The progressive accumulation of senescent cells in vivo strongly contributes to brain aging and neurodegenerative co-morbidities. We report on the establishment of a novel patient-derived brain organoid model of Ataxia-telangiectasia (A-T), a genetic disorder characterized by chronic inflammation, neurodegeneration and premature entry into cellular senescence (Aguado et al, Ageing Research Reviews 2022). Through transcriptome profiling and gene network analysis, we found multiple pro-inflammatory signatures enriched in human brain organoid (hBO) models of A-T. Mechanistically, we show that cGAS and STING inhibition effectively suppresses self-chromatin-triggered senescence-associated secretory phenotype (SASP) expression in A-T hBOs, inhibits astrocyte senescence and neurodegeneration, and ameliorates A-T brain organoid neuropathology (Aguado et al, Aging Cell 2021).
In addition to premature aging disorders, we will also show our unpublished progresses in the characterization of SARS-CoV-2-induced cellular senescence in hBOs, including chromatin changes associated to cellular senescence and DNA damage signaling. Although senolytics – drugs that selectively eliminate senescent cells – alleviate the detrimental effects that arise from these cells, their impact in the aging human brain remains largely uncharacterized. We explore the impact of multiple senolytic interventions on physiologically-aged hBOs as well as hBOs exposed to different variants of SARS-CoV-2. Interestingly, spatial transcriptomic analysis across both experimental conditions and individual senolytic treatments revealed a differential effect in alleviating neuroinflammation. Finally, senolytic interventions in mice overexpressing human ACE2 – an in vivomodel for SARS-CoV-2 neuroinvasion- recapitulated the phenotypes observed in human BOs and further showed increased lifespan and improved the clinical picture of the infected animals.
Overall, our findings suggest a detrimental role for virus-induced senescence in accelerating neuroinflammation and the aging process in the central nervous system, and a potential therapeutic benefit of senolytic interventions in COVID-19 neuropathology.