title: Growth Hormone-Releaser Diet Attenuates Cognitive Dysfunction in Klotho Mutant Mice via Insulin-Like Growth Factor-1 Receptor Activation in a Genetic Aging Model.
abstract: BACKGROUND
  It has been recognized that a defect in klotho gene expression accelerates the degeneration of multiple age-sensitive traits. Accumulating evidence indicates that aging is associated with declines in cognitive function and the activity of growth hormone (GH)/insulin-like growth factor-1 (IGF-1).
  
  
  METHODS
  In this study, we examined whether a GH-releaser diet could be effective in protecting against cognitive impairment in klotho mutant mice.
  
  
  RESULTS
  The GH-releaser diet significantly induced the expression of IGF-1 and IGF-1 receptors in the hippocampus of klotho mutant mice. Klotho mutant mice showed significant memory impairments as compared with wild-type mice. In addition, the klotho mutation significantly decreased the expression of cell survival/antiapoptotic factors, including phospho-Akt (p-Akt)/phospho-glycogen synthase kinase3β (p-GSK3β), phospho-extracellular signal-related kinase (p-ERK), and Bcl-2, but significantly increased those of cell death/proapoptotic factors, such as phospho-c-jun N-terminal kinase (p-JNK), Bax, and cleaved caspase-3 in the hippocampus. Treatment with GH-releaser diet significantly attenuated both decreases in the expression of cell survival/antiapoptotic factors and increases in the expression of cell death/proapoptotic factors in the hippocampus of klotho mutant mice. In addition, klotho mutation-induced oxidative stress was significantly attenuated by the GH-releaser diet. Consequently, a GH-releaser diet significantly improved memory function in the klotho mutant mice. GH-releaser diet-mediated actions were significantly reversed by JB-1, an IGF-1 receptor antagonist.
  
  
  CONCLUSIONS
  The results suggest that a GH-releaser diet attenuates oxidative stress, proapoptotic changes and consequent dysfunction in klotho mutant mice by promoting IGF-1 expression and IGF-1 receptor activation.
authors.affiliation: Neuropsychopharmacology and Toxicology Program, Kangwon National University College of Pharmacy, Chunchon, Korea. ; Ilsong Institute of Life Science, Hallym University, Anyang, Korea.
authors.forename: Seok Joo
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Anatomy, Chung-Ang University College of Medicine, Seoul, Korea.
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Chung
authors.affiliation: Neuropsychopharmacology and Toxicology Program, Kangwon National University College of Pharmacy, Chunchon, Korea.
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Neuropsychopharmacology and Toxicology Program, Kangwon National University College of Pharmacy, Chunchon, Korea.
authors.forename: Duy-Khanh
authors.initials: DK
authors.lastname: Dang
authors.affiliation: Neuropsychopharmacology and Toxicology Program, Kangwon National University College of Pharmacy, Chunchon, Korea. ; Department of Pharmacology, Chung-Ang University College of Medicine, Seoul, Korea.
authors.forename: Yunsung
authors.initials: Y
authors.lastname: Nam
authors.affiliation: Department of Pharmacology, Chung-Ang University College of Medicine, Seoul, Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Ilsong Institute of Life Science, Hallym University, Anyang, Korea.
authors.forename: Yong Sun
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Regional Pharmaceutical Care and Science, Meijo University Graduate School of Pharmaceutical Sciences, Nagoya, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.affiliation: Neuropsychopharmacology and Toxicology Program, Kangwon National University College of Pharmacy, Chunchon, Korea.
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.affiliation: Neuropsychopharmacology and Toxicology Program, Kangwon National University College of Pharmacy, Chunchon, Korea.
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
keywords: Cognitive dysfunction; GH-releaser diet; Receptor, IGF type 1; klotho gene