Senolytic Treatment Fails to Reverse Uterine Fibrosis in Mice
Senolytic drugs that selectively destroy senescent cells in aged tissues have performed quite well in animal studies of fibrosis in heart, lung, and kidney. The therapy reverses fibrosis in those tissues to a larger degree, and with greater reliably, than is the case for any other readily available approaches. Unfortunately small molecule senolytics are all tissue specific to varying degrees in their biodistribution and effects, and so the benefits are not universally realized throughout the body.
As an example of this point, researchers here show that uterine fibrosis and its consequences are unresponsive to dasatinib and quercetin senolytic treatment, though they do not determine whether the compounds reach the uterus to the same degree as is the case for the heart, lung, or kidneys. That leaves the question of exactly why this treatment is ineffective, poor biodistribution of the senolytics versus tissue-specific mechanistic differences in cellular senescence and fibrosis, to be answered at a later date.
The most obvious histological change in the aged uterus is the collagen deposition (fibrosis) in the muscle layers and stroma. Mechanisms involved in this uterine fibrosis remain unclear. 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. Targeting senescent cells with senolytic drugs might slow down or prevent fibrosis processes in different tissues and organs. Currently, quercetin (Q) and dasatinib (D), administered alone or in combination (D+Q), are the most studied senolytic drugs. Different authors have reported anti-fibrotic effects of these drugs in tissues such as kidney, lung, and liver.
Studies about potential antifibrotic and senolytic effects of these drugs in the uterus are few, and there is no published study about effects of the D+Q combination on the uterus. It is important to mention that although these drugs alone have a senolytic potential, their combination selectively targets a broader range of senescent cell types than either agent alone. 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.
The main morphological changes observed during the mice uterine aging were increased uterine volume and fibrosis. In our study, dilated uterus was observed in 35% of the old mice, with no cases observed in any young mice. Interestingly, the D+Q treatment did not reduce the prevalence of uterine dilatation in old mice. The main feature of the uterine fibrosis process is collagen deposition. Age-related fibrosis appears to be a slow and continuous process that might, over time, cause development of serious pathological complications, including those observed in our animals: a dilated uterus. Due to slow development of this age-related disease, D+Q senolytic therapy in the present protocol may not have been continued long enough for attenuating uterine collagen deposition.