Senolytic effects of quercetin in an in vitro model of pre-adipocytes and adipocytes induced senescence

Abstract

The dysfunction of adipose tissue with aging and the accumulation of senescent cells has been implicated in the pathophysiology of chronic diseases. Recently interventions capable of reducing the burden of senescent cells and in particular the identification of a new class of drugs termed senolytics have been object of extensive investigation. We used an in vitro model of induced senescence by treating both pre-adipocytes as well as mature adipocytes with hydrogen peroxide (H2O2) at a sub-lethal concentration for 3 h for three consecutive days, and hereafter with 20 uM quercetin at a dose that in preliminary experiments resulted to be senolytic without cytotoxicity. H2O2 treated pre-adipocytes and adipocytes showed typical senescence-associated features including increased beta-galactosidase activity (SA-ß-gal) and p21, activation of ROS and increased expression of pro-inflammatory cytokines. The treatment with quercetin in senescent pre-adipocytes and adipocytes was associated to a significant decrease in the number of the SA-β-gal positive cells along with the suppression of ROS and of inflammatory cytokines. Besides, quercetin treatment decreased miR-155-5p expression in both models, with down-regulation of p65 and a trend toward an up-regulation of SIRT-1 in complete cell extracts. The senolytic compound quercetin could affect AT ageing by reducing senescence, induced in our in vitro model by oxidative stress. The downregulation of miRNA-155-5p, possibly through the modulation of NF-κB and SIRT-1, could have a key role in the effects of quercetin on both pre-adipocytes and adipocytes.

The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence

“…Quercetin is a flavonol known for its antioxidant, anti-inflammatory, antitumor, and senolytic properties [ 258 ]. Results obtained on different cell lines show that treatment with quercetin significantly lowers the levels of ROS and inflammatory cytokines, reduces the expression of SA-β gal, p16 and p53 and markedly increases that of the antioxidant enzymes SOD and CAT, regardless of the type of oxidative trigger used to induce senescence [ 258 , 259 , 260 , 261 , 262 ]. In addition to promoting the expression of Nrf2 [ 263 ], the beneficial action of quercetin appears to be mediated by the microRNA-155-5p, which is involved in the regulation of SIRT1 and NF-kB [ 262 , 264 ].…”

“…Results obtained on different cell lines show that treatment with quercetin significantly lowers the levels of ROS and inflammatory cytokines, reduces the expression of SA-β gal, p16 and p53 and markedly increases that of the antioxidant enzymes SOD and CAT, regardless of the type of oxidative trigger used to induce senescence [ 258 , 259 , 260 , 261 , 262 ]. In addition to promoting the expression of Nrf2 [ 263 ], the beneficial action of quercetin appears to be mediated by the microRNA-155-5p, which is involved in the regulation of SIRT1 and NF-kB [ 262 , 264 ]. Moreover, as aging is associated with an inefficient protein-degradation (which is required to protect against OS), the effect of quercetin and its derivatives on the restoration of proteasomal functioning is of interest as rejuvenating strategy [ 265 ].…”

Effect of Replicative Senescence on the Expression and Function of Transporters in Human Proximal Renal Tubular Epithelial Cells

“…Cellular senescence has been observed not only in RPTECs but also in various cells and tissues such as skin, liver, lung, adipose tissue, and vascular tissue. 9,[30][31][32][33] Therefore, the maximum limit of the number of passages should be defined for each cell type when primary cultured cells are used to evaluate the pharmacokinetics and toxicity of chemical compounds. In addition, we must also pay attention to other factors promoting cellular senescence.…”

Aging and aging-related diseases: from molecular mechanisms to interventions and treatments

“…570 Dasatinib and quercetin have been found to eliminate both p16 high and p21 high senescent cells in the pancreas and adipose tissues in a T2DM animal model. 571,572 Unexpectedly, it has been reported that treatment with dasatinib and quercetin worsens liver disease progression in a diethylnitrosamine (DEN)/HFD mouse model, slightly increases histological damage and tumorigenesis, and has no effect on senescent cell removal. 573 Moreover, human senescent β cells also respond to senolysis, establishing the foundation for translation.…”