Department of Genes and Environment, Max Planck Institute of Psychiatry, Munich, Germany.
International Max Planck Research School for Translational Psychiatry, Munich, Germany.
Nat Neurosci. 2024 Oct;27(10):2021-2032. doi: 10.1038/s41593-024-01742-z. Epub 2024 Sep 3.
Aging is a complex biological process and represents the largest risk factor for neurodegenerative disorders. The risk for neurodegenerative disorders is also increased in individuals with psychiatric disorders. Here, we characterized age-related transcriptomic changes in the brain by profiling ~800,000 nuclei from the orbitofrontal cortex from 87 individuals with and without psychiatric diagnoses and replicated findings in an independent cohort with 32 individuals. Aging affects all cell types, with LAMP5LHX6 interneurons, a cell-type abundant in primates, by far the most affected. Disrupted synaptic transmission emerged as a convergently affected pathway in aged tissue. Age-related transcriptomic changes overlapped with changes observed in Alzheimer's disease across multiple cell types. We find evidence for accelerated transcriptomic aging in individuals with psychiatric disorders and demonstrate a converging signature of aging and psychopathology across multiple cell types. Our findings shed light on cell-type-specific effects and biological pathways underlying age-related changes and their convergence with effects driven by psychiatric diagnosis.
衰老是一个复杂的生物学过程,是神经退行性疾病的最大风险因素。精神疾病患者神经退行性疾病的风险也会增加。在这里,我们通过对 87 名有和没有精神疾病诊断的个体的眶额皮质的约 800,000 个核进行分析,对大脑的年龄相关转录组变化进行了特征描述,并在一个独立的包含 32 名个体的队列中进行了验证。衰老是所有细胞类型的影响,其中 LAMP5LHX6 中间神经元是一种在灵长类动物中丰富的细胞类型,受影响最大。受损的突触传递在老化组织中作为一个共同受影响的途径出现。与多种细胞类型中的阿尔茨海默病观察到的变化重叠的是与年龄相关的转录组变化。我们在有精神疾病的个体中发现了加速的转录组衰老的证据,并在多种细胞类型中证明了衰老和精神病理学的趋同特征。我们的研究结果揭示了与年龄相关变化及其与精神疾病诊断驱动的变化趋同的细胞类型特异性影响和生物学途径。