title: Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal.
abstract: Impaired insulin and IGF-1 signaling (iIIS) in C. elegans daf-2 mutants extends life span more than 2-fold. Constitutively, iIIS increases mitochondrial activity and reduces reactive oxygen species (ROS) levels. By contrast, acute impairment of daf-2 in adult C. elegans reduces glucose uptake and transiently increases ROS. Consistent with the concept of mitohormesis, this ROS signal causes an adaptive response by inducing ROS defense enzymes (SOD, catalase), culminating in ultimately reduced ROS levels despite increased mitochondrial activity. Inhibition of this ROS signal by antioxidants reduces iIIS-mediated longevity by up to 60%. Induction of the ROS signal requires AAK-2 (AMPK), while PMK-1 (p38) and SKN-1 (NRF-2) are needed for the retrograde response. IIIS upregulates mitochondrial L-proline catabolism, and impairment of the latter impairs the life span-extending capacity of iIIS while L-proline supplementation extends C. elegans life span. Taken together, iIIS promotes L-proline metabolism to generate a ROS signal for the adaptive induction of endogenous stress defense to extend life span.
authors.affiliation: Department of Human Nutrition, Institute of Nutrition, University of Jena, Jena, Germany.
authors.forename: Kim
authors.initials: K
authors.lastname: Zarse
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schmeisser
authors.forename: Marco
authors.initials: M
authors.lastname: Groth
authors.forename: Steffen
authors.initials: S
authors.lastname: Priebe
authors.forename: Gregor
authors.initials: G
authors.lastname: Beuster
authors.forename: Doreen
authors.initials: D
authors.lastname: Kuhlow
authors.forename: Reinhard
authors.initials: R
authors.lastname: Guthke
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Michael
authors.initials: M
authors.lastname: Ristow
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D023421:Models, Animal; D011392:Proline / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D059467:Transcriptome / Q000235:genetics
chemical_list: D000975:Antioxidants; D029742:Caenorhabditis elegans Proteins; D007328:Insulin; D017382:Reactive Oxygen Species; D007334:Insulin-Like Growth Factor I; D011392:Proline; D005947:Glucose