Healthy ageing men have normal reproductive function but display germline-specific molecular changes

Children of older fathers have higher risk for certain diseases. Nevertheless, how ageing specifically affects male germ cells is so far not completely understood. In a cohort of 197 healthy men (18-84 years), we found that semen and reproductive parameters remained normal over six decades. Along with an age-dependent increase in telomere length in sperm (r=0.41, p>0.001), we found accelerated DNA fragmentation, more prominent after the sixth decate of life, and with around 60% of men older than 66 showing abnormal levels of DNA breaks. At the epigenetic level, by whole genome bisulfite sequencing we identified 236 sperm-specific differentially methylated regions between the youngest and oldest group, affecting mostly regions associated with homeobox genes and nervous system development. Therefore, we propose that during ageing, male germ cells are affected by an intrinsic and specific ageing process, distinguishable from the soma. These age-dependent changes might have consequences for fertility and offspring of older men.