Ocean County Foot and Ankle Surgical Associates, P.C.
FacebookGoogle PlusYou Tube (732) 505-4500

Ocean County Foot & Ankle Surgical Associates, P.C.

In The News

« Back to In The News

CELLULAR SENESCENCE

February 22, 2017

Cellular Senescence; What, Why and How
All age-related chronic diseases may be caused in part by convergence of the basic aging mechanisms that underlie age-related tissue dysfunction, including chronic “sterile” (not pathogen-associated) inflammation, macromolecular damage, progenitor cell dysfunction, and cellular senescence (1).

In the past decade, cellular senescence has emerged as a possible cause of general tissue dysfunction and aging phenotypes (2,3). Cellular senescence is an essentially irreversible growth arrest that occurs in response to various cellular stressors, such as telomere erosion, DNA damage, oxidative stress, and oncogenic activation, and has thought to have risen as an antitumor mechanism (4).

Cellular senescence is a stress response that links multiple pathologies of aging, both degenerative and hyperplastic. This degeneration or gradual loss of function occurs at the molecular, cellular, tissue, and organismal levels. Age-related loss of function is a feature of virtually all organisms that age, ranging from single-celled creatures to large, complex animals. In mammals, age-related degeneration gives rise to well-recognized pathologies, such as sarcopenia, atherosclerosis, and heart failure, osteoporosis, macular degeneration, pulmonary insufficiency, renal failure, neural degeneration but including prominent neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, and much more age-related pathologies.

All though species vary in their susceptibilities to specific age-related pathologies, collectively, age-related pathologies generally rise with approximately exponential kinetics, beginning at approximately the mid-point of the species-specific life span (e.g., 50-60 years of age for human) (5,6).

Cellular Senescence: Overview
Cellular senescence refers to the essentially irreversible arrest of cell proliferation (growth) that occurs when cells experience potentially oncogenic stress (7). The permanence of the senescence growth arrest enforces the idea that senescence response evolved at least in part to suppress the development of cancer (8). A senescence arrest is considered irreversible because no known physiologic stimuli can stimulate senescence cells to re-enter the cell cycle. The senescence arrest is stringent. It is established and maintained by at least two major tumor suppressor pathways, the p53/p21 and p16INK4A/pRb pathways that are now recognized as a formidable barrier to malignant tumorigenesis.

In addition to arrested growth, senescence cells show wide spread changes in chromatin organization and gene expression. These changes include the secretion of numerous pro-inflammatory cytokines, chemokines, growth factors, and proteases, a featured term that senescence-associated secretory phenotype (SASP) that will be discussed in detail through this article. The SASP has powerful paracrine activities, the nature of which suggests that senescence response is not solely a mechanism for preventing cancer. Rather cellular senescence and the SASP likely evolve both to suppress the development of cancer and to promote tissue repair or regeneration in the face of injury.

Through the SASP, a low absolute number of senescent cells in a tissue (typically less than 20%) may be able to exert systemic effects (4). For example, obesity-associated senescent cells may promote chronic low-grade sterile inflammation. In this way senescent cells might be a link between obesity and inflammation that contributes to the development and progression of type II diabetes (9,10). Although cellular senescence is normally a defense mechanism against tumor development, presence or persistence of a high number of senescent cells can promote tumor progression because of inflammation, tissue disruption, and growth signals due to the SASP (11). Senescent cells can also initiate a deleterious positive feedback mechanism by promoting the spread of senescence to nearby cells (12,13,14).

Senescent cell burden is low in young individuals but increases with aging in several tissues including Adipost tissue, skeletal muscle, kidney, and skin (15,16,17). In particular, components of the metabolic syndrome, including abdominal obesity, diabetes, hypertension, and atherosclerosis are among the many pathologies that are associated with increased senescent cell burden (18,19,20).

Senescent cell accumulation can occur due to a variety of factors, such as various age-related chronic diseases, oxidative stress, the hormonal milieu, developmental factors, chronic infection (e.g. HIV), certain medications (chemotherapy or certain HIV protease inhibitors), and radiation exposure (2,3,21,22).

There are different types of cellular senescence that have been identified, including oncogene-induced senescence, stress-induced premature senescence as we see in diabetics, and the classical replicative senescence (3).

Therefore, senescent cells can contribute to aging and all age-related pathologies by accelerating loss of tissue regeneration through the depletion of stem cells and progenitor cells. Therefore, cellular senescence is indicated in every pathological condition associated with aging (23).

Cellular Senescence: Causes
Cellular senescence was formally described approximately five decades ago by Hayflick. He showed that after undergoing a certain number of divisions, normal human diploid fibroblast enter an irreversible non-dividing state, turned, replicated senescence. Hayflick et al reported that normal human diploid fibroblast can divide fifty to sixty times but after that they stop dividing irreversibly (26,27). Thus the number of divisions that cells complete reach at the end of their replicative lifespan has been termed as the Hayflick Limit.

Senescence has been reported to occur in a number of other cell types, such as keratinocytes, melanocytes, endothelial cells, epithelial cells, glial cells, adrenocortical cells, T-lymphocytes, and even tissue stem cells (28-35).

Even though senescence is induced by multiple factors such as repeated cell culture, telomere attrition, irradiation, oncogene activation, and oxidative damage, it can also be caused by the perturbation of mitochondrial homeostasis which may accelerate age-related phenotypes. Because mitochondria can generate ROS, it is proposed that excessive mitochondrial ROS is important to establish cellular senescence.

Perturbations of mitochondrial homeostasis will include excessive ROS production, impaired mitochondrial dynamics, electron transport chain defect, bioenergetic imbalance/increase AMPK activity, decrease mitochondrial NAD+ /altered metabolism, and mitochondrial calcium accumulation (39).

There are several causes that can induce cellular senescence, such as telomere shortening, genomic damage, strong mitogen associated signals, epigenomic damage, and activation of tumor suppressors. Replicative senescence is indeed not dependent on chronological time and culture but rather depends on the number of divisions that cells undergo in culture (40,41,42,43). It is thought that telomere shortening, which occurs at each cell division because of incomplete replication, is the counting mechanism for the induction of replicative senescence (44).

Telomeres become critically short after extensive division, and telomere ends are recognized as DNA double-stranded breaks. This aggravates a DNA damage response (DDR) in cell divisions then arrested by the activated DDR, mainly through p53 tumor suppressor activity.

The mechanism behind the finite replicative lifespan of normal cells is now quite understood. Because polymerase that copy DNA templates are unidirectional and require a labile primer, the ends of linear DNA molecules cannot be completely replicated. Thus telomeres, the DNA protein structures that cap the ends of linear chromosomes, shorten with each cell division. Telomere shortening does not occur in cells that express telomerase, the reverse transcriptase that can replenish the repetitive telomeric DNA de novo (49,50).

The numbers and types of telomerase-expressing cells vary widely amongst species. In humans, however, such cells are rare. Telomerase-positive human cells include most cancer cells, embryonic stem cells, certain adult stem cells, and a few somatic cells, for example activated T-cells (51,52,53).

Functional telomeres prevent DNA repair machineries from recognizing chromosome ends as DNA double-stranded breaks (DSBs) to which the cells rapidly respond and attempt repair. In the case of telomeres, repair followed by cell division will cause rampant genomic instability through cycles of chromosome fusion and breakage which are major risk factors for developing cancer. Therefore repeated cell divisions in the absence of telomerase eventually causes one or more telomeres to become critically short and dysfunctional. Dysfunctional telomeres elicit a DNA damage response (DDR) but suppress attempted DNA repair. This DDR in turn, arrest cell division primarily through activities of the p53 tumor suppressor, thereby preventing genomic instability.

Dysfunctional telomeres appear to be irreparable, consequently, cells with such telomeres experience persistent DDR signaling and p53 activation, which enforce the senescence growth arrest. DNA damage response signaling also establishes and maintains the senescence-associated secretory phenotype. The remaining causes of cellular senescence that have been mentioned are beyond the scope of this article. Therefore when we have pathologies that cause DNA damage that is enough to stimulate and prevent repair of DNA, this will stimulate significantly, cellular senescence.

Senescence-associated secretory phenotype
An important feature of many senescent cells is the SASP. The SASP is arguably the most striking feature of senescent cells because it has the potential to explain the role of cellular senescence in organismal aging and age-related pathologies. Consistent with the complexity of the SASP, its biological activities are myriad. The SASP can stimulate cell proliferation, owing to proteins such as growth-related oncogenes and amphiregulin, as well as stimulate new blood vessel formation due to proteins such as VEGF (vascular endothelial growth factor). However the SASP can also include proteins that have complex effects on cells. For example, the biphasic WNT modulator SFRP1 (secreted frizzled related protein 1) and interleukins IL-6 and IL-8, which can stimulate or inhibit WNT signaling cell proliferation, depend on the physiological context.

Chronic WNT signaling can drive both differentiated cells and stem cells into senescence. Also, some SASP factors induce an epithelial to mesenchymal transition in susceptible cells. Thus, these SASP factors, as mentioned above, can alter stem cell proliferation or differentiation or modify stem cell niches (63-73). Also of particular importance to the role of cellular senescence in aging and age-related disease, many SASP components directly or indirectly promote inflammation. These factors include IL-6 and IL-8; a variety of MCP’s (monocyte chemo attractant proteins) and MIPs (macrophage inflammatory proteins); and proteins that regular multiple aspects of inflammation, such as GM-CSF (granulocyte macrophage colony stimulating factor). The secretion of these in similar proteins by senescent cells is predicted to cause chronic inflammation, at least locally and possibly systemically.

Chronic inflammation, of course, is a cause of or an important contributor to, virtually every major age-related disease, both degenerative and hyperplastic (74,61,75,76, 77,60,61,78,79,80,81). Also, the SASP is a plastic phenotype. This means that proteins that are included in the SASP vary among cell types and to some extent with the stimulus that induced the senescence response.

Nevertheless, there is substantial overlap among SASP’s; proinflammatory cytokines are the most highly conserved feature, cutting across many different cell types and senescence-inducing stimuli (68,82,83,84).

Senescent cells and degenerative phenotypes
Senescent cells have been implicated in many age-associated degenerative phenotypes, both normal and pathological. In most cases senescent cells have been shown to drive degenerative changes, largely through their secreted proteins, that is through their SASP. Senescent cells can disrupt normal tissue structures which are essential for normal tissue function. Senescent cells and the SASP can also fuel overt age-related diseases. For example, indirect evidence shows that senescence and associated SASP of astrocytes can promote the age-related neurodegeneration that gives rise to cognitive impairment as well as to Alzheimer’s and Parkinson’s disease (85,86). Also the presence in SASP of senescent chondrocytes, which are prominent in age-related osteophytic joints and degenerated intervertebral discs, are thought to play a major role in etiology and promotion of these pathologies (87,88).

Also, senescent epithelial, endothelial and smooth muscle cells have been implicated in the genesis and promotion of age-related cardiovascular disease (89,90). The list of age-related pathologies in which senescent cells have been observed and proposed to cause or contribute is long: macular degeneration, chronic obstructive pulmonary disease, emphysema, insulin insensitive, etc. Therefore senescent cells are a smoking-gun present at the right time and place to drive these age-related pathologies.

Summary points

1. Aging is characterized by a number of phenotypes and diseases, many of which are thought to derive from a few basic aging processes.

2. Cellular senescence is a stress response that suppresses cancer early in life but it may be a basic aging process that drives aging phenotypes and age-related pathology late in life.

3. Senescent cells accumulate with age in many vertebrae tissues and are present at sites of age-related pathology, both degenerative and hyperplastic.

4. Senescent cells express a senescence-associated secretory phenotype (SASP) which entails the robust secretion of numerous proinflammatory cytokines, as well as chemokines, growth factors, and proteases.

5. The SASP has both deleterious and beneficial effects, each of which depends on the physiological context.

6. Deleterious effects of senescent cells in the SASP include creating local (and possibly systemic) inflammation, disrupting normal tissue structure and function, and fueling late-life and recurrent cancer.

7. Beneficial effects of the senescent cells in the SASP include reinforcing the tumor suppressant growth arrest, stimulating immune clearance of senescent cells, and optimizing the repair of damaged tissues.

8. The transient presence of senescent cells may be beneficial, whereas their chronic presence may be deleterious.

Conclusion

The beneficial effects of senescent cells on tissue repair poses a paradox because wound healing and tissue repair decline with age. Given that senescent cells increase with age and age-related pathology, why does tissue repair not improve with age?

We as physicians have to understand the molecular, cellular, and genomic derangements that are going on within the chronic wound bed. We are trying to stimulate repair and regenerative mechanisms in an area of tissue that is devoid of functional cells, a functional extra cellular matrix, and functional proteins. If we understand that the cells within a chronic wound are non-functional, non-migratory, non-proliferative, why do we utilize acellular treatments in order to reestablish proliferative pathways when these cells are quite dysfunctional as the evidence provided has shown?

Therefore, once we understand that the cellular senescence pathway underlies all age-related pathologies, not just wound healing, we then can start to search for those treatments that resurrect these deficient cellular mechanisms so that we can restore proper cellular function which will lead to proper healing.

Literature cited:

1. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Journal Cell, 2013; 153:1194-1217.

2. Kirkland JL, Tchkonia T. Clinical Strategies in Animal Model for Developing Senolytic Agents. Exp Gerontol. 28October2015, DOI: 10. 1016/J Exger. 2014. 10.012.

3. Munoz-Espin D, Serrano M. Cellular Senescence: From Physiology to Pathology. Nat Rev Mol Cell Biol. 2014;15-482-496.

4. Campisi J, d’Adda di Fagagna F. Cellular Senescence: When Bad Things Happen to Good Cells. Nat Rev Mol Cell Biol: 2007; 8:729-740.

5. Alliance Aging RES. The Silver Book. Chronic Disease and Capitol Medical Innervation in an Aging Nation. 2009.

6. Natl. Cent. Health Stat. Health, United States, 2007. Hyattsville, MD: US Gov. print. OF:2007. P567.

7. Campisi J, d’Adda di Fagagna F. Cellular Senescence: When Bad Things Happen to Good Cells. Nat Rev Mol Cell Biol: 2007; 8:729-740. Pub Med: 17667954.

8. Sager R. Senescence as a Mode of Tumor Suppression. Environ Health Persp. 1991:93:59-62.

9. Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot M. Inflammation as a Link Between Obesity, Metabolic Syndrome, and Type II Diabetes. Diabetes Res Clin Pract. 2014; 105:141-150.

10. Dandona P, Aljada A, Bandyopadhyay A. Inflammation: The Link Between Insulin-Resistance Obesity and Diabetes. Immunol 2004; 25:4-7.

11. Campisi J. Stenosing Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors. Cell 2005; 120:513-522.

12. Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL. Cellular Senescence in the Senescence Secretory Phenotype and Age-related Chronic Diseases. Curr Opin Clin Nutr Metab Care 2014; 17:324-328.

13. Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular Senescence in the Senescence Secretory Phenotype: Therapeutic Opportunities. J Clin Invest 2013:123:966-972.

14. Nelson G, Wordsworth J, Wang C, et al. A Senescence Cell Bystander Effect: Senescence-Induced Senescence. Journal Aging Cell. 2012; 11:345-349.

15. Tchkonia T, Morbeck DE, Von Zglinicki T, et al. Fat Tissue, Aging, and Cellular Senescence. Aging Cell 2010; 9:667-684.

16. Melk A, Schmidt BMW, Vongwiwatana A, Rayner DC, Halloran PF. Increased Expression of Senescence-Associated Cell Cycle Inhibitor p16 INK4a and Deteriorating Renal Transplants and Disease Native Kidney. Journal AM J Transplant 2005; 5:1375-1382.

17. Waaijer ME, Perish WE, Strongitharm BH, et al. The Number of p16 INK4a Positive Cells in Human Skin Reflects Biological Age. Aging Cell 2012; 11:722-725.

18. Minamino T, Orimo M, Shimizu I, et al. A Cumulative Role for Adipose Tissue p53 in the Regulation of Insulin Resistance. Nat Med 2009;15:1082-1087.

19. Minamino T, Komuro I. Vascular Cell Senescence: Contribution to Atherosclerosis. Journal Circ Res 2007; 100:15-26.

20. Westhoff JH, Hilgers KF, Steinbach MP, et al. Hypertension Induces Somatic Cellular Senescence in Rats and Humans by Induction of Cell Cycle Inhibitor p16 INK4a. Journal Hypertension 2008; 52:123-129.

21. Stout MB, Tchkonia T, Pirdskhalava T, et al. Growth Hormone Action Predicts Age-Related White Adipose Tissue Dysfunction and Senescence Cell Burden in Mice. Journal Aging (Albany, New York on-line), 2014; 6:575-586.

22. Tran D, Bergholz J, Zhang H, et al. Insulin-Like Growth Factor-1 Regulates the Sirt 1-p53 Pathway in Cellular Senescence. Journal Aging Cell. 2014; 13:669-678.

23. Campisi J, (2013) Journal Aging. Cellular Senescence in Cancer. Annu. Rev. Physiol. 75, 685-705.

24. Hayflick L. The Limited In-Vitro Lifetime of Human Diploid Cell Strength. Exp Cell Res. 1965; 37:614-636. Pub Med: 14315085.

25. Hayflick L, Moorehead PS. The Serial Cultivation of Human Diploid Cell Strength. Exp Cell Res. 1961; 25:585-621. Pub Med: 13905658.

26. Narita M, Young AR, Arakawua S, Yoshida S, et al. Spacial Coupling of mTOR in Autophagy Augmented Secretory Phenotypes. Science 2011; 332:966-970.

27. Young AR, Narita M. Spatio-Temporal Association Between mTOR in Autophagy During Cellular Senescence. Journal Autophagy. 2011; 7:1387-8.

28. Rheinwald JG, Green H. Serial Cultivation of Strains of Human Epidermal Keratinocytes: The Formation of Keratinizing Colonies from Single Cells. Journal Cell. 1975; 6:331-43.

29. Bandyopadhyay D, Timchenko N, Suwa T, Hornsby PJ, Campisi J. The Human Melanocyte: A Model System to Study the Complexity of Cellular Aging and Transformation in Non-Fibroblastic Cells. Journal Exp Gerontol. 2001; 36:1265-75.

30. Thornton, SC, Mueller SN, Levine EN. Human Endothelial Cells: Use of Heparin in Cloning and Long-Term Serial Cultivation. Journal Science. 1983; 222:623-5.

31. Shelton DN, Chang E, Whittier PS, Choi D, Funk WD. Microarray Analysis of Replicated Senescence. Journal Curr Biol. 1999; 9:939-45.

32. Blomquist E, Westermark B, Ponten J. Aging of Human Glial Cells in Culture: Increase in the Fraction of Non-Dividers as Demonstrated by a Mini Cloning Technique. Journal Mech Ageing Dev. 1980; 12:173-82.

33. McAllister, JM, Hornsby PJ. Improved Clonal and Non-Clonal Growth of Human, Rat, and Bovine Adreo Cortical Cells in Culture. In Vitro Cel Dev Biol. 1987; 23:677-85.

34. Effros RB, Walford RL. T-Cell Cultures in the Hayflick Limit. Hum Immunol. 1984; 9:49-65.

35. Oh J, Lee YD, Wagers AJ. Stem Cell Aging: Mechanisms, Regulators, and Therapeutic Opportunities. Journal Nat Med. 2014; 20:872-80.

36. Shain E, DePinho RA. 2010. Linking Functional Decline of Telomeres, Mitochondrial, and Stem Cells During Aging. Journal Nature 464, 52528.

37. Shain E, DePincho RA. 2012. Access of Aging: Telomeres, p53 and Mitochondrial. Journal Nat. Rev. Mol. Cell Biol. 13, 397-404.

38. Quinlan CL, Perevoshchikova IV, Hey-Mogensen N, Orr AL, Brand MD. 2013. Sites of Reaction Oxygen Species Generation by Mitochondrial Oxidizing Different Substrates. Journal Redox. Biol. #1, 304-312.

39. Ziegler DV, Wylie CD, Velarade M. Mitochondrial Effects of Cellular Senescence: Beyond the Free Radical Theory of Aging. Journal Aging Cell 2015; 14:1-7.

40. Dell-Orco RT, Martins, JG, Kruse PF Jr. Doubly Potential, Calendar Time, and Senescence of Human Diploid Cells in Culture. Journal Exp Cel Res. 1973; 77:356-60.

41. Roberts TW, Smith JR. The Proliferative Potential of Chick Embryo Fibroblasts: The Population Doublings versus Time and Culture. Journal Cell Biol Int Rep. 1980; 4:1057-63.

42. Harley CB, Futcher AB, Greider CW. Telomere Shortening During Aging of Human Fibroblast. Nature. 1990; 345:458-260.

43. Allsopp RC, Chang E, Akashefi-Azam M, Rogaev EI, Shay JW, et al. Telomere Shortening as Associated with Cell Division in-vitro and in-vivo. Journal Exp Cel Res. 1995; 220:194-200.

44. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, et al. Extension of Lifespan by Introduction of Telomeres into Norman Human Cells. Journal Science. 1998; 279:349-52.

45. d’Adda di Fagagna F, Reiper PM, Clay-Farrace L, Fiegler H, et al. A DNA Damage Checkpoint Response in Telomere-Initiated Senescence. Journal Nature. 2003; 426:194-98.

46. Taki H, Smogorzewska A. DNA Damage Phosi at Dysfunctional Telomeres. Journal Curr Biol. 2003; 13:1549-56.

47. Teo SH, Jackson SP, d’Adda di Fagagna F. Functional Links Between Telomeres and Proteins of the DNA Damage Response. Journal Genes Dev. 2004; 18:1781-99.

48. Alsop RC, Chang E, Kashefi-azan M, Rogaev EI, et al. Telomere Shortening is Associated with Cell Division in in-vitro and in in-vivo. Exp Cel Res. 1995; 220:194-220. Pub Med: 7664836.

49. Collins K. Mammalian Telomeres and Telomerase. Journal Curr Opin Cell Biol. 2000; 12:378-83. Pub Med: 10801465.

50. McEachern NG, Krauskopf A, Blackburn EH. Telomeres and Their Control. Journal Annu Rev Genet. 2000; 34:331-58. Pub Med: 11092831.

51. Wang MP, Hodes RJ. The Role of Telomeres Expression and Telomere Length Maintenance in Human and Mouse. J Cilin Immunol. 2000; 20:257-67. Pub Med 10939713.

52. Wright WE, Shay JW. Telomere Dynamics in Cancer Progression and Prevention: Fundamental Differences in Human and Mouse Telomere Biology. Nat Med. 2000; 6:849-51. Pub Med: 10932210.

53. Zeng X, Rao MS. Human Embryonic Stem Cells: Long Term Stability, Absence of Senescence, and a Potential Cell Source for Neural Replacement. Journal Neuroscience. 2007; 145:1348-58. Pub Med: 17055653.

54. Blackburn H. Structure and Function of Telomeres. Journal Nature. 1991; 350:569-73. Pub Med: 17088110.

55. Rodier F, Kim SH, Nijjar T, Yaswen P, Campisi J. Cancer in Aging: The Importance of Telomeres in Genome Maintenance. Journal Int J Biochem Cell Biol. 2005; 37:977-90. Pub Med: 15743672.

56. Reiper PM, Clay-Farrace L, Fiegler H, Carr P, et al. A DNA-Damaged Checkpoint Response in Telomere-Initiated Senescence. Journal Nature. 2003; 426:194-98. Pub Med: 14608368.

57. Takai H, Smogorzewska A, de Lang T. DNA-Damaged Phosi of Dysfunctional Telomeres. Journal Curr Biol. 2003; 13:1549-56. Pub Med: 12956959.

58. Fumagalli M, Rossiello F, Clerici M, Barozzi S, et al. Telomere DNA Damage is Irreparable and Causes Persistent DNA Damage Response Activation. Journal Nat Cell Biol. 2012; 14:355-65. Pub Med: 22426077.

59. von Zglinicki T, Saretzki G, Ladhoff J, Jackson SP. Human Cell Senescence as a DNA Damage Response. Journal Mech Ageing Dev. 2005; 126:111-17. Pub Med: 15610765.

60. Campisi J, Anderson JK, Kapahi P, Melov S. Cellular Senescence: A Link Between Cancer and Age-Related Degenerative Disease? Journal Semin Cancer Biol. 2011; 21:354-59. Pub Med: 21925603.

61. Coppe JP, Desperez PY, Krtolica A, Campisi J. The Senescence Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Journal Annu Rev Pathol Mech Dis. 2010; 5:99-118.

62. Campisi J. Aging, Cellular Senescence in Cancer. Journal Annu Rev Physiol. 2013; 75:685-705.

63. Coppe JP, Patil CK, Rodier F, Krtolica A, et al. A Human-Like Senescence Associated Secretory Phenotype is Conserved in Mouse Cells Dependent on Physiological Oxygen. Journal PLoS One. 2010; 5:e9188. Pub Med: 20169192.

64. Yang G, Rosen DG, Zhang Z, Bast ROC, Mills GB, et al. The Chemokine Growth-Regulated Oncogene One Links RAS Signaling to the Senescence External Fibroblast and Ovarian Tumorigenesis. Journal Proc Natal Acad Sci USA. 2006; 103:16472-77. Pub Med: 17060621.

65. Bavik C, Kolman I, Dean JP, Knudsen B, Plymate S. The Gene Expression Program of Prostate Fibroblast Senescence Modulates Neoplastic Epithelial Cell Proliferation Through Paracrine Mechanisms. Journal Cancer Res. 2006; 66:794-802. Pub Med: 16424011.

66. Coppe JP, Kauser K, Campisi J. Secretion of Vascular Endothelial Growth Factor by Primary Human Fibroblast at Senescence. Journal J Biol Chem. 2006; 281:29568-74. Pub Med: 16880208.

67. Acosta JC, O’Loughlen A, Banito A, Augert A, et al. Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence. Journal Cell. 2008; 133:1006-18. Pub Med: 18555777.

68. Kuilman T, Michaloglou C, Vrederveld LCW, Douma S, et al. Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network. Journal Cell. 2008; 133:1019-31. Pub Med: 18555778.

69. Kartolica A, Larocque N, Genbacev O, Ilic D, Coppe JP, et al. Gro Alpha Regulates Human Embryonic Stem Cell Self-Renewal or Adaption of Neuronal Fate. Journal Differentiation. 2011; 81:222-32. Pub Med: 21396766.

70. Pricola KL, Kuhn NZ, Haleem-Smith H, Song Y, Tuanrs. Interleukin-6 Maintains Bone Marrow-Derived Mesenchymal Stem Cell Stemness by an ERK1/2-Dependent Mechanism. Journal J Celm Biochem. 2009; 108:577-88.

71. Brack S, Conboy MJ, Roy S, Lee M, Kuo CJ, et al. Increased Wnt Signaling During Aging Alters Muscle Stem Cell Fate and Increases Fibrosis. Journal Science. 2007; 317:807-810.

72. Zhang D, Wang H, Tan Y. Wnt/Beta-Catenin Signaling Induces the Aging of Mesochimal Stem Cells Through the DNA Damaged Response and the p53/p21 Pathway. PLoS One. 2011; 6:e21397. Pub Med: 21712954.

73. Adams PD. Healing and Hurting: Molecular Mechanisms, Functions and Pathologies of Cellular Senescence. Journal Mol Cell. 2009; 36:2-14. Pub Med: 19818705.

74. Campisi J, Ladislas R. Cellular Senescence, Role in Aging and Age-Related Diseases. Journal Interdiscip Top Gerontol. 2014; 39:45-61.

75. Davalos AR, Coppe JP, Campisi J. Senescent Cells as the Source of Inflammatory Factors for Tumor Progression. Journal Cancer Metastasis Review. 2010; 29:273-83.

76. Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deurosen J, et al. Fat Tissue, Aging, and Cellular Senescence. Journal Aging Cell. 2010; 9:667-84.

77. Freund A, Orjalo A, Desperzy PY, Campisi J. Inflammatory Networks During Cellular Senescence: Causes and Consequences. Journal Trens Mol Med. 2010; 16:238-48.

78. Chung HY, Cesari N, Anton S, Marzetti E, Giovannini S, et al. Molecular Inflammation: Underpinnings of Aging and Age-Related Diseases. Journal Aging Res Rev. 2009; 8:18-230.

79. Franceschi C. Inflammaging as a Major Characteristic of Old People: Can it be Prevented or Cured? Journal Nutr Rev. 2007; 65:173-76. Pub Med: 17503712.

80. Grivennikov SI, Greten FR, Karin M. Immunity, Inflammation, and Cancer. Journal Cell. 2010; 140:883-99.

81. Hampel B, Fortschegger K, Ressler S, Chang MW, et al. Increased Expression of Extra Cellular Proteins as a Hallmark of Human Endothelial Cell in-vitro Senescence. Journal Exp Gerontol. 2006; 41:474-81.

82. Kang MK, Kameta A, Shin KH, Baluda MA, Kim HR, Park NH. Senescence Associated Genes in Normal Human Oral Keratinocytes. Journal Exp Cell Res. 2003; 287:272-81.

83. Wajapeyee M, Serra RW, Zhu X, Green MR. Oncogenic BRAF Induces Senescence and Apoptosis Through Pathways Mediated by the Secreted Protein IGFBP7. Journal Cell. 2008; 132:363-74.

84. Bitto A, Sell C, Crowe E, Malaguti M, et al. Stress-Induced Senescence in Human and Rodent Astrocytes. Journal Exp Cell Res. 2010; 316:2961-68.

85. Salminen A, Ojala J, Kaarniranta K, Soininen H. Astrocytes in the Aging Brain Express Characteristics of Senescence Associated Secretory Phenotype. Journal Eur J Neurosci. 2011; 34:3-11.

86. Roberts S, Evans EH, Kletsas D, Jaffray DC. Senescence in Human Intervertebral Discs. Journal Euro Spine J. 2006; 15:312-16.

87. Shane-Anderson A, Loeser RF. Why is Osteoarthritis an Age-Related Disease? Best Prac Res Cell In Rheumatol. 2010; 25:15-26.

88. Erusalimsky JD, Kurz DJ. Cellular Senescence In-vivo: Its Relevance in Aging and Cardiovascular Disease. Journal Exp Gerontol. 2005; 40:634-42.

89. Gorenne I, Kavurma M, Scott S, Bennett M. Vascular Muscle Cell Senescence in Atherosclerosis. Journal Cardio Vas Res. 2006; 729:9-17.

« Back to In The News