title: Surgical stress resistance induced by single amino acid deprivation requires Gcn2 in mice.
abstract: Dietary restriction, or reduced food intake without malnutrition, increases life span, health span, and acute stress resistance in model organisms from yeast to nonhuman primates. Although dietary restriction is beneficial for human health, this treatment is not  widely used in the clinic. Here, we show that short-term, ad libitum feeding of diets lacking essential nutrients increased resistance to surgical stress in a mouse model of ischemia reperfusion injury. Dietary preconditioning by 6 to 14 days of total protein deprivation, or removal of the single essential amino acid tryptophan, protected against renal and hepatic ischemic injury, resulting in reduced inflammation and preserved organ function. Pharmacological treatment with halofuginone, which activated the amino acid starvation response within 3 days by mimicking proline deprivation, was also beneficial. Both dietary and pharmacological interventions required the amino acid sensor and eIF2α (eukaryotic translation initiation factor 2α) kinase Gcn2 (general control nonderepressible 2), implicating the amino acid starvation response and translational control in stress protection. Thus, short-term dietary or pharmacological interventions that modulate amino acid sensing can confer stress resistance in models of surgical ischemia reperfusion injury.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.forename: Lauren
authors.initials: L
authors.lastname: Robertson
authors.forename: Jordan
authors.initials: J
authors.lastname: Gallinetti
authors.forename: Pedro
authors.initials: P
authors.lastname: Mejia
authors.forename: Sarah
authors.initials: S
authors.lastname: Vose
authors.forename: Allison
authors.initials: A
authors.lastname: Charlip
authors.forename: Timothy
authors.initials: T
authors.lastname: Chu
authors.forename: James R
authors.initials: JR
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D004044:Dietary Proteins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011392:Proline / Q000494:pharmacology; D011488:Protein Deficiency / Q000150:complications / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D052999:Quinazolinones / Q000494:pharmacology; D015427:Reperfusion Injury / Q000150:complications / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery*; D013312:Stress, Physiological / Q000187:drug effects; D014364:Tryptophan / Q000172:deficiency* / Q000378:metabolism
chemical_list: D004044:Dietary Proteins; D010880:Piperidines; D052999:Quinazolinones; D014364:Tryptophan; D011392:Proline; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; C010176:halofuginone