Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, School of Environmental and Life Sciences, College of Engineering Science and Environment, University of Newcastle, Callaghan, NSW, Australia.
Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
Hum Reprod. 2023 Oct 3;38(10):1861-1871. doi: 10.1093/humrep/dead157.
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.
在现代后转型社会中，人们的生育年龄越来越晚，寿命也越来越长。虽然年龄对女性生殖功能的影响已经得到了充分的研究，但对于年龄与男性生殖的交叉点却知之甚少。我们目前的理解是，随着年龄的增长，男性生育能力逐渐下降，同时伴随着循环睾酮水平的降低和与年龄相关的生殖病理出现，包括良性前列腺增生和勃起功能障碍。父亲的衰老也与精子 DNA 损伤的显著增加、生殖系中出现多种表观遗传变化以及后代突变负荷的升高有关。这些变化的净结果是，衰老男性后代的疾病负担增加，包括显性遗传疾病，如 Apert 综合征和软骨发育不全，以及神经精神疾病，如自闭症和自发性精神分裂症。这些与年龄相关的影响的遗传基础似乎涉及两个基本机制。第一个是正选择机制，其中含有丝裂原激活的蛋白激酶途径突变的干细胞相对于其非突变对应物获得了选择性优势，并随着时间的推移表现出显著的克隆扩张。第二个机制依赖于与年龄相关的氧化应激增加，这会损害莱迪希细胞的甾体生成能力，破坏支持精子细胞正常分化的支持细胞的能力，并破坏精子的功能和遗传完整性。鉴于氧化应激在定义年龄对男性生殖的影响方面的核心重要性，抗氧化剂可能在这一过程的临床管理中发挥作用。虽然动物研究支持这一策略，但如果我们要在临床环境中实现这一方法的治疗潜力，现在就需要精心设计的临床试验。
