Dasatinib Plus Quercetin on Uterine Age-Related Dysfunction and Fibrosis in Mice

Abstract

23Female reproductive function is negatively impacted by age. Animal and human studies show 24 that fibrosis of the uterus contributes to gestational outcomes. Collagen deposition in the 25 myometrial and endometrial layers is the main change related to uterine aging. Senolytic 26 therapies are a potential option for reducing diseases and health complications related to aging. 27 We investigated effects of aging and the senolytic drug combination of dasatinib plus quercetin 28 (D+Q) on uterine fibrosis. A total of 40 mice, 20 young females (03-months) and 20 old females 29 (18-months), were analyzed. Young (Y) and old (O) animals were divided into groups of 10 30 mice, with one treatment (T) group (YT and OT) and another control (C) group (YC and OC).31Comparative analysis of Pi3k/Akt1/mTor and p53 gene expression among the 4 groups was 32 performed to test effects of age and treatment on collagen deposition in uterine tissue. Uterine 33 levels of microRNAs (miR34a, miR34b, miR34c, miR146a, miR449a, miR21a, miR126a, and 34 miR181b) were evaluated. Aging promoted downregulation of genes of the Pi3k/Akt1/mTor 35 signaling pathway (p=0.005, p=0.031, and p=0.028, respectively) as well as a reduction in 36 expression of miR34c (p=0.029), miR126a (p=0.009), and miR181b (p=0.007). D+Q treatment 37 increased p53 gene expression (p=0.041) and decreased levels of miR34a (p=0.016). Our results 38 demonstrate a role for the Pi3k/Akt1/mTor signaling pathway in uterine aging and suggest for the 39 first time a possible anti-fibrotic effect in the uterus of D+Q senolytic therapy.40 Introduction 43 The reproductive profile of women has been changing over the last few decades. Older 44 maternal age by the first gestation and an increased number of pregnancies after 40 years of age 45 are phenomena observed worldwide, impacting directly on gestational results [1]. Studies in 46 humans and animals suggest a strong relationship between pregnancy loss and maternal age [2, 47 3]. In addition to advanced age, other gynecological conditions are related to fertility, such as 48 polycystic ovary syndrome, leiomyomas, and endometriosis [4]. It is known that ovarian 49 dysfunction is the major factor responsible for these poor reproductive outcomes, but other 50 reproductive organs are involved in this complex process [2]. 51 An increase in uterine volume with aging is common in some species of rodents, mostly 52 due to endometrial cystic hyperplasia, as opposed to what occurs in menopausal women, in 53 whom uterine atrophy is usually evident [3, 5]. The most obvious histological change in the aged 54 uterus is the collagen deposition (fibrosis) in the muscle layers and stroma [3]. Mechanisms 55 involved in this uterine fibrosis remain unclear [6]. Collagen deposition in tissues occurs as a 56 result of chronic inflammatory processes involving several pathways: inflammatory interleukins, 57 growth factors, caspases, oxidative stress products, and accumulation of senescent cells [6]. 58 These chronic inflammatory pathways are also involve...

Chloroquine Defeats Aging?

“…8,9 . Furthermore, at the time, azithromycin, quercetin, and HCQ were proposed as "o -the-shelf" treatments for SARS-CoV2 infection 10 .…”