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 LAMP5⁺LHX6⁺ 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过程，是神经退行性疾病的最大风险因素。精神疾病患者患神经退行性疾病的风险也增加。在这里，我们通过分析来自 87 名有和没有精神病诊断的个体的眶额叶皮层的 ~800,000 个细胞核，并在一个有 32 个体的独立队列中复制发现，来表征大脑中与年龄相关的转录组学变化。衰老会影响所有细胞类型，其中 LAMP5⁺LHX6⁺ 中间神经元是灵长类动物中丰富的细胞类型，迄今为止受影响最严重。突触传递中断成为衰老组织中收敛受影响的通路。与年龄相关的转录组变化与在多种细胞类型中观察到的阿尔茨海默病变化重叠。我们发现了精神疾病个体转录组衰老加速的证据，并证明了衰老和精神病理学在多种细胞类型中的融合特征。我们的研究结果阐明了年龄相关变化背后的细胞类型特异性效应和生物途径，以及它们与精神病学诊断驱动的影响的趋同。