Senolytics

Definition

Senolytics are agents studied for their ability to selectively induce death in some senescent cells, with the goal of reducing the burden of persistent senescence in tissues. The idea emerged from observations that senescent cells can depend on survival pathways that differ from those used by non-senescent cells, creating potential vulnerabilities that can be targeted experimentally. [1] [2] [3]

Why It Matters in Ageing Research

Senescent cells accumulate with age in multiple tissues and can contribute to chronic inflammation, remodeling of the tissue environment, and impaired function through the senescence-associated secretory phenotype. Because of that, senolytics are studied as one strategy for probing whether removing at least part of that cell population changes age-related phenotypes or disease processes. [2] [4] [6]

Common Confusion

• Senolytics are not the same as senomorphics: senolytics aim to remove some senescent cells, whereas senomorphics aim to modify senescent-cell behaviour without necessarily killing the cells. [1] [6]
• They are not expected to eliminate every senescent cell, and complete clearance may not be desirable because senescence can also play context-dependent roles in processes such as wound healing and tumour suppression. [2] [5]
• Positive findings in cell culture or animal models do not automatically establish broad anti-ageing effects in humans; early human studies have been small, disease-specific, and preliminary. [1] [6] [7]

Related Reading

• Cellular Senescence
• Senomorphics
• Inflammaging
• The SASP Explained

References

1. Kirkland, J. L., & Tchkonia, T. (2020). Senolytic drugs: From discovery to translation. https://onlinelibrary.wiley.com/doi/10.1111/joim.13056
2. Childs, B. G., Gluscevic, M., Baker, D. J., Laberge, R.-M., Marquess, D., Dananberg, J., & van Deursen, J. M. (2017). Senescent cells: An emerging target for diseases of ageing. https://www.nature.com/articles/nrd.2017.116
3. Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., O'Hara, S. P., LaRusso, N. F., Miller, J. D., Roos, C. M., Verzosa, G. C., LeBrasseur, N. K., Wren, J. D., Farr, J. N., Khosla, S., Stout, M. B., McGowan, S. J., Fuhrmann-Stroissnigg, H., Gurkar, A. U., Zhao, J., Colangelo, D., Dorronsoro, A., Ling, Y. Y., Barghouthy, A. S., Navarro, D. C., Sano, T., Robbins, P. D., Niedernhofer, L. J., Kirkland, J. L., & Tchkonia, T. (2015). The Achilles' heel of senescent cells: From transcriptome to senolytic drugs. https://onlinelibrary.wiley.com/doi/10.1111/acel.12344
4. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. https://www.cell.com/cell/fulltext/S0092-8674(13)00645-4
5. Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., Laberge, R.-M., Vijg, J., Van Steeg, H., Dollé, M. E., Hoeijmakers, J. H. J., de Bruin, A., Hara, E., & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. https://www.sciencedirect.com/science/article/pii/S1534580714007690
6. Gasek, N. S., Kuchel, G. A., Kirkland, J. L., & Xu, M. (2021). Strategies for targeting senescent cells in human disease. https://www.nature.com/articles/s41591-021-01521-0
7. Hickson, L. J., Langhi Prata, L. G. P., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., Herrmann, S. M. S., Jensen, M. D., Jia, Q., Jordan, K. L., Kellogg, T. A., Khosla, S., Koerber, D. M., Lagnado, A. B., Lawson, D. K., LeBrasseur, N. K., Lerman, L. O., McDonald, K. M., McKenzie, T., Passos, J. F., Pignolo, R. J., Pirtskhalava, T., Saadiq, I. M., Schaefer, K. K., Textor, S. C., Victorelli, S. G., Volkman, T. L., Xue, A., Wentworth, M. A., Wissler Gerdes, E. O., Zhu, Y., Tchkonia, T., Kirkland, J. L., & Robbins, P. D. (2019). Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. https://www.ebiomedicine.com/article/S2352-3964(19)30427-1/fulltext