title: Fibroblasts from long-lived mutant mice exhibit increased autophagy and lower TOR activity after nutrient deprivation or oxidative stress.
abstract: Previous work has shown that primary skin-derived fibroblasts from long-lived pituitary dwarf mutants resist the lethal effects of many forms of oxidative and nonoxidative stress. We hypothesized that increased autophagy may protect fibroblasts of Pit-1(dw/dw)  (Snell dwarf) mice from multiple forms of stress. We found that dwarf-derived fibroblasts had higher levels of autophagy, using LC3 and p62 as markers, in response to amino acid deprivation, hydrogen peroxide, and paraquat. Fibroblasts from dwarf mice also showed diminished phosphorylation of mTOR, S6K, and 4EBP1, consistent with the higher levels of autophagy in these cells after stress. Similar results were also observed in fibroblasts from mutant mice lacking growth hormone receptor (GHRKO mice) after amino acid withdrawal. Our results suggested that increased autophagy, regulated by TOR-dependent processes, may contribute to stress resistance in fibroblasts from long-lived mutant mice.
authors.affiliation: Department of Pathology             Geriatrics Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D003470:Culture Media; D039642:Eukaryotic Initiation Factors; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D008136:Longevity / Q000235:genetics* / Q000502:physiology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018384:Oxidative Stress; D010269:Paraquat / Q000633:toxicity; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011986:Receptors, Somatotropin / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D050817:Transcription Factor Pit-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003470:Culture Media; D039642:Eukaryotic Initiation Factors; D006861:Hydrogen Peroxide; D010269:Paraquat; D010750:Phosphoproteins; D011986:Receptors, Somatotropin; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D050817:Transcription Factor Pit-1; C499527:Eif4ebp1 protein, mouse; C494185:Pou1f1 protein, mouse; C546843:mTOR protein, mouse