Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.
Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.
复制标题
DOI：
10.1038/mp.2015.220
复制
发表时间：
2016-11
影响因子：
11
通讯作者：
Inui, A.
中科院分区：
文献类型：
--
作者：
Fujitsuka, N.;Asakawa, A.;Morinaga, A.;Amitani, M. S.;Amitani, H.;Katsuura, G.;Sawada, Y.;Sudo, Y.;Uezono, Y.;Mochiki, E.;Sakata, I.;Sakai, T.;Hanazaki, K.;Yada, T.;Yakabi, K.;Sakuma, E.;Ueki, T.;Niijima, A.;Nakagawa, K.;Okubo, N.;Takeda, H.;Asaka, M.;Inui, A.
热量限制（CR）是已知的延缓衰老和延迟功能衰退以及在大多数生物体中的疾病的发作。Ghrelin响应于CR而从胃中分泌并调节能量代谢。我们假设，在CR中，胃饥饿素在保护衰老相关疾病方面具有作用。我们研究了在衰老过程中的生长激素释放肽系统的生理机制，在三个不同的遗传和生化背景的小鼠品系作为加速或正常的人类衰老的动物模型。在klotho缺陷型小鼠和衰老加速型小鼠prone/8（SAMP 8）小鼠中均观察到血浆生长素释放肽浓度升高。Ghrelin治疗未能刺激klotho缺陷小鼠的食欲和延长存活时间，提示在衰老过程中存在Ghrelin抵抗。然而，ghrelin拮抗剂加速死亡，ghrelin信号增强剂rikkunshito和rhodin改善了几种与年龄相关的疾病，降低了脑中的小胶质细胞活化，延长了klotho缺陷，SAMP 8和老年ICR小鼠的存活时间。在体外实验中，通过cAMP-CREB途径观察到生长激素释放肽和生长激素释放肽增效剂处理后，生长激素释放肽受体1a表达细胞和人脐静脉内皮细胞中sirtuin 1（SIRT 1）活性和蛋白表达升高。此外，rikunshito在所有三种衰老小鼠模型中增加了下丘脑SIRT 1活性和心脏SIRT 1蛋白表达。经力坤石通治疗后，心包炎、心肌钙化、心肌和肌纤维萎缩均得到改善。Ghrelin信号可能代表CR激活的机制之一，增强Ghrelin信号可能有助于延长健康和寿命。
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.
登录
查看更多内容
Sirtuins是否可行的目标可以改善健康状态和寿命？
DOI：
10.1038/nrd3738
发表时间：
2012-06-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Baur JA;Ungvari Z;Minor RK;Le Couteur DG;de Cabo R
通讯作者：
de Cabo R
DOI：
10.1126/science.1173635
发表时间：
2009-07-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Colman RJ;Anderson RM;Johnson SC;Kastman EK;Kosmatka KJ;Beasley TM;Allison DB;Cruzen C;Simmons HA;Kemnitz JW;Weindruch R
通讯作者：
Weindruch R
影响因子：
4.8
作者：
Chen, J;Zhou, YG;Li, G
通讯作者：
Li, G
影响因子：
4.1
作者：
Bedard, Karine;Bedard, Julie;Gaudreau, Pierrette
通讯作者：
Gaudreau, Pierrette
影响因子：
7.7
作者：
Dezaki, K;Hosoda, H;Yada, T
通讯作者：
Yada, T