title: Metabolomic analyses reveal that anti-aging metabolites are depleted by palmitate but increased by oleate in vivo.
abstract: Recently, we reported that saturated and unsaturated fatty acids trigger autophagy through distinct signal transduction pathways. Saturated fatty acids like palmitate (PA) induce autophagic responses that rely on phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3, best known as VPS34) and beclin 1 (BECN1). Conversely, unsaturated fatty acids like oleate (OL) promote non-canonical, PIK3C3- and BECN1-independent autophagy. Here, we explored the metabolic effects of autophagy-inducing doses of PA and OL in mice. Mass spectrometry coupled to principal component analysis revealed that PA and OL induce well distinguishable changes in circulating metabolites as well as in the metabolic profile of the liver, heart, and skeletal muscle. Importantly, PA (but not OL) causes the depletion of multiple autophagy-inhibitory amino acids in the liver. Conversely, OL (but not PA) increased the hepatic levels of nicotinamide adenine dinucleotide (NAD), an obligate co-factor for autophagy-stimulatory enzymes of the sirtuin family. Moreover, PA (but not OL) raised the concentrations of acyl-carnitines in the heart, a phenomenon that perhaps is linked to its cardiotoxicity. PA also depleted the liver from spermine and spermidine, 2 polyamines have been ascribed with lifespan-extending activity. The metabolic changes imposed by unsaturated and saturated fatty acids may contribute to their health-promoting and health-deteriorating effects, respectively.
authors.affiliation: a Equipe 11 labellisée Ligue contre le Cancer; Centre de Recherche des Cordeliers ; Paris , France.
authors.forename: David P
authors.initials: DP
authors.lastname: Enot
authors.forename: Mireia
authors.initials: M
authors.lastname: Niso-Santano
authors.forename: Sylvère
authors.initials: S
authors.lastname: Durand
authors.forename: Alexis
authors.initials: A
authors.lastname: Chery
authors.forename: Federico
authors.initials: F
authors.lastname: Pietrocola
authors.forename: Erika
authors.initials: E
authors.lastname: Vacchelli
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000375:Aging / Q000502:physiology*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D005260:Female; D008099:Liver / Q000378:metabolism; D013058:Mass Spectrometry; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D019301:Oleic Acid / Q000378:metabolism*; D010168:Palmitates / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D025341:Principal Component Analysis; D015398:Signal Transduction / Q000187:drug effects; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism
chemical_list: D000596:Amino Acids; D010168:Palmitates; D009243:NAD; D013096:Spermine; D019301:Oleic Acid; D019869:Phosphatidylinositol 3-Kinases; D013095:Spermidine
keywords: NAD sirtuins; aging; amino acids; autophagy; spermidine