Table1_Proteomic and Biological Analysis of the Effects of Metformin Senomorphics on the Mesenchymal Stromal Cells.XLSX

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.

细胞衰老抑制剂是新型的药物，它们能够在组织中调节细胞衰老现象，并减少与年龄相关的病理病症的发生。细胞衰老抑制剂可分为细胞衰老溶解剂和细胞衰老形态调节剂两大类。细胞衰老溶解剂能够选择性杀伤衰老细胞，而细胞衰老形态调节剂则能够延缓或阻断衰老的发生。二甲双胍作为一种治疗糖尿病的药物，已应用数十年。近期，有研究提出二甲双胍可能具有抗衰老的特性，因为它能够防止DNA损伤和炎症。本研究评估了为期6周的治疗性二甲双胍对人类脂肪间充质干细胞（MSCs）生物学的影响。研究结合了MSCs细胞内和分泌蛋白组成的蛋白质组学分析，以识别与观察到的生物学现象相关的分子通路。二甲双胍降低了与长期体外培养相关的复制性衰老和细胞死亡现象。持续的二甲双胍补充剂延缓或减少了MSCs功能的损害，这可以从二甲双胍处理样本中存在的三个特定通路中得到证实：1）α-肾上腺素能信号通路，该通路有助于调节MSCs的生理分泌活性；2）与MSCs解毒活性相关的信号通路；3）天冬氨酸降解通路，以优化能量产生。二甲双胍的细胞衰老形态调节功能似乎与其清除活性氧（ROS）的能力有关。在二甲双胍处理样本中，CEBPA、TP53和USF1转录因子似乎参与了调节多个因子（如SOD1、SOD2、CAT、GLRX、GSTP1）以阻断ROS的过程。