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Cellular Senescence: When Bad Things Happen to Good Cells

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Cellular Senescence: When Bad Things Happen to Good Cells REVIEWS Cellular senescence: when bad things happen to good cells Judith Campisi* and Fabrizio d’Adda di Fagagna‡ Abstract | Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing. Renewable tissue Cellular senescence was formally described more than of cellular senescence, and the evidence that it is impor- A tissue in which cell four decades ago when Hayflick and colleagues showed tant for suppressing cancer and a possible contributor proliferation is important for that normal cells had a limited ability to proliferate in to ageing. tissue repair or regeneration. culture1 (see BOX 1 for descriptions of different types Renewable tissues typically ) Senescence in an evolutionary context contain, but sometimes recruit, of senescence . These classic experiments showed that mitotic cells upon injury or cell human fibroblasts initially underwent robust cell division To understand how cellular senescence can be both bene- loss. in culture. However, gradually — over many cell doub- ficial and detrimental, and the origins of its regulation, lings — cell proliferation (used here interchangeably it is important to understand the nature of cancer and with cell growth) declined. Eventually, all cells in the the evolutionary theory of ageing. Cancer is often fatal culture lost the ability to divide. The non-dividing cells and therefore poses a major challenge to the longevity remained viable for many weeks, but failed to grow of organisms with renewable tissues. Tissue renewal is despite the presence of ample space, nutrients and essential for the viability of complex organisms such growth factors in the medium. as mammals. However, cell proliferation is essential Soon after this discovery, the finding that normal for tumorigenesis, and renewable tissues are at risk of cells do not indefinitely proliferate spawned two developing cancer2. Moreover, cancer initiates and, to important hypotheses. At the time, both were highly a large extent, progresses owing to somatic mutations3, speculative and seemingly contradictory. The first and proliferating cells acquire mutations more readily hypothesis stemmed from the fact that many cancer than non-dividing cells4. The danger that cancer posed cells proliferate indefinitely in culture. Cellular senes- to longevity was mitigated by the evolution of tumour- *Life Sciences Division, cence was proposed to be an anti-cancer or tumour- suppressor mechanisms. One such mechanism was Lawrence Berkeley suppressive mechanism. In this context, the senescence cellular senescence, which stops incipient cancer cells National Laboratory, response was considered beneficial because it protected from proliferating5–7. 1 Cyclotron Road, Berkeley, organisms from cancer, a major life-threatening disease. The environment in which cellular senescence California 94720, USA; and Buck Institute for The second hypothesis stemmed from the fact that evolved was replete with extrinsic hazards such as Age Research, 8001 tissue regeneration and repair deteriorate with age. infection, predation and starvation. Hence, organismal Redwood Boulevard, Novato, Cellular senescence was proposed to recapitulate the lifespans were relatively short owing to death from California 94945, USA. ageing, or loss of regenerative capacity, of cells in vivo. these hazards. Therefore, tumour-suppressor mecha- ‡IFOM Foundation, FIRC Institute of Molecular In this context, cellular senescence was considered nisms needed to be effective for only a relatively short Oncology, Via Adamello 16, deleterious because it contributed to decrements in interval (a few decades for humans, several months 20139 Milan, Italy. tissue renewal and function. For many years, these for mice). Should such mechanisms be deleterious e-mails: [email protected]; hypotheses were pursued more or less independ- later (for example, if the regenerative capacity were fabrizio.dadda@ifom-ieo- ently. However, as an understanding of the senescence to decline or if dysfunctional senescent cells were to campus.it doi:10.1038/nrm2233 response grew, these hypotheses coalesced, bringing accumulate), there would be little selective pressure Published online new insights to the fields of cancer and ageing. Here, to eliminate the harmful effects. Therefore, some 1 August 2007 we review recent progress in understanding the causes tumour-suppressor mechanisms can be both beneficial NatURE REVieWS | MOLECULAR CELL BIOLOGY VOLUme 8 | sePtemBER 2007 | 729 © 2007 Nature Publishing Group REVIEWS Box 1 | A hitchhiker’s guide to senescence nomenclature Mitotic cells can senesce when they encounter poten- tially oncogenic events (discussed below). When this • Senescence derives from senex, a Latin word meaning old man or old age. occurs, the cells cease proliferation (known as growth In organismal biology, senescence describes deteriorative processes that follow arrest), in essence irreversibly. They often become resis- development and maturation, and the term is used interchangeably with ageing. tant to cell-death signals (apoptosis resistance) and they 1 • The term senescence was applied to cells that ceased to divide in culture , based on acquire widespread changes in gene expression (altered the speculation that their behaviour recapitulated organismal ageing. Consequently, gene expression). Together, these features comprise the cellular senescence is sometimes termed cellular ageing or replicative senescence. senescent phenotype (FIG. 1). • Cells that are not senescent are termed pre-senescent, early passage, proliferating or, sometimes, young. Growth arrest. The hallmark of cellular senescence is an • Telomere shortening provided the first molecular explanation for why many cells inability to progress through the cell cycle. Senescent cells 61,68 cease to divide in culture . Dysfunctional telomeres trigger senescence through arrest growth, usually with a DNA content that is typical the p53 pathway. This response is often termed telomere-initiated cellular 15–18 senescence. of G1 phase, yet they remain metabolically active . Once arrested, they fail to initiate DNA replication despite • Some cells undergo replicative senescence independently of telomere adequate growth conditions. This replication failure is shortening16,53,101. This senescence is due to stress, the nature of which is poorly understood. It increases p16 expression and engages the p16–retinoblastoma protein primarily caused by the expression of dominant cell- (pRB) pathway. This response is termed stress-induced or premature senescence, cycle inhibitors (see below). In contrast to quiescence, stasis or M0 (mortality phase 0). the senescence growth arrest is essentially permanent • Certain mitogenic oncogenes or the loss of anti-mitogenic tumour-suppressor genes (in the absence of experimental manipulation) because induce senescence in normal cells83,92,93,95. This is known as oncogene-induced senescent cells cannot be stimulated to proliferate by senescence. known physiological stimuli. • Cells that do not divide indefinitely are said to have a finite or limited replicative The features and stringency of the senescence growth (or proliferative) lifespan and are (replicatively) mortal. Cells that proliferate arrest vary depending on the species and the genetic indefinitely are termed (replicatively) immortal. background of the cell. For example, most mouse fibro- • Immortal cells are not necessarily transformed (tumorigenic) cells. Although blasts senesce with a G1 DNA content, although a defect historically the terms immortalization and transformation have been used in the stress-signalling kinase MKK7 primarily induces interchangeably, the replicative lifespan of cells can be expanded indefinitely by the a G2–M arrest19. Likewise, some oncogenes (see below) expression of telomerase without the phenotypic changes that are associated with cause a fraction of cells to senesce with a DNA content malignant transformation138. that is typical of G2 phase20–22. Furthermore, tumour cells • Telomere-initiated senescence is sometimes termed M1 (mortality phase 1)153. can senesce with G2- or S-phase DNA contents. Although Some cells (for example, fibroblasts) undergo telomere-initiated senescence with few tumour cells usually proliferate indefinitely in culture, signs of genomic instability. Other cells (for example, some epithelial cells) arrest with some of them retain the ability to undergo a senescence- obvious signs of genomic instability and are termed agonescent154. like arrest, especially in response to certain anti-cancer • Human cells that escape telomere-initiated senescence (M1) or agonescence owing therapies23. Finally, human and rodent cells differ strik- to the loss of p53 function can proliferate until they enter a state that is termed crisis, ingly in the stringency of the senescence growth arrest24. mitotic catastrophe or M2 (mortality phase 2)153. This state is characterized by Like human cells, many mouse and rat cells have a finite extensive genomic instability and cell death. proliferative capacity in culture, although,
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