Until recently, the DNA damage response (DDR) had been shown to induce the Senescence-associated Secretory Phenotype (SASP) only in proliferating cells, such as fibroblasts or epithelial cells.(1) SASP can lead to morphological changes and induction of the release of interleukins, inflammatory cytokines, and mitochondrial dysfunction which, positively, arrests the cell’s proliferation. However, cells exhibiting SASP can affect the microenvironment of neighboring, normal cells inducing a senescent phenotype .(1,2)
In a study conducted by the lab of Jurk, et al, comparing new and old (4 months and 32 months, respectively) Purkinje and cortical neurons of mice, DDR was visualized with immunohistochemical staining antibodies against 53BP1 in both types of neurons from old mice. Immunofluorescence staining for DNA damage foci, immunohistochemical staining for the oxidative stress marker 4-HNE, the pro-inflammatory cytokine IL-6, heterochromatin associated histone, and sen-β-Gal (general marker of the senescent phenotype), further showed DDR in old mice.(2) By visually observing high ROS production and oxidative damage, increase in IL-6, heterochromatinization, and sen-β-Gal, it was shown that SASP is present in postmitotic cells, like mature neurons, termed amitosenescensce.
Unfortunately, thus far the biomarkers overlap between both amitosenescent and senescent cells. However, the work by Jurk, et al has found that the SASP-like phenotype is initiated by DDR related signaling through p21 (CDKN1A), a major target of tumor protein p53.(3) Previously, p53 has been linked to SASP induction, however further investigation into whether both proliferating and postmitotic cells are signaled through p21 could lead to differentiation of biomarkers.
References:
1. Coppé, J., Desprez, P., Krtolica, A., and Campisi, J. The Senescence-associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annual Rev Pathol. 2010, 5, 99-118
2. Jurk, D.; Wang, C.; Miwa, S.; Maddick, M.; Korolchuk, V.; Tsolou, A.; Gonos, E.S.; Thrasivoulou, C.; Saffrey, M.J.; Cameron, K.; et al. Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 2012, 11, 996–1004
3. Wengerodt, D., Schmeer, C., Witte, O., and Kretz, A. Amitosenescence and Pseudoimitosenescence: Putative New Players in the Aging Process. Cells 2019, 8, 1546-1554
Shubhankar Kulkarni Aug 21, 2020