Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

作者：Julio Aguado, Alberto A. Amarilla, Atefeh Taherian Fard, Eduardo A. Albornoz, Alexander Tyshkovskiy, Marius Schwabenland, Harman Kaur 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‐Fernández, Thomas P. Davis, Marco Prinz, Bertram Bengsch, Vadim N. Gladyshev, Trent M. Woodruff, Jessica C. Mar, Daniel Watterson, Ernst J. Wolvetang · 发表于：Nature Aging · 年份：2023 · DOI：10.1038/s43587-023-00519-6 · 被引用次数：70 · 研究领域：Telomeres, Telomerase, and Senescence、Neuroinflammation and Neurodegeneration Mechanisms、Circadian rhythm and melatonin

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.