Instituto Nacional de Geriatría (INGER), Mexico City, Mexico.
Geriatric Medicine Research, Dalhousie University and Nova Scotia Health Authority, Halifax, NS, Canada.
Sci Rep. 2019 Jul 22;9(1):10593. doi: 10.1038/s41598-019-47087-7.
Frailty is an age-associated condition, characterized by an inappropriate response to stress that results in a higher frequency of adverse outcomes (e.g., mortality, institutionalization and disability). Some light has been shed over its genetic background, but this is still a matter of debate. In the present study, we used network biology to analyze the interactome of frailty-related genes at different levels to relate them with pathways, clinical deficits and drugs with potential therapeutic implications. Significant pathways involved in frailty: apoptosis, proteolysis, muscle proliferation, and inflammation; genes as FN1, APP, CREBBP, EGFR playing a role as hubs and bottlenecks in the interactome network and epigenetic factors as HIST1H3 cluster and miR200 family were also involved. When connecting clinical deficits and genes, we identified five clusters that give insights into the biology of frailty: cancer, glucocorticoid receptor, TNF-α, myostatin, angiotensin converter enzyme, ApoE, interleukine-12 and -18. Finally, when performing network pharmacology analysis of the target nodes, some compounds were identified as potentially therapeutic (e.g., epigallocatechin gallate and antirheumatic agents); while some other substances appeared to be toxicants that may be involved in the development of this condition.
衰弱是一种与年龄相关的状况，其特征是对压力的不适当反应，导致不良后果（如死亡率、住院和残疾）的频率更高。其遗传背景已经有了一些了解，但这仍然是一个争论的问题。在本研究中，我们使用网络生物学分析了不同层次与衰弱相关的基因的互作网络，将其与途径、临床缺陷和具有潜在治疗意义的药物联系起来。与衰弱相关的重要途径包括：细胞凋亡、蛋白水解、肌肉增殖和炎症；FN1、APP、CREBBP、EGFR 等基因作为互作网络中的枢纽和瓶颈发挥作用，组蛋白 H3 簇和 miR200 家族等表观遗传因素也参与其中。当连接临床缺陷和基因时，我们确定了五个簇，深入了解了衰弱的生物学：癌症、糖皮质激素受体、TNF-α、肌肉生长抑制素、血管紧张素转换酶、ApoE、白细胞介素-12 和 -18。最后，当对靶节点进行网络药理学分析时，发现一些化合物可能具有治疗作用（如表没食子儿茶素没食子酸酯和抗风湿药）；而其他一些物质似乎是可能参与该病症发展的毒物。
