In Aging Cell, a research team has explained why barrier cells in the human bladder are largely senescent and what might lead them to become cancerous.
Targeting the right cells
It is well-known that people develop urinary problems with advanced age, including increasing frequency and incontinence [1]. However, previous efforts to treat this problem have largely focused on signaling pathways in the smooth muscle in the region rather than the bladder itself, and this has proven to be largely ineffective, with patients often discontinuing prescribed medication [2].
The researchers of this paper note that bladder control is a multifaceted issue, with the brain playing a role [3] along with a decrease in feeling in the area [4] and an increase in fibrosis [5]. This led the researchers to attempt a geroscience-related approach, determining if attempting to treat aging in a broader way might alleviate the issue, focusing specifically on senescent cells in the bladder as a potential therapeutic target to be treated with senolytics.
What they found, however, defied their expectations.
Where senescent cells are necessary
These researchers began their study by determining how senescent cells in the bladders of mice are affected by aging over their lifespans. Interestingly, the researchers only found that, in this area, old female mice had increases in the inflammatory molecules secreted by senescent cells; male mice did not have a statistically significant change.
While the researchers looked at individual molecules in order to establish a pattern, this line of exploration was largely inconclusive, with expected correlations not being established. They used the well-established senescence-associated biomarker SA-β-gal to find these cells, discovering that the only appreciable population was in the surface umbrella cells (UCs), barrier cells that prevent leakage between the bladder and the surrounding tissue.
Unlike most other cells, UCs are normally polyploid: they have multiple copies of chromosomes [6]. These senescent cells were found even in two-month mice, and they increased as the mice matured but did not increase into older ages. Other biomarkers, such as telomere-associated foci (TAF) and γH2AX, which represents damaged DNA, were highly represented in the UC population.
However, there were some crucial differences with aging. The senescent cell marker p16 was not found in this tissue area in middle-aged mice but was found in 10% of the relevant cells of older mice. Genes that prevent death by apoptosis that were expressed in middle-aged mice were less expressed in older mice, while the bladder cells of older mice seemed to be undergoing much more stress.
Being polyploid is likely to mean that UCs are more resistant to stresses and more able to respond to challenges [7], and one paper demonstrated that this is what makes it possible to fulfill their function [8]. However, as polyploidy also makes it much more likely that cells will have problems with missing or extra chromosomes (aneuploidy), there are evolved safeguards against their proliferation, and so previous work has also found that polyploidy is a cause of senescence [9]. These researchers were able to confirm that work, finding that the relevant cell cycle regulator was significantly upregulated in UCs.
Well-known senolytics are ineffective here, and it’s good that they are
While removing senescent cells in this case would not be likely to be beneficial, the researchers tested the well-known combination of dasatinib and quercetin in older mice. The mice’s UC cells were completely unaffected by this treatment: there were no differences in senescent cell population, TAF, nor p16. While there were some changes in gene expression in the whole bladder, the treatment did not offer any appreciable benefits.
Feeding the mice a high-fat diet, which increases systemic inflammation and senescent cell burden, had a small effect on maximum bladder pressure but did not affect other markers, such as the amount voided into corners: while such a diet clearly has some negative effects, it does not recapitulate natural aging. Here, too, senolytics were not found to have any effect.
Injecting the mice with senescent cells had similar effects on maximum pressure. Interesting, injecting mice with proliferating ear fibroblasts seemed to cause the mice to void more in corners.
The researchers note that these senescent cells are clearly necessary for proper function of the bladder, suggesting that they should be treated rather than destroyed, such as by improving their mitochondrial function or reducing their oxidative stress. They also believe that the polyploidy of these cells may be responsible for bladder cancer, as the cell cycle regulator that keeps them senescent is not perfect, and polyploid cells are much more prone to becoming cancerous. The researchers point to this as being part of antagonistic pleiotropy: a benefit earlier in life becomes a danger later on. Time will tell whether this knowledge can be used to develop treatments for bladder problems, including cancer.
Literature
[1] Nordling, J. (2002). The aging bladder—a significant but underestimated role in the development of lower urinary tract symptoms. Experimental gerontology, 37(8-9), 991-999.
[2] Benner, J. S., Nichol, M. B., Rovner, E. S., Jumadilova, Z., Alvir, J., Hussein, M., … & Brubaker, L. (2010). Patient‐reported reasons for discontinuing overactive bladder medication. BJU international, 105(9), 1276-1282.
[3] Zhao, P., Zhang, G., Shen, Y., Wang, Y., Shi, L., Wang, Z., … & Sun, L. (2023). Urinary dysfunction in patients with vascular cognitive impairment. Frontiers in Aging Neuroscience, 14, 1017449.
[4] Pfisterer, M. H. D., Griffiths, D. J., Schaefer, PhD, W., & Resnick, N. M. (2006). The effect of age on lower urinary tract function: a study in women. Journal of the American Geriatrics Society, 54(3), 405-412.
[5] Kullmann, F. A., Birder, L. A., & Andersson, K. E. (2015). Translational research and functional changes in voiding function in older adults. Clinics in geriatric medicine, 31(4), 535.
[6] Wang, J., Batourina, E., Schneider, K., Souza, S., Swayne, T., Liu, C., … & Mendelsohn, C. L. (2018). Polyploid superficial cells that maintain the urothelial barrier are produced via incomplete cytokinesis and endoreplication. Cell reports, 25(2), 464-477.
[7] Bailey, E. C., Kobielski, S., Park, J., & Losick, V. P. (2021). Polyploidy in tissue repair and regeneration. Cold Spring Harbor Perspectives in Biology, 13(10), a040881.
[8] Wang, J., Batourina, E., Schneider, K., Souza, S., Swayne, T., Liu, C., … & Mendelsohn, C. L. (2018). Polyploid superficial cells that maintain the urothelial barrier are produced via incomplete cytokinesis and endoreplication. Cell reports, 25(2), 464-477.
[9] Panopoulos, A., Pacios-Bras, C., Choi, J., Yenjerla, M., Sussman, M. A., Fotedar, R., & Margolis, R. L. (2014). Failure of cell cleavage induces senescence in tetraploid primary cells. Molecular biology of the cell, 25(20), 3105-3118.
