Local non-pituitary growth hormone is induced with aging and facilitates epithelial damage.
Local non-pituitary growth hormone is induced with aging and facilitates epithelial damage.
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DOI：
10.1016/j.celrep.2021.110068
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发表时间：
2021-12-14
期刊：
影响因子：
8.8
通讯作者：
Melmed S
中科院分区：
文献类型：
--
作者：
Chesnokova V;Zonis S;Apostolou A;Estrada HQ;Knott S;Wawrowsky K;Michelsen K;Ben-Shlomo A;Barrett R;Gorbunova V;Karalis K;Melmed S
调节与年龄相关的DNA损伤的微环境因素尚不清楚。非垂体生长激素（npGH）在人结肠、非转化的人结肠细胞和成纤维细胞以及具有年龄相关DNA损伤的三维肠类器官中诱导。自分泌/旁分泌npGH通过诱导TRIM 29和减少ATM磷酸化来抑制p53并减弱DNA损伤反应（DDR），导致DNA修复和DNA损伤积累减少。培养长达4个月的类器官表现出衰老标志物、p16和SA-β-半乳糖苷酶，端粒长度减少，DNA损伤积累，npGH增加，p53抑制，DDR减弱。抑制老年类器官中的GH会增加p53并减少DNA损伤。WT小鼠表现出年龄依赖性的结肠DNA损伤积累，而在缺乏结肠GH信号传导的老年小鼠中，DNA损伤保持较低，p53升高。由于年龄相关的npGH诱导能够促进增殖微环境，因此可以通过阻碍DNA损伤和年龄相关的病理学来靶向废除npGH信号传导作为抗衰老疗法。Chesnokova等人表明，非垂体生长激素（npGH）在衰老的DNA损伤的结肠上皮中被诱导，并通过减弱DNA修复蛋白的磷酸化来抑制DNA损伤反应。npGH诱导促进DNA损伤积累，导致与年龄相关的结肠微环境变化。因此，在衰老小鼠中破坏GH信号传导可以防止累积的DNA损伤。
Microenvironmental factors modulating age-related DNA damage are unclear. Non-pituitary growth hormone (npGH) is induced in human colon, non-transformed human colon cells, and fibroblasts, and in 3-dimensional intestinal organoids with age-associated DNA damage. Autocrine/paracrine npGH suppresses p53 and attenuates DNA damage response (DDR) by inducing TRIM29 and reducing ATM phosphorylation, leading to reduced DNA repair and DNA damage accumulation. Organoids cultured up to 4 months exhibit aging markers, p16, and SA-β-galactosidase and decreased telomere length, as well as DNA damage accumulation, with increased npGH, suppressed p53, and attenuated DDR. Suppressing GH in aged organoids increases p53 and decreases DNA damage. WT mice exhibit age-dependent colon DNA damage accumulation, while in aged mice devoid of colon GH signaling, DNA damage remains low, with elevated p53. As age-associated npGH induction enables a pro-proliferative microenvironment, abrogating npGH signaling could be targeted as anti-aging therapy by impeding DNA damage and age-related pathologies. Chesnokova et al. show that non-pituitary growth hormone (npGH) is induced in aging DNA-damaged colon epithelium and suppresses DNA damage response by attenuating the phosphorylation of DNA repair proteins. npGH induction promotes DNA damage accumulation, resulting in age-associated colon microenvironment changes. Accordingly, disrupted GH signaling in aging mice prevents accumulated DNA damage.
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