Effects of paternal aging on male reproductive biology and on future generations

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Project Summary/Abstract Over the past century, a marked demographic shift in the United States and other wealthy countries has lead to childbearing occurring later and later in life. In addition to the decrease in fecundity that accompanies aging, there is accumulating evidence that paternal age can impact offspring health and disease. This has typically been attributed to the effects of advanced paternal age on genetic changes in sperm that are transmitted to children. Here, we consider an underappreciated possibility – that the aging process affects epigenetic information carried in sperm, with resulting “epimutations” being responsible for the altered phenotypes that manifest in the next generation. Here, we propose to investigate the effects of aging on key male reproductive tissues, including the testis, epididymis, seminal vesicle, and prostate. We will explore the effects of advanced paternal age on a variety of behavioral and metabolic traits in offspring, and will comprehensively analyze molecular differences between sperm obtained from young and old animals. Together, these experiments systematically address the effects of aging on male reproductive function and on future generations, and may provide therapeutic avenues for mitigating the effects of delayed paternity on disease risk in children.