睾丸对男性生殖机能至关重要，年龄逐渐增长导致其功能下降与不育有关。然而，灵长类睾丸衰老的调控机制仍然大多未知。本研究通过建立单核转录组图谱，解决了灵长类睾丸衰老相关的细胞和分子变化。沿着精子形成轨迹的基因表达模式显示了与精原干细胞储备减少、减弱的减数分裂和随时间推移的受损精子生成相关的分子程序。值得注意的是，Sertoli 细胞被确认是最容易受到衰老影响的细胞类型，因为其年龄相关转录谱受到深刻干扰。同时，转录因子Wilms' Tumor 1（WT1）的下调与细胞衰老加速、紧密结合失调和受损细胞身份签名相关联，总体上可能有助于形成不利于精子形成的微环境。总之，我们的研究提供了非人类灵长类动物睾丸衰老的深入转录组特征，为诊断生物标志物和治疗睾丸衰老和与年龄相关的男性生殖疾病提供了潜在的治疗靶点。©The Author(s) 2022. Published by Oxford University Press on behalf of Higher Education Press.

The testis is pivotal for male reproduction, and its progressive functional decline in aging is associated with infertility. However, the regulatory mechanism underlying primate testicular aging remains largely elusive. Here, we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas. Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir, disturbed meiosis and impaired spermiogenesis along the sequential continuum. Remarkably, Sertoli cell was identified as the cell type most susceptible to aging, given its deeply perturbed age-associated transcriptional profiles. Concomitantly, downregulation of the transcription factor Wilms' Tumor 1 (WT1), essential for Sertoli cell homeostasis, was associated with accelerated cellular senescence, disrupted tight junctions, and a compromised cell identity signature, which altogether may help create a hostile microenvironment for spermatogenesis. Collectively, our study depicts in-depth transcriptomic traits of non-human primate (NHP) testicular aging at single-cell resolution, providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.©The Author(s) 2022. Published by Oxford University Press on behalf of Higher Education Press.