Delayed parenthood has become an increasingly common trend in recent decades, driven by a range of economic, social, political, and cultural factors. While medical problems associated with advanced parental age were once primarily attributed to maternal ageing, studies have revealed that men also face reduced chances of achieving pregnancy due to declining sperm quality.
This can lead to increased risks for rare monogenic disorders and complex neurodevelopmental disorders in offspring, as well as subtle impaired neurocognitive outcomes during infancy and childhood. Unlike oocytes, which are meiotically arrested in the fetal germline, the male germline undergoes over 800 times more replication cycles at the age of 50 than at puberty. During each cycle, both the DNA sequence and its epigenetic marks need to be correctly copied to the daughter cells, with epigenetic information having a higher error rate than genetic information. As such, spermatozoa from older males have many more epigenetic than DNA sequence changes.
A recent study by researchers from Julius Maximilians University, Partner Site Göttingen, and Fertility Center Wiesbaden sheds light on one underlying mechanism behind age-related changes in the sperm epigenome. In the study, the researchers performed reduced representation bisulfite sequencing (RRBS) on 73 sperm samples of males attending a fertility centre in Germany. They identified 1,162 (74%) regions that were significantly hypomethylated and 403 regions (26%) that were hypermethylated with age. The findings were published in the journal Aging.
The majority (74%) of age-related differentially methylated regions (ageDMRs) were located within genic regions, including 1,002 genes with symbols. Hypomethylated ageDMRs were closer to the transcription start sites than hypermethylated DMRs, half of which reside in gene-distal regions. In this and related genome-wide studies, so far 2,355 genes have been reported with significant sperm ageDMRs, but most (90%) of them in only one study. The 241 genes that have been replicated at least once showed significant functional enrichments in 41 biological processes associated with the development and the nervous system and in 10 cellular components associated with synapses and neurons.
This supports the hypothesis that paternal age effects on the sperm methylome affect offspring behaviour and neurodevelopment. The researchers found it interesting to note that sperm ageDMRs were not randomly distributed throughout the human genome; chromosome 19 showed a highly significant twofold enrichment with sperm ageDMRs. Although the high gene density and CpG content have been conserved, the orthologous marmoset chromosome 22 did not appear to exhibit an increased regulatory potential by age-related DNA methylation changes.
“Collectively, our data support the conclusion that age-induced methylation changes in the sperm epigenome contribute to the increased offspring disease susceptibility for neurodevelopmental disorders,” the researchers stated. There were no significant correlations with paternal BMI, semen quality, or ART outcome. These findings highlight the need for further research into the mechanisms behind age-related changes in the sperm epigenome and their impact on offspring health and development.