Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.

Akinori Morinaga ,Yasuyuki Sawada ,Yuka Sudo ,Akihiro Asakawa ,Takatoshi Ueki ,Akira Niijima ,Akio Inui ,Naoki Fujitsuka ,Haruka Amitani ,Hiroshi Takeda ,Marie Amitani ,Koji Yakabi ,Takafumi Sakai ,Toshihiko Yada ,Naoto Okubo ,Eisuke Sakuma ,Yasuhito Uezono ,Erito Mochiki ,Ichiro Sakata ,Kazuhiro Hanazaki ,Koji Nakagawa ,Masahiro Asaka ,Goro Katsuura

doi:10.1038/mp.2015.220

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.

Highlights

The increased lifespan of world population illustrates the success of modern medicine; the risk of developing many diseases increases exponentially with old age.[1]
We examined the potential role of ghrelin signaling in klotho-deficient mice
We found that 5-week-old klotho-deficient mice showed an increase in acyl ghrelin, desacyl ghrelin, growth hormone (GH) and corticosterone under fed or fasted conditions, while a decrease in acyl ghrelin/desacyl ghrelin (A/D) ratio suggestive of cachectic state, insulin-like growth factor-1 (IGF-1), insulin and glucose were observed in klotho-deficient mice

Summary

INTRODUCTION

The increased lifespan of world population illustrates the success of modern medicine; the risk of developing many diseases increases exponentially with old age.[1]. We examined the impact of ghrelin signaling on the survival of three mouse strains with different genetic and biochemical backgrounds These animal models mimic accelerated or normal human aging. These models are useful in studying the common protective mechanisms regulating many age-related diseases. Rikkunshito extended the survival of another pathological model of both SAMP8 and aged ICR mice, a model of normal aging. These results suggest the importance of potentiating endogenous ghrelin signaling or attenuation of ghrelin resistance in the extension of lifespan in animal models of human aging. As a protective mechanism against the aging process, ghrelin signaling was considered to be associated with increased SIRT1 activity and decreased microglial activation in the brain

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSION