Restrição calórica e tratamento com senolíticos em camundongos fêmeas jovens em estropausa induzida

Abstract

The world population is aging and there is currently a significant increase in the number of people aged 60 or over, with this population being mostly female. In Brazil, demographic and epidemiological change, as well as improvements in the health system in recent decades, have resulted in both in the progression of the number of elderly women, as in the time they live in menopause. Menopause is commonly associated with changes and chronic diseases that are associated with aging and cellular senescence. Based on this, our objective was to evaluate the effects of caloric restriction (CR) and treatment with the senolytics dasatinib and quercetin (D+Q) or fisetin in a model of chemically induced estropause with 4-vinylcyclohexane diepoxide (VCD) in young females. The intention of this study is to mimic the effects of aging associated with the state of estropause. For this, at two months of age the females were subjected to chemical induction of estropause with VCD for 20 consecutive days and, after confirmation of estropause by vaginal cytology, they were applied to different experimental protocols, with CR or treatment with senolytics. The 30% CR protocol lasted 4 months and D+Q and fisetin treatments were performed for 6 months. Our findings revealed that estropause was associated with a higher average body weight, but had no significant effects on fat accumulation in both experiments. A CR of 30% was able to significantly reduce weight and the amount of body fat, appearing quite intense in estropause in females subjected to CR, however no other clear influences of estropause were observed on the response to CR of 30%. In females treated with senolytics, no relevant effects related to metabolic changes were observed between cyclic females and estropause. Oxidative stress in adipose and liver tissue was also similar between cyclic and estropausal females, regardless of senolytic treatment. However, estropause decreases catalase (CAT) activity in adipose tissue in all groups. Fisetin impairs ROS levels in the liver tissue of estropause females compared to females in the cyclic and estropause placebo groups. Estropause and treatment with senolytics did not influence the activity of beta-galactosidase associated with senescence in adipose and liver tissues. The ovaries of females in estropause showed the highest percentage of senescent cells compared to cyclic females, reinforcing the ovotoxic and localized effect of VCD in the ovary. However, senolytic treatment was not able to reduce ovarian senescence caused by estropause and no differences were observed in the percentage of fibrosis and macrophages between estropause and cyclic females. Overall, our results suggest that estropause generates few metabolic changes in young females and that CR and treatment with senolytics did not have protective effects in relation to oxidative stress and cellular senescence, indicating that these changes may be more associated with the natural process of aging than the state of estropause.