Senolytic 疗法可缓解人脑生理老化和 COVID-19 神经病理学。
Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology.
发表日期：2023 Nov 13
作者：
Julio Aguado, Alberto A Amarilla, Atefeh Taherian Fard, Eduardo A Albornoz, Alexander Tyshkovskiy, Marius Schwabenland, Harman K Chaggar, Naphak Modhiran, Cecilia Gómez-Inclán, Ibrahim Javed, Alireza A Baradar, Benjamin Liang, Lianli Peng, Malindrie Dharmaratne, Giovanni Pietrogrande, Pranesh Padmanabhan, Morgan E Freney, Rhys Parry, Julian D J Sng, Ariel Isaacs, Alexander A Khromykh, Guillermo Valenzuela Nieto, Alejandro Rojas-Fernandez, Thomas P Davis, Marco Prinz, Bertram Bengsch, Vadim N Gladyshev, Trent M Woodruff, Jessica C Mar, Daniel Watterson, Ernst J Wolvetang
来源：
Brain Structure & Function
摘要：
衰老是神经退行性疾病的主要危险因素，而 2019 年冠状病毒病 (COVID-19) 与严重的神经系统表现有关。衰老细胞会导致大脑衰老，但病毒引起的衰老对神经病理学的影响尚不清楚。在这里，我们发现衰老细胞在衰老的人脑类器官中积累，并且衰老药物可以减少与年龄相关的炎症并恢复转录组衰老时钟。在重症 COVID-19 患者死后大脑中，我们观察到与年龄匹配的对照组相比，衰老细胞积累增加。将人脑类器官暴露于严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 会诱导细胞衰老，转录组分析揭示了独特的 SARS-CoV-2 炎症特征。对受感染的脑类器官进行衰老治疗可阻止病毒复制并防止不同神经元群体的衰老。在人类 ACE2 过度表达的小鼠中，senolytics 改善了 COVID-19 的临床结果，促进多巴胺能神经元的存活并减轻病毒和促炎基因的表达。总的来说，我们的结果证明了细胞衰老在驱动大脑衰老和 SARS-CoV-2 诱导的神经病理学中的重要作用，以及 senolytic 治疗的治疗益处。© 2023。作者。
Aging is a major risk factor for neurodegenerative diseases, and coronavirus disease 2019 (COVID-19) is linked to severe neurological manifestations. Senescent cells contribute to brain aging, but the impact of virus-induced senescence on neuropathologies is unknown. Here we show that senescent cells accumulate in aged human brain organoids and that senolytics reduce age-related inflammation and rejuvenate transcriptomic aging clocks. In postmortem brains of patients with severe COVID-19 we observed increased senescent cell accumulation compared with age-matched controls. Exposure of human brain organoids to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced cellular senescence, and transcriptomic analysis revealed a unique SARS-CoV-2 inflammatory signature. Senolytic treatment of infected brain organoids blocked viral replication and prevented senescence in distinct neuronal populations. In human-ACE2-overexpressing mice, senolytics improved COVID-19 clinical outcomes, promoted dopaminergic neuron survival and alleviated viral and proinflammatory gene expression. Collectively our results demonstrate an important role for cellular senescence in driving brain aging and SARS-CoV-2-induced neuropathology, and a therapeutic benefit of senolytic treatments.© 2023. The Author(s).