Reproductive genetics and the aging male

To examine current evidence of the known effects of advanced paternal age on sperm genetic and epigenetic changes and associated birth defects and diseases in offspring. Review of published PubMed literature. Advanced paternal age (> 40 years) is associated with accumulated damage to sperm DNA and mitotic and meiotic quality control mechanisms (mismatch repair) during spermatogenesis. This in turn causes well-delineated abnormalities in sperm chromosomes, both numerical and structural, and increased sperm DNA fragmentation (3%/year of age) and single gene mutations (relative risk, RR 10). An increase in related abnormalities in offspring has also been described, including miscarriage (RR 2) and fetal loss (RR 2). There is also a significant increase in rare, single gene disorders (RR 1.3 to 12) and congenital anomalies (RR 1.2) in offspring. Current research also suggests that autism, schizophrenia, and other forms of psychiatric morbidity are more likely in offspring (RR 1.5 to 5.7) with advanced paternal age. Genetic defects related to faulty sperm quality control leading to single gene mutations and epigenetic alterations in several genetic pathways have been implicated as root causes. Advanced paternal age is associated with increased genetic and epigenetic risk to offspring. However, the precise age at which risk develops and the magnitude of the risk are poorly understood or may have gradual effects. Currently, there are no clinical screenings or diagnostic panels that target disorders associated with advanced paternal age. Concerned couples and care providers should pursue or recommend genetic counseling and prenatal testing regarding specific disorders.