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

Mustafa Burak Acar,Servet Özcan,Umberto Galderisi,Giovanni Di Bernardo,Gianfranco Peluso,Zeynep Gunaydin,Musa Karakukcu,Şerife Ayaz-Güner

doi:10.3389/fbioe.2021.730813

Abstract

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.

Highlights

Following genotoxic stress, caused by either external or internal stimuli, cells undergo senescence, which arrests cell division and induces a loss of cell functions (Campisi and d’Adda di Fagagna, 2007)
We evaluated the effect of metformin on the biology of human adipose mesenchymal stromal cells (MSCs) treated with therapeutic doses of MSCs incubated with 9 mM metformin showed 6.7% of cells in the S-phase (Table 1)
For a complete assessment of metformin senomorphic properties, we evaluated its effects on MSCs, which play a key role in bodily homeostasis and tissue renewal

Summary

Introduction

Following genotoxic stress, caused by either external or internal stimuli, cells undergo senescence, which arrests cell division and induces a loss of cell functions (Campisi and d’Adda di Fagagna, 2007). Some pioneering studies have shown that ablation of senescent cells in tissues prolonged health spans and reduced the risk of agerelated pathologies (ARD) in a mouse model (Kim and Kim 2019). This finding paved the way for the development of a new class of drugs called senotherapeutics, which can modulate senescence phenomena within tissues and reduce the onset of ARD (Niedernhofer and Robbins 2018; Kim and Kim 2019; Myrianthopoulos et al, 2019). The senomorphics may act in one of two ways: they can revert the phenotype of senescent cells back to healthy cells or they can delay or block the onset of senescence following genotoxic stress (Kim and Kim 2019)

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