Cellular senescence, an induced state which involves the cessation of cell division, is largely regarded as the hallmark of aging. Senescent cells can present both negative and positive consequences on human health depending on the period they remain in an organism.
Ample research has found that acute senescent cells, which remain in an organism over a short period can have positive impacts on human health. The role senescent cells play in wound healing is an example of this.
Chronic long-term senescent cells, however, have been associated with the development of disease and age-related dysfunctions. Furthermore, long-term senescent cells have also been shown to secrete pro-inflammatory cytokines, chemokines and tumorigenic factors in a state referred to as senescence-associated secretory phenotype (SASP).
To combat the negative impacts associated with senescent cells, substantial research is being carried out focusing on the removal of senescent cells to improve organ function. Here, potential approaches for the clearance of senescent cells to improve organ function through methods such as the utilization of senolytics and SASP inhibition will be examined.
Clearance of Senescent Cells to Improve Heart Function
An additional feature associated with cellular senescence is the ability of increased numbers of senescent cells to worsen heart function, particularly following cardiac injury. This is because cellular senescence has been associated with decreasing the potency of cardiac progenitor cells, which are essential in the turnover of cardiac monocytes and vascular endothelial cells following cardiac injury.
In a recent study, researchers were able to demonstrate that the use of senolytics to target senescent cells in aged INK‐ATTAC mouse models improved heart function.
The researchers showed that there were increased numbers of cardiac progenitor cells in mice treated with senolytics when compared to mice that were not treated with senolytics. Additionally, an increase in the number of proliferating myocytes was also seen in mouse models treated with senolytics.
In vitro experiments conducted on ‘aged’ heart tissue in the same study showed that SASP factors including matrix metalloproteinase-3, plasminogen activator inhibitor-1, interleukin 6, and 8, and granulocyte-macrophage colony-stimulating factor, could also be inhibited via the same senolytics. These findings demonstrate that clearance of senescent cells in aged mice through senolytics enables SASP factors to be inhibited and the increased activation of cardiomyocytes, overall leading to improved heart function.
Clearance of Senescent Cells to Improve Kidney Function
Researchers were able to show that the utilization of senolytics to target senescent cells in aged organs, which resulted in the promoted survival of aged organs. In experiments using aged donor animals, Iske et al., 2020 showed that treatment with senolytics efficiently reduced the numbers of senescent cells present and improved the functioning of organs including kidney function.
They showed that cyclin-dependent kinase inhibitor p16Ink4a, an established marker of senescent cells, was significantly reduced in experiments using aged C57BL/6 mice (18 months ) following treatment. Results from the study also demonstrated that inflammation associated with senescent cells in the studied kidney ischemia and reperfusion injury-induced mice was decreased. This indicates the potential that senolytics hold as a strategy to remove senescent cells and improve organ function.
Clearance of senescent cells to Improve Lung Function
The removal of senescent cells in a bleomycin-injury idiopathic pulmonary fibrosis model using senolytics has been found to improve lung function in a study by Schafer et al., 2017. This study which also investigates the potential of senolytics in clearing senescent cells showed that pulmonary organ function was improved in transgenic studies as a result of the senolytics treatment given.
The study which highlights that senescent cells can be targeted as a therapeutic approach for idiopathic pulmonary fibrosis demonstrates that pulmonary expression of SASP factors is reduced through the elimination of senescent cells. Through in vitro and in vivo experiments, Schafer et al., 2017 showed the improvement of lung function coinciding with the reduction of SASP factors.
Alternatively, research by Ovadya et al., 2018 has identified a senolytics drug as an approach to remove senescent cells and improve organ function. In investigations utilizing mice with high levels of senescent cells, researchers were remarkably able to find that it extended the healthspan of Prf1−/− mice.
The results obtained from the study showed that organ functionality including lung functionality decreased whereas chronic inflammation increased with a higher accumulation of senescent cells in aged mice. These findings again highlight that the removal of long-term senescent cells with senolytics, could with further research be a potential strategy to improve organ function.
Conclusion
In summary, research although largely performed using mouse models has highlighted the removal of senescent cells as a potential strategy to ultimately improve organ function. These research findings present an exciting opportunity with regards to therapeutic promise for a wide range of age-related diseases that currently exist and continue to increase.
References:
- Iske, J., Seyda, M., Heinbokel, T., Maenosono, R., Minami, K., Nian, Y., Quante, M., Falk, C., Azuma, H., Martin, F., Passos, J., Niemann, C., Tchkonia, T., Kirkland, J., Elkhal, A. and Tullius, S., 2020. Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation. Nature Communications, 11(1).
- Lewis‐McDougall, F., Ruchaya, P., Domenjo‐Vila, E., Shin Teoh, T., Prata, L., Cottle, B., Clark, J., Punjabi, P., Awad, W., Torella, D., Tchkonia, T., Kirkland, J. and Ellison‐Hughes, G., 2019. Aged‐senescent cells contribute to impaired heart regeneration. Aging Cell, 18(3), pp.12931-12946.
- Ovadya, Y., Landsberger, T., Leins, H., Vadai, E., Gal, H., Biran, A., Yosef, R., Sagiv, A., Agrawal, A., Shapira, A., Windheim, J., Tsoory, M., Schirmbeck, R., Amit, I., Geiger, H. and Krizhanovsky, V., 2018. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nature Communications, 9(1).
- Schafer, M., White, T., Iijima, K., Haak, A., Ligresti, G., Atkinson, E., Oberg, A., Birch, J., Salmonowicz, H., Zhu, Y., Mazula, D., Brooks, R., Fuhrmann-Stroissnigg, H., Pirtskhalava, T., Prakash, Y., Tchkonia, T., Robbins, P., Aubry, M., Passos, J., Kirkland, J., Tschumperlin, D., Kita, H. and LeBrasseur, N., 2017. Cellular senescence mediates fibrotic pulmonary disease. Nature Communications, 8(1).
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