Multi-omics integration identifies metabolic and inflammatory pathways underlying familial longevity

Familial longevity, quantified using the Longevity Relatives Count (LRC) score indicating the proportion of ancestral long-lived family members, associates with a pronounced 13 years delayed onset of cardiometabolic disease (CMD). Understanding the molecular basis of familial longevity therefore provides critical insights into mechanisms of cardiometabolic resilience. However, the combined metabolomics and proteomics profile associated with the delayed CMD onset observed in such long-lived family members is not understood yet. Hence, we integrated plasma metabolomics and proteomics in 495 participants from the Leiden Longevity Study to identify molecular signatures associated with (a contrast in) the LRC score. Metabolomics profiling captured 429 features, including amino acid derivatives, nucleosides, and lipid mediators, while proteomics quantified 374 proteins related to cardiovascular, metabolic, and inflammatory pathways. Three within-family analysis approaches were examined and overlapping findings were interpreted. We identified ten metabolites and nine proteins that are associated with increased familial longevity, exemplified by a high LRC score. High LRC scoring individuals exhibited lower levels of amino acid derivatives (prolylhydroxyproline, 5-hydroxy-tryptophan, asymmetric dimethylarginine), nucleosides (2-methylguanosine, 7-methylguanosine, pseudouridine), N-acetylneuraminic acid and quinolinic acid, indicating optimized extracellular matrix integrity, vascular function, and reduced neuroinflammatory activity. Lipid mediators, including elevated 6-keto-PGF1a and reduced 9-HOTrE/alpha-linolenic acid ratio, reflected preserved endothelial homeostasis and attenuated inflammatory signaling. At the proteome level, strong ancestral familial longevity is associated with immune regulators (RETN, NPPB, IGSF8), extracellular matrix components (EFEMP1, EPHB4), and adhesion/signaling molecules (LRP11, ICAM3, KIT, ADGRG2), highlighting coordinated regulation of inflammation, tissue remodeling, and regenerative capacity. Multi-omics pathway analyses indicated convergence on amino acid and nucleotide metabolism, lipid signaling, extracellular matrix remodeling, and receptor-mediated communication. Collectively, these multi-omics systemic signatures define a molecular framework of ancestral familial longevity characterized by reduced inflammation, preserved tissue integrity, and enhanced metabolic and regenerative processes. Our findings provide mechanistic insight into the biology of familial longevity and potentially cardiometabolic resilience.