马萨诸塞大学陈医学院Michael A. Lodato小组的一项最新研究开发出衰老人脑中单细胞转录组学和基因组学的变化。相关论文发表在2025年9月3日出版的《自然》杂志上。

通过单核RNA测序（snRNA-seq）、单细胞全基因组测序（scWGS）和空间转录组学，该课题组研究人员确定了人类前额叶皮层从婴儿到百岁老人的整个生命周期中的基因表达和基因组变化。snRNA-seq鉴定了富含神经发育基因表达的婴儿特异性细胞细胞，以及与年龄相关的细胞必需稳态基因的常见下调，这些基因在核糖体中起作用，跨细胞类型的运输和代谢。相反，神经元特异性基因的表达通常在整个生命过程中保持稳定。

这些发现通过空间转录组学得到了验证。scWGS发现了两个与年龄相关的突变特征，分别与基因转录和基因抑制相关，并揭示了与老年人脑转录组景观相关的神经元体细胞突变的基因长度和表达水平依赖率。他们的结果为人类大脑发育和衰老的关键方面提供了见解，并阐明了转录组学和基因组动力学。

研究人员表示，随着时间的推移，大脑和身体中的细胞会累积损伤，从而导致衰老过程。在人类大脑中，前额叶皮层会经历与年龄相关的变化，这些变化会影响到以后的认知功能。

附：英文原文

Title: Single-cell transcriptomic and genomic changes in the ageing human brain

Author: Jeffries, Ailsa M., Yu, Tianxiong, Ziegenfuss, Jennifer S., Tolles, Allie K., Baer, Christina E., Sotelo, Cesar Bautista, Kim, Yerin, Weng, Zhiping, Lodato, Michael A.

Issue&Volume: 2025-09-03

Abstract: Over time, cells in the brain and in the body accumulate damage, which contributes to the ageing process1. In the human brain, the prefrontal cortex undergoes age-related changes that can affect cognitive functioning later in life2. Here, using single-nucleus RNA sequencing (snRNA-seq), single-cell whole-genome sequencing (scWGS) and spatial transcriptomics, we identify gene-expression and genomic changes in the human prefrontal cortex across lifespan, from infancy to centenarian. snRNA-seq identified infant-specific cell clusters enriched for the expression of neurodevelopmental genes, as well as an age-associated common downregulation of cell-essential homeostatic genes that function in ribosomes, transport and metabolism across cell types. Conversely, the expression of neuron-specific genes generally remains stable throughout life. These findings were validated with spatial transcriptomics. scWGS identified two age-associated mutational signatures that correlate with gene transcription and gene repression, respectively, and revealed gene length- and expression-level-dependent rates of somatic mutation in neurons that correlate with the transcriptomic landscape of the aged human brain. Our results provide insight into crucial aspects of human brain development and ageing, and shed light on transcriptomic and genomic dynamics.

DOI: 10.1038/s41586-025-09435-8

Source: https://www.nature.com/articles/s41586-025-09435-8