Impact of ageing on the human male germline

• Applicant: Dr. Sandra Laurentino
• Subject Area: Reproductive Medicine, Urology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 490722097

The age of parents has been steadily increasing in recent decades, especially in western societies. Although female reproductive ageing has received more attention, the consequences of paternal ageing can be readily observed in the reduced fertility rates, increased rates of monogenic and complex disorders and poorer perinatal outcomes in the offspring of older men. These adverse outcomes cannot be explained solely based on an increased mutation rate in the male germline, but likely stem from age-dependent changes in DNA stability and epigenetic marks in sperm. To fully separate the effects of age from those of age-associated morbidities on the male germline, in the previous funding period we established the Fertility and Ageing in Healthy Men (FAMe) cohort, which included 197 men aged 18 to 84 years. We found that healthy ageing was associated with good reproductive health over this age period. However, we found specific age-associated changes in the germline, which are clearly distinguishable from somatic cell ageing. Namely, we found a sharp increase in sperm DNA instability and profound alterations in sperm DNA methylation with increasing age. Moreover, we identified a compensatory mechanism that allows the maintenance of normal sperm production in older men at the expense of usually quiescent reserve spermatogonial stem cells. Nevertheless, our understanding of the pathways and mechanisms involved in male germline ageing and how they relate to poor reproductive outcomes in older men is still very limited. We hypothesize that, in order to maintain normal sperm production, older men activate molecular pathways in their germline and germ cell niche favouring the activation and proliferation of reserve stem cells, at the expense of germ cell integrity. In this project, we aim to understand the molecular markers of ageing in human germ cells, which ultimately might be associated with reproductive outcome and offspring health of older fathers. We propose to address this by evaluating the association between age and transcriptional drift in human testis, epigenetic drift (at methylome level) in sperm, and the DNA instability and occurrence of DNA breaks in the male germline. For this, the FAMe cohort takes an important role, as it has now been extended by evaluating and obtaining samples from the involved participants 5 to 6 years after their original evaluation. This allows longitudinal analyses of molecular changes in the human male germline with increasing age. Using the planned-for multi-layered approach, we will form a framework for the identification of genes and pathways involved in the human male aged phenotype, building an unprecedented image of the effects of age on the male germline.

• DFG Programme: Research Grants
• International Connection: Canada
• Co-Investigator: Professor Dr. Jörg Gromoll
• Cooperation Partner: Professor Dr. Guylain Boissonneault