Metabolic signatures of extreme longevity in northern Italian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism

• Published in: PloS one 2013-03, Vol.8 (3), p.e56564-e56564
• Main Authors: Collino, Sebastiano, Montoliu, Ivan, Martin, François-Pierre J, Scherer, Max, Mari, Daniela, Salvioli, Stefano, Bucci, Laura, Ostan, Rita, Monti, Daniela, Biagi, Elena, Brigidi, Patrizia, Franceschi, Claudio, Rezzi, Serge
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Age; Aged; Aged, 80 and over; Aging; Amino acids; Amino Acids - metabolism; Arachidonic acid; Biological activity; Biological products; Biology; Biomarkers - blood; Biomarkers - urine; Centenarians; Child; Chromatography, Liquid; Cohort Studies; Cresol; Cytochrome; Cytochrome P450; Demography; Detoxification; Disease; Eicosanoids - blood; Enzymatic activity; Enzyme activity; Fatty acids; Female; Gastrointestinal Tract - microbiology; Genotype & phenotype; Geriatrics; Health sciences; Humans; Inflammation; Intestinal microflora; Italy; Linoleic acid; Lipid Metabolism; Lipid peroxidation; Lipids; Longevity; Longevity - physiology; Low density lipoprotein; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Medicine; Metabolism; Metabolome; Metabolomics; Metagenome - physiology; Microbiota; Microbiota (Symbiotic organisms); Middle Aged; Mortality; NMR; Nuclear magnetic resonance; Older people; Oldest old people; p-Cresol; Pathology; Peroxidation; Pharmaceutical sciences; Phenotype; Physiological aspects; Proteomics; Rheumatoid arthritis; Shading; Sphingolipids; Sulfates; Tryptophan; Unsaturated fatty acids; Urine; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0056564

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.