SnapShot: Cellular Senescence in Pathophysiology

SnapShot: Cellular Senescence in Pathophysiology Ricardo Iván Martínez-Zamudio, Lucas Robinson, Pierre-François Roux, and Oliver Bischof INSERM, U993, 75015 Paris, France; Equipe Labellisée Fondation ARC pour la recherche sur le cancer, 94803 Villejuif, France; Institut Pasteur, Molecular and Cellular Biology of Cellular Senescence and Age-Related Pathologies Group, Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection, 75015 Paris, France Immune surveillance Cellular plasticity/ tissue regeneration

Development

Tumor suppression

Recruitment

Autocrine loop

SASP Cellular plasticity/tissue regeneration

Lysosomal activity

Senescent cell

Tumor suppression

Paracrine senescence

Accumulation of senescent cells

SASP

Aging

Age-related pathologies Cardiovascular diseases

Diabetes

Tumor promotion

Tissue dysfunction

Alzheimers

Osteoporosis

1044 Cell 170, August 24, 2017 © 2017 Elsevier Inc.  DOI http://dx.doi.org/10.1016/j.cell.2017.08.025

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SnapShot: Cellular Senescence in Pathophysiology Ricardo Iván Martínez-Zamudio, Lucas Robinson, Pierre-François Roux, and Oliver Bischof INSERM, U993, 75015 Paris, France; Equipe Labellisée Fondation ARC pour la recherche sur le cancer, 94803 Villejuif, France; Institut Pasteur, Molecular and Cellular Biology of Cellular Senescence and Age-Related Pathologies Group, Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection, 75015 Paris, France

Cellular Senescence in (Patho)physiology and Aging Cellular senescence plays important roles during development, modulation of the (pre)cancerous state, and reprogramming/regeneration and is implicated in aging and age-related pathologies. In many instances, senescent cells exert their effects through the senescence associated secretory phenotype (SASP). Development Senescent cells have been observed in transient developmental structures, including the mesonephros, the apical ectodermal ridge (AER), the endolymphatic sac, and the neural roof plate, where they are thought to facilitate tissue growth and patterning, after which they are cleared by macrophages through a SASP-dependent mechanism. Cellular Plasticity The SASP enhances cellular plasticity and tissue regeneration in the context of senescence induced by cellular reprograming and oncogene induced senescence (OIS). These processes are generally completed with the removal of senescent cells by the immune system. Cancer Senescence is a potent, cell-autonomous tumor-suppressor mechanism effectively arresting the proliferation of pre-cancerous cells. Through the SASP, it further limits tumorigenic risk, cell non-autonomously, via paracrine senescence and immune surveillance. However, many SASP factors secreted by senescent cells can promote tumor development in vivo and malignant phenotypes such as proliferation and invasiveness in cell culture models. Thus, the role of senescence in cancer is time- and contextdependent. Aging and Age-Related Pathologies Diverse tissues of aging organisms accumulate CDNK2A-expressing senescent cells, which can compromise tissue function by loss of structural integrity and/or depletion of tissue-specific stem cell pools, thus contributing to age-related pathology and morbidity. Remarkably, depletion of CDKN2A-expressing cells in mice promotes tissue fitness and prolongs lifespan. Perspective It is becoming increasingly clear that senescence cannot be treated as a single-cell fate. Rather, it is a collection of phenotypes that share certain key features but otherwise are specific to the triggering stimulus and follow specific kinetics. As such, it is likely that these specific senescence programs are reflected in the physiological and pathological consequences of the senescence phenotype. Collectively, our present knowledge suggests that the senescence phenotype has its evolutionary origins in tissue regeneration and has been co-opted successively to other physiological processes. Finally, senescence therapies hold great potential to substantially improve health-span. ACKNOWLEDGMENTS This work was supported by grants from ANR-BMFT, Fondation ARC pour la recherche sur le Cancer, Association La Ligue National Contre le Cancer LNCC, INSERM, and the National Cancer Institute of the National Institutes of Health under Award Number R01CA136533. R.I.M.-Z. is a member of the Mexican National Investigator System (SNI). O.B. is a CNRS fellow. REFERENCES Acosta, J.C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J.P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013). Nat. Cell Biol. 15, 978–990. Baker, D.J., Childs, B.G., Durik, M., Wijers, M.E., Sieben, C.J., Zhong, J., Saltness, R.A., Jeganathan, K.B., Verzosa, G.C., Pezeshki, A., et al. (2016). Nature 530, 184–189. Dörr, J.R., Yu, Y., Milanovic, M., Beuster, G., Zasada, C., Däbritz, J.H.M., Lisec, J., Lenze, D., Gerhardt, A., Schleicher, K., et al. (2013). Nature 501, 421–425. Kuilman, T., Michaloglou, C., Mooi, W.J., and Peeper, D.S. (2010). Genes Dev. 24, 2463–2479. Muñoz-Espín, D., and Serrano, M. (2014). Nat. Rev. Mol. Cell Biol. 15, 482–496. Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M.C., Morton, J.P., Sansom, O.J., Zender, L., and Keyes, W.M. (2017). Genes Dev. 31, 1–12. Xue, W., Zender, L., Miething, C., Dickins, R.A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., and Lowe, S.W. (2007). Nature 445, 656–660.

1044.e1 Cell 170, August 24, 2017 © 2017 Elsevier Inc.  DOI http://dx.doi.org/10.1016/j.cell.2017.08.025