Male reproductive ageing: a radical road to ruin

Abstract

In modern post-transition societies, we are reproducing later and living longer. While the impact of age on female reproductive function has been well studied, much less is known about the intersection of age and male reproduction. Our current understanding is that advancing age brings forth a progressive decline in male fertility accompanied by a reduction in circulating testosterone levels and the appearance of age-dependent reproductive pathologies including benign prostatic hypertrophy and erectile dysfunction. Paternal ageing is also associated with a profound increase in sperm DNA damage, the appearance of multiple epigenetic changes in the germ line and an elevated mutational load in the offspring. The net result of such changes is an increase in the disease burden carried by the progeny of ageing males, including dominant genetic diseases such as Apert syndrome and achondroplasia, as well as neuropsychiatric conditions including autism and spontaneous schizophrenia. The genetic basis of these age-related effects appears to involve two fundamental mechanisms. The first is a positive selection mechanism whereby stem cells containing mutations in a mitogen-activated protein kinase pathway gain a selective advantage over their non-mutant counterparts and exhibit significant clonal expansion with the passage of time. The second is dependent on an age-dependent increase in oxidative stress which impairs the steroidogenic capacity of the Leydig cells, disrupts the ability of Sertoli cells to support the normal differentiation of germ cells, and disrupts the functional and genetic integrity of spermatozoa. Given the central importance of oxidative stress in defining the impact of chronological age on male reproduction, there may be a role for antioxidants in the clinical management of this process. While animal studies are supportive of this strategy, carefully designed clinical trials are now needed if we are to realize the therapeutic potential of this approach in a clinical context.

Prevalence and Predictors of Erectile Dysfunction among Filipino men: A cross-sectional study

“…Increasing age remains a single predictor of ED among general population of men worldwide (Aitken, 2023). In this current study, the multivariate regression analysis shows that age does not have effect on the total IIEF score.…”

Relationship between male aging and semen quality: a retrospective study on over 2500 men

“…Advancing age, indeed, is associated with a significant increase in the percentage of spermatozoa with mitochondrial depolarization, as an expression of natural senescence processes of biological structures and progressive accumulation of mutations in mitochondrial DNA [ 16 ]. The age-dependent increase in oxidative stress can not only impair the functional and genetic integrity of spermatozoa, but also Leydig cell steroidogenesis and the ability of Sertoli cells to support normal germ cell differentiation [ 31 ]. The effects of oxidative stress can be heightened during infections, and accordingly, in a study by Rolf et al [ 32 ], total sperm count decreased significantly with advancing age only in patients with an infection of the accessory glands.…”

What is driving the global decline of human fertility? Need for a multidisciplinary approach to the underlying mechanisms

“…Further to such genetic considerations, we should not forget the potential impact of epigenetic changes on fertility. A variety of lifestyle and environmental factors are known to impact the epigenetic status of the germ line including obesity ( 199 ) and environmental toxicants ( 200 ). Via such means, the germ line is able to respond dynamically, and sometimes aberrantly, to changes in the parental environment by inducing alterations in patterns of DNA methylation and small non-coding RNA species within the male and female germ lines ( 201 , 202 ).…”