Fertility in the aging male: a systematic review

Abstract

The negative effect of advanced female age on fertility and offspring health is well understood. In comparison, much less is known about the implications of male age on fertility, with many studies showing conflicting results. Nevertheless, increasing evidence suggests that advanced paternal age has negative effects on sperm parameters, reproductive success, and offspring health. Herein, we summarize the current body of knowledge on this controversial topic, with the belief that this review will serve as a resource for the clinicians providing fertility counseling to couples with older male partners.

Keywords: Male infertility; andrology; paternal age.

Figure 1 -

Schematic diagram of oxidative-stress induced DNA damage and mutation (A) Sperm DNA chromatin decondensation, as a function of increased paternal age, has been hypothesized as a mechanism underlying increased DNA fragmentation rates. Specifically, sperm DNA decondensation exposes the DNA to reactive oxygen species (ROS) generated from several sources, including mitochondrial dysfunction. These ROS can induce DNA damage in the form of double- or single-stranded breaks (yellow star). (B) Oxidative stress can result in the conversion of the guanine nucleotide to 8-oxoguanine (orange). During subsequent rounds of replication, if left unrepaired, 8-oxoguanine will complement adenine rather than cytosine. Further replication of the strand harboring adenine (red, middle panel) will result in a complementary strand harboring a thymine nucleotide at the site formerly occupied by a guanine nucleotide (red, bottom panel). Figure made with biorender.

Figure 2 -

Source of male germline de novo mutations (A) We provide a schematic diagram of James Crow’s estimates(87) which describe the number of cell divisions mature sperm would undergo as a function of male age. Here, we aim to highlight the years elapsed post-puberty (after roughly 16 years), which contributes to the non-linear increase in spermatogonial stem cell divisions by age 20 and 40. (B) As discussed in Cioppi et al.(88), several processes can introduce male germline de novo mutations, including dysfunctional DNA repair mechanisms, environmental mutagens such as smoking, and DNA replication error - the latter of which is related to age-dependent differences in spermatogonial stem cell divisions. Figure made with biorender.