The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.

海马体在学习和记忆中起着至关重要的作用，其随着年龄的增长而逐渐退化，在功能上与多种人类神经退行性疾病有关。然而，仍然缺乏对灵长类动物各种海马细胞类型的衰老影响的系统分析。在这里，我们报告了灵长类海马体的各种新的与衰老相关的表型变化。其中特别包括随着时间的推移，DNA 损伤和异染色质侵蚀增加，同时蛋白质稳态丧失和炎症加剧。为了了解其细胞和分子原因，我们建立了第一个灵长类海马衰老的单核转录组图谱。在 12 种已确定的细胞类型中，神经瞬时放大祖细胞 (TAPC) 和小胶质细胞受衰老影响最大。对基因表达动态的深入剖析揭示了神经发生轨迹上 TAPC 分裂受损和神经元功能受损；此外，衰老的小胶质细胞和少突胶质细胞中促炎症反应的升高，以及衰老内皮细胞中凝血途径的失调可能会导致神经发生的不利微环境。这种了解灵长类海马衰老的丰富资源可能为与年龄相关的神经退行性疾病提供潜在的诊断生物标志物和治疗干预措施。