This study compares the relative effects of advancing male age on multiple genomic defects in human sperm [DNA fragmentation index (DFI), chromatin integrity, gene mutations, and numerical chromosomal abnormalities], characterizes the relationships among these defects and with semen quality, and estimates the incidence of susceptible individuals for a well characterized nonclinical nonsmoking group of 97 men (22-80 years). Adjusting for confounders, we found major associations between age and the frequencies of sperm with DFI and fibroblast growth factor receptor 3 gene (FGFR3) mutations associated with achondroplasia (P < 0.01) with no evidence for age thresholds. However, we found no associations between age and the frequencies of sperm with immature chromatin, aneuploidies͞diploidies, FGFR2 mutations (Apert syndrome), or sex ratio in this cohort. There were also no consistent correlations among genomic and semen-quality endpoints, except between DFI and sperm motility (r ؍ ؊0.65, P < 0.001). These findings suggest there are multiple spermatogenic targets for genomically defective sperm with substantially variable susceptibilities to age. Our findings predict that as healthy males age, they have decreased pregnancy success with trends beginning in their early reproductive years, increased risk for producing offspring with achondroplasia mutations, and risk of fathering offspring with Apert syndrome that may vary across cohorts, but with no increased risk for fathering aneuploid offspring (Down, Klinefelter, Turner, triple X, and XYY syndromes) or triploid embryos. Our findings also suggest that the burden of genomic damage in sperm cannot be inferred from semen quality, and that a small fraction of men are at increased risk for transmitting multiple genetic and chromosomal defects.DNA fragmentation ͉ human sperm ͉ achondroplasia ͉ sperm FISH ͉ Apert syndrome I t has become more socially acceptable to delay fatherhood, but the heritable consequences of this trend remain poorly understood. Since 1980, U.S. birth rates have increased up to 40% for men 35-49 years and have decreased up to 20% for men under 30 (1). Although it is well known that as women age, they are at increased risk for infertility, spontaneous abortion, and genetic and chromosomal defects among offspring, the association of male aging with these outcomes has been less well characterized (2).Advancing paternal age has been implicated in a broad range of abnormal reproductive and genetic outcomes (3, 4), including diminished semen quality (5), reduced fertility (6), increased frequencies of spontaneous abortions (7, 8), Ϸ20 autosomal dominant diseases including achondroplasia (ACH) and Apert syndrome (AS; see refs. 3 and 9), and several diseases of complex etiology such as schizophrenia (10). Among transmitted chromosomal defects, sex-chromosomal aneuploidy syndromes show substantial paternal contributions with some evidence of paternal-age effects (11-13).However, the mechanisms for age dependency of paternally transmitted genomic defects are ...