title: Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.
abstract: Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.|Tsumura Research Laboratories, Tsumura, Ibaraki, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Fujitsuka
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Asakawa
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Morinaga
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: M S
authors.initials: MS
authors.lastname: Amitani
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Amitani
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Katsuura
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sawada
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sudo
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Uezono
authors.affiliation: Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Mochiki
authors.affiliation: Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Sakata
authors.affiliation: Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Department of Surgery, Kochi Medical School, Kochi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hanazaki
authors.affiliation: Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yada
authors.affiliation: Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yakabi
authors.affiliation: Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Sakuma
authors.affiliation: Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ueki
authors.affiliation: Department of Physiology, Niigata University School of Medicine, Niigata, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Niijima
authors.affiliation: Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Okubo
authors.affiliation: Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.|Hokkaido University Hospital Gastroenterological Medicine, Sapporo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Cancer Preventive Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Asaka
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Inui
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D031204:Caloric Restriction; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000378:metabolism / Q000627:therapeutic use; D054439:Ghrelin / Q000378:metabolism* / Q000502:physiology*; D007031:Hypothalamus; D051379:Mice; D008813:Mice, Inbred ICR; D054440:Receptors, Ghrelin / Q000235:genetics; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism* / Q000502:physiology
chemical_list: D004365:Drugs, Chinese Herbal; D054439:Ghrelin; D054440:Receptors, Ghrelin; C084136:liu-jun-zi-tang; D056564:Sirtuin 1
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