Mechanisms of vascular aging

Vascular aging plays a key role in morbidity and mortality in the elderly. With age, the vasculature undergoes changes characterized by endothelial dysfunction, wall thickening, decreased elongation, and arterial stiffness. The review focuses on the main cellular and molecular mechanisms of aging, including oxidative stress, endothelial dysfunction, inflammation, increased arterial stiffness, and molecular genetic aspects. Their role in the pathogenesis of diseases associated with aging is considered. Some of the molecular mechanisms underlying these processes include increased expression and activation of matrix metalloproteinases, activation of transforming growth factor β1 signaling, increased levels of C-reactive protein, interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)α, and N-terminal pro B-type natriuretic peptide (NT-pro-BNP), and activation of proinflammatory signaling pathways. These events can be caused by vasoactive agents, such as angiotensin II and endothelin-1, the levels of which increase with aging. For prevention of cardiovascular diseases, it is important to understand the mechanisms underlying age-related pathophysiological changes in the blood vessels.

1. Lu J., Huang Y., Wang Y., Li Y., Zhang Y., Wu J. et al. Profiling plasma peptides for the identification of potential ageing biomarkers in Chinese Han adults. PLoS One. 2012;7(7):e39726. DOI: 10.1371/journal.pone.0039726.

2. Wagner K.H., Cameron-Smith D., Wessner B., Franzke B. Biomarkers of aging: from function to molecular biology. Nutrients. 2016;8(6):338. DOI: 10.3390/nu8060338.

3. Laina A., Stellos K., Stamatelopoulos K. Vascular ageing: Underlying mechanisms and clinical implications. Exp. Gerontol. 2018;109:16–30. DOI: 10.1016/j.exger.2017.06.007.

4. Sepúlveda C., Palomo I., Fuentes E. Mechanisms of endothelial dysfunction during aging: predisposition to thrombosis. Mech. Ageing Dev. 2017;164:91–99. DOI: 10.1016/j.mad.2017.04.011.

5. Ungvari Z., Tarantini S., Donato A.J., Galvan V., Csiszar A. Mechanisms of vascular aging. Circ. Res. 2018;123(7):849– 867. DOI: 10.1161/CIRCRESAHA.118.311378.

6. El Assar M., Angulo J., Rodríguez-Mañas L. Oxidative stress and vascular inflammation in aging. Free Radic. Biol. Med. 2013;65:380–401. DOI: 10.1016/j.freeradbiomed.2013.07.003.

7. Tan B.L., Norhaizan M.E. Carotenoids: How effective are they to prevent age-related diseases? Molecules. 2019;24(9):1801. DOI: 10.3390/molecules24091801.

8. Meschiari C.A., Ero O.K., Pan H., Finkel T., Lindsey M.L. The impact of aging on cardiac extracellular matrix. GeroScience. 2017; 39(1):7–18. DOI: 10.1007/s11357-017-9959-9.

9. Wang M., Jiang L., Monticone R.E., Lakatta E.G. Proinflammation: the key to arterial aging. Trends Endocrinol. Metab. 2014;25(2):72–79. DOI: 10.1016/j.tem.2013.10.002.

10. Donato A.J., Machin D.R., Lesniewski L.A. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ. Res. 2018;123(7):825–848. DOI: 10.1161/CIRCRESAHA.118.312563.

11. Jia G., Aroor A.R., Jia C., Sowers J.R. Endothelial cell senescence in aging-related vascular dysfunction. Biochim. Biophys. Acta Mol. Basis. Dis. 2019;1865(7):1802–1809. DOI: 10.1016/j.bbadis.2018.08.008.

12. Rossman M.J., LaRocca T.J., Martens C.R., Seals D.R. Healthy lifestyle-based approaches for successful vascular aging. J. Appl. Physiol. 2018;125(6):1888–1900. DOI: 10.1152/japplphysiol.00521.2018.

13. Giudetti A.M., Salzet M., Cassano T. Oxidative stress in aging brain: nutritional and pharmacological interventions for neurodegenerative disorders. Oxid. Med. Cell Longev. 2018;2018:3416028. DOI: 10.1155/2018/3416028.

14. Liu Z., Zhou T., Ziegler A.C., Dimitrion P., Zuo L. Oxidative stress in neurodegenerative diseases: from molecular mechanisms to clinical applications. Oxid. Med. Cell Longev. 2017;2017:2525967. DOI: 10.1155/2017/2525967

15. Park S., Lakatta E.G. Role of inflammation in the pathogenesis of arterial stiffness. Yonsei Med. J. 2012;53(2):258–261. DOI: 10.3349/ymj.2012.53.2.258.

16. Feldman N., Rotter-Maskowitz A., Okun E. DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res. Rev. 2015;24(Pt.A):29–39. DOI: 10.1016/j.arr.2015.01.003.

17. Michaud M., Balardy L., Moulis G., Gaudin C., Peyrot C., Vellas B. et al. Proinflammatory cytokines, aging, and age-related diseases. J. Am. Med. Dir. Assoc. 2013;14(12):877–882. DOI: 10.1016/j.jamda.2013.05.009.

18. Shaw A.C., Goldstein D.R., Montgomery R.R. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 2013;13(12):875–887. DOI: 10.1038/nri3547.

19. Tuttle C.S.L., Thang L.A.N., Maier A.B. Markers of inflammation and their association with muscle strength and mass: A systematic review and meta-analysis. Ageing Res. Rev. 2020;64:101185. DOI: 10.1016/j.arr.2020.101185.

20. Visser M., Pahor M., Taaffe D.R., Goodpaster B.H., Simonsick E.M., Newman A.B. et al. Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women: the Health ABC Study. J. Gerontol. A. Biol. Sci. Med. Sci. 2002;57(5):M326–332. DOI: 10.1093/gerona/57.5.m326.

21. Kaptoge S., Di Angelantonio E., Lowe G., Pepys MB., Thompson S.G., Collins R. et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375(9709):132– 140. DOI: 10.1016/S0140-6736(09)61717-7.

22. Kabagambe E.K., Judd S.E., Howard V.J., Zakai N.A., Jenny N.S., Hsieh M. et al. Inflammation biomarkers and risk of allcause mortality in the reasons for geographic and racial differ ences in stroke cohort. Am. J. Epidemiol. 2011;174(3):284– 292. DOI: 10.1093/aje/kwr085.

23. Cohen A.A., Milot E., Li Q., Bergeron P., Poirier R., Dusseault-Bélanger F. et al. Detection of a novel, integrative aging process suggests complex physiological integration. PLoS One. 2015;10(3):e0116489. DOI: 10.1371/journal.pone.0116489

24. Arai Y., Martin-Ruiz C.M., Takayama M., Abe Y., Takebayashi T., Koyasu S. et al. Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians. EBioMedicine. 2015;2(10):1549–1558. DOI: 10.1016/j.ebiom.2015.07.029.

25. Salvioli S., Capri M., Bucci L., Lanni C., Racchi M., Uberti D. et al. Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53. Cancer Immunol. Immunother. 2009;58(12):1909–1917. DOI: 10.1007/s00262-008-0639-6.

26. Ragino Y.I., Stakhneva E.M., Polonskaya Y.V., Kashtanova E.V. The role of secretory activity molecules of visceral adipocytes in abdominal obesity in the development of cardiovascular disease: a review. Biomolecules. 2020; 10(3):374– 392. DOI:10.3390/biom10030374.

27. Gulcelik N.E., Halil M., Ariogul S., Usman A. Adipocytokines and aging: adiponectin and leptin. Minerva Endocrinol. 2013;38(2):203–210.

28. Poehls J., Wassel C.L., Harris T.B., Havel P.J., Swarbrick M.M., Cummings S.R. et al. Health ABC Study. Association of adiponectin with mortality in older adults: the Health, Aging, and Body Composition Study. Diabetologia. 2009;52(4):591–595. DOI: 10.1007/s00125-009-1261-7.

29. Kistorp C., Raymond I., Pedersen F., Gustafsson F., Faber J., Hildebrandt P. N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. JAMA. 2005;293(13):1609–1616. DOI: 10.1001/jama.293.13.1609.

30. Nadrowski P., Chudek J., Grodzicki T., Mossakowska M., Skrzypek M., Wiecek A. et al. Plasma level of N-terminal pro brain natriuretic peptide (NT-proBNP) in elderly population in Poland--the PolSenior Study. Exp. Gerontol. 2013;48(9):852– 857. DOI: 10.1016/j.exger.2013.05.060.

31. Clerico A., Fortunato A., Ripoli A., Prontera C., Zucchelli G.C., Emdin M. Distribution of plasma cardiac troponin I values in healthy subjects: pathophysiological considerations. Clin. Chem. Lab. Med. 2008;46(6):804–808. DOI: 10.1515/CCLM.2008.162.

32. Harvey A., Montezano A.C., Lopes R.A., Rios F., Touyz R.M. Vascular fibrosis in aging and hypertension: molecular mechanisms and clinical implications. Can. J. Cardiol. 2016;32(5):659–668. DOI: 10.1016/j.cjca.2016.02.070.

33. Nilsson P.M., Boutouyrie P., Cunha P., Kotsis V., Narkiewicz K., Parati G. et al. Early vascular ageing in translation: from laboratory investigations to clinical applications in cardiovascular prevention. J. Hypertens. 2013;31(8):1517–1526. DOI: 10.1097/HJH.0b013e328361e4bd.

34. Nilsson P.M. Early vascular aging in hypertension. Front. Cardiovasc. Med. 2020;7:6. DOI: 10.3389/fcvm.2020.00006.

35. Wang M., Kim S.H., Monticone R.E., Lakatta E.G. Matrix metalloproteinases promote arterial remodeling in aging, hypertension, and atherosclerosis. Hypertension. 2015;65(4):698–703. DOI: 10.1161/HYPERTENSIONAHA.114.03618.

36. Carrick-Ranson G., Spinale F.G., Bhella P.S., Sarma S., Shibata S., Fujimoto N. et al. Plasma matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs and aging and lifelong exercise adaptations in ventricular and arterial stiffness. Exp. Gerontol. 2019;123:36–44. DOI: 10.1016/j.exger.2019.05.004.

37. Panwar P., Butler G.S., Jamroz A., Azizi P., Overall C.M., Brömme D. Aging-associated modifications of collagen affect its degradation by matrix metalloproteinases. Matrix. Biol. 2018;65:30–44. DOI: 10.1016/j.matbio.2017.06.004.

38. Struewing I.T., Durham S.N., Barnett C.D., Mao C.D. Enhanced endothelial cell senescence by lithium-induced matrix metalloproteinase-1 expression. The Journal of Biological Chemistry. 2009; 284(26):17595–17606. DOI: 10.1074/jbc.M109.001735.

39. Мясоедова Е.И. Содержание матриксной металлопротеиназы‐1 и ее ингибитора у пациентов с ишемической кардиомиопатией. Вестник новых медицинских технологий. 2016;23(4):50–53. DOI: 10.12737/23850.

40. Shapiro S., Khodalev O., Bitterman H., Auslender R., Lahat N. Different activation forms of mmp-2 oppositely affect the fate of endothelial cells. American journal of physiology. Cell Physiology. 2010;298(4):C942–951. DOI: 10.1152/ajpcell.00305.2009.

41. Momi S., Falcinelli E., Giannini S., Ruggeri L., Cecchetti L., Corazzi T. et al. Loss of matrix metalloproteinase 2 in platelets reduces arterial thrombosis in vivo. The Journal of Experimental Medicine. 2009; 206(11):2365–2379. DOI: 10.1084/jem.20090687.

42. Kollarova M., Puzserova A., Balis P., Radosinska D., Tothova L., Bartekova M. et al. Age- and phenotype-dependent changes in circulating MMP-2 and MMP-9 activities in normotensive and hypertensive rats. Int. J. Mol. Sci. 2020;21(19):7286. DOI: 10.3390/ijms21197286.

43. Cancemi P., Aiello A., Accardi G., Caldarella R., Candore G., Caruso C. et al. The role of matrix metalloproteinases (MMP-2 and MMP-9) in ageing and longevity: focus on sicilian long-living individuals (LLIs). Mediators Inflamm. 2020;2020:8635158. DOI: 10.1155/2020/8635158.

44. Iyer R.P., Chiao Y.A., Flynn E.R., Hakala K., Cates C.A., Weintraub S.T. et al. Matrix metalloproteinase-9- dependent mechanisms of reduced contractility and increased stiffness in the aging heart. Proteomics Clin. Appl. 2016;10(1):92–107. DOI: 10.1002/prca.201500038.

45. Chiao Y.A., Dai Q., Zhang J., Lin J., Lopez E.F., Ahuja S.S et al. Multi-analyte profiling reveals matrix metalloproteinase-9 and monocyte chemotactic protein-1 as plasma biomarkers of cardiac aging. Circ. Cardiovasc. Genet. 2011;4(4):455–462. DOI: 10.1161/CIRCGENETICS.111.959981.

46. Franzke B., Neubauer O., Wagner K.H. Super DNAging-New insights into DNA integrity, genome stability and telomeres in the oldest old. Mutat. Res. Rev. Mutat. Res. 2015;766:48–57. DOI: 10.1016/j.mrrev.2015.08.001.

47. Lovell M.A., Markesbery W.R. Oxidative DNA damage in Nucleic. Acids Res. 2007;35(22):7497–7504. DOI: 10.1093/nar/gkm821.

48. Martin-Ruiz C., Dickinson H.O., Keys B., Rowan E., Kenny R.A., Von Zglinicki T. Telomere length predicts poststroke mortality, dementia, and cognitive decline. Ann. Neurol. 2006;60(2):174–180. DOI: 10.1002/ana.20869.

49. Hazane F., Sauvaigo S., Douki T., Favier A., Beani J.C. Age-dependent DNA repair and cell cycle distribution of human skin fibroblasts in response to UVA irradiation. J. Photochem. Photobiol. B. 2006;82(3):214–223. DOI: 10.1016/j.jphotobiol.2005.10.004.

50. Franzke B., Halper B., Hofmann M., Oesen S., Peherstorfer H., Krejci K. et al. Vienna Active Ageing Study Group. The influence of age and aerobic fitness on chromosomal damage in Austrian institutionalised elderly. Mutagenesis. 2014;29(6):441–445. DOI: 10.1093/mutage/geu042.

51. Sanders J.L., Newman A.B. Telomere length in epidemiology: a biomarker of aging, age-related disease, both, or neither? Epidemiol. Rev. 2013;35(1):112–131. DOI: 10.1093/epirev/mxs008.

52. Inukai S., Slack F. MicroRNAs and the genetic network in aging. J. Mol. Biol. 2013;425(19):3601–3608. DOI: 10.1016/j.jmb.2013.01.023.

53. Keller A., Meese E. Can circulating miRNAs live up to the promise of being minimal invasive biomarkers in clinical settings? Wiley Interdiscip. Rev. RNA. 2016;7(2):148–156. DOI: 10.1002/wrna.1320

54. López-Otín C., Blasco M.A., Partridge L., Serrano M., Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194– 1217. DOI: 10.1016/j.cell.2013.05.039.

55. McGregor R.A., Poppitt S.D., Cameron-Smith D. Role of microRNAs in the age-related changes in skeletal muscle and diet or exercise interventions to promote healthy aging in humans. Ageing Res. Rev. 2014;17:25–33. DOI: 10.1016/j.arr.2014.05.001.

56. Olivieri F., Bonafè M., Spazzafumo L., Gobbi M., Prattichizzo F., Recchioni R. et al. Age- and glycemia-related miR-126- 3p levels in plasma and endothelial cells. Aging (Albany NY). 2014;6(9):771–787. DOI: 10.18632/aging.100693.

57. Seeger T., Boon R.A. MicroRNAs in cardiovascular ageing. J. Physiol. 2016;594(8):2085–2094. DOI: 10.1113/JP270557.

58. Fu Z., Wang M., Everett A., Lakatta E., Van Eyk J. Can proteomics yield insight into aging aorta? Proteomics Clin. Appl. 2013;7(7–8):477–489. DOI: 10.1002/prca.201200138.

59. Fu Z., Wang M., Gucek M., Zhang J., Wu J., Jiang L. et al. Milk fat globule protein epidermal growth factor-8: a pivotal relay element within the angiotensin II and monocyte chemoattractant protein-1 signaling cascade mediating vascular smooth muscle cells invasion. Circ. Res. 2009;104(12):1337– 1346. DOI: 10.1161/CIRCRESAHA.108.187088.