Intestinal oxysterol remodeling underlies severe COVID-19 in an aged hamster model.

Age is a critical determinant of COVID-19 severity, yet the underlying metabolic mechanisms driving disease progression remain poorly understood. Using a well-characterized Syrian hamster model, we investigated how aging shapes intestinal and systemic sterol metabolism during SARS-CoV-2 infection. Young (7-10 weeks) and aged (12 months) hamsters were intranasally infected, and clinical outcomes were integrated with virological, histopathological, and lipidomic profiles across intestinal tissues, lungs, and serum. Despite comparable pulmonary pathology, aged hamsters exhibited significantly higher intestinal viral loads and more pronounced clinical decline than young counterparts. We identified a clear age-dependent divergence in sterol responses: young hamsters mounted a robust systemic induction of antiviral side-chain oxysterols, notably 25-hydroxycholesterol (25-HC) and 27-hydroxycholesterol (27-HC), in both intestinal tissues and serum. In contrast, this protective response was markedly blunted in aged animals. Moreover, aged hosts displayed a selective accumulation of ring oxysterols, particularly colonic 4β-hydroxycholesterol (4β-HC), which correlated positively with viral burden and clinical severity. Correlation analyses revealed a functional intestinal-systemic axis, where gut-derived and circulating side-chain oxysterols were inversely associated with lung cholesterol levels and clinical scores. These findings suggest that youthful metabolic responses may limit viral spread and disease progression by reducing cellular entry through modulation of pulmonary cholesterol homeostasis, while oxysterols may additionally exert direct antiviral effects-a defense mechanism that diminishes with advancing age. Collectively, these findings identify the intestine as a potential contributor to the systemic metabolic alterations associated with age-dependent COVID-19 severity and suggest oxysterol pathways as promising candidates for future mechanistic investigations and therapeutic exploration.