Multiomics reprogramming reverses disease susceptibility in Magallana gigas during aging

Aging is a progressive and irreversible biological process that typically increases susceptibility to infectious diseases. However, unexpectedly, the opposite outcome was observed in oysters: older oysters exhibit increased tolerance to Pacific oyster mortality syndrome (POMS), a panzootic disease responsible for severe losses worldwide. We investigated this pattern by challenging four biparental families of oysters aged 4, 16, and 28 months. We conducted an integrative multiomics analysis, which included epigenomics, transcriptomics, and metabolomics, on the two families that exhibited the greatest age-related increase in survival. Our results reveal that aging is characterized by coordinated epigenetic, transcriptional, and metabolic reprogramming that reduces host permissiveness to POMS. We show that the epigenetic remodeling of immune regulators (e.g., toll-like receptors and myeloid differentiation primary response 88; MyD88) aligns with the transcriptional rewiring of the nuclear factor-kappa B (NF-κB) and ubiquitin pathways, producing a tuned state with enhanced antiviral activity. We also identify age-related repression of mechanistic target of rapamycin (mTOR) signaling, which likely promotes autophagy and enhances viral control. These changes are tightly linked to metabolic adjustments, including reduced activity of the tricarboxylic acid cycle (TCA), altered nitrogen metabolism, and altered glutathione dynamics, supporting a stress-tolerant, energy-conserving phenotype. Together, our findings reveal juveniles prioritize growth at the cost of viral susceptibility, whereas adults invest in cellular maintenance and antiviral preparedness.