Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology
-
Published:2023-11-13
Issue:12
Volume:3
Page:1561-1575
-
ISSN:2662-8465
-
Container-title:Nature Aging
-
language:en
-
Short-container-title:Nat Aging
Author:
Aguado JulioORCID, Amarilla Alberto A., Taherian Fard AtefehORCID, Albornoz Eduardo A.ORCID, Tyshkovskiy AlexanderORCID, Schwabenland MariusORCID, Chaggar Harman K., Modhiran Naphak, Gómez-Inclán Cecilia, Javed Ibrahim, Baradar Alireza A., Liang BenjaminORCID, Peng LianliORCID, Dharmaratne Malindrie, Pietrogrande Giovanni, Padmanabhan PraneshORCID, Freney Morgan E., Parry RhysORCID, Sng Julian D. J.ORCID, Isaacs Ariel, Khromykh Alexander A., Valenzuela Nieto Guillermo, Rojas-Fernandez Alejandro, Davis Thomas P.ORCID, Prinz MarcoORCID, Bengsch BertramORCID, Gladyshev Vadim N.ORCID, Woodruff Trent M.ORCID, Mar Jessica C., Watterson Daniel, Wolvetang Ernst J.ORCID
Abstract
AbstractAging 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.
Publisher
Springer Science and Business Media LLC
Subject
Neuroscience (miscellaneous),Geriatrics and Gerontology,Aging
Reference63 articles.
1. Nalbandian, A. et al. Post-acute COVID-19 syndrome. Nat. Med. 27, 601–615 (2021). 2. Choutka, J., Jansari, V., Hornig, M. & Iwasaki, A. Unexplained post-acute infection syndromes. Nat. Med. 28, 911–923 (2022). 3. Taquet, M., Geddes, J. R., Husain, M., Luciano, S. & Harrison, P. J. 6-Month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry 8, 416–427 (2021). 4. Monje, M. & Iwasaki, A. The neurobiology of long COVID. Neuron 110, 3484–3496 (2022). 5. Ceban, F. et al. Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav. Immun. 101, 93–135 (2022).
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|