학술논문
Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology
Document Type
Original Paper
Author
Aguado, Julio; Amarilla, Alberto A.; Taherian Fard, Atefeh; Albornoz, Eduardo A.; Tyshkovskiy, Alexander; Schwabenland, Marius; Chaggar, Harman K.; Modhiran, Naphak; Gómez-Inclán, Cecilia; Javed, Ibrahim; Baradar, Alireza A.; Liang, Benjamin; Peng, Lianli; Dharmaratne, Malindrie; Pietrogrande, Giovanni; Padmanabhan, Pranesh; Freney, Morgan E.; Parry, Rhys; Sng, Julian D. J.; Isaacs, Ariel; Khromykh, Alexander A.; Valenzuela Nieto, Guillermo; Rojas-Fernandez, Alejandro; Davis, Thomas P.; Prinz, Marco; Bengsch, Bertram; Gladyshev, Vadim N.; Woodruff, Trent M.; Mar, Jessica C.; Watterson, Daniel; Wolvetang, Ernst J.
Source
Nature Aging. 3(12):1561-1575
Subject
Language
English
ISSN
2662-8465
Abstract
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.
Aguado et al. show that SARS-CoV-2 induces senescence in human brain organoids and in the brains of COVID-19-infected mice and humans. They demonstrate the therapeutic potential of senolytic therapy in protection against COVID-19-induced brain aging.
Aguado et al. show that SARS-CoV-2 induces senescence in human brain organoids and in the brains of COVID-19-infected mice and humans. They demonstrate the therapeutic potential of senolytic therapy in protection against COVID-19-induced brain aging.