title: Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans.
abstract: BACKGROUND
  Little is known about the role of amino acids in cellular signaling pathways, especially as it pertains to pathways that regulate the rate of aging. However, it has been shown that methionine or tryptophan restriction extends lifespan in higher eukaryotes and increased proline or tryptophan levels increase longevity in C. elegans. In addition, leucine strongly activates the TOR signaling pathway, which when inhibited increases lifespan.
  
  
  RESULTS
  Therefore each of the 20 proteogenic amino acids was individually supplemented to C. elegans and the effects on lifespan were determined. All amino acids except phenylalanine and aspartate extended lifespan at least to a small extent at one or more of the 3 concentrations tested with serine and proline showing the largest effects. 11 of the amino acids were less potent at higher doses, while 5 even decreased lifespan. Serine, proline, or histidine-mediated lifespan extension was greatly inhibited in eat-2 worms, a model of dietary restriction, in daf-16/FOXO, sir-2.1, rsks-1 (ribosomal S6 kinase), gcn-2, and aak-2 (AMPK) longevity pathway mutants, and in bec-1 autophagy-defective knockdown worms. 8 of 10 longevity-promoting amino acids tested activated a SKN-1/Nrf2 reporter strain, while serine and histidine were the only amino acids from those to activate a hypoxia-inducible factor (HIF-1) reporter strain. Thermotolerance was increased by proline or tryptophan supplementation, while tryptophan-mediated lifespan extension was independent of DAF-16/FOXO and SKN-1/Nrf2 signaling, but tryptophan and several related pyridine-containing compounds induced the mitochondrial unfolded protein response and an ER stress response. High glucose levels or mutations affecting electron transport chain (ETC) function inhibited amino acid-mediated lifespan extension suggesting that metabolism plays an important role. Providing many other cellular metabolites to C. elegans also increased longevity suggesting that anaplerosis of tricarboxylic acid (TCA) cycle substrates likely plays a role in lifespan extension.
  
  
  CONCLUSIONS
  Supplementation of C. elegans with 18 of the 20 individual amino acids extended lifespan, but lifespan often decreased with increasing concentration suggesting hormesis. Lifespan extension appears to be caused by altered mitochondrial TCA cycle metabolism and respiratory substrate utilization resulting in the activation of the DAF-16/FOXO and SKN-1/Nrf2 stress response pathways.
authors: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA. cbedward@mail.usf.edu.
authors: Clare
authors: C
authors: Edwards
authors: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA. jmc2@mail.usf.edu.
authors: John
authors: J
authors: Canfield
authors: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA. ncopes@mail.usf.edu.
authors: Neil
authors: N
authors: Copes
authors: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA. abrito2@mail.usf.edu.
authors: Andres
authors: A
authors: Brito
authors: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA. mrehan@mail.usf.edu.
authors: Muhammad
authors: M
authors: Rehan
authors: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA. delipps@mail.usf.edu.
authors: David
authors: D
authors: Lipps
authors: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA. jlhoskin@mail.usf.edu.
authors: Jessica
authors: J
authors: Brunquell
authors: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA. swesterheide@usf.edu.
authors: Sandy D
authors: SD
authors: Westerheide
authors: Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, 33620, USA. pbradsha@usf.edu.
authors: Patrick C
authors: PC
authors: Bradshaw
mesh_terms: D000596:Amino Acids / Q000008:administration & dosage / Q000737:chemistry*; D000818:Animals; D001343:Autophagy; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D004032:Diet; D042967:Electron Transport Complex I / Q000235:genetics; D042963:Electron Transport Complex II / Q000235:genetics; D059865:Endoplasmic Reticulum Stress; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018869:Heat-Shock Response; D008136:Longevity; D008928:Mitochondria / Q000378:metabolism; D023421:Models, Animal; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000596:Amino Acids; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C541178:HIF-1 protein, C elegans; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C073702:skn-1 protein, C elegans; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I
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