DataSheet1_Proteomic and Biological Analysis of the Effects of Metformin Senomorphics on the Mesenchymal Stromal Cells.PDF

Senotherapeutics are new drugs that can modulate senescence phenomena within tissues and reduce the onset of age-related pathologies. Senotherapeutics are divided into senolytics and senomorphics. The senolytics selectively kill senescent cells, while the senomorphics delay or block the onset of senescence. Metformin has been used to treat diabetes for several decades. Recently, it has been proposed that metformin may have anti-aging properties as it prevents DNA damage and inflammation. We evaluated the senomorphic effect of 6 weeks of therapeutic metformin treatment on the biology of human adipose mesenchymal stromal cells (MSCs). The study was combined with a proteome analysis of changes occurring in MSCs’ intracellular and secretome protein composition in order to identify molecular pathways associated with the observed biological phenomena. The metformin reduced the replicative senescence and cell death phenomena associated with prolonged in vitro cultivation. The continuous metformin supplementation delayed and/or reduced the impairment of MSC functions as evidenced by the presence of three specific pathways in metformin-treated samples: 1) the alpha-adrenergic signaling, which contributes to regulation of MSCs physiological secretory activity, 2) the signaling pathway associated with MSCs detoxification activity, and 3) the aspartate degradation pathway for optimal energy production. The senomorphic function of metformin seemed related to its reactive oxygen species (ROS) scavenging activity. In metformin-treated samples, the CEBPA, TP53 and USF1 transcription factors appeared to be involved in the regulation of several factors (SOD1, SOD2, CAT, GLRX, GSTP1) blocking ROS.

细胞老衰调节药物（Senotherapeutics）是一类能够调节组织内细胞衰老现象并减少与年龄相关疾病发生的新药。细胞老衰调节药物可分为老衰溶解剂和老衰形态剂两大类。老衰溶解剂能够选择性杀伤衰老细胞，而老衰形态剂则能够延迟或阻断衰老的发生。甲巯咪唑（Metformin）作为治疗糖尿病的药物，已经使用了数十年。近期研究表明，甲巯咪唑可能具有抗衰老特性，因为它能够防止DNA损伤和炎症。本研究评估了为期六周的治疗性甲巯咪唑对人类脂肪间充质干细胞（MSCs）生物学的影响。研究结合了对MSCs细胞内和分泌蛋白组成变化进行的蛋白质组学分析，以识别与观察到的生物学现象相关的分子途径。甲巯咪唑减少了与长期体外培养相关的复制性衰老和细胞死亡现象。持续补充甲巯咪唑延缓并或减少了MSCs功能的损伤，这在甲巯咪唑处理样本中三种特定途径的存在得到了证实：1）α-肾上腺素能信号通路，该通路有助于调节MSCs的生理分泌活动；2）与MSCs解毒活性相关的信号通路；3）天冬氨酸降解途径，以优化能量生成。甲巯咪唑的老衰形态功能似乎与其清除活性氧（ROS）的能力相关。在甲巯咪唑处理样本中，CEBPA、TP53和USF1转录因子似乎参与调节多个因素（SOD1、SOD2、CAT、GLRX、GSTP1），这些因素能够阻断ROS。