Researchers commonly determine the presence of senescent cells through the use of the p16ink4a (p16) and β-galactosidase biomarkers. Senescent cells are known to exhibit both of these biomarkers, but it seems that they are not the only cells that do this, and the concern is that therapies that target these biomarkers may also be removing cells that are not senescent.
A study was published recently, and it shows that some cells that are not necessarily senescent share these two biomarkers [3]. This new study is by the same research team that investigated cellular senescence in the immune system last year with a focus on macrophages [4].
So, could this mean that older people have a partially senescent macrophage population, or does it mean that these cells are not harmful and just exhibit some of the same markers that senescent cells do?
This new study suggests that the latter may be the case, although it has not yet been determined if the macrophages exhibiting these commonly shared biomarkers are harmful.
So is this an issue for senolytics?
Fortunately, we are aware of no research group developing senolytics that target β-galactosidase. The use of β-galactosidase is limited to assessing the presence and numbers of senescent cells but is not actually the target of therapies.
However, p16 is a potential issue, as at least one company, Oisin Biotechnology (we interviewed its CEO here) does use this biomarker to target senescent cells. Its approach uses target genes and their level of expression in order to target cells for destruction. Oisin will no doubt be doing its due diligence in determining the effect of removing p16-positive macrophages as part of its ongoing development process.
That said, one of the first proof-of-concept studies used p16 as the target for senescent cell removal, and positive health results were seen [5]. So, it is worth bearing in mind that, in this case, p16 cells, regardless of the source, were removed in a broad stroke in this study, yet positive benefits were observed.
Therefore, it may be that case that removing them is not a significant problem, and earlier studies strongly suggest that removing senescent cells is beneficial, even taking into account the risk of removing non-senescent cells.
Conclusion
The paper’s authors conclude that the importance of senescent cells in the aging process and removing senescent cells is not in question, and their findings do not suggest that developing senolytics is a bad idea.
The points raised here are that we need to better refine how we identify senescent cells and that we need to improve our understanding of how to determine if a cell is senescent. Therefore, we need to develop better biomarkers to identify senescent cells.
Considering the research community’s intense focus on senescent cells and the considerable funding behind the development of senolytics, those gaps in our knowledge will likely not remain in place for long.
Given the pace of progress in this particular area, it is reasonable to believe that such issues may be resolved in the near future once more studies are concluded.
Literature
[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
[2] van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446.
[3] Hall, B. M., Balan, V., Gleiberman, A. S., Strom, E., Krasnov, P., Virtuoso, L. P., … & Leonova, K. I. (2017). p16 (Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging.
[4] Hall, B. M., Balan, V., Gleiberman, A. S., Strom, E., Krasnov, P., Virtuoso, L. P., … & Leonova, K. (2016). Aging of mice is associated with p16 (Ink4a)-and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging (Albany NY), 8(7), 1294.
[5] Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., … & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232.
