Inflammaging-Induced Bioenergetic Gap Exhausts Pulmonary Nucleotide Pools to Exacerbate SARS-CoV‑2 Outcomes in Early Stage Aging

Age
is a key risk factor for morbidity in coronavirus disease 2019
(COVID-19). This study investigates how “inflammaging”
predisposes older hosts to severe SARS-CoV-2 outcomes through systemic
and localized metabolic shifts. SARS-CoV-2 infection experiments were
conducted respectively on 8 week-old mice and 16 week-old mice. An
integrated multiomics approach was employed to delineate age-dependent
molecular signatures and metabolic-immune crosstalk. 16 week-old mice
exhibited significantly exacerbated weight loss and pulmonary pathology,
successfully recapitulating age-related susceptibility. Multiomics
integration revealed a “systemic bioenergetic gap”:
suppressed plasma TCA cycle metabolites correlated with depleted pulmonary
nucleotide pools (AMP, GMP, UMP and uracil). This metabolic failure
led to a paradoxical proteomic profile: despite interferon pathway
activation, key antiviral effectors (RSAD2, ISG15, IFIT3B) were downregulated,
while stress markers (CYP1A1, MAPK8) increased. Furthermore, threonic
acid, betaine, and d-ribose were identified as robust, age-dependent
biomarkers of infection severity. Our findings suggest that COVID-19
severity in the aging host is driven by the failure of a systemic-to-local
metabolic-immune axis. The exhaustion of circulating energetic precursors
constrains localized pulmonary nucleotide metabolism, thereby impairing
essential antiviral responses and tissue repair. This study identifies
the “systemic bioenergetic gap” as a novel therapeutic
target, suggesting that systemic metabolic resuscitation may improve
clinical outcomes in elderly populations.