Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans.
Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans.
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DOI：
10.1126/scitranslmed.3001845
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发表时间：
2011-02-16
影响因子：
17.1
通讯作者：
Longo VD
中科院分区：
文献类型：
--
作者：
Guevara-Aguirre J;Balasubramanian P;Guevara-Aguirre M;Wei M;Madia F;Cheng CW;Hwang D;Martin-Montalvo A;Saavedra J;Ingles S;de Cabo R;Cohen P;Longo VD
生长信号通路中的寿命延长突变可保护酵母菌免受年龄依赖性DNA损伤，并降低小鼠的胰岛素抵抗和癌症。为了测试它们对人类的影响，我们对厄瓜多尔受试者进行了22年的监测，这些受试者的生长激素受体基因突变导致严重的生长激素受体（GHR）和IGF-I缺乏，并将这些信息与调查相结合，以确定在此期间死亡的受试者的死亡原因和年龄。GHR缺乏（GHRD）的个体仅表现出一种非致命性恶性肿瘤，没有糖尿病病例，而对照组中癌症患病率为17%，糖尿病患病率为5%。体外研究可能揭示了癌症发病率非常低的一个可能解释：GHRD受试者的血清减少了DNA断裂，但增加了用过氧化氢处理的人乳腺上皮细胞（HMEC）的凋亡。我们还观察到GHRD个体的胰岛素浓度降低（1.4 μU/ml vs. 4.4μU/ml，未受影响的亲属）和胰岛素抵抗（HOMA-IR）指数（0.34 vs. 0.96，未受影响的亲属）的稳态模型评估非常低，表明胰岛素敏感性增加，这可以解释这些受试者没有糖尿病。用GHRD血清孵育HMEC还导致RAS、PKA和TOR的表达减少，以及SOD 2的上调，这些变化促进了模型生物体中的细胞保护和寿命延长。这些结果为进化保守途径在促进人类衰老和疾病中的作用提供了证据，并确定了延长健康寿命的候选药物靶点。
Life span extending mutations in growth signaling pathways protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian subjects with mutations in the growth hormone receptor gene leading to severe growth hormone receptor (GHR) and IGF-I deficiencies and combined this information with surveys to identify the cause and age of death for subjects who died before this period. The individuals with GHR deficiency (GHRD) exhibited only one non-lethal malignancy and no cases of diabetes, in contrast to 17% cancer and 5% diabetes prevalence in the controls. A possible explanation for the very low incidence of cancer may be revealed by in vitro studies: serum from GHRD subjects reduced DNA breaks but increased apoptosis in human mammary epithelial cells (HMECs) treated with hydrogen peroxide. We also observed reduced insulin concentrations (1.4 μU/ml vs. 4.4μU/ml in unaffected relatives) and a very low homoeostasis model assessment of insulin resistance (HOMA-IR) index (0.34 vs. 0.96 in unaffected relatives) in GHRD individuals, indicating increased insulin sensitivity, which could explain the absence of diabetes in these subjects. Incubation of HMECs with GHRD serum also resulted in reduced expression of RAS, PKA and TOR, and up-regulation of SOD2, changes that promote cellular protection and life span extension in model organisms. These results provide evidence for a role of evolutionarily conserved pathways in promoting aging and diseases in humans and identify a candidate drug target for healthy life span extension.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
4.8
作者：
Coschigano, KT;Holland, AN;Kopchick, JJ
通讯作者：
Kopchick, JJ
影响因子：
5.8
作者：
Aguiar-Oliveira, Manuel H.;Oliveira, Francielle T.;Salvatori, Roberto
通讯作者：
Salvatori, Roberto
影响因子：
5.8
作者：
Bramnert, M;Segerlantz, M;Groop, L
通讯作者：
Groop, L
影响因子：
6.2
作者：
Bachrach, LK;Marcus, R;Guevara-Aguirre, J
通讯作者：
Guevara-Aguirre, J