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

被引：31

作者：

Aguado, Julio ^{[1
]}

Amarilla, Alberto A. ^{[2
]}

Fard, Atefeh Taherian ^{[1
]}

Albornoz, Eduardo A. ^{[3
]}

Tyshkovskiy, Alexander ^{[4
,5
]}

Schwabenland, Marius ^{[6
,7
]}

Chaggar, Harman K. ^{[1
]}

Modhiran, Naphak ^{[1
,2
]}

Gomez-Inclan, Cecilia ^{[1
]}

Javed, Ibrahim ^{[1
,8
]}

Baradar, Alireza A. ^{[1
]}

Liang, Benjamin ^{[2
]}

Peng, Lianli ^{[1
]}

Dharmaratne, Malindrie ^{[1
]}

Pietrogrande, Giovanni ^{[1
]}

Padmanabhan, Pranesh ^{[9
]}

Freney, Morgan E. ^{[2
]}

Parry, Rhys ^{[2
]}

Sng, Julian D. J. ^{[2
]}

Isaacs, Ariel ^{[2
]}

Khromykh, Alexander A. ^{[2
,10
]}

Nieto, Guillermo Valenzuela ^{[11
,12
]}

Rojas-Fernandez, Alejandro ^{[13
,14
]}

Davis, Thomas P. ^{[1
]}

Prinz, Marco ^{[6
,7
,15
,16
]}

Bengsch, Bertram ^{[15
,16
,17
]}

Gladyshev, Vadim N. ^{[4
,18
]}

Woodruff, Trent M. ^{[3
]}

Mar, Jessica C. ^{[1
]}

Watterson, Daniel ^{[2
]}

Wolvetang, Ernst J. ^{[1
]}

机构：

[1] Univ Queensland, Australian Inst Bioengn & Nanotechnol, St Lucia, Qld, Australia

[2] Univ Queensland, Sch Chem & Mol Biosci, St Lucia, Qld, Australia

[3] Univ Queensland, Fac Med, Sch Biomed Sci, St Lucia, Qld, Australia

[4] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA USA

[5] Moscow State Univ, Belozersky Inst Physicochem Biol, Moscow, Russia

[6] Univ Freiburg, Inst Neuropathol, Freiburg, Germany

[7] Univ Freiburg, Fac Med, Ctr Basics NeuroModulat, Freiburg, Germany

[8] Univ South Australia, Ctr Pharmaceut Innovat, Sch Pharm & Med Sci, UniSA Clin & Hlth Sci, Adelaide, SA, Australia

[9] Univ Queensland, Queensland Brain Inst, Clem Jones Ctr Ageing Dementia Res, Brisbane, Qld, Australia

[10] Australian Infect Dis Res Ctr, Global Virus Network Ctr Excellence, Brisbane, Qld, Australia

[11] Univ Austral Chile, Inst Med, Fac Med, Valdivia, Chile

[12] Univ Austral Chile, Ctr Interdisciplinary Studies Nervous Syst, CISNE, Valdivia, Chile

[13] Univ Oxford, Nuffield Dept Med, Oxford, England

[14] Berking Biotechnol, Valdivia, Chile

[15] Univ Freiburg, Signalling Res Ctr BIOSS, Freiburg, Germany

[16] Univ Freiburg, CIBSS, Freiburg, Germany

[17] Univ Med Ctr Freiburg, Fac Med, Clin Internal Med Gastroenterol Hepatol Endocrinol, Freiburg, Germany

[18] Broad Inst MIT & Harvard, Cambridge, MA USA

来源：

NATURE AGING | 2023年 / 3卷 / 12期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

MOLECULAR SIGNATURES; CELLULAR SENESCENCE; DNA-DAMAGE; INFECTION;

D O I：

10.1038/s43587-023-00519-6

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1561 / 1575

页数：27

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