Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk¹. Brain ageing is complex and is accompanied by many cellular changes². Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in ageing tissues have not yet been developed. Here we generate a spatially resolved single-cell transcriptomics brain atlas of 4.2 million cells from 20 distinct ages across the adult lifespan and across two rejuvenating interventions—exercise and partial reprogramming. We build spatial ageing clocks, machine learning models trained on this spatial transcriptomics atlas, to identify spatial and cell-type-specific transcriptomic fingerprints of ageing, rejuvenation and disease, including for rare cell types. Using spatial ageing clocks and deep learning, we find that T cells, which increasingly infiltrate the brain with age, have a marked pro-ageing proximity effect on neighbouring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating proximity effect on neighbouring cells. We also identify potential mediators of the pro-ageing effect of T cells and the pro-rejuvenating effect of neural stem cells on their neighbours. These results suggest that rare cell types can have a potent influence on their neighbours and could be targeted to counter tissue ageing. Spatial ageing clocks represent a useful tool for studying cell–cell interactions in spatial contexts and should allow scalable assessment of the efficacy of interventions for ageing and disease.

老年与认知功能下降和神经退行性疾病风险增加有关¹。大脑衰老很复杂，并伴有许多细胞变化²。此外，衰老细胞对邻近细胞的影响以及这如何导致组织衰退尚不清楚。更一般地说，在衰老组织中系统地解决这个问题的工具尚未开发出来。在这里，我们生成了一个空间分辨的单细胞转录组学脑图谱，其中包含来自 20 个不同年龄的 420 万个细胞，贯穿整个成年期和两种恢复活力的干预措施——运动和部分重编程。我们构建空间衰老时钟，即在此空间转录组学图谱上训练的机器学习模型，以识别衰老、年轻化和疾病的空间和细胞类型特异性转录组指纹，包括稀有细胞类型。利用空间衰老时钟和深度学习，我们发现随着年龄的增长，T 细胞越来越多地浸润到大脑中，对邻近细胞具有明显的促衰老邻近效应。令人惊讶的是，神经干细胞对邻近细胞具有很强的促年轻化效应。我们还确定了 T 细胞促衰老作用和神经干细胞对其邻居的促年轻化作用的潜在介质。这些结果表明，稀有细胞类型可以对其邻居产生有效影响，并可能成为对抗组织衰老的目标。空间衰老时钟是研究空间背景下细胞间相互作用的有用工具，应该允许对衰老和疾病干预措施的疗效进行可扩展评估。