Senescence is a form of cell-cycle arrest linked to tumor suppression and aging. However, it remains controversial and has not been documented in nonpathologic states.
Two studies published in Cell describe senescence as a normal and critical process during embryogenesis. They attribute a completely new and unexpected role to this process, which was always linked to aging and cancer.
“For the first time, these studies clearly show that senescence is a programmed developmental mechanism. This new description helps us to understand the role and significance of senescence as a normal cellular process”, explains Bill Keyes, head of the Mechanisms of Cancer and Aging laboratory at the CRG. “Our work demonstrates that in the embryo, the senescent cells are required, and through their normal secretory function, instruct tissue growth and patterning”, adds Dr. Keyes.
Keyes and collaborators describe senescence as a fundamental part of the biology of two major signalling centres in the embryo that helps to control normal limb and nervous system development. Likewise, the CNIO study led by Manuel Serrano, and postdoctoral researcher Daniel Munoz-Espin, identified identical processes in two other tissues, in the developing kidneys and ear.
Both studies show how the coordinated removal of senescent cells by macrophages plays a key role in the remodelling of the developing tissues, a process that is required for normal patterning. Interestingly, the tissues where the researchers describe the occurrence of senescence are among those most frequently affected by congenital birth defects, suggesting that an investigation of the mechanisms that regulate senescence in the embryo might help to explain the causes of some developmental abnormalities.
Thanks to this new perspective of senescence, the scientists suggest that senescence related to aging and cancer is an evolutionary adaptation of a developmental mechanism. “Hopefully, with the identification of senescence in a normal setting in the embryo, this will allow us to identify new mediators and biomarkers of senescence in future studies” says Mekayla Storer, a PhD student in the CRG and first author on the study, adding that “these findings change the way we understood senescence in the past, and give us novel important information to tackle cancer and aging”.
Embryonic senescent cells are nonproliferative and share features with oncogene-induced senescence (OIS), including expression of p21, p15, and mediators of the senescence-associated secretory phenotype (SASP). Interestingly, mice deficient in p21 have defects in embryonic senescence, AER maintenance, and patterning. Surprisingly, the underlying mesenchyme was identified as a source for senescence instruction in the AER, whereas the ultimate fate of these senescent cells is apoptosis and macrophage-mediated clearance. We propose that senescence is a normal programmed mechanism that plays instructive roles in development, and that OIS is an evolutionarily adapted reactivation of a developmental process.