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.
Highlights
The dysfunction of adipose tissue with aging and the accumulation of senescent cells has been implicated in the pathophysiology of chronic diseases
In order to study the senolytic effects of quercetin in Adipose tissue (AT), we established an in vitro model of preadipocytes as well as mature adipocytes cultures by using 3T3-L1 cells. 3T3-L1 cells were induced and differentiated according to previous reports that described into details the morphological and functional changes of pre-adipocytes and adipocytes in the different stages of growth and aging27–29. 3T3-L1 cells during differentiation show significant morphological changes with a progressive increase in lipid accumulation and cell area from preadipocytes to young (PID5) until mature adipocytes (PID 10) (Fig. 1)
Our study shows that quercetin may act as a potential senolytic and anti-inflammatory agent in senescent adipocytes as well as in senescent pre-adipocytes
Summary
The dysfunction of adipose tissue with aging and the accumulation of senescent cells has been implicated in the pathophysiology of chronic diseases. 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. Pre-adipocytes become dysfunctional with aging with a reduced capacity for proliferation and differentiation, leading to an impaired fatty acid handling[8,9]. These dysfunctional pre-adipocytes assume the phenotype of mesenchymal adipocyte-like default cells (MAD)[8], producing pro-inflammatory cytokines, like TNF-α, involved in the onset of inflammation of aged A T10,11. The differential expression of a particular class of gene regulatory elements, the microRNAs (miRNAs), has been studied in different aged tissues and has been hypothesized to be involved in the dysfunction of A T7,16,17
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