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

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.

Cellular senescence and premature aging in Down Syndrome.

Down syndrome (DS) is a genetic disorder caused by an extra copy of chromosome 21, resulting in cognitive impairment, physical abnormalities, and an increased risk of age-related co-morbidities. Individuals with DS exhibit accelerated aging, which has been attributed to several cellular mechanisms, including cellular senescence, a state of irreversible cell cycle arrest that is associated with aging and age-related diseases. Emerging evidence suggests that cellular senescence may play a key role in the pathogenesis of DS and the development of age-related disorders in this population. Importantly, cellular senescence may be a potential therapeutic target in alleviating age-related DS pathology. Here, we discuss the importance of focusing on cellular senescence to understand accelerated aging in DS. We review the current state of knowledge regarding cellular senescence and other hallmarks of aging in DS, including its putative contribution to cognitive impairment, multi-organ dysfunction, and premature aging phenotypes.

Nucleocapsid Specific Diagnostics for the Detection of Divergent SARS-CoV-2 Variants.

Since the start of the COVID-19 pandemic, multiple waves of SARS-CoV-2 variants have emerged. Of particular concern is the omicron variant, which harbors 28 mutations in the spike glycoprotein receptor binding and N-terminal domains relative to the ancestral strain. The high mutability of SARS-CoV-2 therefore poses significant hurdles for development of universal assays that rely on spike-specific immune detection. To address this, more conserved viral antigens need to be targeted. In this work, we comprehensively demonstrate the use of nucleocapsid (N)-specific detection across several assays using previously described nanobodies C2 and E2. We show that these nanobodies are highly sensitive and can detect divergent SARS-CoV-2 ancestral, delta and omicron variants across several assays. By comparison, spike-specific antibodies S309 and CR3022 only disparately detect SARS-CoV-2 variant targets. As such, we conclude that N-specific detection could provide a standardized universal target for detection of current and emerging SARS-CoV-2 variants of concern.