Post-acute sequelae of SARS-CoV-2 infection, or Long-COVID, affects millions globally and is characterized by persistent symptoms affecting multiple organs, yet the underlying mechanisms remain poorly defined. Here, we used Golden Syrian Hamsters (GSH) infected with the SARS-CoV-2 to investigate how sex and age shape viral persistence, organ-specific pathology, immune responses, and neurological outcomes during acute infection and Long-COVID. We show that during Long-COVID, viral RNA persists only in the lungs of male hamsters. Lung pathology revealed sustained inflammation and tissue remodeling, with young females exhibiting greater fibrosis. Transcriptomic profiling across brain, lung, and heart identified pronounced sex- and age-dependent regulation of gene expression spanning immune, neuroinflammatory, and neurotransmitter signaling pathways. These transcriptomic alterations were accompanied by sex-specific behavioral changes and persistent microstructural remodeling in cognition-associated brain regions. Additionally, SARS-CoV-2 altered α-synuclein homeostasis and microglial activation alongside gut microbiome composition in a sex- and age-dependent manner. Together, our findings demonstrate that, in GSH Long-COVID is strongly modulated by sex and age, influencing viral RNA persistence, immune and neurobiological responses, and gut microbiota composition mirroring clinical outcomes reported in human cohorts. This study establishes SARS-CoV-2-infected GSH as a model for dissecting the mechanisms of Long-COVID and informing targeted prevention strategies.
