Metabolomics of immunosenescence: bridging blood biomarkers and metabolic pathways in aging

Abstract

Immunosenescence—the progressive decline in immune competence with advancing age—contributes substantially to increased infection susceptibility, reduced vaccine efficacy, and heightened chronic inflammatory disease burden in older adults. Despite extensive characterization of immunological changes, the metabolic underpinnings of immunosenescence remain incompletely understood. Metabolomics, the comprehensive profiling of small-molecule metabolites, offers an unbiased approach to identify biochemical pathways associated with immune aging. This review synthesizes current evidence linking metabolomic signatures to immunosenescence, with particular focus on lipid metabolism (including sphingolipids, phospholipids, and oxylipins), amino acid metabolism (tryptophan-kynurenine pathway, branched-chain amino acids), and energy metabolism (tricarboxylic acid cycle intermediates, ketone bodies). Emerging data suggest that specific metabolite classes—particularly acylcarnitines, ceramides, and kynurenine/tryptophan ratio—correlate with T cell senescence markers, inflammaging phenotypes, and clinical outcomes including frailty and vaccine non-response. Conversely, routine clinical parameters including white blood cell count, platelet count, and hemoglobin level show associations with hematopoietic-inflammatory burden in community-dwelling older adults, raising the hypothesis that they may reflect underlying metabolic dysregulation. Key challenges remain, including establishing causality versus epiphenomenon, standardizing metabolomics platforms across studies, and validating metabolite panels in diverse populations. Future directions include integrating metabolomics with other -omics approaches (genomics, proteomics), leveraging machine learning for multi-marker signature development, and testing whether metabolite-targeted interventions in preclinical models can attenuate immunosenescence. Understanding the metabolomics of immunosenescence may identify candidate biomarkers for immune risk stratification and generate hypotheses for metabolic interventions to promote healthy aging.