www.aging-us.com AGING 2021, Vol. 13, No. 13 Editorial Senescence in neurons: an open issue Jordi Bruna, Aina Calls, Victor J. Yuste Senescence and aging are two very close linked (senescence and tumorigenesis) are reinforced by the concepts, not always with clear boundaries, a situation loss of efficiency of the immune system, also affected that often induces an undifferentiated use of these terms by the aging process, in the clearance of damaged cells. and misinterpretations regarding their intercalate roles. The preferential exit route adopted by a cell in front of Outside of teleonomic hypothesis, aging can be critical damage is currently unknown or, at least, accepted as the process of functional decline of cells difficult to predict. Probably, it might depend, or be and organs over time, mechanistically induced by the influenced, by the intensity of the damage (extension progressive convergence of damage onto DNA (nuclear and velocity of instauration), by the cell cycle status of and mitochondrial), inefficiently counterbalanced by the affected cells (quiescent, proliferative or DNA repair mechanisms [1]. In contrast, senescence (or differentiated), by the effectiveness of DNA repair more accurate, aging-related senescence) is a stress mechanisms and antioxidant neutralization systems, and cellular response that constricts its onset to a more by the regenerative capacity of the affected tissue. limited time window. This cellular state was formerly So, an improvement of definitions is needed, either characterized by the stable cell cycle arrest despite through the identification of differential molecular mitogenic stimulus, and resistance to apoptosis, but now and/or metabolic signatures for each process, or by the it is also recognized that it comes along with hetero- delimitation of a ‘critical damage tolerance’ concept. geneous morphological and functional changes, and Until this is achieved, it would be more clarifying to secretion of pro-inflammatory mediators that can restrict the use of ´senescence´ for cellular processes spread this response to surrounding cells (paracrine and aging for tissues and systems. Alternatively, it senescence) [2]. could be also useful to apply a time-functional The ambiguity in the use of both concepts is furnished perspective to the use of these terms. Loss of normal by the nonscientific language meaning, and because function in a ‘short period of time’ in response to both processes share triggers (i.e., DNA damage, certain inducers, for senescence; and progressive telomeres shortening, epigenetic changes, and acquisition of the typical phenotypic response mitochondrial dysfunction), show persistent activation (persistent DNA repair pathways, proteostatic stress, of DNA Damage Response pathways, proteostatic and inflammation) without critical loss of function, for stress, and chronic low-grade inflammation, to finally aging. end in a loss-of-normal cellular or organ function. Recently, the International Cell Senescence Association Moreover, the heterogeneity in the transcriptomic defined and discussed the key molecular and cellular profile in senescence cells and the lack of specific features of senescence [2]. Despite they acknowledged markers, which depend on the inducer, the elapsed time that post-mitotic cells can acquire senescence-like until cell evaluation, and the cell type [3], along with phenotypes, their recommendations are mainly focused the controversial role about the accumulation of in dividing cells, and maintain the cell-cycle arrest as senescent cells in aging tissues as causality or one of the defining characteristics of the senescence consequence factor, set problems to stablish a clear phenotype. This feature does not fit post-mitotic terminology use, and even arise doubts upon if they differentiated cells, such as neurons. In any case, at the really are two different processes or, on the contrary, beginning of the past decade, Diana Jurk and cols. they are interconnected behaviors. identified other recognized senescence markers in Conceivably, cells cumulate DNA alterations and neurons of aged mice [4]. In the same way, we recently sustained activation of repair pathways throughout life demonstrated that the DNA damage induced by (aging), until they achieve a ‘critical damage tolerance’ platinum drugs in the cisplatin-induced peripheral that can turn out in three potential outcomes. The neuropathy does not induce apoptosis but a senescence- reactivation of programs enabled during embryogenesis like response in the dorsal root ganglia neurons. This and morphogenesis (the apoptosis’ triggering or noxious stimulus upregulates the Cdkn1a gene and its alternatively, the entry into senescence), and the protein product, increase the expression of senescence- neoplastic transformation that in turn, can be stimulated associated β-galactosidase, phospho-H2AX, nuclear by a senescent microenvironment. These outcomes factor-kappa B (NF-kB)–p65 proteins, and causes www.aging-us.com 16902 AGING cellular morphological changes, all of them typically 7. Saleh T, et al. Cancer Res. 2019; 79:1044–46. recognized as senescence hallmarks [5]. However, if https://doi.org/10.1158/0008-5472.CAN-18-3437 senescence in proliferative cells is only a set of PMID:30803994 pleiotropic cellular outcomes, defined by general state categories (such as cell-cycle arrest, the secretion status, Jordi Bruna: Neuro-Oncology Unit, Hospital Universitari de macromolecular damage, energy metabolic dys- Bellvitge-ICO L'Hospitalet (IDIBELL), Barcelona, Spain regulation, and certain epigenetic changes) without specific markers, how can we fit similar stress Correspondence: Jordi Bruna responses in neurons? What are the frontiers to Email: 35078jbe@comb.cat differentiate such stress response from those adaptive Keywords: neuron, senescence, cisplatin, neurotoxicity, physiological cellular responses? Is it necessary to chemotherapy-induced peripheral neuropathy identify signs of previous aberrant activation of Copyright: © 2021 Bruna et al. This is an open access neuronal cell cycle, as other authors report in neuro- article distributed under the terms of the Creative degenerative diseases [6], to recognize a senescence Commons Attribution License (CC BY 3.0), which permits response in neurons? Certainly, it is important to clarify unrestricted use, distribution, and reproduction in any the meaning of cellular senescence, not only for the medium, provided the original author and source are progress in the understanding of age-related and credited neurodegenerative diseases, but also for prevalent neurological complications of cancer treatment, like the Received: June 29, 2021 peripheral neuropathies and probably, the chemobrain, Published: July 14, 2021 particularly, when senolytic and senomorphic treat- ments are emerging. In addition, the full comprehension of post-mitotic senescence-like response can provide new clues about how other phenotypically senescent cells can exceptionally re-enter in the cell-cycle, such as the case of some malignant tumor cells, acquiring in this evolution, drug resistance mechanisms that raise their aggressive behavior [7]. REFERENCES 1. Schumacher B, et al. Nature. 2021; 592:695–703. https://doi.org/10.1038/s41586-021-03307-7 PMID:33911272 2. Gorgoulis V, et al. Cellular Senescence: Defining a Path Forward. Cell. 2019; 179:813–27. https://doi.org/10.1016/j.cell.2019.10.005 PMID:31675495 3. Hernandez-Segura A, et al. Curr Biol. 2017; 27:2652– 2660.e4. https://doi.org/10.1016/j.cub.2017.07.033 PMID:28844647 4. Jurk D, et al. Aging Cell. 2012; 11:996–1004. https://doi.org/10.1111/j.1474-9726.2012.00870.x PMID:22882466 5. Calls A, et al. Neuro-oncol. 2021; 23:88–99. https://doi.org/10.1093/neuonc/noaa151 PMID:32597980 6. Chauhan M, et al. Cell Death Dis. 2020; 11:441. https://doi.org/10.1038/s41419-020-2647-1 PMID:32513985 www.aging-us.com 16903 AGING