Abstract
Life‐long sperm production leads to the assumption that male fecundity remains unchanged throughout life. However, recently it was shown that paternal age has profound consequences for male fertility and offspring health. Paternal age effects are caused by an accumulation of germ cell mutations over time, causing severe congenital diseases. Apart from these well‐described cases, molecular patterns of ageing in germ cells and their impact on DNA integrity have not been studied in detail. In this study, we aimed to assess the effects of ‘pure’ ageing on male reproductive health and germ cell quality. We assembled a cohort of 198 healthy men (18–84 years) for which end points such as semen and hormone profiles, sexual health and well‐being, and sperm DNA parameters were evaluated. Sperm production and hormonal profiles were maintained at physiological levels over a period of six decades. In contrast, we identified a germ cell‐specific ageing pattern characterized by a steady increase of telomere length in sperm and a sharp increase in sperm DNA instability, particularly after the sixth decade. Importantly, we found sperm DNA methylation changes in 236 regions, mostly nearby genes associated with neuronal development. By in silico analysis, we found that 10 of these regions are located in loci which can potentially escape the first wave of genome‐wide demethylation after fertilization. In conclusion, human male germ cells present a unique germline‐specific ageing process, which likely results in diminished fecundity in elderly men and poorer health prognosis for their offspring.
Highlights
In developed countries, couples postpone parenthood mainly for socio-political and cultural reasons [1,2,3]
We evaluated reproductive parameters in 197 healthy men, who were stratified into six age groups (Table 1)
Considering the hallmarks of ageing already known for other tissues and cells, it is evident that male germ cells age, but the ageing process is different from that of somatic cells
Summary
Couples postpone parenthood mainly for socio-political and cultural reasons [1,2,3]. If and how ageing itself causes a decline in men’s reproductive health is unclear because selection criteria for clinical studies are inconsistent and some studies indicate only a subtle change during ageing [5, 6] which might in part be due to unhealthy lifestyles or age-related somatic diseases [7]. Among the hypotheses put forward to explain the detrimental effects of age on male fertility and offspring health, epigenetic changes to the DNA stand out. Our unique cross-sectional observation study on healthy ageing men [Fertility and Ageing in Healthy Men (FAMe)] was conducted in order to exclude the effects of age-related mobidities and evaluate the impacts of age to male reproductive health. Our ultimate goal was to identify the fundamental processes involved in male germline ageing which are caused exclusively by age
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