leads to oxidative stress, impaired spermatogenesis, and altered reproductive outcomes. Finally, we discuss novel interventions to prevent premature testicular aging and emphasize the need for public health policies and counseling guidelines for men seeking paternity.