PMID- 26830139 OWN - NLM STAT- MEDLINE DCOM- 20170919 LR - 20181113 IS - 1476-5578 (Electronic) IS - 1359-4184 (Print) IS - 1359-4184 (Linking) VI - 21 IP - 11 DP - 2016 Nov TI - Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1. PG - 1613-1623 LID - 10.1038/mp.2015.220 [doi] AB - 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. FAU - Fujitsuka, N AU - Fujitsuka N AD - Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. AD - Tsumura Research Laboratories, Tsumura, Ibaraki, Japan. FAU - Asakawa, A AU - Asakawa A AD - Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Morinaga, A AU - Morinaga A AD - Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Amitani, M S AU - Amitani MS AD - Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Amitani, H AU - Amitani H AD - Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Katsuura, G AU - Katsuura G AD - Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. FAU - Sawada, Y AU - Sawada Y AD - Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan. FAU - Sudo, Y AU - Sudo Y AD - Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan. FAU - Uezono, Y AU - Uezono Y AD - Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan. FAU - Mochiki, E AU - Mochiki E AD - Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan. FAU - Sakata, I AU - Sakata I AD - Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan. FAU - Sakai, T AU - Sakai T AD - Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan. FAU - Hanazaki, K AU - Hanazaki K AD - Department of Surgery, Kochi Medical School, Kochi, Japan. FAU - Yada, T AU - Yada T AD - Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan. FAU - Yakabi, K AU - Yakabi K AD - Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama, Japan. FAU - Sakuma, E AU - Sakuma E AD - Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. FAU - Ueki, T AU - Ueki T AD - Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. FAU - Niijima, A AU - Niijima A AD - Department of Physiology, Niigata University School of Medicine, Niigata, Japan. FAU - Nakagawa, K AU - Nakagawa K AD - Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. FAU - Okubo, N AU - Okubo N AD - Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. FAU - Takeda, H AU - Takeda H AD - Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. AD - Hokkaido University Hospital Gastroenterological Medicine, Sapporo, Japan. FAU - Asaka, M AU - Asaka M AD - Cancer Preventive Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan. FAU - Inui, A AU - Inui A AD - Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160202 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 RN - 0 (Drugs, Chinese Herbal) RN - 0 (Ghrelin) RN - 0 (Receptors, Ghrelin) RN - 0 (liu-jun-zi-tang) RN - EC 3.5.1.- (Sirtuin 1) SB - IM MH - Aging/physiology MH - Animals MH - Caloric Restriction MH - Disease Models, Animal MH - Drugs, Chinese Herbal/metabolism/therapeutic use MH - Ghrelin/*metabolism/*physiology MH - Hypothalamus MH - Mice MH - Mice, Inbred ICR MH - Receptors, Ghrelin/genetics MH - Signal Transduction MH - Sirtuin 1/*metabolism/physiology PMC - PMC5078860 COIS- AI has received grant support from Tsumura. The other authors declare no conflict of interest. EDAT- 2016/10/21 06:00 MHDA- 2017/09/20 06:00 PMCR- 2016/10/25 CRDT- 2016/02/03 06:00 PHST- 2015/05/15 00:00 [received] PHST- 2015/12/01 00:00 [revised] PHST- 2015/12/15 00:00 [accepted] PHST- 2016/10/21 06:00 [pubmed] PHST- 2017/09/20 06:00 [medline] PHST- 2016/02/03 06:00 [entrez] PHST- 2016/10/25 00:00 [pmc-release] AID - mp2015220 [pii] AID - 10.1038/mp.2015.220 [doi] PST - ppublish SO - Mol Psychiatry. 2016 Nov;21(11):1613-1623. doi: 10.1038/mp.2015.220. Epub 2016 Feb 2.