The aging spermatogonial stem cell niche

Abstract Adult male fertility is dependent on spermatogonial stem cells (SSCs) that self-renew and generate differentiating daughter cells to support continual gamete production. With advancing age, there is a decline in male reproductive function reflected in decreased pregnancy rates and an increased risk of siring children with congenital disorders. Molecular mechanisms underlying this age-associated decline in SSC function and male fertility are poorly understood although highly relevant for men delaying parenthood. The maintenance and regulation of SSC function is unequivocally dependent on the cellular microenvironment or “niche” within the testis. A variety of cell types contribute to the SSC niche and provide essential support and molecular cues that regulate SSC maintenance and spermatogenesis under distinct physiological conditions including development, homeostasis plus upon tissue damage and aging. It is proposed that dysfunction or loss of SSCs during aging underlies the decline in male reproductive function. Importantly, studies in both rodents and fruit flies have revealed the central role played by declining function of the SSC niche in loss of germline integrity with age. However, given the complex and poorly defined nature of the SSC niche in mammals, it has remained challenging to define the primary causes of age-dependent SSC dysfunction. Moreover, recent studies have delineated SSC-intrinsic mechanisms that lead to loss of spermatogenic potential with age, suggesting that the decline in SSC function and fertility can be dependent on both cell autonomous and non-autonomous mechanisms. This chapter provides an overview of our current understanding of effects of aging on the male germline and highlights areas for future study.