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Aging and Cardiovascular Diseases: The Role of Cellular Senescence

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Oxidative Stress in Heart Diseases

Abstract

Aging, which is associated with several undesirable processes, is a complex phenomenon. Aging mechanisms are not fully comprehended yet, however, diseased and aged cells are correlated with accumulation of senescent cells. Various studies have revealed that aging leads to structural and functional changes in cardiac cells. During aging, stresses such as telomere shortening and reactive oxygen species (ROS) induce cellular senescence which is characterized by permanent cell cycle arrest and secretion of inflammatory proteins that affect tissue environment. Especially, the effect of oxidative stress and ROS generation on macromolecules have been considered important in the modulation of various age-associated chronic disorders and the lifespan. Recent studies have shown the presence senescent phenotype in endothelial cells and smooth muscle cells of patients with heart failure, diabetes, and atherosclerosis. Existence of senescent vascular cells indicates that cellular senescence has a causative role in the pathology of cardiovascular diseases. There is also accumulating evidence that impairment in systemic metabolism is connected by cellular senescence. Therefore, clearance of senescent cells or suppression of cellular senescence is suggested as an important field for future investigation and the discovery of senolytics is seen as a promising therapy of vascular diseases. This chapter describes the phenomenon of cellular senescence with emphasis to its link to oxidative stress during aging and its essential role on the pathology of the vascular system.

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Abbreviations

AAA:

Abdominal aortic aneurysm

CVD:

Cardiovascular disease

DDR:

DNA damage response

DNA:

Deoxyribonucleic acid

EC:

Endothelial cells

ER:

Endoplasmic reticulum

ETC:

Electron transport chain

HFpEF:

Heart failure with a preserved ejection fraction

IL:

Interleukin

Keap1:

Kelch-like ECH associated protein 1

LV:

Left ventricular

MCP:

Monocyte chemoattractant protein 1

mTOR:

Mammalian target of rapamycin

NAD:

Nicotinamide adenine dinucleotide

NFκB:

Nuclear factor kappa B

NO:

Nitric oxide

NOS:

Nitric oxide synthase

NOX:

NADPH oxidases

Nrf2:

Nuclear factor erythroid 2–related factor 2:

oxLDL:

Oxidized low-density lipoproteins:

PGC-1α:

PPAR-γ coactivator 1 alpha

ROS:

Reactive oxygen species

SAHF:

Senescence-associated heterochromatin foci

SAMP8:

Senescence accelerated mice prone 8

SASP:

Senescence-associated secretory phenotype:

SA-β-gal:

Senescence-associated beta-galactosidase

SIPS:

Stress-induced premature senescence

SIRT:

Sirtuin

SMC:

Smooth muscle cells

SOD:

Superoxide dismutase

TGFβ:

Transforming growth factor β

TNFα:

Tumor necrosis factor

VSMC:

Vascular smooth muscle cell

References

  1. Forman DE, Alexander K, Brindis RG, Curtis AB, Maurer M, Rich MW, Sperling L, Wenger NK (2016) Improved cardiovascular disease outcomes in older adults. F1000Res 5(F1000 Faculty Rev):112

    Article  Google Scholar 

  2. Lakatta EG (2003) Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part III: cellular and molecular clues to heart and arterial aging. Circulation 107:490–497

    Article  PubMed  Google Scholar 

  3. Lakatta EG (1993) Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 73(2):413–467

    Article  CAS  PubMed  Google Scholar 

  4. Hao Y, Pickering GP (2016) Cellular senescence and vascular disease: novel routes to better understanding and therapy. Can J Cardiol 32:612–623

    Article  Google Scholar 

  5. Forman K, Vara E, Garcia C, Kireev R, Cuesta S, Escames G, Tresguerres JA (2011) Effect of a combined treatment with growth hormone and melatonin in the cardiological aging on male SAMP8 mice. J Gerontol A Biol Sci Med Sci 66:823–834

    Article  PubMed  CAS  Google Scholar 

  6. Cevenini E, Caruso C, Candore G, Capri M, Nuzzo D, Duro G, Rizzo C, Colonna-Romano G, Lio D, Di Carlo D, Palmas MG, Scurti M, Pini E, Franceschi C, Vasto S (2010) Age-related inflammation: the contribution of different organs, tissues and systems. How to face it for therapeutic approaches. Curr Pharm Des 16:609–618

    Article  CAS  PubMed  Google Scholar 

  7. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153(6):1194–1217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. de Cabo R, Carmona-Gutierrez D, Bernier M, Hall MN, Madeo F (2014) The search for antiaging interventions: from elixirs to fasting regimens. Cell 157(7):1515–1526

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621

    Article  CAS  PubMed  Google Scholar 

  10. Storer M, Mas A, Robert-Moreno A et al (2013) Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155:1119–1130

    Article  CAS  PubMed  Google Scholar 

  11. Childs BG, Durik M, Baker DJ, Deursen JMV (2015) Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med 21(12):1424–1435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang JC, Bennett M (2012) Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res 111(2):245–259

    Article  CAS  PubMed  Google Scholar 

  13. Yoshida Y, Shimizu I, Katsuumi G, Jiao S, Suda M, Hayashi Y et al (2015) p53-induced inflammation exacerbates cardiac dysfunction during pressure overload. J Mol Cell Cardiol 85:183–198

    Article  CAS  PubMed  Google Scholar 

  14. Yokoyama M, Okada S, Nakagomi A, Moriya J, Shimizu I, Nojima A et al (2014) Inhibition of endothelial p53 improves metabolic abnormalities related to dietary obesity. Cell Rep 7(5):1691–1703

    Article  CAS  PubMed  Google Scholar 

  15. North BJ, Sinclair DA (2012) The intersection between aging and cardiovascular disease. Circ Res 110(8):1097–1108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Drummond GR, Sobey CG (2014) Endothelial NADPH oxidases: which NOX to target in vascular disease? Trends Endocrinol Metab 25(9):452–463

    Article  CAS  PubMed  Google Scholar 

  17. Kovacic JC, Moreno P, Nabel EG, Hachinski V, Fuster V (2011) Cellular senescence, vascular disease, and aging: part 2 of a 2-part review: clinical vascular disease in the elderly. Circulation 123:1900–1910

    Article  PubMed  Google Scholar 

  18. Corti R, Fuster V, Badimon JJ (2003) Pathogenetic concepts of acute coronary syndromes. J Am Coll Cardiol 41:7S–14S

    Article  CAS  PubMed  Google Scholar 

  19. Chen B, Lu Y, Chen Y, Cheng J (2015) The role of Nrf2 in oxidative stress-induced endothelial injuries. J Endocrinol 225:R83–R99

    Article  CAS  PubMed  Google Scholar 

  20. Reiter RJ, Tan DX, Galano A (2014) Melatonin: exceeding expectations. Physiology (Bethesda) 29:325–333

    CAS  Google Scholar 

  21. Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75:685–705

    Article  CAS  PubMed  Google Scholar 

  22. Bodnar AG, Ouellette M, Frolkis M et al (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279:349–352

    Article  CAS  PubMed  Google Scholar 

  23. Tan FC, Hutchison ER, Eitan E et al (2014) Are there roles for brain cell senescence in aging and neurodegenerative disorders? Biogerontology 15:643–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. van Deursen JM (2014) The role of senescent cells in ageing. Nature 509:439–446

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Dimri GP (2005) What has senescence got to do with cancer? Cancer Cell 7:505–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Correia-Melo C, Hewitt G, Passos JF (2014) Telomeres, oxidative stress and inflammatory factors: partners in cellular senescence? Longev Healthspan 3(1):1

    Article  PubMed  PubMed Central  Google Scholar 

  27. Hewitt G, Jurk D, Marques FD et al (2012) Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat Commun 3:708

    Article  PubMed  CAS  Google Scholar 

  28. Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 123:966–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Barascu A, Le Chalony C, Pennarun G et al (2012) Oxidative stress induces an ATM-independent senescence pathway through p38 MAPK-mediated lamin B1 accumulation. EMBO J 31:1080–1094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sebastian C, Lloberas J, Celada A (2009) Molecular and cellular aspects of macrophage aging. In: Fulop T (ed) Handbook on immunosenescence. Springer, Dordrecht, pp 919–945

    Chapter  Google Scholar 

  31. Acosta JC, Banito A, Wuestefeld T et al (2013) A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 15:978–990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Stewart SA, Weinberg RA (2006) Telomeres: cancer to human aging. Annu Rev Cell Dev Biol 22:531–557

    Article  CAS  PubMed  Google Scholar 

  33. Lane DP (1992) Cancer. p53, guardian of the genome. Nature 358(6381):15–16

    Article  CAS  PubMed  Google Scholar 

  34. Green DR, Chipuk JE (2006) p53 and metabolism: inside the TIGAR. Cell 126(1):30–32

    Article  CAS  PubMed  Google Scholar 

  35. Sano M, Minamino T, Toko H, Miyauchi H, Orimo M, Qin Y et al (2007) p53- induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature 446(7134):444–448

    Article  CAS  PubMed  Google Scholar 

  36. Chen Q, Fischer A, Reagan JD, Yan LJ, Ames BN (1995) Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci U S A 92:4337–4341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jeyapalan JC, Sedivy JM (2008) Cellular senescence and organismal aging. Mech Ageing Dev 129:467–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P et al (2003) Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 22(16):4212–4222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120(4):513–522

    Article  CAS  PubMed  Google Scholar 

  40. Voghel G, Thorin-Trescases N, Farhat N et al (2007) Cellular senescence in endothelial cells from atherosclerotic patients is accelerated by oxidative stress associated with cardiovascular risk factors. Mech Ageing Dev 128:662–671

    Article  CAS  PubMed  Google Scholar 

  41. Voghel G, Thorin-Trescases N, Farhat N et al (2008) Chronic treatment with N-acetyl-cystein delays cellular senescence in endothelial cells isolated from a subgroup of atherosclerotic patients. Mech Ageing Dev 129:261–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Varela I, Cadinanos J, Pendas AM, Gutierrez-Fernandez A, Folgueras AR, Sanchez LM et al (2005) Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Nature 437(7058):564–568

    Article  CAS  PubMed  Google Scholar 

  43. Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C et al (2007) Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448(7151):375–379

    Article  CAS  PubMed  Google Scholar 

  44. Garcia-Cao I, Garcia-Cao M, Martin-Caballero J, Criado LM, Klatt P, Flores JM et al (2002) “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J 21(22):6225–6235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tomas-Loba A, Flores I, Fernandez-Marcos PJ, Cayuela ML, Maraver A, Tejera A et al (2008) Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135(4):609–622

    Article  CAS  PubMed  Google Scholar 

  46. Baker DJ, Weaver RL, van Deursen JM (2013) p21 both attenuates and drives senescence and aging in BubR1 progeroid mice. Cell Rep 3(4):1164–1174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dimri GP, Lee X, Basile G et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92:9363–9367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Salama R, Sadaie M, Hoare M, Narita M (2014) Cellular senescence and its effector programs. Genes Dev 28(2):99–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Carpi A, Menabo R, Kaludercic N et al (2009) The cardioprotective effects elicited by p66(Shc) ablation demonstrate the crucial role of mitochondrial ROS formation in ischemia/reperfusion injury. Biochim Biophys Acta 1787:774–780

    Article  CAS  PubMed  Google Scholar 

  50. Fan Q, Chen L, Cheng S, Li F, Lau WB, Wang Le F et al (2014) Aging aggravates nitrate-mediated ROS/RNS changes. Oxidative Med Cell Longev 376515:2014

    Google Scholar 

  51. Correia-Melo C, Marques FD, Anderson R et al (2016) Mitochondria are required for proageing features of the senescent phenotype. EMBO J 35:724–742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chen Q, Fischer A, Reagan JD et al (1995) Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci U S A 92:4337–4341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Parrinello S, Samper E, Krtolica A et al (2003) Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol 5:741–747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Colavitti R, Finkel T (2005) Reactive oxygen species as mediators of cellular senescence. IUBMB Life 57:277–281

    Article  CAS  PubMed  Google Scholar 

  55. d’Adda di Fagagna F, Reaper PM, Clay-Farrace L et al (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194–198

    Article  PubMed  CAS  Google Scholar 

  56. Passos JF, Nelson G, Wang C et al (2010) Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol 6:347

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Wiley CD, Velarde MC, Lecot P et al (2016) Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab 23:303–314

    Article  CAS  PubMed  Google Scholar 

  58. Kuilman T, Peeper DS (2009) Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 9:81–94

    Article  CAS  PubMed  Google Scholar 

  59. Bayram B, Ozcelik B, Grimm S, Roeder T, Schrader C, Ernst IM, Wagner AE, Grune T, Frank J, Rimbach G (2012) A diet rich in olive oil phenolics reduces oxidative stress in the heart of SAMP8 mice by induction of Nrf2-dependentgene expression. Rejuvenation Res 15:71–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Karuppagounder V, Arumugam S, Thandavarayan RA, Sreedhar R, Giridharan VV, Watanabe K (2016) Molecular targets of quercetin with anti-inflammatory properties in atopic dermatitis. Drug Discov Today 21:632–639

    Article  CAS  PubMed  Google Scholar 

  61. Rodriguez MI, Carretero M, Escames G, Lopez LC, Maldonado MD, Tan DX, Reiter RJ, Acuna-Castroviejo D (2007) Chronic melatonin treatment prevents age-dependent cardiac mitochondrial dysfunction in senescence-accelerated mice. Free Radic Res 41:15–24

    Article  CAS  PubMed  Google Scholar 

  62. Miquel J (1998) An update on the oxygen stress-mitochondrial mutation theory of aging: genetic and evolutionary implications. Exp Gerontol 33:113–126

    Article  CAS  PubMed  Google Scholar 

  63. Spencer NF, Poynter ME, Im SY, Daynes RA (1997) Constitutive activation of NF-kappa B in an animal model of aging. Int Immunol 9(10):1581–1588

    Article  CAS  PubMed  Google Scholar 

  64. Ziegler DV, Wiley CD, Velarde MC (2015) Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging. Aging Cell 14:1–7

    Article  CAS  PubMed  Google Scholar 

  65. Nakahara H, Kanno T, Inai Y, Utsumi K, Hiramatsu M, Mori A, Packer L (1998) Mitochondrial dysfunction in the senescence accelerated mouse (SAM). Free Radic Biol Med 24:85–92

    Article  CAS  PubMed  Google Scholar 

  66. Sreedhar R, Giridharan VV, Arumugam S, Karuppagounder V, Palaniyandi SS, Krishnamurthy P, Quevedo J, Watanabe K, Konishi T, Thandavarayan RA (2016) Role of MAPK-mediated endoplasmic reticulum stress signaling in the heart during aging in senescence-accelerated prone mice. Biofactors 42(4):368–375

    Article  CAS  PubMed  Google Scholar 

  67. Gomes AP, Price NL, Ling AJ et al (2013) Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155:1624–1638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ruderman NB, Xu XJ, Nelson L et al (2010) AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab 298:E751–E760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhang H, Ryu D, Wu Y et al (2016) NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352(6292):1436–1443

    Article  CAS  PubMed  Google Scholar 

  70. Passos JF, Saretzki G, Ahmed S et al (2007) Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol 5:e110

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Blackburn EH, Epel ES, Lin J (2015) Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science 350:1193–1198

    Article  CAS  PubMed  Google Scholar 

  72. Rodriguez MI, Escames G, Lopez LC, Garcia JA, Ortiz F, Lopez A, Acuna-Castroviejo D (2007) Melatonin administration prevents cardiac and diaphragmatic and diaphragmatic mitochondrial oxidative damage in senescence-accelerated mice. J Endocrinol 194:637–643

    Article  CAS  PubMed  Google Scholar 

  73. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300

    Article  CAS  PubMed  Google Scholar 

  74. Harman D (2006) Free radical theory of aging: an update: increasing the functional lifespan. Ann N Y Acad Sci 1067:10–21

    Article  CAS  PubMed  Google Scholar 

  75. Tatchum-Talom R, Martin DS (2004) Tempol improves vascular function in the mesenteric vascular bed of senescent rats. Can J Physiol Pharmacol 82(3):200–207

    Article  CAS  PubMed  Google Scholar 

  76. Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, Losonczy G (2011) Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. AmJ Physiol Heart Circ Physiol 301:H363–H372

    Article  CAS  Google Scholar 

  77. Zhao W, Zheng XL, Peng DQ, Zhao SP (2015) Myocyte enhancer factor 2A regulates hydrogen peroxide-induced senescence of vascular smooth muscle cells via microRNA-143. J Cell Physiol 230(9):2202–2211

    Article  CAS  PubMed  Google Scholar 

  78. Fyhrquist F, Saijonmaa O, Strandberg T (2013) The roles of senescence and telomere shortening in cardiovascular disease. Nat Rev Cardiol 10:274–283

    Article  CAS  PubMed  Google Scholar 

  79. Minamino T, Miyauchi H, Yoshida T et al (2004) The role of vascular cell senescence in atherosclerosis: antisenescence as a novel therapeutic strategy for vascular aging. Curr Vasc Pharmacol 2:141–148

    Article  CAS  PubMed  Google Scholar 

  80. Migliaccio E, Giorgio M, Mele S et al (1999) The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402:309–313

    Article  CAS  PubMed  Google Scholar 

  81. Suski JM, Karkucinska-Wieckowska A, Lebiedzinska M et al (2011) p66Shc aging protein in control of fibroblasts cell fate. Int J Mol Sci 12:5373–5389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Cosentino F, Francia P, Camici GG et al (2008) Final common molecular pathways of aging and cardiovascular disease: role of the p66Shc protein. Arterioscler Thromb Vasc Biol 28:622–628

    Article  CAS  PubMed  Google Scholar 

  83. Franzeck FC, Hof D, Spescha RD et al (2012) Expression of the aging gene p66Shc is increased in peripheral blood monocytes of patients with acute coronary syndrome but not with stable coronary artery disease. Atherosclerosis 220:282–286

    Article  CAS  PubMed  Google Scholar 

  84. Rodríguez-Mañas L, El-Assar M, Vallejo S, López-Dóriga P, Solís J, Petidier R, Montes M, Nevado J, Castro M, Gómez-Guerrero C (2009) Endothelial dysfunction in aged humans is related with oxidative stress and vascular inflammation. Aging Cell 8(3):226–238

    Article  PubMed  CAS  Google Scholar 

  85. Mavrogonatou DE, Sklirou A, Kletsas D (2015) Oxidative stress inhibits the proliferation, induces premature senescence and promotes a catabolic phenotype in human nucleus pulposus intervertebral disc cells. Eur Cell Mater 30:89

    Article  PubMed  Google Scholar 

  86. Muñozespín D, Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15(7):482–496

    Article  CAS  Google Scholar 

  87. Ke Y, Li D, Zhao M et al (2018) Gut flora-dependent metabolite Trimethylamine-N-oxide accelerates endothelial cell senescence and vascular aging through oxidative stress. Free Radic Biol Med 116:88–100

    Article  CAS  PubMed  Google Scholar 

  88. Agabiti-Rosei C et al (2017) Effect of long-term treatment with melatonin on vascular markers of oxidative stress/inflammation and on the anticontractile activity of perivascular fat in aging mice. Hypertens Res 40:41–50

    Article  CAS  PubMed  Google Scholar 

  89. Borlaug BA (2014) The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 11(9):507–515

    Article  CAS  PubMed  Google Scholar 

  90. Shih H, Lee B, Lee RJ, Boyle AJ (2011) The aging heart and post-infarction left ventricular remodeling. J Am Coll Cardiol 57(1):9–17

    Article  PubMed  Google Scholar 

  91. Mohammed SF, Redfield MM (2015) Response to letters regarding article, “coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction”. Circulation 132(16):e206

    Article  PubMed  PubMed Central  Google Scholar 

  92. Paulus WJ, Tschope C (2013) A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 62(4):263–271

    Article  PubMed  Google Scholar 

  93. Rebrin I, Zicker S, Wedekind KJ, Paetau-Robinson I, Packer L, Sohal RS (2005) Effect of antioxidant-enriched diets on glutathione redox status in tissue homogenates and mitochondria of the senescence-accelerated mouse. Free Radic Biol Med 39:549–557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS et al (1984) Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 311(13):819–823

    Article  CAS  PubMed  Google Scholar 

  95. Gogiraju R, Xu X, Bochenek ML, Steinbrecher JH, Lehnart SE, Wenzel P et al (2015) Endothelial p53 deletion improves angiogenesis and prevents cardiac fibrosis and heart failure induced by pressure overload in mice. J Am Heart Assoc 4(2):e001770

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Morgan RG, Ives SJ, Lesniewski LA, Cawthon RM, Andtbacka RH, Noyes RD et al (2013) Age-related telomere uncapping is associated with cellular senescence and inflammation independent of telomere shortening in human arteries. Am J Physiol Heart Circ Physiol 305(2):H251–H258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Satoh M, Ishikawa Y, Takahashi Y, Itoh T, Minami Y, Nakamura M (2008) Association between oxidative DNA damage and telomere shortening in circulating endothelial progenitor cells obtained from metabolic syndrome patients with coronary artery disease. Atherosclerosis 198(2):347–353

    Article  CAS  PubMed  Google Scholar 

  98. van der Harst P, van der Steege G, de Boer RA, Voors AA, Hall AS, Mulder MJ et al (2007) Telomere length of circulating leukocytes is decreased in patients with chronic heart failure. J Am Coll Cardiol 49(13):1459–1464

    Article  PubMed  CAS  Google Scholar 

  99. Haycock PC, Heydon EE, Kaptoge S, Butterworth AS, Thompson A, Willeit P (2014) Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis. BMJ 349(3):g4227

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Salpea KD, Humphries SE (2010) Telomere length in atherosclerosis and diabetes. Atherosclerosis 209(1):35–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gevaert AB, Shakeri H, Leloup AJ, van Hove CE, de Meyer GRY, Vrints CJ et al (2017) Endothelial senescence contributes to heart failure with preserved ejection fraction in an aging mouse model. Circ Heart Fail 10(6):e003806

    Article  CAS  PubMed  Google Scholar 

  102. Navab M, Berliner JA, Watson AD et al (1996) The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture. Arterioscler Thromb Vasc Biol 16:831–842

    Article  CAS  PubMed  Google Scholar 

  103. Spina M, Garbisa S, Hinnie J, Hunter JC, Serafini-Fracassini A (1983) Age-related changes in composition and mechanical properties of the tunica media of the upper thoracic human aorta. Arteriosclerosis 3(1):64–76

    Article  CAS  PubMed  Google Scholar 

  104. Gerstenblith G, Frederiksen J, Yin FC, Fortuin NJ, Lakatta EG, Weisfeldt ML (1977) Echocardiographic assessment of a normal adult aging population. Circulation 56(2):273–278

    Article  CAS  PubMed  Google Scholar 

  105. Katsuumi G, Shimizu I, Yoshida Y, Minamino T (2018) Vascular senescence in cardiovascular and metabolic diseases. Front Cardiovasc Med 5:18

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Chien Y, Scuoppo C, Wang X et al (2011) Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity. Genes Dev 25:2125–2136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Freund A, Patil CK, Campisi J (2011) p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J 30:1536–1548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Csiszar A, Wang M, Lakatta EG et al (2008) Inflammation and endothelial dysfunction during aging: role of NF-kappaB. J Appl Physiol (1985) 105:1333–1341

    Article  CAS  Google Scholar 

  109. Eren M, Boe AE, Murphy SB et al (2014) PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proc Natl Acad Sci U S A 111:7090–7095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kuro-o M (2008) Klotho as a regulator of oxidative stress and senescence. Biol Chem 389:233–241

    Article  CAS  PubMed  Google Scholar 

  111. Cafueri G, Parodi F, Pistorio A, Bertolotto M, Ventura F, Gambini C et al (2012) Endothelial and smooth muscle cells from abdominal aortic aneurysm have increased oxidative stress and telomere attrition. PLoS One 7(4):e35312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gorenne I, Kavurma M, Scott S, Bennett M (2006) Vascular smooth muscle cell senescence in atherosclerosis. Cardiovasc Res 72:9–17

    Article  CAS  PubMed  Google Scholar 

  113. Wang J, Uryga AK, Reinhold J et al (2015) Vascular smooth muscle cell senescence promotes atherosclerosis and features of plaque vulnerability. Circulation 132:1909–1919

    Article  CAS  PubMed  Google Scholar 

  114. Herbert KE, Mistry Y, Hastings R, Poolman T, Niklason L, Williams B (2008) Angiotensin II-mediated oxidative DNA damage accelerates cellular senescence in cultured human vascular smooth muscle cells via telomere dependent and independent pathways. Circ Res 102(2):201–208

    Article  CAS  PubMed  Google Scholar 

  115. Minamino T, Miyauchi H, Yoshida T et al (2002) Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105:1541–1544

    Article  CAS  PubMed  Google Scholar 

  116. Lin JR, Shen WL, Yan C, Gao PJ (2015) Downregulation of dynamin-related protein 1 contributes to impaired autophagic flux and angiogenic function in senescent endothelial cells. Arterioscler Thromb Vasc Biol 35(6):1413–1422

    Article  CAS  PubMed  Google Scholar 

  117. Warboys CM, de Luca A, Amini N, Luong L, Duckles H, Hsiao S et al (2014) Disturbed flow promotes endothelial senescence via a p53-dependent pathway. Arterioscler Thromb Vasc Biol 34(5):985–995

    Article  CAS  PubMed  Google Scholar 

  118. Gardner SE, Humphry M, Bennett MR, Clarke MCH (2016) Senescent vascular smooth muscle cells drive inflammation through an interleukin-1α-dependent senescence-associated secretory phenotype. Atherosclerosis 244:e5

    Article  Google Scholar 

  119. Kunieda T, Minamino T, Nishi J et al (2006) 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

    Article  CAS  PubMed  Google Scholar 

  120. Faggiotto A, Ross R, Harker L (1984) Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation. Arteriosclerosis 4(4):323–340

    Article  CAS  PubMed  Google Scholar 

  121. Miao SB, Xie XL, Yin YJ, Zhao LL, Zhang F, Shu YN et al (2017) Accumulation of smooth muscle 22α protein accelerates senescence of vascular smooth muscle cells via stabilization of p53 in vitro and in vivo. Arterioscler Thromb Vasc Biol 37(10):1849–1859. https://doi.org/10.1161/ATVBAHA.117.309378

    Article  CAS  PubMed  Google Scholar 

  122. Matthews C, Gorenne I, Scott S, Figg N, Kirkpatrick P, Ritchie A et al (2006) Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress. Circ Res 99(2):156–164

    Article  CAS  PubMed  Google Scholar 

  123. Mercer J, Figg N, Stoneman V, Braganza D, Bennett MR (2005) Endogenous p53 protects vascular smooth muscle cells from apoptosis and reduces atherosclerosis in ApoE knockout mice. Circ Res 96:667–674

    Article  CAS  PubMed  Google Scholar 

  124. Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM (2016) Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354(6311):472–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Cawthon RM, Smith KR, O'Brien E, Sivatchenko A, Kerber RA (2003) Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361(9355):393–395

    Article  CAS  PubMed  Google Scholar 

  126. Calvert PA, Liew TV, Gorenne I, Clarke M, Costopoulos C, Obaid DR et al (2011) Leukocyte telomere length is associated with high-risk plaques on virtual histology intravascular ultrasound and increased proinflammatory activity. Arterioscler Thromb Vasc Biol 31(9):2157–2164

    Article  CAS  PubMed  Google Scholar 

  127. Cudejko C, Wouters K, Fuentes L, Hannou SA, Paquet C, Bantubungi K et al (2011) p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages. Blood 118(9):2556–2566

    Article  CAS  PubMed  Google Scholar 

  128. Wang M, Monticone RE, Lakatta EG (2010) Arterial aging: a journey into subclinical arterial disease. Curr Opin Nephrol Hypertens 19(2):201–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Barja G (2013) Updating the mitochondrial free radical theory of aging: an integrated view, key aspects, and confounding concepts. Antioxid Redox Signal 19(12):1420–1445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kotsis V, Stabouli S, Karafillis I, Nilsson P (2011) Early vascular aging and the role of central blood pressure. J Hypertens 29(10):1847–1853

    Article  CAS  PubMed  Google Scholar 

  131. Morgan RG, Ives SJ, Walker AE, Cawthon RM, Andtbacka RH, Noyes D et al (2014) Role of arterial telomere dysfunction in hypertension: relative contributions of telomere shortening and telomere uncapping. J Hypertens 32(6):1293–1299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Durik M, Kavousi M, van der Pluijm I, Isaacs A, Cheng C, Verdonk K et al (2012) Nucleotide excision DNA repair is associated with age-related vascular dysfunction. Circulation 126(4):468–478. https://doi.org/10.1161/CIRCULATIONAHA.112.104380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Westhoff JH, Hilgers KF, Steinbach MP, Hartner A, Klanke B, Amann K et al (2008) Hypertension induces somatic cellular senescence in rats and humans by induction of cell cycle inhibitor p16INK4a. Hypertension 52(1):123–129

    Article  CAS  PubMed  Google Scholar 

  134. Boe AE, Eren M, Murphy SB, Kamide CE, Ichimura A, Terry D et al (2013) Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-nitro-L-arginine methyl ester-induced hypertension and vascular senescence. Circulation 128(21):2318–2324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Vasa M, Breitschopf K, Zeiher AM, Dimmeler S (2000) Nitric oxide activates telomerase and delays endothelial cell senescence. Circ Res 87(7):540–542

    Article  CAS  PubMed  Google Scholar 

  136. Rubio-Ruiz ME, Perez-Torres I, Soto ME, Pastelin G, Guarner-Lans V (2014) Aging in blood vessels. Medicinal agents FOR systemic arterial hypertension in the elderly. Ageing Res Rev 18:132–147

    Article  CAS  PubMed  Google Scholar 

  137. Singh T, Newman AB (2011) Inflammatory markers in population studies of aging. Ageing Res Rev 10:319–329

    Article  CAS  PubMed  Google Scholar 

  138. Nabha L, Garbern JC, Buller CL, Charpie JR (2005) Vascular oxidative stress precedes high blood pressure in spontaneously hypertensive rats. Clin Exp Hypertens 27:71–82

    Article  CAS  PubMed  Google Scholar 

  139. Ward NC, Hodgson JM, Puddey IB, Mori TA, Beilin LJ, Croft KD (2004) Oxidative stress in human hypertension: association with antihypertensive treatment, gender, nutrition, and lifestyle. Free Radic Biol Med 36:226–232

    Article  CAS  PubMed  Google Scholar 

  140. Touyz RM, Schiffrin EL (2001) Increased generation of superoxide by angiotensin II in smooth muscle cells from resistance arteries of hypertensive patients: role of phospholipase D-dependent NAD(P)H oxidase-sensitive pathways. J Hypertens 19:1245–1254

    Article  CAS  PubMed  Google Scholar 

  141. Wind S, Beuerlein K, Armitage ME, Taye A, Kumar AH, Janowitz D et al (2010) Oxidative stress and endothelial dysfunction in aortas of aged spontaneously hypertensive rats by NOX1/2 is reversed by NADPH oxidase inhibition. Hypertension 56(3):490–497

    Article  CAS  PubMed  Google Scholar 

  142. Montezano AC, Burger D, Ceravolo GS, Yusuf H, Montero M, Touyz RM (2011) Novel Nox homologues in the vasculature: focusing on Nox4 and Nox5. Clin Sci (Lond) 120(4):131–141

    Article  CAS  Google Scholar 

  143. Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N (2014) Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract 105:141–150

    Article  CAS  PubMed  Google Scholar 

  144. Kim CS, Park HS, Kawada T et al (2006) Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J Obes (Lond) 30:1347–1355

    Article  CAS  Google Scholar 

  145. Utsal L, Tillmann V, Zilmer M et al (2012) Elevated serum IL-6, IL-8, MCP-1, CRP, and IFN-g levels in 10- to 11-year-old boys with increased BMI. Horm Res Paediatr 78:31–39

    Article  CAS  PubMed  Google Scholar 

  146. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM (2001) C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286:327–334

    Article  CAS  PubMed  Google Scholar 

  147. Schneider DJ, Sobel BE (2012) PAI-1 and diabetes: a journey from the bench to the bedside. Diabetes Care 35:1961–1967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Xu H, Barnes GT, Yang Q et al (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Stern DM, Yan SD, Yan SF, Schmidt AM (2002) Receptor for advanced glycation endproducts (RAGE) and the complications of diabetes. Ageing Res Rev 1:1–15

    Article  CAS  PubMed  Google Scholar 

  150. Palmer AK et al (2015) Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes 64:2289–2298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Chen J, Brodsky SV, Goligorsky DM et al (2002) Glycated collagen I induces premature senescence-like phenotypic changes in endothelial cells. Circ Res 90:1290–1298

    Article  CAS  PubMed  Google Scholar 

  152. Tchkonia T, Morbeck DE, Von Zglinicki T et al (2010) Fat tissue, aging, and cellular senescence. Aging Cell 9:667–684

    Article  CAS  PubMed  Google Scholar 

  153. Hamm JK, el Jack AK, Pilch PF, Farmer SR (1999) Role of PPAR gamma in regulating adipocyte differentiation and insulin-responsive glucose uptake. Ann N Y Acad Sci 892:134–145

    Article  CAS  PubMed  Google Scholar 

  154. Tchkonia T, Corkey BE, Kirkland JL (2006) Current views of the fat cell as an endocrine cell: lipotoxicity. In: Bray GA, Ryan DH (eds) Overweight and the metabolic syndrome: from bench to bedside (endocrine updates). Springer, New York, pp 105–118

    Chapter  Google Scholar 

  155. 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  CAS  PubMed  Google Scholar 

  156. Uchida T, Nakamura T, Hashimoto N et al (2005) Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice. Nat Med 11:175–182

    Article  CAS  PubMed  Google Scholar 

  157. Tavana O, Puebla-Osorio N, Sang M, Zhu C (2010) Absence of p53-dependent apoptosis combined with nonhomologous end-joining deficiency leads to a severe diabetic phenotype in mice. Diabetes 59:135–142

    Article  CAS  PubMed  Google Scholar 

  158. Verzola D, Gandolfo MT, Gaetani G et al (2008) Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy. Am J Physiol Renal Physiol 295:F1563–F1573

    Article  CAS  PubMed  Google Scholar 

  159. Zhu Y, Tchkonia T, Pirtskhalava T et al (2015) The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14:644–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Wang E (1995) Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res 55:2284–2292

    CAS  PubMed  Google Scholar 

  161. Montero JC, Seoane S, Ocana A, Pandiella A (2011) Inhibition of SRC family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors. Clin Cancer Res 17:5546–5552

    Article  CAS  PubMed  Google Scholar 

  162. Bruning A (2013) Inhibition of mTOR signaling by quercetin in cancer treatment and prevention. Anti Cancer Agents Med Chem 13:1025–1031

    Article  CAS  Google Scholar 

  163. Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J et al (2016) Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 22(1):78–83

    Article  CAS  PubMed  Google Scholar 

  164. Raez LE, Papadopoulos K, Ricart AD et al (2013) A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 71:523–530

    Article  CAS  PubMed  Google Scholar 

  165. van der Veer E, Ho C, O’Neil C et al (2007) Extension of human cell lifespan by nicotinamide phosphoribosyltransferase. J Biol Chem 282:10841–10845

    Article  PubMed  CAS  Google Scholar 

  166. Borradaile NM, Pickering JG (2009) Nicotinamide phosphoribosyltransferase imparts human endothelial cells with extended replicative lifespan and enhanced angiogenic capacity in a high glucose environment. Aging Cell 8:100–112

    Article  CAS  PubMed  Google Scholar 

  167. Canto C, Auwerx J (2012) Targeting sirtuin 1 to improve metabolism: all you need is NAD(ş)? Pharmacol Rev 64:166–187

    Article  CAS  PubMed  Google Scholar 

  168. Yin H, van der Veer E, Frontini MJ et al (2012) Intrinsic directionality of migrating vascular smooth muscle cells is regulated by NAD(ş)biosynthesis. J Cell Sci 125:5770–5780

    Article  CAS  PubMed  Google Scholar 

  169. Mahmoudi M, Gorenne I, Mercer J et al (2008) Statins use a novel Nijmegen breakage syndrome-1-dependent pathway to accelerate DNA repair in vascular smooth muscle cells. Circ Res 103:717–725

    Article  CAS  PubMed  Google Scholar 

  170. Dong W, Quo W, Wang F, Li C, Xie Y, Zheng X, Shi H (2015) Electroacupuncture upregulates SIRT1-Dependent PGC-1alpha expression in SAMP8 mice. Med Sci Monit 21:3356–3362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Pole A, Dimri M, Dimri G (2016) Oxidative stress, cellular senescence and aging. AIMS Mol Sci 3(3):300–324

    Article  CAS  Google Scholar 

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Acknowledgment

This work was supported by The Scientific and Technological Council of Turkey (TUBITAK) 2219 Grant Program.

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Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey

    Perinur Bozaykut

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  1. Perinur Bozaykut
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Editors and Affiliations

  1. Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

  2. Institute of Cardiovascular Sciences, St Boniface Hospital, Albrechtsen Research Centre, Winnipeg, MB, Canada

    Naranjan S Dhalla

  3. Translational Health Science and Technology (THSTI), Department of Biotechnology, Faridabad, India

    Nirmal K Ganguly

  4. Translational Health Science and Technology (THSTI), Department of Biotechnology, Faridabad, India

    Madhu Dikshit

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Bozaykut, P. (2019). Aging and Cardiovascular Diseases: The Role of Cellular Senescence. In: Chakraborti, S., Dhalla, N., Ganguly, N., Dikshit, M. (eds) Oxidative Stress in Heart Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-13-8273-4_10

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