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bioRxiv · 10.1101/823229

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

Cavalcante, M. B.·Saccon, T. D.·Nunes, A. D. C.·Kirkland, J. L.·Tchkonia, T.·Schneider, A.·Masternak, M. M.
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Abstract

Female reproductive function is negatively impacted by age. Animal and human studies show that fibrosis of the uterus contributes to gestational outcomes. Collagen deposition in the myometrial and endometrial layers is the main change related to uterine aging. Senolytic therapies are a potential option for reducing diseases and health complications related to aging. We investigated effects of aging and the senolytic drug combination of dasatinib plus quercetin (D+Q) on uterine fibrosis. A total of 40 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 (C) group (YC and OC). Comparative analysis of Pi3k/Akt1/mTor and p53 gene expression among the 4 groups was performed to test effects of age and treatment on collagen deposition in uterine tissue. Uterine levels of microRNAs (miR34a, miR34b, miR34c, miR146a, miR449a, miR21a, miR126a, and miR181b) were evaluated. Aging promoted downregulation of genes 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 levels of 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.

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Cavalcante, M. B., Saccon, T. D., Nunes, A. D. C., Kirkland, J. L., Tchkonia, T., Schneider, A., Masternak, M. M.. 2019-10-29. Dasatinib Plus Quercetin on Uterine Age-Related Dysfunction and Fibrosis in Mice. https://doi.org/10.1101/823229

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