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Cellular Senescence: Putting the Paradoxes in Perspective Judith Campisi1,2

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Cellular Senescence: Putting the Paradoxes in Perspective Judith Campisi1,2 This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright Author's personal copy Available online at www.sciencedirect.com Cellular senescence: putting the paradoxes in perspective Judith Campisi1,2 Cellular senescence arrests the proliferation of potential cancer Under some circumstances, senescent cells can promote cells, and so is a potent tumor suppressive mechanism, akin to tumor progression, in obvious and apparent contradiction apoptosis. Or is it? Why did cells evolve an anti-cancer to its being tumor suppressive. And under other circum- mechanism that arrests, rather than kills, would-be tumor cells? stances, senescent cells appear to aid tissue repair. Emer- Recent discoveries that senescent cells secrete growth factors, ging data now provide a framework for understanding proteases and cytokines provide a shifting view—from the strikingly different consequences of cellular senes- senescence as a cell autonomous suppressor of tumorigenesis cence, and suggest strategies for harnessing the benefits to senescence as a means to mobilize the systemic and local of this process, while mitigating its potentially deleterious tissue milieu for repair. In some instances, this mobilization effects. benefits the organism, but in others it can be detrimental. These discoveries provide potential mechanisms by which cellular Senescent cells—in culture and in vivo senescence might contribute to the diverse, and seemingly Cell culture experiments have identified several hall- incongruent, processes of tumor suppression, tumor marks of senescent cells, which have been used to promotion, tissue repair, and aging. identify these cells in mammalian tissues. However, there Addresses is as yet no single marker or characteristic that is unique to 1 Buck Institute for Age Research, 8001 Redwood Blvd, Novato, CA senescent cells. Further, not all senescent cells express all 94945, USA possible senescence markers. Nonetheless, senescent 2 Lawrence Berkeley National Laboratory, 1 Cyclotron Rd, Berkeley, CA cells can be identified by an aggregate of phenotypes 94720, USA (Figure 1). Some prominent senescence-associated Corresponding author: Campisi, Judith ([email protected]) characteristics are: 1) The classic hallmark of cellular senescence is an Current Opinion in Genetics & Development 2011, 21:107–112 essentially irreversible growth arrest, generally in This review comes from a themed issue on response to potentially oncogenic stimuli [2]. The Genetic and cellular mechanisms of oncogenesis irreversibility of the arrest – and fact that senescence is Edited by Chris Marshall and Karen Vousden an oncogenic stress response – distinguish senescent cells from quiescent or terminally differentiated cells. Available online 17th November 2010 2) A potent inducer of senescence is (epi)genomic stress, 0959-437X/$ – see front matter which can result from direct DNA damage, dysfunc- # 2010 Elsevier Ltd. All rights reserved. tional telomeres, disrupted chromatin, or strong mitogenic signals, such as those caused by certain DOI 10.1016/j.gde.2010.10.005 oncogenes [2]. These stressors generate persistent DNA damage response (DDR) signals that emanate from stable, cytologically detectable nuclear foci [3] Introduction or DNA-SCARS (DNA segments with chromatin Cellular senescence was first formally described nearly 5 alterations reinforcing senescence) [4]. The persist- decades ago as the process that limits the proliferation ent DDR foci sustain the activity of the p53 tumor (growth) of normal human cells in culture [1]. This early suppressor [4,5], which maintains the senescence study included two prescient – but seemingly contra- growth arrest by stimulating the transcription of genes dictory – speculations. First, it speculated that the cellular that inhibit cell cycle progression [2]. changes associated with the growth arrest might reflect 3) Senescent cells generally adopt an enlarged degenerative changes that are hallmarks of organismal morphology [1], and express a senescence-associated aging. Second, it speculated that the senescence growth beta-galactosidase (SA-Bgal) activity that is cytologi- arrest might suppress the development of cancer in vivo. cally detectable in freshly fixed cells or tissues [6]. 4) Many senescent cells express p16INK4a, a cyclin- In the ensuing five decades, remarkable progress has been dependent kinase inhibitor and tumor suppressor [7]. made in understanding the causes and nature of cellular p16INK4a is an upstream activator of the pRB tumor senescence. There is now substantial evidence that the suppressor, which, in some cells, orchestrates the senescence response suppresses malignant tumorigen- formation of cytologically detectable senescence- esis, and mounting, albeit still indirect, evidence that it associated heterochromatin foci (SAHF) [8,9]. These can promote aging. Further, recent findings paint an foci silence the expression of genes that are needed for increasingly complex picture of cellular senescence. cell cycle progression. www.sciencedirect.com Current Opinion in Genetics & Development 2011, 21:107–112 Author's personal copy 108 Genetic and cellular mechanisms of oncogenesis Figure 1 Characteristics and documented presence of senescent cells. Potentially oncogenic stimuli induce cellular senescence via activation of the p53 and pRB tumor suppressor pathways. The senescent phenotype develops over several days in culture, and, depending on the type of cell and stimulus, includes expression of SA-Bgal activity and p16INK4a, development of DNA-SCARS that provide continuous DDR signals and SAHF, and the expression of a SASP. To varying extents, these senescence-associated characteristics have been used to identify senescent cells in vivo in mouse, non-human primate and human tissues. Conditions under which senescence cells have been identified in vivo include normal aging, damaged or wounded tissues, degenerative pathologies of aging, and hyperplastic, preneoplastic, and early neoplastic lesions. 5) Senescent cells that harbor DNA-SCARS secrete Do senescent cells reflect the aging process and/or the numerous cytokines, growth factors, and proteases that development of age-related pathology? Or do they play have wide-ranging autocrine and paracrine activities causative roles in aging and/or age-related disease? At [10 ]. This senescence-associated secretory pheno- present, there are no definitive answers to these ques- type (SASP), as discussed below, is key to un- tions. It has not yet been possible, for example, to derstanding many of the diverse effects attributed eliminate senescent cells and demonstrate improved tis- to senescent cells. sue function or amelioration of age-related pathology. Nonetheless, recent data suggest two mechanisms by Most division-competent cells, including some tumor which cellular senescence might actively drive aging cells, can undergo senescence when appropriately and age-related pathology. stressed [2,11]. Further, the senescence-associated characteristics and markers described above (Figure 1) First, most adult stem cells are capable of undergoing have been used to identify senescent cells in a variety of senescence, and cellular senescence may account at least mammalian tissues. So, when and where are these cells partly for the age-related decline in the number and/or found? function of certain stem cells in adult organisms [19–23]. Thus, an accumulation of senescent stem cells may Cellular senescence and aging contribute to the decline in tissue repair and regeneration The first studies of cellular senescence in vivo showed that is a hallmark of aging organisms. Second, the SASP that senescent cells increase with age (Figure 1), support- includes factors that control many vital processes within ing one of the two prescient early speculations. The tissues—cell growth, motility, and differentiation, as increase in senescent cells occurs mainly in tissues that well as tissue structure and vascularization [24,25] contain mitotically competent cells, and has now been (Table 1). Factors secreted by senescent cells might documented in many rodent, non-human primate, and therefore disrupt normal tissue structures and functions human tissues (e.g. see [6,12–14]). Moreover, senescent [26], including stem cell niches [27]. Finally, the SASP cells have been identified at sites of several degenerative also includes many potent inflammatory cytokines and age-related pathologies (Figure 1)—examples include mediators of inflammatory reactions [28,29](Table 1). atherosclerosis, renal tubulointerstitial fibrosis and This aspect of the SASP is noteworthy because a wide- glomerulosclerosis, osteoarthritis, slow healing venous spread feature of aging tissues is low-level chronic inflam- ulcers, and degenerating intervertebral discs [13,15–18]. mation, without obvious microbial infection; furthermore, Current Opinion in Genetics & Development 2011, 21:107–112
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