Metabolomic Signatures of Longevity in Bivalves Reveal Reorganization of TCA Cycle and Amino Acid Metabolism.

Mitochondria are central regulators of cellular metabolism, integrating energy production, redox balance, and signaling pathways that shape aging trajectories. If mitochondrial organization contributes to lifespan divergence, exceptionally long-lived species should exhibit distinctive metabolic signatures reflecting adaptations promoting long-term cellular maintenance. Comparative approaches across species with extreme lifespan variation provide a powerful framework for identifying potential metabolic strategies underlying longevity. We conducted targeted metabolomic profiling of five marine bivalve species spanning a lifespan gradient from approximately 30 to more than 500 years, including the exceptionally long-lived ocean quahog, Arctica islandica. Fifty metabolites were quantified in gill and mantle tissue to determine whether lifespan variation is associated with coordinated changes in metabolic organization. Lifespan emerged as a dominant axis of metabolomic variation across species. Long-lived bivalves exhibited a distinct metabolic phenotype characterized by a global reduction in free amino acid pools and coordinated changes in metabolites associated with mitochondrial metabolism. Longevity was associated with increased succinate-to-fumarate ratios, reduced fumarate and malate concentrations, and reduced engagement of pyruvate-derived anaerobic pathways under basal conditions. Although these patterns varied in magnitude across tissues, they converged on a common longevity-associated metabolic signature. Together, these patterns suggest that exceptional longevity is associated with a distinct organization of mitochondrial-related metabolism and a more selective allocation of metabolic resources, rather than a generalized suppression of metabolism. Our findings identify metabolomic signatures associated with exceptional longevity across the bivalve species studied and support the hypothesis that long lifespan is characterized by a distinctive metabolic architecture favoring long-term cellular maintenance.