Zhou Hongjing, Pu Shiyun, Zhou Houfeng, Guo Yuanxin
Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Front Pharmacol. 2021 Oct 19;12:755366. doi: 10.3389/fphar.2021.755366. eCollection 2021.
The protein Klotho can significantly delay aging, so it has attracted widespread attention. Abnormal downregulation of Klotho has been detected in several aging-related diseases, such as Alzheimer's disease, kidney injury, cancer, chronic obstructive pulmonary disease (COPD), vascular disease, muscular dystrophy and diabetes. Conversely, many exogenous and endogenous factors, several drugs, lifestyle changes and genetic manipulations were reported to exert therapeutic effects through increasing Klotho expression. In recent years, Klotho has been identified as a potential autophagy regulator. How Klotho may contribute to reversing the effects of aging and disease became clearer when it was linked to autophagy, the process in which eukaryotic cells clear away dysfunctional proteins and damaged organelles: the abovementioned diseases involve abnormal autophagy. Interestingly, growing evidence indicates that Klotho plays a dual role as inducer or inhibitor of autophagy in different physiological or pathological conditions through its influence on IGF-1/PI3K/Akt/mTOR signaling pathway, Beclin 1 expression and activity, as well as aldosterone level, which can help restore autophagy to beneficial levels. The present review examines the role of Klotho in regulating autophagy in Alzheimer's disease, kidney injury, cancer, COPD, vascular disease, muscular dystrophy and diabetes. Targeting Klotho may provide a new perspective for preventing and treating aging-related diseases.
蛋白质α-klotho可显著延缓衰老，因此备受关注。在多种与衰老相关的疾病中，如阿尔茨海默病、肾损伤、癌症、慢性阻塞性肺疾病（COPD）、血管疾病、肌肉萎缩症和糖尿病，均检测到α-klotho异常下调。相反，据报道，许多外源性和内源性因素、几种药物、生活方式的改变以及基因操作可通过增加α-klotho的表达发挥治疗作用。近年来，α-klotho已被确定为一种潜在的自噬调节因子。当α-klotho与自噬联系起来时，它如何有助于逆转衰老和疾病的影响变得更加清晰，自噬是真核细胞清除功能失调的蛋白质和受损细胞器的过程：上述疾病均涉及自噬异常。有趣的是，越来越多的证据表明，α-klotho在不同的生理或病理条件下，通过影响胰岛素样生长因子-1/磷脂酰肌醇-3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（IGF-1/PI3K/Akt/mTOR）信号通路、Beclin 1的表达和活性以及醛固酮水平，作为自噬的诱导剂或抑制剂发挥双重作用，这有助于将自噬恢复到有益水平。本综述探讨了α-klotho在阿尔茨海默病、肾损伤、癌症、COPD、血管疾病、肌肉萎缩症和糖尿病中调节自噬的作用。以α-klotho为靶点可能为预防和治疗与衰老相关的疾病提供新的视角。
