Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related disease, and it is an attractive target for therapeutic exploitation. A wealth of information about senescence in cultured cells has been acquired over the past half century; however, senescence in living organisms is poorly understood, largely because of technical limitations relating to the identification and characterization of senescent cells in tissues and organs. Furthermore, newly recognized beneficial signaling functions of senescence suggest that indiscriminately targeting senescent cells or modulating their secretome for anti-aging therapy may have negative consequences. Here we discuss current progress and challenges in understanding the stressors that induce senescence in vivo, the cell types that are prone to senesce, and the autocrine and paracrine properties of senescent cells in the contexts of aging and age-related diseases as well as disease therapy.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Flatt, T. A new definition of aging? Front. Genet. 3, 148 (2012).
Ungewitter, E. & Scrable, H. Antagonistic pleiotropy and p53. Mech. Ageing Dev. 130, 10–17 (2009).
Giaimo, S. & d'Adda di Fagagna, F. Is cellular senescence an example of antagonistic pleiotropy? Aging Cell 11, 378–383 (2012).
Sharpless, N.E. et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86–91 (2001).
Sager, R. Senescence as a mode of tumor suppression. Environ. Health Perspect. 93, 59–62 (1991).
Baker, D.J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).
Baker, D.J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat. Cell Biol. 10, 825–836 (2008).
Baker, D.J. et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat. Genet. 36, 744–749 (2004).
Hoenicke, L. & Zender, L. Immune surveillance of senescent cells—biological significance in cancer- and non-cancer pathologies. Carcinogenesis 33, 1123–1126 (2012).
Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008).
Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007).
Kang, T.W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).
Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).
Muñoz-Espín, 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).
Hayflick, L. & Moorhead, P.S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).
Alcorta, D.A. et al. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc. Natl. Acad. Sci. USA 93, 13742–13747 (1996).
Takahashi, A. et al. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat. Cell Biol. 8, 1291–1297 (2006).
Beauséjour, C.M. et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 22, 4212–4222 (2003).
Shaulian, E. et al. The mammalian UV response: c-Jun induction is required for exit from p53-imposed growth arrest. Cell 103, 897–907 (2000).
Webley, K. et al. Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Mol. Cell. Biol. 20, 2803–2808 (2000).
Qu, K. et al. [Cisplatin induces cell cycle arrest and senescence via upregulating P53 and P21 expression in HepG2 cells.]. Nan Fang Yi Ke Da Xue Xue Bao 33, 1253–1259 (2013).
Ge, H. et al. Dexamethasone reduces sensitivity to cisplatin by blunting p53-dependent cellular senescence in non-small cell lung cancer. PLoS ONE 7, e51821 (2012).
Maejima, Y., Adachi, S., Ito, H., Hirao, K. & Isobe, M. Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage. Aging Cell 7, 125–136 (2008).
Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).
Chen, Z. et al. Differential p53-independent outcomes of p19(Arf) loss in oncogenesis. Sci. Signal. 2, ra44 (2009).
Lazzerini Denchi, E., Attwooll, C., Pasini, D. & Helin, K. Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland. Mol. Cell. Biol. 25, 2660–2672 (2005).
Cipriano, R. et al. TGF-beta signaling engages an ATM-CHK2-p53-independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells. Proc. Natl. Acad. Sci. USA 108, 8668–8673 (2011).
van Deursen, J.M. The role of senescent cells in ageing. Nature 509, 439–446 (2014).
Johmura, Y. et al. Necessary and sufficient role for a mitosis skip in senescence induction. Mol. Cell 55, 73–84 (2014).
Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014).
Martínez, P. & Blasco, M.A. Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nat. Rev. Cancer 11, 161–176 (2011).
Sousa-Victor, P., Perdiguero, E. & Munoz-Canoves, P. Geroconversion of aged muscle stem cells under regenerative pressure. Cell Cycle 13, 3183–3190 (2014).
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).
Hampel, B. et al. Apoptosis resistance of senescent human fibroblasts is correlated with the absence of nuclear IGFBP-3. Aging Cell 4, 325–330 (2005).
Ryu, S.J., Oh, Y.S. & Park, S.C. Failure of stress-induced downregulation of Bcl-2 contributes to apoptosis resistance in senescent human diploid fibroblasts. Cell Death Differ. 14, 1020–1028 (2007).
Chen, W. et al. p53-related apoptosis resistance and tumor suppression activity in UVB-induced premature senescent human skin fibroblasts. Int. J. Mol. Med. 21, 645–653 (2008).
Pasillas, M.P. et al. Proteomic analysis reveals a role for Bcl2-associated athanogene 3 and major vault protein in resistance to apoptosis in senescent cells by regulating ERK1/2 activation. Mol. Cell. Proteomics 14, 1–14 (2015).
Gniadecki, R., Hansen, M. & Wulf, H.C. Resistance of senescent keratinocytes to UV-induced apoptosis. Cell. Mol. Biol. 46, 121–127 (2000).
Coppé, J.P. et al. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PLoS ONE 5, e9188 (2010).
Salminen, A., Kauppinen, A. & Kaarniranta, K. Emerging role of NF-kappaB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell. Signal. 24, 835–845 (2012).
Nelson, G. et al. A senescent cell bystander effect: senescence-induced senescence. Aging Cell 11, 345–349 (2012).
Karaman, M.W. et al. A quantitative analysis of kinase inhibitor selectivity. Nat. Biotechnol. 26, 127–132 (2008).
Burd, C.E. et al. Monitoring tumorigenesis and senescence in vivo with a p16(INK4a)-luciferase model. Cell 152, 340–351 (2013).
Jun, J.I. & Lau, L.F. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat. Cell Biol. 12, 676–685 (2010).
Rajagopalan, S. HLA-G-mediated NK cell senescence promotes vascular remodeling: implications for reproduction. Cell. Mol. Immunol. 11, 460–466 (2014).
Dhomen, N. et al. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell 15, 294–303 (2009).
Ness, K.K. et al. Frailty in childhood cancer survivors. Cancer 121, 1540–1547 (2015).
Marcoux, S. et al. Expression of the senescence marker p16INK4a in skin biopsies of acute lymphoblastic leukemia survivors: a pilot study. Radiat. Oncol. 8, 252 (2013).
Baker, D.J. & Sedivy, J.M. Probing the depths of cellular senescence. J. Cell Biol. 202, 11–13 (2013).
Ohanna, M. et al. Senescent cells develop a PARP-1 and nuclear factor-κB-associated secretome (PNAS). Genes Dev. 25, 1245–1261 (2011).
Freund, A., Patil, C.K. & Campisi, J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 30, 1536–1548 (2011).
Maskey, R.S. et al. Spartan deficiency causes genomic instability and progeroid phenotypes. Nat. Commun. 5, 5744 (2014).
Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009).
Kim, G. et al. The heat shock transcription factor Hsf1 is downregulated in DNA damage-associated senescence, contributing to the maintenance of senescence phenotype. Aging Cell 11, 617–627 (2012).
Cao, K. et al. Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts. J. Clin. Invest. 121, 2833–2844 (2011).
Benson, E.K., Lee, S.W. & Aaronson, S.A. Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence. J. Cell Sci. 123, 2605–2612 (2010).
Shimizu, I. et al. p53-induced adipose tissue inflammation is critically involved in the development of insulin resistance in heart failure. Cell Metab. 15, 51–64 (2012).
Minamino, T. et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat. Med. 15, 1082–1087 (2009).
Ryan, A.S. Insulin resistance with aging: effects of diet and exercise. Sports Med. 30, 327–346 (2000).
Walters, M.S. et al. Smoking accelerates aging of the small airway epithelium. Respir. Res. 15, 94 (2014).
Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004).
Gruber, H.E., Ingram, J.A., Norton, H.J. & Hanley, E.N. Jr. Senescence in cells of the aging and degenerating intervertebral disc: immunolocalization of senescence-associated beta-galactosidase in human and sand rat discs. Spine 32, 321–327 (2007).
Geng, Y.Q., Guan, J.T., Xu, X.H. & Fu, Y.C. Senescence-associated beta-galactosidase activity expression in aging hippocampal neurons. Biochem. Biophys. Res. Commun. 396, 866–869 (2010).
Yang, H.C. et al. The PPARgamma agonist pioglitazone ameliorates aging-related progressive renal injury. J. Am. Soc. Nephrol. 20, 2380–2388 (2009).
Baker, D.J., Weaver, R.L. & van Deursen, J.M. p21 both attenuates and drives senescence and aging in BubR1 progeroid mice. Cell Rep. 3, 1164–1174 (2013).
Kaszubowska, L. Telomere shortening and ageing of the immune system. J. Physiol. Pharmacol. 59 (suppl. 9), 169–186 (2008).
Titus, S. et al. Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans. Sci. Transl. Med. 5, 172ra121 (2013).
Brown, M.K. & Naidoo, N. The endoplasmic reticulum stress response in aging and age-related diseases. Front. Physiol. 3, 263 (2012).
Morin, C.L., Pagliassotti, M.J., Windmiller, D. & Eckel, R.H. Adipose tissue-derived tumor necrosis factor-alpha activity is elevated in older rats. J. Gerontol. A Biol. Sci. Med. Sci. 52, B190–B195 (1997).
Starr, M.E., Saito, M., Evers, B.M. & Saito, H. Age-associated increase in cytokine production during systemic inflammation-II: the role of IL-1beta in age-dependent IL-6 upregulation in adipose tissue. J. Gerontol. A Biol. Sci. Med. Sci. doi:10.1093/gerona/glu197 (24 October 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. Nat. Med. 20, 265–271 (2014).
Geiger, H., de Haan, G. & Florian, M.C. The ageing haematopoietic stem cell compartment. Nat. Rev. Immunol. 13, 376–389 (2013).
Lee, H.W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998).
Pricola, K.L., Kuhn, N.Z., Haleem-Smith, H., Song, Y. & Tuan, R.S. Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism. J. Cell. Biochem. 108, 577–588 (2009).
Jang, Y.C., Sinha, M., Cerletti, M., Dall'Osso, C. & Wagers, A.J. Skeletal muscle stem cells: effects of aging and metabolism on muscle regenerative function. Cold Spring Harb. Symp. Quant. Biol. 76, 101–111 (2011).
Liu, D. & Hornsby, P.J. Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res. 67, 3117–3126 (2007).
O'Connor, J.C. et al. Regulation of IGF-I function by proinflammatory cytokines: at the interface of immunology and endocrinology. Cell. Immunol. 252, 91–110 (2008).
Gong, Z. et al. Reductions in serum IGF-1 during aging impair health span. Aging Cell 13, 408–418 (2014).
Brown, O.A., Sosa, Y.E., Dardenne, M., Pleau, J. & Goya, R.G. Growth hormone-releasing activity of thymulin on pituitary somatotropes is age dependent. Neuroendocrinology 69, 20–27 (1999).
Schaap, L.A. et al. Higher inflammatory marker levels in older persons: associations with 5-year change in muscle mass and muscle strength. J. Gerontol. A Biol. Sci. Med. Sci. 64, 1183–1189 (2009).
Moellendorf, S. et al. IGF-IR signaling attenuates the age-related decline of diastolic cardiac function. Am. J. Physiol. Endocrinol. Metab. 303, E213–E222 (2012).
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).
Liton, P.B. et al. Cellular senescence in the glaucomatous outflow pathway. Exp. Gerontol. 40, 745–748 (2005).
Martin, J.A., Brown, T.D., Heiner, A.D. & Buckwalter, J.A. Chondrocyte senescence, joint loading and osteoarthritis. Clin. Orthop. Relat. Res. 427 (suppl.), S96–S103 (2004).
Zhou, X., Perez, F., Han, K. & Jurivich, D.A. Clonal senescence alters endothelial ICAM-1 function. Mech. Ageing Dev. 127, 779–785 (2006).
Thangavel, C. et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr. Relat. Cancer 18, 333–345 (2011).
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).
Kong, X. et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 56, 1150–1159 (2012).
Roos, E.M. Joint injury causes knee osteoarthritis in young adults. Curr. Opin. Rheumatol. 17, 195–200 (2005).
Loeser, R.F. Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis Cartilage 17, 971–979 (2009).
Martin, J.A., Brown, T., Heiner, A. & Buckwalter, J.A. Post-traumatic osteoarthritis: the role of accelerated chondrocyte senescence. Biorheology 41, 479–491 (2004).
Matthews, C. et al. Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress. Circ. Res. 99, 156–164 (2006).
Ferrara, A., Barrett-Connor, E. & Shan, J. Total, LDL, and HDL cholesterol decrease with age in older men and women. The Rancho Bernardo Study 1984–1994. Circulation 96, 37–43 (1997).
Wilcox, G. Insulin and insulin resistance. Clin. Biochem. Rev. 26, 19–39 (2005).
Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).
Roden, M. et al. Mechanism of free fatty acid-induced insulin resistance in humans. J. Clin. Invest. 97, 2859–2865 (1996).
Costes, S., Langen, R., Gurlo, T., Matveyenko, A.V. & Butler, P.C. β-Cell failure in type 2 diabetes: a case of asking too much of too few? Diabetes 62, 327–335 (2013).
Guo, N. et al. Short telomeres compromise beta-cell signaling and survival. PLoS ONE 6, e17858 (2011).
Sone, H. & Kagawa, Y. Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia 48, 58–67 (2005).
Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443, 453–457 (2006).
Nieto-Vazquez, I., Fernandez-Veledo, S., de Alvaro, C. & Lorenzo, M. Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle. Diabetes 57, 3211–3221 (2008).
Harder-Lauridsen, N.M. et al. Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 306, E769–E778 (2014).
Gao, D. et al. Interleukin-1beta mediates macrophage-induced impairment of insulin signaling in human primary adipocytes. Am. J. Physiol. Endocrinol. Metab. 307, E289–E304 (2014).
González-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).
Yang, T.K. et al. Davallialactone from mushroom reduced premature senescence and inflammation on glucose oxidative stress in human diploid fibroblast cells. J. Agric. Food Chem. 61, 7089–7095 (2013).
Liu, J. et al. Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling. Cell. Signal. 26, 110–121 (2014).
Mortuza, R., Chen, S., Feng, B., Sen, S. & Chakrabarti, S. High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway. PLoS ONE 8, e54514 (2013).
Kim, Y.J. et al. miR-486–5p induces replicative senescence of human adipose tissue-derived mesenchymal stem cells and its expression is controlled by high glucose. Stem Cells Dev. 21, 1749–1760 (2012).
Jialal, I. & Devaraj, S. The role of oxidized low density lipoprotein in atherogenesis. J. Nutr. 126, 1053S–1057S (1996).
Ilhan, F. & Kalkanli, S.T. Atherosclerosis and the role of immune cells. World J. Clin. Cases 3, 345–352 (2015).
Heidenreich, P.A. et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation 123, 933–944 (2011).
Salpea, K.D. & Humphries, S.E. Telomere length in atherosclerosis and diabetes. Atherosclerosis 209, 35–38 (2010).
Kawashima, S. & Yokoyama, M. Dysfunction of endothelial nitric oxide synthase and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 24, 998–1005 (2004).
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. [Contribution of vascular cell senescence to atherogenesis]. Nippon Ronen Igakkai Zasshi 45, 295–298 (2008).
Bürrig, K.F. The endothelium of advanced arteriosclerotic plaques in humans. Arterioscler. Thromb. 11, 1678–1689 (1991).
Zhang, J., Patel, J.M. & Block, E.R. Enhanced apoptosis in prolonged cultures of senescent porcine pulmonary artery endothelial cells. Mech. Ageing Dev. 123, 613–625 (2002).
Krouwer, V.J., Hekking, L.H., Langelaar-Makkinje, M., Regan-Klapisz, E. & Post, J.A. Endothelial cell senescence is associated with disrupted cell-cell junctions and increased monolayer permeability. Vasc. Cell 4, 12 (2012).
Hogg, N. & Kalyanaraman, B. Nitric oxide and lipid peroxidation. Biochim. Biophys. Acta 1411, 378–384 (1999).
Rippe, C. et al. MicroRNA changes in human arterial endothelial cells with senescence: relation to apoptosis, eNOS and inflammation. Exp. Gerontol. 47, 45–51 (2012).
Finn, A.V., Nakano, M., Narula, J., Kolodgie, F.D. & Virmani, R. Concept of vulnerable/unstable plaque. Arterioscler. Thromb. Vasc. Biol. 30, 1282–1292 (2010).
Coppé, 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).
Robert, L., Robert, A.M. & Jacotot, B. Elastin-elastase-atherosclerosis revisited. Atherosclerosis 140, 281–295 (1998).
Coppé, 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).
Minamino, T., Miyauchi, H., Yoshida, T. & Komuro, I. Endothelial cell senescence in human atherosclerosis: role of telomeres in endothelial dysfunction. J. Cardiol. 41, 39–40 (2003).
Kunieda, T. et al. Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway. Circulation 114, 953–960 (2006).
Yamada, N. Telomere shortening, atherosclerosis, and metabolic syndrome. Intern. Med. 42, 135–136 (2003).
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).
van Vlijmen, B.J. et al. Macrophage p53 deficiency leads to enhanced atherosclerosis in APOE*3-Leiden transgenic mice. Circ. Res. 88, 780–786 (2001).
Khanna, A.K. Enhanced susceptibility of cyclin kinase inhibitor p21 knockout mice to high fat diet induced atherosclerosis. J. Biomed. Sci. 16, 66 (2009).
Matsushita, H. et al. eNOS activity is reduced in senescent human endothelial cells: Preservation by hTERT immortalization. Circ. Res. 89, 793–798 (2001).
Sabin, R.J. & Anderson, R.M. Cellular senescence—its role in cancer and the response to ionizing radiation. Genome Integr. 2, 7 (2011).
Dörr, J.R. et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421–425 (2013).
Crescenzi, E., Palumbo, G., de Boer, J. & Brady, H.J. Ataxia telangiectasia mutated and p21CIP1 modulate cell survival of drug-induced senescent tumor cells: implications for chemotherapy. Clin. Cancer Res. 14, 1877–1887 (2008).
Ablain, J. et al. Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure. Nat. Med. 20, 167–174 (2014).
Wu, C.H. et al. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc. Natl. Acad. Sci. USA 104, 13028–13033 (2007).
Toso, A. et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 9, 75–89 (2014).
Serrano, M. SHP2: a new target for pro-senescence cancer therapies. EMBO J. 34, 1439–1441 (2015).
Cadoo, K.A., Gucalp, A. & Traina, T.A. Palbociclib: an evidence-based review of its potential in the treatment of breast cancer. Breast Cancer 6, 123–133 (2014).
Zhang, K.J. et al. [Mechanism of radiation induced premature senescence of bone marrow stromal cells: experiment with murine bone marrow stromal cells.]. Zhonghua Yi Xue Za Zhi 86, 3431–3434 (2006).
Cmielova, J. et al. Gamma radiation induces senescence in human adult mesenchymal stem cells from bone marrow and periodontal ligaments. Int. J. Radiat. Biol. 88, 393–404 (2012).
Ness, K.K. et al. Physiologic frailty as a sign of accelerated aging among adult survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study. J. Clin. Oncol. 31, 4496–4503 (2013).
Brinkman, T.M. et al. Cognitive function and social attainment in adult survivors of retinoblastoma: a report from the St. Jude Lifetime Cohort Study. Cancer 121, 123–131 (2015).
Gudmundsdottir, T. et al. Cardiovascular disease in Adult Life after Childhood Cancer in Scandinavia: a population-based cohort study of 32,308 one-year survivors. Int. J. Cancer 137, 1176–1186 (2015).
Chkhotua, A.B., Abendroth, D., Froeba, G. & Schelzig, H. Up-regulation of cell cycle regulatory genes after renal ischemia/reperfusion: differential expression of p16(INK4a), p21(WAF1/CIP1) and p27(Kip1) cyclin-dependent kinase inhibitor genes depending on reperfusion time. Transpl. Int. 19, 72–77 (2006).
Chkhotua, A. et al. Replicative senescence in organ transplantation-mechanisms and significance. Transpl. Immunol. 9, 165–171 (2002).
Braun, H. et al. Cellular senescence limits regenerative capacity and allograft survival. J. Am. Soc. Nephrol. 23, 1467–1473 (2012).
Melk, A. et al. Effects of donor age and cell senescence on kidney allograft survival. Am. J. Transplant. 9, 114–123 (2009).
Koppelstaetter, C. et al. Markers of cellular senescence in zero hour biopsies predict outcome in renal transplantation. Aging Cell 7, 491–497 (2008).
Gingell-Littlejohn, M. et al. Pre-transplant CDKN2A expression in kidney biopsies predicts renal function and is a future component of donor scoring criteria. PLoS ONE 8, e68133 (2013).
Baker, D.J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat. Cell Biol. 10, 825–836 (2008).
Zhu, Y. et al. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015).
Liu, W. & Sharpless, N.E. Senescence-escape in melanoma. Pigment Cell Melanoma Res. 25, 408–409 (2012).
Childs, B.G., Baker, D.J., Kirkland, J.L., Campisi, J. & van Deursen, J.M. Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep. 15, 1139–1153 (2014).
Shi, H., Zhang, C.J., Chen, G.Y.J. & Yao, S.Q. Cell-based proteome profiling of potential dasatinib targets by use of affinity-based probes. J. Am. Chem. Soc. 134, 3001–3014 (2012).
Saul, N., Pietsch, K., Menzel, R. & Steinberg, C.E.W. Quercetin-mediated longevity in Caenorhabditis elegans: is DAF-16 involved? Mech. Ageing Dev. 129, 611–613 (2008).
Kampkötter, A. et al. Increase of stress resistance and lifespan of Caenorhabditis elegans by quercetin. Comp. Biochem. Physiol. B 149, 314–323 (2008).
Boots, A.W., Haenen, G.R. & Bast, A. Health effects of quercetin: from antioxidant to nutraceutical. Eur. J. Pharmacol. 585, 325–337 (2008).
Chondrogianni, N. et al. Anti-ageing and rejuvenating effects of quercetin. Exp. Gerontol. 45, 763–771 (2010).
Lu, J. et al. Quercetin activates AMP-activated protein kinase by reducing PP2C expression protecting old mouse brain against high cholesterol-induced neurotoxicity. J. Pathol. 222, 199–212 (2010).
Price, J.S. et al. The role of chondrocyte senescence in osteoarthritis. Aging Cell 1, 57–65 (2002).
Mun, G.I. & Boo, Y.C. Identification of CD44 as a senescence-induced cell adhesion gene responsible for the enhanced monocyte recruitment to senescent endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 298, H2102–H2111 (2010).
Grupp, S.A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).
Gomez-Cabrera, M.C. et al. Decreasing xanthine oxidase-mediated oxidative stress prevents useful cellular adaptations to exercise in rats. J. Physiol. (Lond.) 567, 113–120 (2005).
Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005).
Akbar, A.N. & Henson, S.M. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat. Rev. Immunol. 11, 289–295 (2011).
Bursuker, I., Rhodes, J.M. & Goldman, R. Beta-galactosidase—an indicator of the maturational stage of mouse and human mononuclear phagocytes. J. Cell. Physiol. 112, 385–390 (1982).
We are grateful to R. Naylor for reading the manuscript and providing helpful discussion. The US National Institutes of Health (J.M.v.D. R01CA96985 and AG41122-01P2), the Paul F. Glenn Foundation (D.J.B. and J.M.v.D.), the Ellison Medical Foundation (D.J.B.), and the Noaber Foundation (J.M.v.D.) provided financial support to the authors during the writing of the review.
The authors declare no competing financial interests.
About this article
Cite this article
Childs, B., Durik, M., Baker, D. et al. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med 21, 1424–1435 (2015). https://doi.org/10.1038/nm.4000
Uncoupled inflammatory, proliferative, and cytoskeletal responses in senescent human gingival fibroblasts
Journal of Periodontal Research (2020)
International Journal of Radiation Oncology*Biology*Physics (2020)
Experimental Dermatology (2020)
Journal of Oral Pathology & Medicine (2020)
Ageing Research Reviews (2020)