Evolution optimizes for reproductive success, and thus it should be no surprise to find that reproductive organs influence the entire body, and thus their aging has sizable effects on the aging of other organs. Researchers here review the mechanisms of aging that act to degrade structure and function of the testes, and in turn affect the production of androgens that influence tissue function elsewhere in the body.
The testis, a male-specific organ, plays a critical role in maintaining spermatogenesis and androgen production. As men age, testicular function declines, compromising not only reproductive capacity but also overall health and quality of life. Testicular ageing is characterized by progressive degeneration of the seminiferous epithelium and interstitial compartments, leading to endocrine dysfunction, impaired spermatogenesis, and heightened risk of age-related disease.
Although mechanistic insights are advancing rapidly, most therapeutic studies remain rooted in reductionist single-cell models that overlook the integrated dynamics of the testicular microenvironment. In reality, testicular ageing reflects a coordinated decline of germ cells, Sertoli and Leydig cells, and their niches. This process is driven by interconnected mechanisms, including oxidative stress, defective DNA repair and autophagy, dysregulated endocrine homeostasis, impaired protein quality control, and aberrant activation of ageing-related signalling pathways, which act synergistically.
Testicular ageing is accompanied by a progressive collapse of energy metabolism. Impaired fatty acid utilisation, reduced glucose uptake, and widespread mitochondrial dysfunction collectively drive metabolic remodelling that deteriorates the testicular microenvironment. Moreover, senescent somatic cells acquire a senescence-associated secretory phenotype (SASP), releasing pro-inflammatory cytokines such as IL-6 and IL-1β, while testicular macrophages adopt a pro-inflammatory state that recruits adaptive immune cells. Together, these changes establish a chronic inflammatory microenvironment that reinforces cellular senescence and accelerates testicular ageing.
Priorities for future research include clarifying cell-microenvironment interactions, establishing non-invasive biomarkers for early detection, and resolving metabolic pathways that may guide senolytic strategies. As therapeutic paradigms evolve, emerging interventions - particularly stem-cell-based approaches - may extend beyond the limits of conventional pharmacology to enable more precise and effective mitigation of testicular ageing.
Link: https://doi.org/10.1080/07853890.2026.2624183
View the full article at FightAging
