Research published in Aging has shed new light on the relationship between certain liver diseases and cellular senescence.
Clogged bile ducts and senescence
There are multiple documented causes of cellular senescence, such as radiation and chemical insults, which are frequently performed in experiments to test senescence and therapies against it. However, a few forms of physical damage, including liver diseases [1], can indirectly lead to senescence as well. Previous research has demonstrated that cholangiocytes, the cells that line the bile ducts of the liver, become senescent due to damage or obstruction of these ducts [2], and the SASP excreted by these senescent cells turns ordinary liver cells (hepatocytes) senescent as well [3].
While directly addressing this senescence has been shown to be effective in mouse models [4], some specific diseases have gone unexplored. Here, the researchers take a look at cellular senescence in biliary atresia, a childhood disease that leads to fibrous bile duct blockage, biliary cirrhosis, and, ultimately, liver failure [5].
Cellular senescence in the livers of children
The authors began with an examination of 30 livers that were taken out of patients before transplantation (the late-stage group), another 5 samples from livers undergoing surgery (the early-stage group), and a control group of 10 livers.
Markers of senescence were found to largely increase with disease progression. Interestingly, there was a wide spread among the late-stage livers; some appeared to have only slightly elevated markers of certain senescence biomarkers, such as SA-ß-gal, p16, and IL-8, while others had relatively low levels of the relevant genes and proteins. However, on average, this study found that cellular senescence is significantly and strongly associated with biliary atresia.
A principal component analysis of the SASP confirmed these findings. Of particular note was CCL2, which has been previously implicated as a major part of what drives hepatocytes senescent in bile duct diseases [6]. These researchers found that CCL2 is significantly elevated in biliary atresia as well.
Experiments with duct blockage in rats
To verify that blocking the bile ducts is the cause of this slide towards senescence, the researchers tied the bile ducts of rats. As expected, these animals’ liver biomarkers of cellular senescence increased over time, similarly to the livers of children with biliary atresia.
The researchers then treated these rats with human allogenic liver-derived progenitor cells (HALPC). This treatment decreased senescence in these rats’ livers, although not to the levels of rats with open bile ducts. The well-known senolytic combination of dasatinib and quercetin, on the other hand, was surprisingly found to be ineffective in this case.
Do other physical issues lead to senescence?
While the authors of this paper note that this line of research may lead to senolytic or cellular therapies for these sorts of liver diseases, they also provide clear evidence for a rarely-considered topic. Cellular senescence is normally considered as purely age-related or caused by molecular damage. It may also be the case that some other injuries and diseases also lead to undiscovered or rarely-considered forms of senescence, and not just in the liver. Surgeries or other treatments that restore physical function to certain tissues and systems may also have downstream senotherapeutic effects, potentially providing surprising benefits for healthspan and lifespan.
Literature
[1] Wiemann, S. U., Satyanarayana, A., Tsahuridu, M., Tillmann, H. L., Zender, L., Klempnauer, J., … & Rudolph, K. L. (2002). Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. The FASEB journal, 16(9), 935-942.
[2] Ferreira-Gonzalez, S., Rodrigo-Torres, D., Gadd, V. L., & Forbes, S. J. (2021, January). Cellular senescence in liver disease and regeneration. In Seminars in liver disease (Vol. 41, No. 01, pp. 050-066). Thieme Medical Publishers, Inc.
[3] Ferreira-Gonzalez, S., Lu, W. Y., Raven, A., Dwyer, B., Man, T. Y., O’Duibhir, E., … & Forbes, S. J. (2018). Paracrine cellular senescence exacerbates biliary injury and impairs regeneration. Nature communications, 9(1), 1020.
[4] Alsuraih, M., O’Hara, S. P., Woodrum, J. E., Pirius, N. E., & LaRusso, N. F. (2021). Genetic or pharmacological reduction of cholangiocyte senescence improves inflammation and fibrosis in the Mdr2-/-mouse. JHEP Reports, 3(3), 100250.
[5] Bezerra, J. A., Wells, R. G., Mack, C. L., Karpen, S. J., Hoofnagle, J. H., Doo, E., & Sokol, R. J. (2018). Biliary atresia: clinical and research challenges for the twenty-first century. Hepatology, 68(3), 1163-1173.
6] Sasaki, M., Miyakoshi, M., Sato, Y., & Nakanuma, Y. (2010). Modulation of the microenvironment by senescent biliary epithelial cells may be involved in the pathogenesis of primary biliary cirrhosis. Journal of hepatology, 53(2), 318-325.
