Abstract
<title>Abstract</title> <p>Astrocytes were generated from PBMC-derived iPSCs of centenarians (≥100 years) who recovered from asymptomatic to moderate COVID-19 and from adults (<45 years) who experienced critical disease. Cells were infected with either the ancestral Wuhan SARS-CoV-2 or the more virulent Gamma (P.1) variant and analyzed 48 hours post-infection. Despite comparable infection rates across groups, astrocytes infected with the P.1 variant released higher levels of viral particles than the ancestral Wuhan, indicating strain-dependent differences in post-entry viral dynamics. Notably, centenarian-derived astrocytes exhibited a more restrained inflammatory response, with reduced secretion of CXCL8 with Wuhan infection and CXCL10 with P.1 infection. Quantitative proteomic profiling revealed extensive infection-driven remodeling of the astrocyte proteome, with a largely conserved global response across all groups. However, centenarian astrocytes showed reduced detection of antigen presentation-related proteins and distinct regulation of metabolic pathways, whereas astrocytes from severe cases displayed broader dysregulation of stress- and immune-related processes and increased NRP1 abundance without corresponding changes in infection susceptibility. These differences may reflect intrinsic cellular states associated with resilience and contribute to a more controlled response to the viral challenge in centenarians.</p>