Advanced Paternal Age and Its Impact on Reproductive and Offspring Health: Integrating Evidence from Clinical and Translational Studies

Background: Advanced paternal age (APA) has emerged as a critical factor in reproductive health outcomes. Objective: To comprehensively review the effects of increasing paternal age on fertility parameters, embryo quality, and offspring well-being through integration of clinical trials, observational data, and molecular analyses. Methods: This comprehensive review analyzed key studies examining the relationship between paternal age and semen parameters, DNA fragmentation, chromosomal anomalies, spontaneous abortion risk, and neurodevelopmental disorders. New data from multicentric randomized controlled trials on antioxidant intervention were incorporated along with evidence from recent clinical studies. Results: APA significantly impacts multiple reproductive parameters. Paternal aging increases the sperm DNA fragmentation index beyond the 30% threshold, correlating with reduced fertilization rates and impaired embryo development. Spontaneous abortion risk increases with advancing paternal age due to elevated DNA fragmentation and oxidative stress. Embryos from fathers >45 years demonstrate slower development rates during IVF treatment. While recent studies suggest the relationship between paternal age and embryonic aneuploidy may be less pronounced than previously thought, neurodevelopmental disorders, including autism spectrum disorders and schizophrenia, show strong correlations with APA. Antioxidant interventions demonstrated significant improvements in semen parameters and DNA fragmentation in men aged 40 and above. Conclusions: APA significantly compromises male reproductive potential through elevated DNA fragmentation, increased spontaneous abortion risk, and impaired embryo development, while also increasing risks for neurodevelopmental disorders in offspring. Age-specific counseling and antioxidant interventions represent viable strategies to mitigate these risks.