Significance of cellular senescence in aging and cancer.

Cellular senescence is a mechanism that induces an irreversible growth arrest in all somatic cells. Senescent cells are metabolically active but lack the capacity to replicate. Evolutionary theories suggest that cellular senescence is related to the organismal decline occurring in aging organisms. Also, such theories describe senescence as an antagonistically pleiotropic process that can have beneficial or detrimental effect on the organism. Cellular senescence is believed to be involved in the cellular changes observed as aging progresses. Accumulation of senescent cells appears to occur widely as the organism ages. Furthermore, senescence is a key element of the tumor suppressor pathways. Therefore, it is part of the natural barrier against the uncontrolled proliferation observed in cellular development of malignancies in multicellular organisms. Activation of the senescence process guarantees a limited number of cellular replications. The genetic network led by p53 is responsible for activation of senescence in response to DNA damage and genomic instability that could lead to cancer. A better comprehension of the genetic networks that control the cell cycle and induce senescence is important to analyze the association of senescence to longevity and diseases related to aging. For these reasons, experimental research both in vitro and in vivo aims to develop anticancer therapies based on senescence activation. The last decade of research on role and function of senescence in aging and cancer are discussed in this paper.

[1]  K. Davies,et al.  Protein oxidation and degradation during cellular senescence of human BJ fibroblasts: part I— effects of proliferative senescence , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  S. Lowe,et al.  Rb-Mediated Heterochromatin Formation and Silencing of E2F Target Genes during Cellular Senescence , 2003, Cell.

[3]  A. Yashin,et al.  What evidence is there for the existence of individual genes with antagonistic pleiotropic effects? , 2005, Mechanisms of Ageing and Development.

[4]  M. Rose,et al.  Mutation Accumulation Affects Male Virility in Drosophila Selected for Later Reproduction , 2007, Physiological and Biochemical Zoology.

[5]  D. Mittelman,et al.  DNA end joining becomes less efficient and more error-prone during cellular senescence. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  C. Sherr,et al.  Tumor surveillance via the ARF-p53 pathway. , 1998, Genes & development.

[7]  J. Campisi Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors , 2005, Cell.

[8]  C. Perrins,et al.  Age-dependent genetic variance in a life-history trait in the mute swan , 2006, Proceedings of the Royal Society B: Biological Sciences.

[9]  K. Hughes,et al.  A test of evolutionary theories of aging , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[10]  N. Gueven,et al.  The complexity of p53 stabilization and activation , 2006, Cell Death and Differentiation.

[11]  H. Riethman,et al.  Telomere length and the expression of natural telomeric genes in human fibroblasts. , 2003, Human molecular genetics.

[12]  E. Medrano,et al.  Dynamic assembly of chromatin complexes during cellular senescence: implications for the growth arrest of human melanocytic nevi , 2007, Aging cell.

[13]  A. Hendry,et al.  Adaptive variation in senescence: reproductive lifespan in a wild salmon population , 2004, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[14]  Soyoung Lee,et al.  A Senescence Program Controlled by p53 and p16INK4a Contributes to the Outcome of Cancer Therapy , 2002, Cell.

[15]  Subramanya,et al.  p16 Translation Suppressed by miR-24 , 2008 .

[16]  R. Weinberg,et al.  When cells get stressed: an integrative view of cellular senescence. , 2004, The Journal of clinical investigation.

[17]  J. Shay,et al.  BRAFE600-associated senescence-like cell cycle arrest of human naevi , 2005, Nature.

[18]  D. Promislow,et al.  A Theory of Age-Dependent Mutation and Senescence , 2008, Genetics.

[19]  I. Mian,et al.  The thorny path linking cellular senescence to organismal aging , 2005, Mechanisms of Ageing and Development.

[20]  J. Shay,et al.  Hallmarks of senescence in carcinogenesis and cancer therapy , 2004, Oncogene.

[21]  W. Swindell,et al.  Inbreeding Depression and Male Survivorship in Drosophila: Implications for Senescence Theory , 2006, Genetics.

[22]  L. Giudice,et al.  Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. , 1998, Cancer research.

[23]  D. Woods,et al.  Senescence of human fibroblasts induced by oncogenic Raf. , 1998, Genes & development.

[24]  Margaret A. Strong,et al.  The Shortest Telomere, Not Average Telomere Length, Is Critical for Cell Viability and Chromosome Stability , 2001, Cell.

[25]  D. Peeper,et al.  Oncogene-induced cell senescence--halting on the road to cancer. , 2006, The New England journal of medicine.

[26]  Masashi Narita,et al.  Reversal of human cellular senescence: roles of the p53 and p16 pathways , 2003, The EMBO journal.

[27]  J. Barrett,et al.  Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks , 2004, Nature Cell Biology.

[28]  S. Joel,et al.  DNA damage is able to induce senescence in tumor cells in vitro and in vivo. , 2002, Cancer research.

[29]  E. Crescenzi,et al.  Bcl-2 activates a programme of premature senescence in human carcinoma cells. , 2003, The Biochemical journal.

[30]  S. Ozanne,et al.  DNA damage, cellular senescence and organismal ageing: causal or correlative? , 2007, Nucleic acids research.

[31]  T. Kirkwood,et al.  Mitochondrial Dysfunction Accounts for the Stochastic Heterogeneity in Telomere-Dependent Senescence , 2007, PLoS biology.

[32]  D. Feldser,et al.  Short telomeres limit tumor progression in vivo by inducing senescence. , 2007, Cancer cell.

[33]  Daniel E L Promislow,et al.  Testing an ‘aging gene’ in long‐lived Drosophila strains: increased longevity depends on sex and genetic background , 2003, Aging cell.

[34]  Goberdhan P Dimri,et al.  Mechanisms of cellular senescence in human and mouse cells , 2004, Biogerontology.

[35]  P. Klatt,et al.  Increased gene dosage of Ink4a/Arf results in cancer resistance and normal aging. , 2004, Genes & development.

[36]  Dimitris Kletsas,et al.  Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints , 2006, Nature.

[37]  K. Jha,et al.  Senescence of immortal human fibroblasts by the introduction of normal human chromosome 6. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Lewis A. Chodosh,et al.  Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis , 2007, Nature Cell Biology.

[39]  G. Peters,et al.  Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence , 1996, Molecular and cellular biology.

[40]  T. Mackay,et al.  Sex-specific quantitative trait loci affecting longevity in Drosophila melanogaster. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[41]  W. Hahn,et al.  A Two-Stage, p16INK4A- and p53-Dependent Keratinocyte Senescence Mechanism That Limits Replicative Potential Independent of Telomere Status , 2002, Molecular and Cellular Biology.

[42]  J. Campisi,et al.  Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[43]  M. Hollstein,et al.  Ser46 Phosphorylation Regulates p53-Dependent Apoptosis and Replicative Senescence , 2006, Cell cycle.

[44]  Judith Campisi,et al.  Cancer and ageing: rival demons? , 2003, Nature Reviews Cancer.

[45]  Goberdhan P Dimri,et al.  Regulation of cellular senescence by p53. , 2001, European journal of biochemistry.

[46]  Z B Zeng,et al.  Genotype-environment interaction for quantitative trait loci affecting life span in Drosophila melanogaster. , 2000, Genetics.

[47]  A. Mills,et al.  p63: A New Link Between Senescence and Aging , 2006, Cell cycle.

[48]  A. Marusyk,et al.  p53 Mediates Senescence-Like Arrest Induced by Chronic Replicational Stress , 2007, Molecular and Cellular Biology.

[49]  O. Pereira-smith,et al.  Replicative Senescence: Implications for in Vivo Aging and Tumor Suppression , 1996, Science.

[50]  S. Lowe,et al.  Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a , 1997, Cell.

[51]  H. Jacobs,et al.  Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[52]  Pier Paolo Pandolfi,et al.  PML regulates p53 acetylation and premature senescence induced by oncogenic Ras , 2000, Nature.

[53]  P. Klatt,et al.  'Super p53' mice exhibit enhanced DNA damage response, are tumor resistant and age normally , 2002, The EMBO journal.

[54]  M. Narita,et al.  Cellular senescence and chromatin organisation , 2007, British Journal of Cancer.

[55]  A. Smogorzewska,et al.  Senescence Induced by Altered Telomere State, Not Telomere Loss , 2002, Science.

[56]  J. Ventura,et al.  Bcl-2 protects against oxidative stress while inducing premature senescence. , 2006, Free radical biology & medicine.

[57]  S. Lowe,et al.  Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas , 2011, Nature.

[58]  M. Blasco,et al.  Many ways to telomere dysfunction: in vivo studies using mouse models , 2002, Oncogene.

[59]  A. Mackay,et al.  Transcriptional networks and cellular senescence in human mammary fibroblasts. , 2004, Molecular biology of the cell.

[60]  K Watanabe,et al.  Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[61]  C Roskelley,et al.  A biomarker that identifies senescent human cells in culture and in aging skin in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[62]  A. Multani,et al.  Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53‐dependent cellular senescence , 2007, EMBO reports.

[63]  Frédérick A. Mallette,et al.  Human fibroblasts require the Rb family of tumor suppressors, but not p53, for PML-induced senescence , 2004, Oncogene.

[64]  D. Martinez,et al.  Mortality Patterns Suggest Lack of Senescence in Hydra , 1998, Experimental Gerontology.

[65]  Bai-Lin Wu,et al.  High Intensity ras Signaling Induces Premature Senescence by Activating p38 Pathway in Primary Human Fibroblasts* , 2004, Journal of Biological Chemistry.

[66]  J. McDougall,et al.  Genetic and epigenetic changes in human epithelial cells immortalized by telomerase. , 2000, The American journal of pathology.

[67]  Ronit Vogt Sionov,et al.  The cellular response to p53: the decision between life and death , 1999, Oncogene.

[68]  J. R. Smith,et al.  The genetics of cellular senescence. , 1998, American journal of human genetics.

[69]  A. Fersht,et al.  Structure–function–rescue: the diverse nature of common p53 cancer mutants , 2007, Oncogene.

[70]  B. Dörken,et al.  Cellular senescence in cancer treatment: friend or foe? , 2004, The Journal of clinical investigation.

[71]  T. Jacks,et al.  Restoration of p53 function leads to tumour regression in vivo , 2007, Nature.

[72]  K. Hughes,et al.  Age-specific inbreeding depression and components of genetic variance in relation to the evolution of senescence. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[73]  J. Shay,et al.  Cellular senescence as a tumor-protection mechanism: the essential role of counting. , 2001, Current opinion in genetics & development.

[74]  H. Stein,et al.  Oncogene-induced senescence as an initial barrier in lymphoma development , 2005, Nature.

[75]  Aaron Bensimon,et al.  Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication , 2006, Nature.

[76]  S. Drăghici,et al.  Epigenetic silencing of multiple interferon pathway genes after cellular immortalization , 2003, Oncogene.

[77]  S. Lowe,et al.  Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. , 1998, Genes & development.

[78]  Lin He,et al.  The guardian's little helper: microRNAs in the p53 tumor suppressor network. , 2007, Cancer research.

[79]  L. Kruuk,et al.  The rate of senescence in maternal performance increases with early-life fecundity in red deer. , 2006, Ecology letters.

[80]  J. Campisi,et al.  Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation , 2004, Journal of Cell Science.

[81]  J. Campisi Cellular senescence as a tumor-suppressor mechanism. , 2001, Trends in cell biology.

[82]  I. Kola,et al.  Elevation in the ratio of Cu/Zn-superoxide dismutase to glutathione peroxidase activity induces features of cellular senescence and this effect is mediated by hydrogen peroxide. , 1996, Human molecular genetics.

[83]  W. Hahn,et al.  Human Keratinocytes That Express hTERT and Also Bypass a p16INK4a-Enforced Mechanism That Limits Life Span Become Immortal yet Retain Normal Growth and Differentiation Characteristics , 2000, Molecular and Cellular Biology.

[84]  V. Ferrans,et al.  Ras Proteins Induce Senescence by Altering the Intracellular Levels of Reactive Oxygen Species* , 1999, The Journal of Biological Chemistry.

[85]  E. Blackburn,et al.  Rapid Inhibition of Cancer Cell Growth Induced by Lentiviral Delivery and Expression of Mutant-Template Telomerase RNA and Anti-telomerase Short-Interfering RNA , 2004, Cancer Research.

[86]  J. P. D. Magalhães From cells to ageing: a review of models and mechanisms of cellular senescence and their impact on human ageing. , 2004 .

[87]  N. Carter,et al.  A DNA damage checkpoint response in telomere-initiated senescence , 2003, Nature.

[88]  M. Oshimura,et al.  Restoration of the Cellular Senescence Program and Repression of Telomerase by Human Chromosome 3 , 1995, Japanese journal of cancer research : Gann.

[89]  O. Pereira-smith,et al.  Expression of Human Telomerase (hTERT) Does Not Prevent Stress-induced Senescence in Normal Human Fibroblasts but Protects the Cells from Stress-induced Apoptosis and Necrosis* , 2002, The Journal of Biological Chemistry.

[90]  J. Sedivy,et al.  Expression of catalytically active telomerase does not prevent premature senescence caused by overexpression of oncogenic Ha-Ras in normal human fibroblasts. , 1999, Cancer research.

[91]  S. Lowe,et al.  Oncogenic ras and p53 Cooperate To Induce Cellular Senescence , 2002, Molecular and Cellular Biology.

[92]  T. Lendvay,et al.  Senescence mutants of Saccharomyces cerevisiae with a defect in telomere replication identify three additional EST genes. , 1996, Genetics.

[93]  Hong Jiang,et al.  Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation , 2006, Nature Genetics.

[94]  Rugang Zhang,et al.  Molecular Dissection of Formation of Senescence-Associated Heterochromatin Foci , 2007, Molecular and Cellular Biology.

[95]  O. Pereira-smith,et al.  p53 is preferentially recruited to the promoters of growth arrest genes p21 and GADD45 during replicative senescence of normal human fibroblasts. , 2006, Cancer research.

[96]  S. Leachman,et al.  Absence of senescence-associated beta-galactosidase activity in human melanocytic nevi in vivo. , 2007, The Journal of investigative dermatology.