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Aging biology entails a cell/tissue deregulated metabolism that affects all levels of biological organization. Therefore, the application of “omic” techniques that are closer to phenotype, such as metabolomics, to the study of the aging process should be a turning point in the definition of cellular processes involved. The main objective of the present study was to describe the changes in plasma metabolome associated with biological aging and the role of sex in the metabolic regulation during aging. A high-throughput untargeted metabolomic analysis was applied in plasma samples to detect hub metabolites and biomarkers of aging incorporating a sex/gender perspective. A cohort of 1030 healthy human adults (45.9% females, and 54.1% males) from 50 to 98 years of age was used. Results were validated using two independent cohorts (1: n = 146, 53% females, 30–100 years old; 2: n = 68, 70% females, 19–107 years old). Metabolites related to lipid and aromatic amino acid (AAA) metabolisms arose as the main metabolic pathways affected by age, with a high influence of sex. Globally, we describe changes in bioenergetic pathways that point to a decrease in mitochondrial β-oxidation and an accumulation of unsaturated fatty acids and acylcarnitines that could be responsible for the increment of oxidative damage and inflammation characteristic of this physiological process. Furthermore, we describe for the first time the importance of gut-derived AAA catabolites in the aging process describing novel biomarkers that could contribute to better understand this physiological process but also age-related diseases. This research was funded by the Spanish Ministry of Science,Innovation, and Universities (grant RTI2018-099200-B- I00, and PID2022-143140OB-I00, co-funded by the European Regional Development Fund. “A way to build Europe”), and the Generalitat of Catalonia (Agency for Management of University and Research Grants [2021SGR00990] and Department of Health [SLT002/16/00250])to R.P. The work is also supported by “la Caixa” Foundation (Grant Agreement LCF/PR/HR21/52410002) to M.J. IRBLleida is a CERCAProgramme/Generalitat of Catalonia. This work was also partiallysupported by Instituto de Salud Carlos III (Madrid, Spain) through the research grants PI15/01934, PI18/01022, PI20/01090, and PI21/01361 (co-funded by the European Regional Development Fund. “A way to make Europe”), and the Catalan Government (AGAUR,#SGR2017-0734, ICREA Academia Award 2021) to J.M.F-R. |
