Metformin alleviates ageing cellular phenotypes in Hutchinson-Gilford progeria syndrome dermal fibroblasts
Metformin alleviates ageing cellular phenotypes in Hutchinson-Gilford progeria syndrome dermal fibroblasts
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DOI：
10.1111/exd.13323
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发表时间：
2017-10-01
影响因子：
3.6
通讯作者：
Shin, Ok Sarah
中科院分区：
文献类型：
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作者：
Park, Seul-Ki;Shin, Ok Sarah
二甲双胍是一种常用的抗糖尿病双胍类药物，已被认为是治疗癌症和预防衰老的候选药物。Hutchinson-Gilford早衰综合征（HGPS）是一种以过早衰老和导致死亡的严重年龄相关并发症为特征的毁灭性疾病。二甲双胍对HGPS真皮成纤维细胞的影响在很大程度上仍未确定。在这项研究中，我们研究了二甲双胍是否可以对HGPS患者来源的成纤维细胞的核异常和延缓衰老产生有益作用。二甲双胍治疗部分恢复正常的核表型，延缓衰老，激活磷酸化的AMP-活化蛋白激酶和减少活性氧形成的HGPS真皮成纤维细胞。有趣的是，与对照组相比，二甲双胍减少了磷酸化组蛋白变体H2 AX阳性DNA损伤灶的数量，并抑制了早老蛋白的表达。此外，二甲双胍补充老年小鼠脾细胞增殖和抗氧化酶，超氧化物歧化酶2的mRNA表达比对照组小鼠。总的来说，我们的研究结果表明，二甲双胍治疗可消除HGPS成纤维细胞的核缺陷和过早老化表型。因此，二甲双胍可以被认为是延长HGPS寿命的一种有前景的治疗方法。
Metformin is a popular antidiabetic biguanide, which has been considered as a candidate drug for cancer treatment and ageing prevention. Hutchinson-Gilford progeria syndrome (HGPS) is a devastating disease characterized by premature ageing and severe age-associated complications leading to death. The effects of metformin on HGPS dermal fibroblasts remain largely undefined. In this study, we investigated whether metformin could exert a beneficial effect on nuclear abnormalities and delay senescence in fibroblasts derived from HGPS patients. Metformin treatment partially restored normal nuclear phenotypes, delayed senescence, activated the phosphorylation of AMP-activated protein kinase and decreased reactive oxygen species formation in HGPS dermal fibroblasts. Interestingly, metformin reduced the number of phosphorylated histone variant H2AX-positive DNA damage foci and suppressed progerin protein expression, compared to the control. Furthermore, metformin-supplemented aged mice showed higher splenocyte proliferation and mRNA expression of the antioxidant enzyme, superoxide dismutase 2 than the control mice. Collectively, our results show that metformin treatment alleviates the nuclear defects and premature ageing phenotypes in HGPS fibroblasts. Thus, metformin can be considered a promising therapeutic approach for life extension in HGPS.