Senescent Cells in the Human Brain
Study of the biochemistry of the human brain is hindered by the difficulty of accessing tissue samples. Most work is conducted on post-mortem tissue rather than samples taken from a living brain (such as during surgery), and few research groups have the necessary connections to obtain these materials. Thus the development of brain organoids is important in this part of the medical research field, even given that most present organoid recipes result in a poor substitute for actual tissue. Here, researchers use post-mortem tissue and organoids to demonstrate that senescent cells are important in the aging of the brain, and in the effects of COVID-19. This is one of many data points to suggest that treatment with senolytics capable of passing the blood-brain barrier (such as the dasatinib and quercetin combination) will be beneficial in older individuals.
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.