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.
Highlights
Stem cell senescence is considered an important hallmark of aging in vivo[1,2]
While short incubations did not affect HyPer-index, 6-hour treatments resulted in attenuated HyPer oxidation in proliferating cells (Fig. 1D) which proved that employed AO treatments did not cause pro-oxidative effects in endometrial mesenchymal stem cells (eMSCs)-HyPer cells
Since the irreversibility of self-renewal block is often associated with DNA damage response, we examined DNA integrity in AO-exposed eMSCs
Summary
Stem cell senescence is considered an important hallmark of aging in vivo[1,2]. Recently, it has been found that premature senescence of stem cells is associated with preliminary aging disorders, including Werner syndrome and Hutchinson-Gilford progeria syndrome[3,4]. It was proven that along with fibroblasts, many other normal human cells (including stem cells) are susceptible to SIPS program activation[2,5,9,13]. Since oxidative stress is a well-known inducer of premature senescence, a lot of research showing beneficial effects of antioxidants (AOs) has been performed both in vitro and in vivo[22,23]. In most of these studies, protective and anti-aging antioxidant (AO) effects occurred in the case of induced oxidative stress conditions. We conclude that anti-aging properties are highly dependent on the applied doses of AOs
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