Abstract
The uterine fibrosis contributes to gestational outcomes. Collagen deposition in the uterus is related to uterine aging. Senolytic therapies are an option for reducing health complications related to aging. We investigated effects of aging and the senolytic drug combination of dasatinib plus quercetin (D+Q) on uterine fibrosis. Forty mice, 20 young females (03-months) and 20 old females (18-months), were analyzed. Young (Y) and old (O) animals were divided into groups of 10 mice, with one treatment (T) group (YT and OT) and another control © group (YC and OC). Comparative analysis of Pi3k/Akt1/mTor and p53 gene expression and related microRNAs (miR34a, miR34b, miR34c, miR146a, miR449a, miR21a, miR126a, and miR181b) among groups was performed to test effects of age and treatment on collagen deposition pathways. Aging promoted downregulation of the Pi3k/Akt1/mTor signaling pathway (P = 0.005, P = 0.031, and P = 0.028, respectively) as well as a reduction in expression of miR34c (P = 0.029), miR126a (P = 0.009), and miR181b (P = 0.007). D+Q treatment increased p53 gene expression (P = 0.041) and decreased miR34a (P = 0.016). Our results demonstrate a role for the Pi3k/Akt1/mTor signaling pathway in uterine aging and suggest for the first time a possible anti-fibrotic effect in the uterus of D+Q senolytic therapy.
Highlights
The reproductive profile of women has been changing over the last few decades
Our results demonstrate a role for the phosphoinositide 3-kinase (Pi3k)/Akt1/mammalian target of rapamycin (mTor) signaling pathway in uterine aging and suggest for the first time a possible anti-fibrotic effect in the uterus of dasatinib plus quercetin (D+Q) senolytic therapy
Collagen deposition was significantly higher in old mice compared to young mice and there was no difference in fibrosis in treated groups compared to placebo
Summary
The reproductive profile of women has been changing over the last few decades. Older maternal age by the first gestation and an increased number of pregnancies after 40 years of age are phenomena observed worldwide, impacting directly on gestational results [1]. The most obvious histological change in the aged uterus is the collagen deposition (fibrosis) in the muscle layers and stroma [3] Mechanisms involved in this uterine fibrosis remain unclear [7]. Collagen deposition in tissues occurs as a result of chronic inflammatory processes involving several pathways: inflammatory interleukins, growth factors, caspases, oxidative stress products, and accumulation of senescent cells [7]. These chronic inflammatory pathways are involved in undesired obstetric outcomes such as loss of pregnancies and preterm delivery [8]
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