Abstract
Neuronal senescence, triggered by telomere shortening, oncogene activation, DNA damage, or oxidative stress, has been associated with neurodegenerative diseases' pathogenesis. Therefore, preventing neuronal senescence could be a novel treatment strategy for neurodegenerative diseases. Lithium (Li), the first-line treatment against bipolar disorder, has been shown to have neuroprotective effects in clinical, pre-clinical, and in vitro studies. Li can protect cells from senescence, and its effect on neuronal senescence was investigated in our study. Furthermore, we also investigated the effects of Li on the senescence-associated miR-34a/Sirt1/p53 pathway. In this study, hydrogen peroxide was used as an inducer for the "stress-induced premature senescence" model. In the senescence model, we have assessed Li's effects on senescence by analyzing β-galactosidase activity, Sudan Black B, and senescence-associated heterochromatin foci (SAHF) stainings, and on cell cycle arrest by BrdU staining. Furthermore, expression levels of senescence and cell cycle arrest-related proteins (p53, p21, p16INK4a, and SIRT1) by western blotting. Finally, the effects of Li on senescence-associated miR-34a levels were measured by quantitative PCR. We show via Sudan Black B staining, β-Gal activity assay, and by detecting SAHF, Li protects against senescence in neuronal cells. Then, Li's effect on signaling has also been determined on pathways involved in senescence and cell cycle arrest. Moreover, we have observed that Li has a modulatory effect on miR-34a expression. Therefore, we posit that Li suppresses senescence in neuronal cells and that this effect is mediated through miR-34a/Sirt1/p53 axis.
Highlights
Cellular senescence is a state of permanent cell cycle arrest that results in tissue dysfunction and is associated with aging and age-related diseases [1]
We show via Sudan Black B staining, β-Gal activity assay, and by detecting senescence-associated heterochromatin foci (SAHF), that lithium protects against senescence in SH-SY5Y cells
We have observed that lithium has a modulatory effect on miR-34a-5p, a miRNA that is associated with aging [29, 30] and targets –among others- the mRNA of SIRT1 [31], a longevity associated protein that boosts mitochondrial function [32]
Summary
Cellular senescence is a state of permanent cell cycle arrest that results in tissue dysfunction and is associated with aging and age-related diseases [1]. The two nearly universal senescence factors are DDR, whether caused by telomere attrition, mitochondrial dysfunction/reactive oxygen species (ROS), or ionizing radiation; and elevated activity of the tumor-suppressor proteins p53 or p16/INK4a [6, 7]. The first biochemical marker of senescence that is still commonly used is increased activity of the β-galactosidase enzyme, usually termed "senescence-associated β-galactosidase (or SA-β-gal)" [9]. While this was initially shown only in cultured cells' replicative senescence, later in vivo studies have reported β-gal activity in senescentlike cells in animals [10, 11]
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