Epigenetic links between paternal age, reproduction, and offspring health: a focus on sncRNAs.

Abstract: As men age, their reproductive capacity changes. Although males do not have a defined 'biological clock', evidence suggests that paternal age plays a pivotal role in male reproduction and offspring health. Epigenetic mechanisms, which influence how genes are expressed in all cells, are important in gametogenesis and can be influenced by endogenous factors such as diet, toxin exposure, stress, and age. Hence, an altered paternal environment can generate epigenetic modifications that can be passed onto the offspring via the ejaculate. In humans, more couples in developed countries are delaying parenthood and are relying on assisted reproductive techniques. Although research has focused on maternal age, growing evidence shows that advanced paternal age (APA) can influence the epigenetic pathways in embryos and offspring. There are several known epigenetic mechanisms that may link APA to downstream fitness effects in offspring: DNA methylation, histone post-translational modifications, chromatin remodelling, and small noncoding RNA (sncRNA) expression. Sperm RNAs were once considered residual products of sperm maturation. Now, small RNAs have emerged as key players in male fertility. sncRNA expression tightly regulates the sperm cell cycle and maturation, and embryo development. Despite their importance in epigenetic inheritance, the relationship between paternal age, sncRNA expression, and reproductive outcomes is unclear. Given the role of sncRNA expression in gametogenesis and embryogenesis, understanding how age influences sncRNA expression could provide insights into the underlying factors of failed natural and assisted fertility. This review explores the links between paternal age, sperm epigenetics, reproduction, and offspring health, with a focus on sncRNA expression. Lay summary: Unlike women, men do not have a clear biological clock. However, research shows that a man's age can affect his fertility and the health of his children. As men get older, the way genes are turned on and off in sperm changes and these changes can be passed on to their children. Lifestyle factors such as diet, stress, and exposure to toxins can affect how genes are controlled. Much research has focused on the effects of maternal age, but there is growing evidence that advanced paternal age (APA) can influence fertility and embryo development. A key area of interest is small sperm molecules that influence early development. Once thought to be mere by-products of sperm development, these molecules are now known to play crucial roles in sperm function and embryo development. This review examines how a father's age affects these small sperm molecules and their role in fertility and offspring health.