title: Metabolic signatures of extreme longevity in northern Italian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism.
abstract: The aging phenotype in humans has been thoroughly studied but a detailed metabolic profiling capable of shading light on the underpinning biological processes of longevity is still missing. Here using a combined metabonomics approach compromising holistic (1)H-NMR profiling and targeted MS approaches, we report for the first time the metabolic phenotype of longevity in a well characterized human aging cohort compromising mostly female centenarians, elderly, and young individuals. With increasing age, targeted MS profiling of blood serum displayed a marked decrease in tryptophan concentration, while an unique alteration of specific glycerophospholipids and sphingolipids are seen in the longevity phenotype. We hypothesized that the overall lipidome changes specific to longevity putatively reflect centenarians' unique capacity to adapt/respond to the accumulating oxidative and chronic inflammatory conditions characteristic of their extreme aging phenotype. Our data in centenarians support promotion of cellular detoxification mechanisms through specific modulation of the arachidonic acid metabolic cascade as we underpinned increased concentration of 8,9-EpETrE, suggesting enhanced cytochrome P450 (CYP) enzyme activity. Such effective mechanism might result in the activation of an anti-oxidative response, as displayed by decreased circulating levels of 9-HODE and 9-oxoODE, markers of lipid peroxidation and oxidative products of linoleic acid. Lastly, we also revealed that the longevity process deeply affects the structure and composition of the human gut microbiota as shown by the increased extrection of phenylacetylglutamine (PAG) and p-cresol sulfate (PCS) in urine of centenarians. Together, our novel approach in this representative Italian longevity cohort support the hypothesis that a complex remodeling of lipid, amino acid metabolism, and of gut microbiota functionality are key regulatory processes marking exceptional longevity in humans.
authors.affiliation: Proteomics and Metabonomics, Nestlé Institute of Health Sciences SA, Campus EPFL, Quartier de l'innovation, Lausanne, Switzerland. sebastiano.collino@rd.nestle.com
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Collino
authors.forename: Ivan
authors.initials: I
authors.lastname: Montoliu
authors.forename: François-Pierre J
authors.initials: FP
authors.lastname: Martin
authors.forename: Max
authors.initials: M
authors.lastname: Scherer
authors.forename: Daniela
authors.initials: D
authors.lastname: Mari
authors.forename: Stefano
authors.initials: S
authors.lastname: Salvioli
authors.forename: Laura
authors.initials: L
authors.lastname: Bucci
authors.forename: Rita
authors.initials: R
authors.lastname: Ostan
authors.forename: Daniela
authors.initials: D
authors.lastname: Monti
authors.forename: Elena
authors.initials: E
authors.lastname: Biagi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Brigidi
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
authors.forename: Serge
authors.initials: S
authors.lastname: Rezzi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000596:Amino Acids / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002648:Child; D002853:Chromatography, Liquid; D015331:Cohort Studies; D003710:Demography; D015777:Eicosanoids / Q000097:blood; D005260:Female; D041981:Gastrointestinal Tract / Q000382:microbiology*; D006801:Humans; D007558:Italy; D050356:Lipid Metabolism; D008136:Longevity / Q000502:physiology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D055442:Metabolome; D055432:Metabolomics; D054892:Metagenome / Q000502:physiology*; D008875:Middle Aged; D010641:Phenotype; D055815:Young Adult
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D015777:Eicosanoids