Cellular senescence, discovered in 1961 by Leonard Hayflick and Paul Moorhead, is a state in which cells no longer perform their functions, instead emitting harmful chemicals that turn other cells senescent. Senescence is primarily caused by telomere shortening and DNA damage, and senescent cells are known to contribute to multiple diseases, such as Alzheimer’s, Parkinson’s, and dementia.
One method of removing senescent cells is caloric restriction, which is a temporary reduction of food calories. This has been shown to be one of the most effective methods to decrease and slow the onset of aging phenotypes [1].
This is related to autophagy, which is the cell’s natural method of breaking down parts of itself when it doesn’t have immediate access to food [2]. Autophagy has been shown to both promote and prevent senescence. It removes damaged macromolecules or organelles, such as mitochondria, which would otherwise cause cellular senescence. However, some of the processes that cause autophagy cause cellular senescence as well [3].
People have invented a new method of eradicating senescent cells: senolytics. These are compounds that initiate apoptosis in senescent cells without harming healthy cells [4].
The heterogeneity of senescent cells
However, there is no single senolytic that has been shown to target all of our senescent cells. This is because senescent cells are heterogeneous, meaning that they’re very diverse, and they have different characteristics.
To add to the problem, the senescent cell phenotype is also dynamic and can change at various points after senescence occurs, which makes it even harder to find a single senolytic capable of destroying all the problem cells at once.
Essentially, each of these sub-populations of senescent cells residing in our tissues and organs is using a different pro-survival pathway to avoid apoptosis and destruction, and a single drug is unlikely to kill them all unless a common target can be identified.
This has sparked a race to find a universal biomarker that we are able to target and initiate apoptosis with. For example, researchers have been considering senescent-associated β-galactosidase as a universal biomarker. However, it was shown that not all senescent cells contain it [5].
Metformin, dasatinib, quercetin, and FOXO4-DRI all target senescent cells in different ways. Metformin upregulates GPx7 [6], dasatinib affects dependence receptors/tyrosine kinase senescent cell anti-apoptotic pathways (SCAPs), quercetin affects the the BCL-2/BCL-XL, PI3K/AKT, and p53/p21/serpine SCAPs [7], and FOXO4-DRI blocks the FOXO4-p53 pathway [8]. However, dasatinib and quercetin were unable to affect doxorubicin-induced β-gal-positive senescent cells [9].
Currently, multiple companies are moving into this field, trying to find universal biomarkers and drugs that can target all senescent cell types at once. One example is Cleara Biotechnologies, whose founder, Dr. Peter De Keizer, has talked about senolytic “cocktails” and the problem of heterogeneity in senescent cell populations. We interviewed Peter back in 2018, and he touched upon this issue during our conversation:
The field still considers “senescent cells” as if they are one thing, like cancer. There is not one cancer, and there is not one senescence. This puts us on the wrong track. It’s something that I think more and more people realize, but now we actually have to identify the subgroups.
Other researchers are also working on this problem. Dr. Judith Campisi, one of the pioneering researchers of cellular senescence, is making great strides in this area [10]. In an April interview with us, she talked about how important understanding the heterogeneity of senescent cells is, and she is currently investigating this issue at the Buck Institute.
Conclusion
Senescent cells are thought to greatly contribute to aging, and researchers are currently working to develop therapies for them. However, these cells are heterogeneous, and we will need to work to find a universal biomarker of senescent cells or create the right “cocktail”.
There are many great companies working on this problem and many researchers as well. However, there are a few things you can do to help the development of senolytics and other rejuvenation biotechnologies:
- Donate to longevity funding services and help crowdfund their projects, which are working to help extend healthspan!
- One seemingly obvious one is to work as a researcher. This is a career path and a lifelong commitment.
- Be an advocate. Public support is always needed to help us get therapies to market faster, and a lack of this support is a large barrier to longevity research.
Literature
[1] Fontana, Luigi, et al. “Caloric Restriction and Cellular Senescence.” Mechanisms of Ageing and Development, vol. 176, 2018, pp. 19–23., doi:10.1016/j.mad.2018.10.005
[2] Mizushima, Noboru, et al. “Autophagy Fights Disease through Cellular Self-Digestion.” Nature, vol. 451, no. 7182, 2008, pp. 1069–1075., doi:10.1038/nature06639
[3] Autophagy Is Pro-Senescence When Seen in Close-Up, but Anti-Senescence in Long-Shot. (2017). Molecules and Cells. doi: 10.14348/molcells.2017.0151
[4] Xu, Ming, et al. “Senolytics Improve Physical Function and Increase Lifespan in Old Age.” Nature Medicine, vol. 24, no. 8, 2018, pp. 1246–1256., doi:10.1038/s41591-018-0092-9
[5] Cotter, M. A., Florell, S. R., Leachman, S. A., & Grossman, D. (2007). Absence of Senescence-Associated β-Galactosidase Activity in Human Melanocytic Nevi In Vivo. Journal of Investigative Dermatology, 127(10), 2469-2471. doi:10.1038/sj.jid.570090
[6] Fang, J., Yang, J., Wu, X., Zhang, G., Li, T., Wang, X., . . . Wang, L. (2018). Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell, 17(4). doi:10.1111/acel.12765
[7] Kirkland, J. L., & Tchkonia, T. (2017). Cellular Senescence: A Translational Perspective. EBioMedicine, 21, 21-28. doi:10.1016/j.ebiom.2017.04.013
[8] Bourgeois, B., & Madl, T. (2018). Regulation of cellular senescence via the FOXO4-p53 axis. FEBS Letters, 592(12), 2083-2097. doi:10.1002/1873-3468.13057
[9] Kovacovicova, K., Skolnaja, M., Heinmaa, M., Mistrik, M., Pata, P., Pata, I., . . . Vinciguerra, M. (2018). Senolytic Cocktail Dasatinib Quercetin (D Q) Does Not Enhance the Efficacy of Senescence-Inducing Chemotherapy in Liver Cancer. Frontiers in Oncology, 8. doi:10.3389/fonc.2018.00459
[10] Hernandez-Segura, Alejandra, et al. “Unmasking Transcriptional Heterogeneity in Senescent Cells.” Current Biology, vol. 27, no. 17, 2017, doi:10.1016/j.cub.2017.07.033
