Researchers publishing in Aging Cell have investigated the biology of skin cells taken from people who don’t produce the senescence-related compound p16.
A necessary evil
The aging community has published a lot of papers on p16INK4a (p16) and its SASP-associated dangers, as excessive SASP production is a key driver of aging. However, p16 is a protein that must be coded for by the genome, so what happens if a mutation deprives that gene (CDKN2A) of function? There is already a name for this condition: familial melanoma syndrome (FMS) [1], and it leads to both melanoma and pancreatic cancer [2].
The relationship beween senescence and cancer is well-known. While excessive amounts of senescence can drive cancer, it serves a protective function under normal circumstances [3]. As cellular senescence is highly heterogenous, the removal of one of its compounds affects some cells more than others. As expected, correlating with its associated cancers, CDKN2A mutations primarily affect the skin.
While previous work has been done to investigate what such mutations do, that research is somewhat dated [4]. These researchers decided to take a modern look at the problem, investigating skin cells taken from people with CDKN2A mutations and seeing how they behave.
The benefits of less p16 don’t outweigh the risks
This study used cells derived from 16 patients aged 18 to 68 recruited in London. The majority of these patients had missense mutations that reduced the binding ability of the created proteins. These cells did not produce no p16 at all; rather, compared to healthy controls, the number of p16-expressing cells was the same, but the amount of this protein in each cell was significantly reduced. While there were only three male patients, there were no sex differences discovered. Unlike the control group, older people with these FMS mutations did not have more p16 than similar younger people did.
Pigment-producing melanocytes were found to be more prone to DNA damage than skin fibroblasts in both the control and FMS groups. Interestingly, the FMS group had slightly less senescence-related DNA damage than the control group, as measured by the co-location of the damage marker H2AX with telomeres. This was particularly noticeable in the melanocytes. Also interestingly, cellular proliferation, as measured by the marker ki67, was not different in skin cells between the groups.
Dermal fibroblasts could be driven senescent by chemicals or radiation. Under both methods, this senescence occurred through the p21 pathway in the FMS group, while the control group used p16. However, melanocytes were not able to produce as much p21; they are more reliant on the p16 pathway, which corroborates previous research [5].
When left to replicate themselves into senescence, fibroblasts derived from FMS patients did go senescent over time, but they divided more and for longer, even when the cells were derived from older people. Replicative senescence occurred in all of the normal cells in less than a year; all of the FMS cells took longer than a year to become senescent. The cells still accumulated some DNA damage as measured by H2AX; it simply did not stop them from proliferating as quickly.
This was accompanied by less immune activity. The number of active immune cells, including lymphocytes and T cells, was significantly less in the skin of FMS patients than in the control group. These immune cells, isolated and examined, were found to behave similarly; it was the lack of SASP expression that discouraged them from appearing in the skin at normal levels in the FMS group.
In total, while a lack of p16 appears to have significant benefits, none of them outweigh the increased risk of cancer. Therefore, anyone developing a therapy that involves affecting the SASP, or anyone seeking a drug that reduces the SASP, should keep research such as this in mind.
Literature
[1] Potrony, M., Badenas, C., Aguilera, P., Puig-Butille, J. A., Carrera, C., Malvehy, J., & Puig, S. (2015). Update in genetic susceptibility in melanoma. Annals of translational medicine, 3(15).
[2] Mize, D. E., Bishop, M., Resse, E., & Sluzevich, J. (2009). Cancer Syndromes.
[3] Campisi, J. (2013). Aging, cellular senescence, and cancer. Annual review of physiology, 75(1), 685-705.
[4] Sviderskaya, E. V., Gray-Schopfer, V. C., Hill, S. P., Smit, N. P., Evans-Whipp, T. J., Bond, J., … & Bennett, D. C. (2003). p16/cyclin-dependent kinase inhibitor 2A deficiency in human melanocyte senescence, apoptosis, and immortalization: possible implications for melanoma progression. Journal of the National Cancer Institute, 95(10), 723-732.
[5] Sviderskaya, E. V., Hill, S. P., Evans-Whipp, T. J., Chin, L., Orlow, S. J., Easty, D. J., … & Bennett, D. C. (2002). p16Ink4a in melanocyte senescence and differentiation. Journal of the National Cancer Institute, 94(6), 446-454.
