Skip to main content
SpringerLink
Log in

Cellular senescence, ageing and disease

  • Published:
AGE Aims and scope Submit manuscript

Abstract

Cellular senescence is the irreversible growth arrest of individual mitotic cells, which as a consequence display a radically altered phenotype that is thought to impair tissue function and predispose tissues to disease development and/or progression as they gradually accumulate. However, in the past, research into mechanisms of ageing has commonly been researched and treated separately from disease development. This may partly be due to the lack of understanding concerning mechanisms of ageing and the difficulty in implementing what was known into models of disease development. Only in the last 10 years, with increasing knowledge of the senescent phenotype and the ability to detect senescent cells in human tissues, have biologists been able to investigate the relationship between cellular senescence and disease. This review therefore brings together and discusses recent findings which suggest that cellular senescence does contribute to ageing and the development/progression of disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Alexis F, Rhee JW, Richie JP, Radovic-Moreno AF, Langer R, Farokhzad OC (2008) New frontiers in nanotechnology for cancer treatment Urologic Oncology. Semin Original Invest 26:74–85

    Article  CAS  Google Scholar 

  • Bavik C, Coleman I, Dean JP, Knudsen B, Plymate S, Nelson PS (2006) The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Res 66:794–802

    Article  PubMed  CAS  Google Scholar 

  • Boyle M, Wong C, Rocha M, Jones DL (2007) Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis. Cell Stem Cell 1:470–478

    Article  PubMed  CAS  Google Scholar 

  • Burton DGA, Allen MC, Bird JLE, Faragher RGA (2005) Bridging the gap: ageing, pharmacokinetics and pharmacodynamics. J Pharm Pharmacol 57:671–679

    Article  PubMed  CAS  Google Scholar 

  • Burton DGA, Sheerin A, Ostler EL, Smith K, Giles PJ, Lowe J et al (2007) Cyclin D1 over-expression permits the reproducible detection of senescent human vascular smooth muscle cells. Ann N Y Acad Sci 1119:20–31

    Article  PubMed  CAS  Google Scholar 

  • Campisi J (1997a) Aging and cancer: the double-edged sword of replicative senescence. J Am Geriatr Soc 45:482–488

    PubMed  CAS  Google Scholar 

  • Campisi J (1997b) The biology of replicative senescence. Eur J Cancer 33:703–709

    Article  PubMed  CAS  Google Scholar 

  • Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120:513–522

    Article  PubMed  CAS  Google Scholar 

  • Cannon RO 3rd (1998) Role of nitric oxide in cardiovascular disease: focus on the endothelium. Clin Chem 44:1809–1819

    PubMed  CAS  Google Scholar 

  • Cavallaro U, Castelli V, Ugo DM, Soria MR (2000) Phenotypic alterations in senescent large-vessel and microvascular endothelial cells. Mol Cell Biol Res Commun 4:117–121

    Article  PubMed  CAS  Google Scholar 

  • Chan CW, Housseau F (2008) The ‘kiss of death’ by dendritic cells to cancer cells. Cell Death Differ 15:58–69

    Article  PubMed  CAS  Google Scholar 

  • Chen QM, Bartholomew JC, Campisi J, Acosta M, Reagan JD, Ames BN (1998) Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts: p53 and Rb control G1 arrest but not cell replication. Biochem J 332(Pt 1):43–50

    PubMed  CAS  Google Scholar 

  • Choi J, Shendrik I, Peacocke M, Peehl D, Buttyan R, Ikeguchi EF et al (2000) Expression of senescence-associated beta-galactosidase in enlarged prostates from men with benign prostatic hyperplasia. Urology 56:160–166

    Article  PubMed  CAS  Google Scholar 

  • Coppe JP, Kauser K, Campisi J, Beausejour CM (2006) Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem 281:29568–29574

    Article  PubMed  CAS  Google Scholar 

  • Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C et al (2006) Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444:638–642

    Article  PubMed  Google Scholar 

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367

    Article  PubMed  CAS  Google Scholar 

  • Effros RB (2004a) Replicative senescence of CD8 T cells: effect on human ageing. Exp Gerontol 39:517–524

    Article  PubMed  CAS  Google Scholar 

  • Effros RB (2004b) T cell replicative senescence: pleiotropic effects on human aging. Ann NY Acad Sci 1019:123–126

    Article  PubMed  CAS  Google Scholar 

  • Gallin JSR (1999) Inflammation: basic principles and clinical correlates, 3rd edn. Lippincott William and Wilkins, Philadelphia

    Google Scholar 

  • Gillies ER, Fréchet JMJ (2005) Dendrimers and dendritic polymers in drug delivery. Drug Discov Today 10:35–43

    Google Scholar 

  • Ginaldi L, Benedetto MC, De Martinis M (2005) Osteoporosis, inflammation and ageing. Immun Ageing 2:14

    Article  PubMed  Google Scholar 

  • Gorgoulis VG, Pratsinis H, Zacharatos P, Demoliou C, Sigala F, Asimacopoulos PJ et al (2005) p53-dependent ICAM-1 overexpression in senescent human cells identified in atherosclerotic lesions. Lab Invest 85:502–511

    Article  PubMed  CAS  Google Scholar 

  • Gutierrez-Ruiz MC, Robles-Diaz G, Kershenobich D (2002) Emerging concepts in inflammation and fibrosis. Arch Med Res 33:595–599

    Article  PubMed  Google Scholar 

  • Hampel B, Wagner M, Teis D, Zwerschke W, Huber LA, Jansen-Durr P (2005) Apoptosis resistance of senescent human fibroblasts is correlated with the absence of nuclear IGFBP-3. Aging Cell 4:325–330

    Article  PubMed  CAS  Google Scholar 

  • Hornebeck W (2003) Down-regulation of tissue inhibitor of matrix metalloprotease-1 (TIMP-1) in aged human skin contributes to matrix degradation and impaired cell growth and survival. Pathol Biol (Paris) 51:569–573

    CAS  Google Scholar 

  • Itahana K, Zou Y, Itahana Y, Martinez JL, Beausejour C, Jacobs JJ et al (2003) Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol Cell Biol 23:389–401

    Article  PubMed  CAS  Google Scholar 

  • Joosten SA, van Ham V, Nolan CE, Borrias MC, Jardine AG, Shiels PG et al (2003) Telomere shortening and cellular senescence in a model of chronic renal allograft rejection. Am J Pathol 162:1305–1312

    PubMed  Google Scholar 

  • Kalashnik L, Bridgeman CJ, King AR, Francis SE, Mikhalovsky S, Wallis C et al (2000) A cell kinetic analysis of human umbilical vein endothelial cells. Mech Ageing Dev 120:23–32

    Article  PubMed  CAS  Google Scholar 

  • Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, Klingelhutz AJ (1998) Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 396:84–88

    Article  PubMed  CAS  Google Scholar 

  • Kletsas D, Pratsinis H, Mariatos G, Zacharatos P, Gorgoulis VG (2004) The proinflammatory phenotype of senescent cells: the p53-mediated ICAM-1 expression. Ann N Y Acad Sci 1019:330–332

    Article  PubMed  CAS  Google Scholar 

  • Krtolica A, Campisi J (2002) Cancer and aging: a model for the cancer promoting effects of the aging stroma. Int J Biochem Cell Biol 34:1401–1414

    Article  PubMed  CAS  Google Scholar 

  • Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA 98:12072–12077

    Article  PubMed  CAS  Google Scholar 

  • Le Maitre CL, Freemont AJ, Hoyland JA (2007) Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration. Arthritis Res Ther 9:R45

    Article  PubMed  Google Scholar 

  • Li L, Neaves WB (2006) Normal stem cells and cancer stem cells: the niche matters. Cancer Res 66:4553–4557

    Article  PubMed  CAS  Google Scholar 

  • Libby P (2006) Inflammation and cardiovascular disease mechanisms. Am J Clin Nutr 83(Suppl):456S–460S

    PubMed  CAS  Google Scholar 

  • Lin LH, Taktakishvili O, Talman WT (2007) Identification and localization of cell types that express endothelial and neuronal nitric oxide synthase in the rat nucleus tractus solitarii. Brain Res 1171:42–51

    Article  PubMed  CAS  Google Scholar 

  • Logar DB, Komadina R, Prezelj J, Ostanek B, Trost Z, Marc J (2007) Expression of bone resorption genes in osteoarthritis and in osteoporosis. J Bone Miner Metab 25:219–225

    Article  PubMed  CAS  Google Scholar 

  • Lynch MD (2006) How does cellular senescence prevent cancer. DNA Cell Biol 25:69–78

    Article  PubMed  CAS  Google Scholar 

  • Marcotte R, Lacelle C, Wang E (2004) Senescent fibroblasts resist apoptosis by downregulating caspase-3. Mech Ageing Dev 125:777–783

    Article  PubMed  CAS  Google Scholar 

  • Matsuda T, Okamura K, Sato Y, Morimoto A, Ono M, Kohno K et al (1992) Decreased response to epidermal growth factor during cellular senescence in cultured human microvascular endothelial cells. J Cell Physiol 150:510–516

    Article  PubMed  CAS  Google Scholar 

  • Matsushita H, Chang E, Glassford AJ, Cooke JP, Chiu CP, Tsao PS (2001) eNOS activity is reduced in senescent human endothelial cells: Preservation by hTERT immortalization. Circ Res 89:793–798

    Article  PubMed  CAS  Google Scholar 

  • Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I (2002) Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105:1541–1544

    Article  PubMed  CAS  Google Scholar 

  • Minamino T, Yoshida T, Tateno K, Miyauchi H, Zou Y, Toko H et al (2003) Ras induces vascular smooth muscle cell senescence and inflammation in human atherosclerosis. Circulation 108:2264–2269

    Article  PubMed  CAS  Google Scholar 

  • Muller KC, Welker L, Paasch K, Feindt B, Erpenbeck VJ, Hohlfeld JM et al (2006) Lung fibroblasts from patients with emphysema show markers of senescence in vitro. Respir Res 7:32

    Article  PubMed  Google Scholar 

  • Nanni S, Melandri G, Hanemaaijer R, Cervi V, Tomasi L, Altimari A et al (2007) Matrix metalloproteinases in premature coronary atherosclerosis: influence of inhibitors, inflammation, and genetic polymorphisms. Transl Res 149:137–144

    Article  PubMed  CAS  Google Scholar 

  • Nishio K, Inoue A (2005) Senescence-associated alterations of cytoskeleton: extraordinary production of vimentin that anchors cytoplasmic p53 in senescent human fibroblasts. Histochem Cell Biol 123:263–273

    Article  PubMed  CAS  Google Scholar 

  • O’Rourke MF, Hashimoto J (2007) Mechanical factors in arterial aging: a clinical perspective. J Am Collf Cardiol 50:1–13

    Article  PubMed  Google Scholar 

  • Paradis V, Youssef N, Dargere D, Ba N, Bonvoust F, Deschatrette J et al (2001) Replicative senescence in normal liver, chronic hepatitis C, and hepatocellular carcinomas. Hum Pathol 32:327–332

    Article  PubMed  CAS  Google Scholar 

  • Payne GP (2006) Effect of inflammation on the aging microcirculation: impact on skeletal muscle blood flow control. Microcirculation 13:343–352

    Article  PubMed  CAS  Google Scholar 

  • Price JS, Waters JG, Darrah C, Pennington C, Edwards DR, Donell ST et al (2002) The role of chondrocyte senescence in osteoarthritis. Aging Cell 1:57–65

    Article  PubMed  CAS  Google Scholar 

  • Reed MJ, Corsa AC, Kudravi SA, McCormick RS, Arthur WT (2000) A deficit in collagenase activity contributes to impaired migration of aged microvascular endothelial cells. J Cell Biochem 77:116–126

    Article  PubMed  CAS  Google Scholar 

  • Robles SJ, Adami GR (1998) Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts. Oncogene 16:1113–1123

    Article  PubMed  CAS  Google Scholar 

  • Roggia C, Gao Y, Cenci S, Weitzmann MN, Toraldo G, Isaia G et al (2001) Up-regulation of TNF-producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc Natl Acad Sci USA 98:13960–13965

    Article  PubMed  CAS  Google Scholar 

  • Ruiz-Torres A, Lozano R, Melón J, Carraro R (2003) Age-dependent decline of in vitro migration (basal and stimulated by IGF-1 or insulin) of human vascular smooth muscle cells. J Gerontol A Biol Sci Med Sci 58:B1074–B1077

    PubMed  Google Scholar 

  • Ruzankina Y, Brown EJ (2007) Relationships between stem cell exhaustion, tumour suppression and ageing. Br J Cancer 97:1189–1193

    Article  PubMed  CAS  Google Scholar 

  • Ruzankina Y, Asare A, Brown EJ (2008) Replicative stress, stem cells and aging. Mech Ageing Dev 129:460–466

    Article  PubMed  CAS  Google Scholar 

  • Salvioli S, Capri M, Valensin S, Tieri P, Monti D, Ottaviani E, Franceschi C (2006) Inflamm-aging, cytokines and aging: state of the art, new hypotheses on the role of mitochondria and new perspectives from systems biology. Curr Pharm Des 12:3161–3171

    Article  PubMed  CAS  Google Scholar 

  • Sandeman SR, Allen MC, Liu C, Faragher RG, Lloyd AW (2000) Human keratocyte migration into collagen gels declines with in vitro ageing. Mech Ageing Dev 119:149–157

    Article  PubMed  CAS  Google Scholar 

  • Sandeman SR, Faragher RG, Allen MC, Liu C, Lloyd AW (2001) Does MMP-2 expression and secretion change with increasing serial passage of keratocytes in culture. Mech Ageing Dev 122:157–167

    Article  PubMed  CAS  Google Scholar 

  • Schnabl B, Purbeck CA, Choi YH, Hagedorn CH, Brenner D (2003) Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype. Hepatology 37:653–664

    Article  PubMed  CAS  Google Scholar 

  • Schneider EL, Mitsui Y (1976) The relationship between in vitro cellular aging and in vivo human age. Proc Natl Acad Sci USA 73:3584–3588

    Article  PubMed  CAS  Google Scholar 

  • Sharpless NE, DePinho RA (2007) How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 8:703–713

    Article  PubMed  CAS  Google Scholar 

  • Shawi M, Autexier C (2008) Telomerase, senescence and ageing. Mech Ageing Dev 129:3–10

    Article  PubMed  CAS  Google Scholar 

  • Sheron N, Bird G, Koskinas J, Portmann B, Ceska M, Lindley I et al (1993) Circulating and tissue levels of the neutrophil chemotaxin interleukin-8 are elevated in severe acute alcoholic hepatitis, and tissue levels correlate with neutrophil infiltration. Hepatology 18:41–46

    PubMed  CAS  Google Scholar 

  • Shurin MS, Shurin GV, Chatta GS (2007) Aging and the dendritic cell system: Implications for cancer. Crit Rev Oncol Hematol 64:90–105

    Article  PubMed  Google Scholar 

  • Sis B, Tasanarong A, Khoshjou F, Dadras F, Solez K, Halloran PF (2007) Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease. Kidney Int 71:218–226

    Article  PubMed  CAS  Google Scholar 

  • Smart S, Riley PR (2008) The stem cell movement. Circ Res 102:1155–1168

    Article  PubMed  CAS  Google Scholar 

  • Sone H, Kagawa Y (2005) Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia 48:58–67

    Article  PubMed  CAS  Google Scholar 

  • Sue W, Griffin T (2006) Inflammation and neurodegenerative diseases. Am J Clin Nutr 83(Suppl):470S–474S

    Google Scholar 

  • Trak-Smayra V, Contreras J, Dondero F, Durand F, Dubois S, Sommacale D et al (2004) Role of replicative senescence in the progression of fibrosis in hepatitis C virus (HCV) recurrence after liver transplantation. Transplantation 77:1755–1760

    Article  PubMed  Google Scholar 

  • Tsuji T, Aoshiba K, Nagai A (2004) Cigarette smoke induces senescence in alveolar epithelial cells. Am J Respir Cell Mol Biol 31:643–649

    Article  PubMed  CAS  Google Scholar 

  • von Zglinicki T, Pilger R, Sitte N (2000) Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic Biol Med 28:64–74

    Article  Google Scholar 

  • Wang E, Lee MJ, Pandey S (1994) Control of fibroblast senescence and activation of programmed cell death. J Cell Biochem 54:432–439

    Article  PubMed  CAS  Google Scholar 

  • West MD, Pereira-Smith OM, Smith JR (1989) Replicative senescence of human skin fibroblasts correlates with a loss of regulation and overexpression of collagenase activity. Exp Cell Res 184:138–147

    Article  PubMed  CAS  Google Scholar 

  • Wiencken AE, Casagrande VA (1999) Endothelial nitric oxide synthetase (eNOS) in astrocytes: another source of nitric oxide in neocortex. Glia 26:280–290

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Pharmacy and Biomolecular Sciences, Cockcroft Building, University of Brighton, Brighton, East Sussex, BN2 4GJ, UK

    D. G. A. Burton

Authors
  1. D. G. A. Burton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D. G. A. Burton.

About this article

Cite this article

Burton, D.G.A. Cellular senescence, ageing and disease. AGE 31, 1–9 (2009). https://doi.org/10.1007/s11357-008-9075-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-008-9075-y

Keywords

Search

Navigation