Cellular senescence is a process that is mainly designed to eliminate unwanted cells by inducing tissue remodelling.
In general, cellular senescence promotes tissue remodelling through three sequential processes: a stable proliferative arrest; a secretory phenotype (SASP) that recruits immune cells and modifies the extracellular matrix; and the mobilization of nearby progenitors that repopulate the tissue. We refer to this sequence of events as the senescence–clearance–regeneration model.
During normal embryonic development, cellular senescence contributes to tissue remodelling and morphogenesis by the elimination of transient structures and by regulating the relative abundance of different cell populations.
Senescence is also activated upon cellular damage as a defence mechanism. In the case of oncogenic damage, senescence limits tumour progression. Following tissue damage, senescence coordinates tissue remodelling, thereby participating in multiple pathologies, including fibrotic diseases, vascular disorders, obesity, type 2 diabetes, renal diseases and sarcopenia.
In these pathologies, cellular senescence usually has antagonistic roles. Initially, it functions to limit the fibrotic response (by inducing senescence in the damaged cells and in the activated fibroblasts), and it also triggers an immune response that clears the damaged cells. However, at advanced pathological stages, senescent cells are not efficiently removed but accumulate and contribute to aggravate the pathological manifestations.
Both pro-senescent and antisenescent approaches can be desirable depending on the therapeutic context. Pro-senescent therapies can be useful for cancer treatment and for ongoing tissue repair processes, whereas antisenescent therapies can be beneficial to eliminate the burden of senescent cells associated with stabilized fibrotic scars that accumulate during ageing or chronic damage.
Proof of principle for pro-senescent and antisenescent therapies is discussed.
Recent discoveries are redefining our view of cellular senescence as a trigger of tissue remodelling that acts during normal embryonic development and upon tissue damage. To achieve this, senescent cells arrest their own proliferation, recruit phagocytic immune cells and promote tissue renewal. This sequence of events — senescence, followed by clearance and then regeneration — may not be efficiently completed in aged tissues or in pathological contexts, thereby resulting in the accumulation of senescent cells. Increasing evidence indicates that both pro-senescent therapies and antisenescent therapies can be beneficial. In cancer and during active tissue repair, pro-senescent therapies contribute to minimize the damage by limiting proliferation and fibrosis, respectively. Conversely, antisenescent therapies may help to eliminate accumulated senescent cells and to recover tissue function.
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Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).
Campisi, J. & d'Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nature Rev. Mol. Cell Biol. 8, 729–740 (2007).
Collado, M., Blasco, M. A. & Serrano, M. Cellular senescence in cancer and aging. Cell 130, 223–233 (2007).
Collado, M. & Serrano, M. Senescence in tumours: evidence from mice and humans. Nature Rev. Cancer 10, 51–57 (2010).
Gorgoulis, V. G. & Halazonetis, T. D. Oncogene-induced senescence: the bright and dark side of the response. Curr. Opin. Cell Biol. 22, 816–827 (2010).
van Deursen, J. M. The role of senescent cells in ageing. Nature 509, 439–446 (2014).
Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper, D. S. The essence of senescence. Genes Dev. 24, 2463–2479 (2010).
Salama, R., Sadaie, M., Hoare, M. & Narita, M. Cellular senescence and its effector programs. Genes Dev. 28, 99–114 (2014).
Chicas, A. et al. Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence. Cancer Cell 17, 376–387 (2010).
Galluzzi, L. et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 19, 107–120 (2012).
Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990).
Parrinello, S. et al. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nature Cell Biol. 5, 741–747 (2003).
Passos, J. F. et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol. Syst. Biol. 6, 347 (2010).
Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nature Cell Biol. 14, 355–365 (2012).
Kim, W. Y. & Sharpless, N. E. The regulation of INK4/ARF in cancer and aging. Cell 127, 265–275 (2006).
Gil, J. & Peters, G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nature Rev. Mol. Cell Biol. 7, 667–677 (2006).
Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004).
Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999).
Bracken, A. P. et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 21, 525–530 (2007).
Velimezi, G. et al. Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer. Nature Cell Biol. 15, 967–977 (2013).
Evangelou, K. et al. The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis. Cell Death Differ. 20, 1485–1497 (2013).
Passos, J. F., Simillion, C., Hallinan, J., Wipat, A. & von Zglinicki, T. Cellular senescence: unravelling complexity. Age 31, 353–363 (2009).
Debacq-Chainiaux, F., Boilan, E., Dedessus Le Moutier, J., Weemaels, G. & Toussaint, O. p38(MAPK) in the senescence of human and murine fibroblasts. Adv. Exp. Med. Biol. 694, 126–137 (2010).
Chen, Q., Fischer, A., Reagan, J. D., Yan, L. J. & Ames, B. N. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc. Natl Acad. Sci. USA 92, 4337–4341 (1995).
Lee, A. C. et al. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J. Biol. Chem. 274, 7936–7940 (1999).
Macip, S. et al. Inhibition of p21-mediated ROS accumulation can rescue p21-induced senescence. EMBO J. 21, 2180–2188 (2002).
Sun, P. et al. PRAK is essential for ras-induced senescence and tumor suppression. Cell 128, 295–308 (2007).
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).
Alimonti, A. et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J. Clin. Invest. 120, 681–693 (2010).
Courtois-Cox, S. et al. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 10, 459–472 (2006).
Young, A. P. et al. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nature Cell Biol. 10, 361–369 (2008).
Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).
Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).
Efeyan, A. & Serrano, M. p53: guardian of the genome and policeman of the oncogenes. Cell Cycle 6, 1006–1010 (2007).
Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).
Evan, G. I. & d'Adda di Fagagna, F. Cellular senescence: hot or what? Curr. Opin. Genet. Dev. 19, 25–31 (2009).
Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).
Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).
Kuilman, T. & Peeper, D. S. Senescence-messaging secretome: SMS-ing cellular stress. Nature Rev. Cancer 9, 81–94 (2009).
Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).
Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008).
Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).
Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007).
Hoenicke, L. & Zender, L. Immune surveillance of senescent cells—biological significance in cancer- and non-cancer pathologies. Carcinogenesis 33, 1123–1126 (2012).
Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nature Cell Biol. 15, 978–990 (2013).
Nelson, G. et al. A senescent cell bystander effect: senescence-induced senescence. Aging Cell 11, 345–349 (2012).
Hubackova, S., Krejcikova, K., Bartek, J. & Hodny, Z. IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'bystander senescence'. Aging 4, 932–951 (2012).
Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013).
Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013). References 48 and 49 report for the first time that senescence is a biological process during embryogenesis, which participates in morphogenesis and tissue remodelling.
Nacher, V. et al. The quail mesonephros: a new model for renal senescence? J. Vasc. Res. 43, 581–586 (2006).
Huang, T. & Rivera-Perez, J. A. Senescence-associated beta-galactosidase activity marks the visceral endoderm of mouse embryos but is not indicative of senescence. Genesis 52, 300–308 (2014).
Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).
Fuchs, Y. & Steller, H. Programmed cell death in animal development and disease. Cell 147, 742–758 (2011).
Lindsten, T. et al. The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol. Cell 6, 1389–1399 (2000).
Ren, D. et al. BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science 330, 1390–1393 (2010).
Besancenot, R. et al. A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation. PLoS Biol. 8, e1000476 (2010).
Chuprin, A. et al. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev. 27, 2356–2366 (2013). Shows, together with reference 56, that senescence occurs in physiological processes in adult organisms, particularly, in megakaryocytes and in placental syncytiotrophoblasts. Suggests that senescence could be a general outcome of polyploidization.
Ullah, Z., Lee, C. Y., Lilly, M. A. & DePamphilis, M. L. Developmentally programmed endoreduplication in animals. Cell Cycle 8, 1501–1509 (2009).
Kopp, H. G., Hooper, A. T., Shmelkov, S. V. & Rafii, S. β-galactosidase staining on bone marrow. The osteoclast pitfall. Histol. Histopathol. 22, 971–976 (2007).
Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007).
Michaud, K. et al. Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res. 70, 3228–3238 (2010).
Thangavel, C. et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr. Relat. Cancer 18, 333–345 (2011).
Rader, J. et al. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin. Cancer Res. 19, 6173–6182 (2013).
Leonard, J. P. et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 119, 4597–4607 (2012).
Guha, M. Blockbuster dreams for Pfizer's CDK inhibitor. Nature Biotech. 31, 187 (2013).
Dickson, M. A. et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J. Clin. Oncol. 31, 2024–2028 (2013). Demonstrates, together with references 64 and 65, clinical activity of pro-senescent chemotherapy against various cancers.
Sun, Y. et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nature Med. 18, 1359–1368 (2012).
Wiemann, S. U. et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 16, 935–942 (2002).
Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). Demonstrates, for the first time, the role of senescence in limiting a fibrotic disease, in this case, chemically-induced liver fibrosis.
Borkham-Kamphorst, E. et al. The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-beta signaling. Biochim. Biophys. Acta 1843, 902–914 (2014).
Kim, K. H., Chen, C. C., Monzon, R. I. & Lau, L. F. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol. Cell. Biol. 33, 2078–2090 (2013).
Wolstein, J. M. et al. INK4a knockout mice exhibit increased fibrosis under normal conditions and in response to unilateral ureteral obstruction. Am. J. Physiol. Renal Physiol. 299, F1486–1495 (2010).
Ramakrishna, G. et al. Role of cellular senescence in hepatic wound healing and carcinogenesis. Eur. J. Cell Biol. 91, 739–747 (2012).
Kong, X. et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 56, 1150–1159 (2012).
Klein, S. et al. Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats. Lab Invest. 92, 1440–1450 (2012).
Jun, J. I. & Lau, L. F. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nature Cell Biol. 12, 676–685 (2010). Demonstrates, in an elegant and compelling manner, the role of senescence in limiting fibrosis in skin wound healing. Shows the pivotal role of CCN1 in converting wound-activated fibroblasts into senescent fibroblasts.
Jun, J. I. & Lau, L. F. Cellular senescence controls fibrosis in wound healing. Aging 2, 627–631 (2010).
Pitiyage, G. N. et al. Senescent mesenchymal cells accumulate in human fibrosis by a telomere-independent mechanism and ameliorate fibrosis through matrix metalloproteinases. J. Pathol. 223, 604–617 (2011).
Naesens, M. Replicative senescence in kidney aging, renal disease, and renal transplantation. Discov. Med. 11, 65–75 (2011).
Joosten, S. A. et al. Telomere shortening and cellular senescence in a model of chronic renal allograft rejection. Am. J. Pathol. 162, 1305–1312 (2003).
Melk, A. Senescence of renal cells: molecular basis and clinical implications. Nephrol. Dial Transplant 18, 2474–2478 (2003).
Ding, G. et al. Tubular cell senescence and expression of TGF-β1 and p21(WAF1/CIP1) in tubulointerstitial fibrosis of aging rats. Exp. Mol. Pathol. 70, 43–53 (2001).
Liu, J. et al. Accelerated senescence of renal tubular epithelial cells is associated with disease progression of patients with immunoglobulin A (IgA) nephropathy. Transl. Res. 159, 454–463 (2012).
Verzola, D. et al. Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy. Am. J. Physiol. Renal Physiol. 295, F1563–1573 (2008).
Westhoff, J. H. et al. Hypertension induces somatic cellular senescence in rats and humans by induction of cell cycle inhibitor p16INK4a. Hypertension 52, 123–129 (2008).
Clements, M. E., Chaber, C. J., Ledbetter, S. R. & Zuk, A. Increased cellular senescence and vascular rarefaction exacerbate the progression of kidney fibrosis in aged mice following transient ischemic injury. PLoS ONE 8, e70464 (2013).
Dirocco, D. et al. CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury. Am. J. Physiol. Renal Physiol. 306, F379–388 (2013).
Braun, H. et al. Cellular senescence limits regenerative capacity and allograft survival. J. Am. Soc. Nephrol. 23, 1467–1473 (2012).
Zhu, F. et al. Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS ONE 8, e74535 (2013). Demonstrates the role of senescence in limiting cardiac fibrosis after myocardial infarction and the detrimental effect of loss of p53.
Erusalimsky, J. D. Vascular endothelial senescence: from mechanisms to pathophysiology. J. Appl. Physiol. 106, 326–332 (2009).
Fyhrquist, F., Saijonmaa, O. & Strandberg, T. The roles of senescence and telomere shortening in cardiovascular disease. Nature Rev. Cardiol 10, 274–283 (2013).
Wang, J. C. & Bennett, M. Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ. Res. 111, 245–259 (2012).
Minamino, T. et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105, 1541–1544 (2002).
Holdt, L. M. et al. Expression of Chr9p21 genes CDKN2B (p15INK4b), CDKN2A (p16INK4a, 14ARF) and MTAP in human atherosclerotic plaque. Atherosclerosis 214, 264–270 (2011).
Ihling, C. et al. Topographical association between the cyclin-dependent kinases inhibitor P21, p53 accumulation, and cellular proliferation in human atherosclerotic tissue. Arterioscler Thromb. Vasc. Biol. 17, 2218–2224 (1997).
Gonzalez-Navarro, H. et al. p19ARF deficiency reduces macrophage and vascular smooth muscle cell apoptosis and aggravates atherosclerosis. J. Am. Coll. Cardiol 55, 2258–2268 (2010).
Mercer, J., Figg, N., Stoneman, V., Braganza, D. & Bennett, M. R. Endogenous p53 protects vascular smooth muscle cells from apoptosis and reduces atherosclerosis in ApoE knockout mice. Circ. Res. 96, 667–674 (2005).
Mercer, J. & Bennett, M. The role of p53 in atherosclerosis. Cell Cycle 5, 1907–1909 (2006).
Khanna, A. K. Enhanced susceptibility of cyclin kinase inhibitor p21 knockout mice to high fat diet induced atherosclerosis. J. Biomed. Sci. 16, 66 (2009).
Diez-Juan, A. & Andres, V. The growth suppressor p27Kip1 protects against diet-induced atherosclerosis. FASEB J. 15, 1989–1995 (2001).
Sanz-Gonzalez, S. M. et al. Increased p53 gene dosage reduces neointimal thickening induced by mechanical injury but has no effect on native atherosclerosis. Cardiovasc. Res. 75, 803–812 (2007).
Hayashi, T. et al. Endothelial cellular senescence is inhibited by liver X receptor activation with an additional mechanism for its atheroprotection in diabetes. Proc. Natl Acad. Sci. USA 111, 1168–1173 (2014).
Sharpless, N. E. & DePinho, R. A. How stem cells age and why this makes us grow old. Nature Rev. Mol. Cell Biol. 8, 703–713 (2007).
Jeck, W. R., Siebold, A. P. & Sharpless, N. E. Review: a meta-analysis of GWAS and age-associated diseases. Aging Cell 11, 727–731 (2012).
Liu, Y. et al. INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis. PLoS ONE 4, e5027 (2009).
Visel, A. et al. Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 464, 409–412 (2010).
Kuo, C. L. et al. Cdkn2a is an atherosclerosis modifier locus that regulates monocyte/macrophage proliferation. Arterioscler Thromb. Vasc. Biol. 31, 2483–2492 (2011).
Noureddine, H. et al. Pulmonary artery smooth muscle cell senescence is a pathogenic mechanism for pulmonary hypertension in chronic lung disease. Circ. Res. 109, 543–553 (2011).
Mizuno, S. et al. p53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 300, L753–761 (2011).
Mouraret, N. et al. Activation of lung p53 by Nutlin-3a prevents and reverses experimental pulmonary hypertension. Circulation 127, 1664–1676 (2013).
Geiger, H., de Haan, G. & Florian, M. C. The ageing haematopoietic stem cell compartment. Nature Rev. Immunol. 13, 376–389 (2013).
Alder, J. K. et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc. Natl Acad. Sci. USA 105, 13051–13056 (2008).
Armanios, M. Y. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007).
Chilosi, M., Carloni, A., Rossi, A. & Poletti, V. Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema. Transl. Res. 162, 156–173 (2013).
Aoshiba, K., Tsuji, T. & Nagai, A. Bleomycin induces cellular senescence in alveolar epithelial cells. Eur. Respir. J. 22, 436–443 (2003).
Aoshiba, K. et al. Senescence-associated secretory phenotype in a mouse model of bleomycin-induced lung injury. Exp. Toxicol. Pathol. 65, 1053–1062 (2013).
Minagawa, S. et al. Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-β-induced senescence of human bronchial epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 300, L391–401 (2011).
Hecker, L. et al. Reversal of persistent fibrosis in aging by targeting nox4-nrf2 redox imbalance. Sci. Transl Med. 6, 231ra47 (2014). Shows that senescence aggravates lung fibrosis through a mechanism that involves NOX4-mediated ROS. Reports the proof of principle that chemical inhibitors of NOX4 can revert lung fibrosis in mice.
Shivshankar, P. et al. Caveolin-1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice. Am. J. Respir. Cell. Mol. Biol. 47, 28–36 (2012).
Lv, X. X. et al. Rupatadine protects against pulmonary fibrosis by attenuating PAF-mediated senescence in rodents. PLoS ONE 8, e68631 (2013).
Gregor, M. F. & Hotamisligil, G. S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2011).
Minamino, T. et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nature Med. 15, 1082–1087 (2009). Reports on the role of senescence in the adipose tissue and its detrimental effects on metabolism.
Tchkonia, T. et al. Fat tissue, aging, and cellular senescence. Aging Cell 9, 667–684 (2010).
Markowski, D. N. et al. HMGA2 expression in white adipose tissue linking cellular senescence with diabetes. Genes Nutr. 8, 449–456 (2013).
Baker, D. J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nature Cell Biol. 10, 825–836 (2008).
Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). Demonstrates, for the first time, the beneficial effects of senescent cell removal from a progeroid mouse model.
Donath, M. Y., Dalmas, E., Sauter, N. S. & Boni-Schnetzler, M. Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell. Metab. 17, 860–872 (2013).
Sone, H. & Kagawa, Y. Pancreatic β cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia 48, 58–67 (2005).
Wang, Z., Moro, E., Kovacs, K., Yu, R. & Melmed, S. Pituitary tumor transforming gene-null male mice exhibit impaired pancreatic beta cell proliferation and diabetes. Proc. Natl Acad. Sci. USA 100, 3428–3432 (2003).
Chesnokova, V. et al. Diminished pancreatic β-cell mass in securin-null mice is caused by β-cell apoptosis and senescence. Endocrinology 150, 2603–2610 (2009).
Campaner, S. et al. Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nature Cell Biol. 12, 54–59 (2010).
Tavana, O., Puebla-Osorio, N., Sang, M. & Zhu, C. Absence of p53-dependent apoptosis combined with nonhomologous end-joining deficiency leads to a severe diabetic phenotype in mice. Diabetes 59, 135–142 (2010).
Tavana, O. & Zhu, C. Too many breaks (brakes): pancreatic β-cell senescence leads to diabetes. Cell Cycle 10, 2471–2484 (2011).
Doria, A., Patti, M. E. & Kahn, C. R. The emerging genetic architecture of type 2 diabetes. Cell. Metab. 8, 186–200 (2008).
Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443, 453–457 (2006).
Gonzalez-Navarro, H. et al. Increased dosage of Ink4/Arf protects against glucose intolerance and insulin resistance associated with aging. Aging Cell 12, 102–111 (2013).
Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014).
Cosgrove, B. D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nature Med. 20, 255–264 (2014).
Du, J. et al. Aging increases CCN1 expression leading to muscle senescence. Am. J. Physiol. Cell Physiol. 306, C28–36 (2014).
Bernet, J. D. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nature Med. 20, 265–271 (2014). Shows, together with references 137–139, that muscle stem cells undergo senescence with ageing, and reversal of senescence rescues their regenerative potential.
Iglesias-Bartolome, R. et al. mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis. Cell Stem Cell 11, 401–414 (2012).
Wei, H. et al. Changes and function of circulating endothelial progenitor cells in patients with cerebral aneurysm. J. Neurosci. Res. 89, 1822–1828 (2011).
Fukazawa, R. et al. Coronary artery aneurysm induced by Kawasaki disease in children show features typical senescence. Circ. J. 71, 709–715 (2007).
Yasuno, K. et al. Genome-wide association study of intracranial aneurysm identifies three new risk loci. Nature Genet. 42, 420–425 (2010).
Golledge, J. & Kuivaniemi, H. Genetics of abdominal aortic aneurysm. Curr. Opin. Cardiol 28, 290–296 (2013).
Liton, P. B. et al. Cellular senescence in the glaucomatous outflow pathway. Exp. Gerontol. 40, 745–748 (2005).
Ozel, A. B. et al. Genome-wide association study and meta-analysis of intraocular pressure. Hum. Genet. 133, 41–57 (2014).
Ng, S. K., Casson, R. J., Burdon, K. P. & Craig, J. E. Chromosome 9p21 primary open-angle glaucoma susceptibility locus: a review. Clin. Experiment Ophthalmol. 42, 25–32 (2014).
Bhat, R. et al. Astrocyte senescence as a component of Alzheimer's disease. PLoS ONE 7, e45069 (2012).
Chinta, S. J. et al. Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson's disease? J. Intern. Med. 273, 429–436 (2013).
Hamshere, M. L. et al. Genome-wide linkage analysis of 723 affected relative pairs with late-onset Alzheimer's disease. Hum. Mol. Genet. 16, 2703–2712 (2007).
Zuchner, S. et al. Linkage and association study of late-onset Alzheimer disease families linked to 9p21.3. Ann. Hum. Genet. 72, 725–731 (2008).
Fischer, B. M. et al. Increased expression of senescence markers in cystic fibrosis airways. Am. J. Physiol. Lung Cell. Mol. Physiol. 304, L394–400 (2013).
Sohn, J. J. et al. Macrophages, nitric oxide and microRNAs are associated with DNA damage response pathway and senescence in inflammatory bowel disease. PLoS ONE 7, e44156 (2012).
Martin, J. A., Brown, T. D., Heiner, A. D. & Buckwalter, J. A. Chondrocyte senescence, joint loading and osteoarthritis. Clin. Orthop. Relat. Res. 427, S96–103 (2004).
Price, J. S. et al. The role of chondrocyte senescence in osteoarthritis. Aging Cell 1, 57–65 (2002).
Roberts, S., Evans, E. H., Kletsas, D., Jaffray, D. C. & Eisenstein, S. M. Senescence in human intervertebral discs. Eur. Spine J. 15 (Suppl. 3), S312–316 (2006).
Le Maitre, C. L., Freemont, A. J. & Hoyland, J. A. Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration. Arthritis Res. Ther. 9, R45 (2007).
Mishima, K. et al. Senescence-associated β-galactosidase histochemistry for the primate eye. Invest. Ophthalmol. Vis. Sci. 40, 1590–1593 (1999).
Zhu, D., Wu, J., Spee, C., Ryan, S. J. & Hinton, D. R. BMP4 mediates oxidative stress-induced retinal pigment epithelial cell senescence and is overexpressed in age-related macular degeneration. J. Biol. Chem. 284, 9529–9539 (2009).
Salazar, L. M. & Herrera, A. M. Fibrotic response of tissue remodeling in COPD. Lung 189, 101–109 (2011).
Tsuji, T., Aoshiba, K. & Nagai, A. Cigarette smoke induces senescence in alveolar epithelial cells. Am. J. Respir. Cell. Mol. Biol. 31, 643–649 (2004).
Tsuji, T., Aoshiba, K. & Nagai, A. Alveolar cell senescence exacerbates pulmonary inflammation in patients with chronic obstructive pulmonary disease. Respiration 80, 59–70 (2010).
Fitzner, B. et al. Senescence determines the fate of activated rat pancreatic stellate cells. J. Cell. Mol. Med. 16, 2620–2630 (2012).
Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005).
Nardella, C., Clohessy, J. G., Alimonti, A. & Pandolfi, P. P. Pro-senescence therapy for cancer treatment. Nature Rev. Cancer 11, 503–511 (2011).
Collado, M. & Serrano, M. The power and the promise of oncogene-induced senescence markers. Nature Rev. Cancer 6, 472–476 (2006).
Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).
Kurz, D. J., Decary, S., Hong, Y. & Erusalimsky, J. D. Senescence-associated β-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J. Cell Sci. 113, 3613–3622 (2000).
Young, A. R. et al. Autophagy mediates the mitotic senescence transition. Genes Dev. 23, 798–803 (2009).
Georgakopoulou, E. A. et al. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging 5, 37–50 (2013).
Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716 (2003).
Zhang, R. et al. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev. Cell 8, 19–30 (2005).
Di Micco, R. et al. Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer. Nature Cell Biol. 13, 292–302 (2011).
Scaffidi, P. & Misteli, T. Lamin A-dependent nuclear defects in human aging. Science 312, 1059–1063 (2006).
Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005).
Shimi, T. et al. The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev. 25, 2579–2593 (2011).
Freund, A., Laberge, R. M., Demaria, M. & Campisi, J. Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 23, 2066–2075 (2012).
Herbig, U., Ferreira, M., Condel, L., Carey, D. & Sedivy, J. M. Cellular senescence in aging primates. Science 311, 1257 (2006).
Wang, C. et al. DNA damage response and cellular senescence in tissues of aging mice. Aging Cell 8, 311–323 (2009).
Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
Freund, A., Orjalo, A. V., Desprez, P. Y. & Campisi, J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol. Med. 16, 238–246 (2010).
Naylor, R. M., Baker, D. J. & van Deursen, J. M. Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin. Pharmacol. Ther. 93, 105–116 (2013).
Campisi, J. Aging, tumor suppression and cancer: high wire-act! Mech. Ageing Dev. 126, 51–58 (2005).
Rajagopalan, S. & Long, E. O. Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling. Proc. Natl Acad. Sci. USA 109, 20596–20601 (2012)
Dorr, J. R. et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421–425 (2013).
D.M.-E. has been funded by the Juan de la Cierva Programme. Work in the laboratory of M.S. is funded by the Spanish National Cancer Research Centre (CNIO), by grants from the European Research Council (Advanced ERC Grant), the Framework Programme 7 of the European Union (RISK-IR), the Spanish Ministry of Economy (SAF), the Regional Government of Madrid, the Botín Foundation, the Ramón Areces Foundation and the AXA Foundation.
The authors declare no competing financial interests.
Refers to a mode of signalling in which the cell responding to a signalling molecule is near the cell secreting the molecule.
Activation of cellular receptors by ligands produced by the same cell.
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Muñoz-Espín, D., Serrano, M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15, 482–496 (2014). https://doi.org/10.1038/nrm3823
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