High doses of synthetic antioxidants induce premature senescence in cultivated mesenchymal stem cells

Abstract

Stress-induced premature senescence program is known to be activated in cells by various genotoxic stressors, and oxidative stress is considered to be the main of those. To this end, many studies discover antioxidants as protective anti-aging agents. In the current study, we examined the effects of different antioxidants (Tempol, resveratrol, NAC, DPI) on the mesenchymal stem cells maintained in normal physiological conditions. We used high, but non-cytotoxic antioxidant doses which are widely used in laboratory practice to protect cells from oxidative damage. We show that these substances induce reversible block of cell proliferation and do not cause any genotoxic effects when applied to the quiescent cells. However, the same doses of the same substances, when applied to the proliferating cells, can induce irreversible cell cycle arrest, DNA strand breaks accumulation and DNA damage response activation. As a consequence, antioxidant-induced DNA damage results in the stress-induced premature senescence program activation. We conclude that high doses of antioxidants, when applied to the proliferating cells that maintain physiological levels of reactive oxygen species, can cause DNA damage and induce premature senescence which suggests to re-estimate believed unconditional anti-aging antioxidant properties.

Potential Adverse Effects of Resveratrol: A Literature Review

“…RE also decreased the viability of 3T6 fibroblasts and HL60 tumor cells [165]. In mesenchymal stem cells, 0.1 µM RE promoted self-renewal, whereas concentrations above 5 mM increased senescence rate and inhibited self-renewal [166,167]. As such, further studies are needed to assert the safety of RE against normal healthy cell lines, especially before promoting RE as an anti-cancer agent.…”

Insights into superoxide dismutase 3 in regulating biological and functional properties of mesenchymal stem cells

“…The treatment of MSCs with antioxidants found to ameliorate the therapeutic potential of MSCs in various disease models [57,58]. In contrast, it has been reported that high but non-toxic doses of antioxidants, when subjected to the proliferating MSCs, can cause DNA damage and induce premature senescence [59]. Therefore, it is also very important to assess or consider the possible detrimental effects such as extracellular H 2 O 2 generated by SOD3 which has been reported to induce angiogenesis by promoting endothelial cell proliferation and migration [60] and stimulates various redox signaling which is involved in pathological conditions by Fenton type reaction and peroxidase activity.…”

Potential of resveratrol in enrichment of neural progenitor-like cells induction of human stem cells from apical papilla

“…The application of resveratrol to mesenchymal stem cell-based regenerative medicine has been demonstrated in various in vitro bioactivities, including self-renewal, multipotency (33), senescence (21), cell aging (34), osteogenic differentiation (35), adipogenic differentiation (36), and neuronal differentiation (12). Moreover, resveratrol has an e ciently therapeutic effect on in vivo models, including enhancing liver regeneration (37), cardiogenic differentiation in cardiomyopathy (38).…”