Yaşlanma Ve Böbrek
Bülent Kaya, Neslihan Seyrek, İbrahim KarayaylalıYaşlanma, hastalık ve ölüm riskinde artışla sonuçlanan, dış veya iç strese uyum sağlayan hemostaz kapasitesinde önemli bir düşüşle birlikte ilerleyici bir fonksiyonel rezerv kaybı olarak tanımlanır1 . İyileştirilmiş yaşam koşulları, sosyoekonomik durum ve sağlık hizmetleri nedeniyle, son yıllarda yaşam beklentisi önemli ölçüde artarken ölüm oranı önemli ölçüde azalmıştır. Yaşı 65 ve üstünde olan bireylerin 2030 yılında Amerika’daki nüfusun yaklaşık %20’sini oluşturacağı, 2060 yılında ise Avrupa’daki nüfusun %28’ini oluşturacağı tahmin edilmektedir2 . Artan bu yaşlı birey sayısı kaçınılmaz olarak yaşa bağlı böbrek yetmezliği tanılarının artmasına yol açacaktır. Yaşlanma, böbrekler dahil olmak üzere çeşitli organ sistemlerinde moleküler, yapısal ve fonksiyonel değişikliklerle ilişkilidir. Bu değişiklikler sonucunda böbrekler istirahatte ve hasarlanmaya yanıt olarak hemodinamik ve fizyolojik davranışlarını değiştirir. Bu değişiklikler, böbreğin yaralanmaya dayanma ve iyileşme yeteneğini bozar, yaşlı popülasyonun akut böbrek yetmezliğine artmış duyarlılığına ve sonraki ilerleyici kronik böbrek hasarı geliştirme eğilimlerinin artmasına yol açar. Yaşlanma sürecinde böbreklerde, makroskopik ve mikroskobik değişikliklerin yanı sıra ilerleyici fonksiyonel düşüş görülür. Renal yaşlanmada genetik, çevresel faktörler ve hücresel işlev bozukluğunun karmaşık etkileşimi, karakteristik yapısal ve fonksiyonel değişikliklere yol açar. Yaşlanmanın kesin hücresel ve moleküler sinyal mekanizmaları hala belirsizdir. Bu derleme, böbrekte yaşa bağlı değişiklikleri ve sonuçlarına ilişkin mevcut durumu özetlemektedir.
Referanslar
- 74. de Cavanagh EM, Piotrkowski B, Basso N, Stella I, Inserra F, Ferder L, Fraga CG. Enalapril and losartan attenuate mitochondrial dysfunction in aged rats. FASEB J. 2003 Jun;17(9):1096-8. google scholar
- 75. Panickar KS, Jewell DE. The beneficial role of anti-inflammatory dietary ingredients in attenuating markers of chronic low-grade inflammation in aging. Horm Mol Biol Clin Investig. 2015 Aug;23(2):59-70. google scholar
- 76. Vlassara H, Torreggiani M, Post JB, Zheng F, Uribarri J, Striker GE. Role of oxidants/inflammation in dec-lining renal function in chronic kidney disease and normal aging. Kidney Int Suppl. 2009 Dec;(114):S3-11. google scholar
- 77. Pole, A., Dimri, M. & P. Dimri, G. Oxidative stress, cellular senescence and ageing. AIMS Mol Sci 3, 300-324 (2016). google scholar
- 78. Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science (1979) 279, (1998). google scholar
- 79. Melk, A. et al. Telomere shortening in kidneys with age. Journal of the American Society of Nephrology 11, (2000). google scholar
- 80. Raschenberger, J. et al. Association of relative telomere length with progression of chronic kidney disease in two cohorts: Effect modification by smoking and diabetes. Sci Rep 5, (2015). google scholar
- 81. Raschenberger J, Kollerits B, Titze S, Köttgen A, Barthlein B, Ekici AB, at al. ; GCKD study Investigators. Association of relative telomere length with cardiovascular disease in a large chronic kidney disease cohort: the GCKD study. Atherosclerosis. 2015 Oct;242(2):529-34. google scholar
- 82. Boxall MC, Goodship TH, Brown AL, Ward MC, von Zglinicki T. Telomere shortening and haemodialysis. Blood Purif. 2006;24(2):185-9. google scholar
- 83. Sturmlechner I, Durik M, Sieben CJ, Baker DJ, van Deursen JM. Cellular senescence in renal ageing and disease. Nat Rev Nephrol. 2017 Feb;13(2):77-89. google scholar
- 84. Wen, J. et al. Aging increases the susceptibility of cisplatin-induced nephrotoxicity. Age (Omaha) 37, (2015). google scholar
- 85. Wolstein, J. M. et al. INK4a knockout mice exhibit increased fibrosis under normal conditions and in response to unilateral ureteral obstruction. Am J Physiol Renal Physiol 299, (2010). google scholar
- 86. van Deursen JM. The role of senescent cells in ageing. Nature. 2014 May 22;509(7501):439-46. google scholar
- 87. Baker, D. J. et al. Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. Nature 530, (2016). google scholar
- 88. Schmitt R, Susnik N, Melk A. Molecular aspects of renal senescence. Curr Opin Organ Transplant. 2015 Aug;20(4):412-6. google scholar
- 89. von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002 Jul;27(7):339-44. google scholar
- 90. Sedelnikova, O. A. et al. Senescing human cells and ageing mice accumulate DNA lesions with unrepai-rable double-strand breaks. Nat Cell Biol 6, (2004). google scholar
- 91. Wiley, C. D. et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab 23, (2016). google scholar
- 92. Westhoff JH, Hilgers KF, Steinbach MP, Hartner A, Klanke B, Amann K, Melk A. Hypertension induces somatic cellular senescence in rats and humans by induction of cell cycle inhibitor p16INK4a. Hyperten-sion. 2008 Jul;52(1):123-9. google scholar
- 93. Epstein FH, Prasad P. Effects of furosemide on medullary oxygenation in younger and older subjects. Kidney Int. 2000 May;57(5):2080-3. google scholar
- 94. Kasiske BL. Relationship between vascular disease and age-associated changes in the human kidney. Kidney Int. 1987 May;31(5):1153-9. google scholar
- 95. Costello-White R, Ryff CD, Coe CL. Aging and low-grade inflammation reduce renal function in midd-le-aged and older adults in Japan and the USA. Age (Dordr). 2015 Aug;37(4):9808. google scholar
- 96. Sarkar D, Fisher PB. Molecular mechanisms of aging-associated inflammation. Cancer Lett. 2006 May 8;236(1):13-23. google scholar
- 97. Asanuma K, Mundel P. The role of podocytes in glomerular pathobiology. Clin Exp Nephrol. 2003 Dec;7(4):255-9. google scholar
- 98. Ziyadeh FN, Wolf G. Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev. 2008 Feb;4(1):39-45. google scholar
- 99. Hodgin, J. B. et al. Glomerular aging and focal global glomerulosclerosis: A podometric perspective. Journal of the American Society of Nephrology 26, (2015). google scholar
- 100. Jin, H. et al. Epithelial innate immunity mediates tubular cell senescence after kidney injury. JCI Insight 4, (2019). google scholar
- 101. Luo, C. et al. Wnt9a promotes renal fibrosis by accelerating cellular senescence in tubular epithelial cells. Journal of the American Society of Nephrology 29, (2018). google scholar
- 102. Saran R, Robinson B, Abbott KC, Agodoa LYC, Bhave N, Bragg-Gresham J, at al. US Renal Data System 2017 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis. 2018 Mar;71(3 Suppl 1):A7. doi: 10.1053/j.ajkd.2018.01.002. google scholar
- 103. Hsu, R. K., McCulloch, C. E., Dudley, R. A., Lo, L. J. & Hsu, C. Y. Temporal changes in incidence of dialysis-requiring AKI. Journal of the American Society of Nephrology 24, (2013). google scholar
- 104. Minutolo, R., Borrelli, S. & de Nicola, L. CKD in the Elderly: Kidney Senescence or Blood Pressure-Re-lated Nephropathy? American Journal of Kidney Diseases vol. 66 Preprint at https://doi.org/10.1053/j. ajkd.2015.05.004 (2015). google scholar
- 105. Zhang, L. et al. Prevalence of chronic kidney disease in China: A cross-sectional survey. The Lancet 379, (2012). google scholar
- 106. Tonelli M, Riella MC. World Kidney Day 2014: CKD and the aging population. Am J Kidney Dis. 2014 Mar;63(3):349-53. google scholar
- 107. Silva FG. The aging kidney: a review--part II. Int Urol Nephrol. 2005;37(2):419-32. google scholar
- 108. Sis, B. et al. Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease. Kidney Int 71, (2007). google scholar
- 109. Macrae, J., Friedman, A. L., Friedman, E. A. & Eggers, P. Live and deceased donor kidney transplantation in patients aged 75 years and older in the United States. Int Urol Nephrol 37, (2005). google scholar
- 110. Molnar, M. Z. et al. Age and the associations of living donor and expanded criteria donor kidneys with kidney transplant outcomes. American Journal of Kidney Diseases 59, (2012). google scholar
- 111. Tullius, S. G. et al. The combination of donor and recipient age is critical in determining host immuno-responsiveness and renal transplant outcome. Ann Surg 252, (2010). google scholar
- 112. Zhou, X. J. et al. The aging kidney. Kidney Int 74, 710-720 (2008). google scholar
- 113. Peters-Sengers, H. et al. Stretching the limits of renal transplantation in elderly recipients of grafts from elderly deceased donors. Journal of the American Society of Nephrology 28, (2017). google scholar
- 114. Massie, A. B. et al. Quantifying postdonation risk of ESRD in living kidney donors. Journal of the American Society of Nephrology 28, (2017). google scholar
- 115. McCay, C. M., Crowell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition 5, (1989). google scholar
- 116. Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science (1979) 325, (2009). google scholar
- 117. Weindruch, R. & Sohal, R. S. Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. N Engl J Med 337, (1997). google scholar
- 118. Calvo-Rubio, M. et al. Dietary fat composition influences glomerular and proximal convoluted tubule cell structure and autophagic processes in kidneys from calorie-restricted mice. Aging Cell 15, (2016). google scholar
- 119. Walford, R. L., Mock, D., Verdery, R. & MacCallum, T. Calorie restriction in biosphere 2: Alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. Journals of Gerontology - Series A Biological Sciences and Medical Sciences 57, (2002). google scholar
- 120. Benigni, A. et al. Disruption of the Ang II type 1 receptor promotes longevity in mice. Journal of Clinical Investigation 119, (2009). google scholar
- 121. Yang, H. C. et al. The PPARgamma agonist pioglitazone ameliorates aging-related progressive renal injury. J Am Soc Nephrol 20, 2380-2388 (2009). google scholar
- 122. Wanner, C. et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. New England Journal of Medicine 375, (2016). google scholar
- 123. Kitada, K. et al. Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy. J Diabetes Complications 28, (2014). google scholar
- 124. Kawai, M., Kinoshita, S., Ozono, K. & Michigami, T. Inorganic phosphate activates the AKT/mTORC1 pathway and shortens the life span of an a?klotho-deficient model. Journal of the American Society of Nephrology 27, (2016). google scholar
- 125. Iglesias-Bartolome, R. et al. MTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis. Cell Stem Cell 11, (2012). google scholar
- 126. Li J, Gui Y, Ren J, Liu X, Feng Y, Zeng Z, He W, Yang J, Dai C. Metformin Protects Against Cisplatin-In-duced Tubular Cell Apoptosis and Acute Kidney Injury via AMPKa-regulated Autophagy Induction. Sci Rep. 2016 Apr 7;6:23975. google scholar
- 1. Grimley Evans, J. 21st Century: Review: Ageing and medicine. J Intern Med 247, (2000). google scholar
- 2. O’Sullivan ED, Hughes J, Ferenbach DA. Renal Aging: Causes and Consequences. J Am Soc Nephrol. 2017 Feb;28(2):407-420. google scholar
- 3. Long DA, Mu W, Price KL, Johnson RJ. Blood vessels and the aging kidney. Nephron Exp Nephrol. 2005;101(3):e95-9. google scholar
- 4. Hommos MS, Glassock RJ, Rule AD. Structural and Functional Changes in Human Kidneys with Healthy Aging. J Am Soc Nephrol. 2017 Oct;28(10):2838-2844. google scholar
- 5. Chin, H. J., Ro, H., Lee, H. J., Na, K. Y. & Chae, D. W. The clinical significances of simple renal cyst: Is it related to hypertension or renal dysfunction? Kidney Int 70, (2006). google scholar
- 6. Grantham JJ. Solitary renal cysts: worth a second look? Am J Kidney Dis. 2012 May;59(5):593-4. google scholar
- 7. Al-Said J, O’Neill WC. Reduced kidney size in patients with simple renal cysts. Kidney Int. 2003 Sep;64(3):1059-64. google scholar
- 8. Al-Said, J., Brumback, M. A., Moghazi, S., Baumgarten, D. A. & O’Neill, W. C. Reduced renal function in patients with simple renal cysts. Kidney Int 65, (2004). google scholar
- 9. Roseman, D. A. et al. Clinical associations of total kidney volume: The Framingham Heart Study. Neph-rology Dialysis Transplantation 32, (2017). google scholar
- 10. Emamian, S. A., Nielsen, M. B., Pedersen, J. F. & Ytte, L. Kidney dimensions at sonography: Correlation with age, sex, and habitus in 665 adult volunteers. American Journal of Roentgenology 160, (1993). google scholar
- 11. Nyengaard, J. R. & Bendtsen, T. F. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec 232, (1992). google scholar
- 12. Rule, A. D. et al. The association between age and nephrosclerosis on renal biopsy among healthy adults. Ann Intern Med 152, (2010). google scholar
- 13. Denic, A. et al. The substantial loss of nephrons in healthy human kidneys with aging. Journal of the American Society of Nephrology 28, (2017). google scholar
- 14. Brenner, B. M. Hemodynamically mediated glomerular injury and the progressive nature of kidney disease. Kidney Int 23, (1983). google scholar
- 15. Newbold, K. M., Sandison, A. & Howie, A. J. Comparison of size of juxtamedullary and outer cortical glomeruli in normal adult kidney. Virchows Arch A Pathol Anat Histopathol 420, (1992). google scholar
- 16. Chan, K. W., Leung, C. Y. & Chan, C. W. Age-related glomerular sclerosis: Baseline values in Hong Kong. Pathology 22, (1990). google scholar
- 17. Silva FG. The aging kidney: a review -- part I. Int Urol Nephrol. 2005;37(1):185-205. google scholar
- 18. Gibson, I. W., Downie, T. T., More, I. A. R. & Lindop, G. B. M. Atubular glomeruli and glomerular cysts - A possible pathway for nephron loss in the human kidney? Journal of Pathology 179, (1996). google scholar
- 19. Li, Z. & Wang, Z. Aging kidney and aging-related disease. in Advances in Experimental Medicine and Biology vol. 1086 (2018). google scholar
- 20. Bolignano D, Mattace-Raso F, Sijbrands EJ, Zoccali C. The aging kidney revisited: a systematic review. Ageing Res Rev. 2014 Mar;14:65-80. google scholar
- 21. Glassock RJ, Rule AD. Aging and the Kidneys: Anatomy, Physiology and Consequences for Defining Chronic Kidney Disease. Nephron. 2016;134(1):25-9. google scholar
- 22. Schaeffner, E. S. et al. Two novel equations to estimate kidney function in persons aged 70 years or older. Ann Intern Med 157, (2012). google scholar
- 23. Schmitt R, Melk A. Molecular mechanisms of renal aging. Kidney Int. 2017 Sep;92(3):569-579. google scholar
- 24. James, M. T. et al. Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: A cohort study. The Lancet 376, (2010). google scholar
- 25. Nitta, K., Okada, K., Yanai, M. & Takahashi, S. Aging and Chronic Kidney Disease. Kidney Blood Press Res 38, 109-120 (2013). google scholar
- 26. Michelis, M. F. Hyperkalemia in the Elderly. American Journal of Kidney Diseases 16, (1990). google scholar
- 27. Mimran, A., Ribstein, J. & Jover, B. Aging and sodium homeostasis. in Kidney International, Supplement (1992). google scholar
- 28. Sands, J. M. Urine concentrating and diluting ability during aging. Journals of Gerontology - Series A Biological Sciences and Medical Sciences 67, (2012). google scholar
- 29. Mc Greevy, C. et al. A study of tubular potassium secretory capacity in older patients with hyperkalaemia. Journal of Nutrition, Health and Aging 12, (2008). google scholar
- 30. Musso, C. et al. Correlation between creatinine clearance and transtubular potassium concentration gradient in old people and chronic renal disease patients. Saudi J Kidney Dis Transpl 18, (2007). google scholar
- 31. Luckey AE, Parsa CJ. Fluid and electrolytes in the aged. Arch Surg. 2003 Oct;138(10):1055-60. google scholar
- 32. Eisenstaedt, R., Penninx, B. W. J. H. & Woodman, R. C. Anemia in the elderly: Current understanding and emerging concepts. Blood Rev 20, (2006). google scholar
- 33. Arnaud CD, Sanchez SD. The role of calcium in osteoporosis. Annu Rev Nutr. 1990;10:397-414. google scholar
- 34. Takazakura, E. et al. Intrarenal vascular changes with age and disease. Kidney Int 2, 224-230 (1972). google scholar
- 35. Fuiano, G. et al. Renal hemodynamic response to maximal vasodilating stimulus in healthy older subjects. Kidney Int 59, (2001). google scholar
- 36. Kielstein JT, Bode-Böger SM, Haller H, Fliser D. Functional changes in the ageing kidney: is there a role for asymmetric dimethylarginine? Nephrol Dial Transplant. 2003 Jul;18(7):1245-8. google scholar
- 37. Fliser, D., Zeier, M., Nowack, R. & Ritz, E. Renal functional reserve in healthy elderly subjects. Journal of the American Society of Nephrology 3, (1993). google scholar
- 38. Mulkerrin, E. C. et al. Reduced Renal Hemodynamic Response to Atrial Natriuretic Peptide in Elderly Volunteers. American Journal of Kidney Diseases 22, (1993). google scholar
- 39. Kielstein, J. T. et al. Asymmetric dimethylarginine, blood pressure, and renal perfusion in elderly subjects. Circulation 107, (2003). google scholar
- 40. Sverdlov, A. L., Ngo, D. T. M., Chan, W. P. A., Chirkov, Y. Y. & Horowitz, J. D. Aging of the nitric oxide system: Are we as old as our NO? J Am Heart Assoc 3, (2014). google scholar
- 41. Ahmed, S. B., Fisher, N. D. L. & Hollenberg, N. K. Gender and the renal nitric oxide synthase system in healthy humans. Clinical Journal of the American Society of Nephrology 2, (2007). google scholar
- 42. Nath, K. A. et al. Age sensitizes the kidney to heme protein-induced acute kidney injury. Am J Physiol Renal Physiol 304, (2013). google scholar
- 43. Ferenbach, D. A. et al. The induction of macrophage hemeoxygenase-1 is protective during acute kidney injury in aging mice. Kidney Int 79, (2011). google scholar
- 44. Maddens, B. et al. Severity of sepsis-induced acute kidney injury in a novel mouse model is age dependent. Crit Care Med 40, (2012). google scholar
- 45. Clements, M. E., Chaber, C. J., Ledbetter, S. R. & Zuk, A. Increased Cellular Senescence and Vascular Rarefaction Exacerbate the Progression of Kidney Fibrosis in Aged Mice Following Transient Ischemic Injury. PLoS One 8, (2013). google scholar
- 46. Kaushik S, Tasset I, Arias E, Pampliega O, Wong E, Martinez-Vicente M, Cuervo AM. Autophagy and the hallmarks of aging. Ageing Res Rev. 2021 Dec;72:101468. google scholar
- 47. Iurciuc, S., Cimpean, A. M., Mitu, F., Heredea, R. & Iurciuc, M. Vascular aging and subclinical atherosc-lerosis: Why such a “never ending” and challenging story in cardiology? Clin Interv Aging 12, (2017). google scholar
- 48. Kurosu, H. et al. Physiology: Suppression of aging in mice by the hormone Klotho. Science (1979) 309, (2005). google scholar
- 49. Sopjani, M., Rinnerthaler, M., Kruja, J. & Dermaku-Sopjani, M. Intracellular Signaling of the Aging Suppressor Protein Klotho. Curr Mol Med 15, (2015). google scholar
- 50. Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, (1997). google scholar
- 51. Razzaque, M. S., Sitara, D., Taguchi, T., St-Arnaud, R. & Lanske, B. Prematüre aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process . The FASEB Journal 20, (2006). google scholar
- 52. Shimada, T. et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. Journal of Clinical Investigation 113, (2004). google scholar
- 53. John, G. B., Cheng, C. Y. & Kuro-O, M. Role of klotho in aging, phosphate metabolism, and CKD. Ame-rican Journal of Kidney Diseases 58, (2011). google scholar
- 54. Kuro-o M. Klotho as a regulator of oxidative stress and senescence. Biol Chem. 2008 Mar;389(3):233-41. google scholar
- 55. Liu, Q. F. et al. Ameliorating effect of klotho on endoplasmic reticulum stress and renal fibrosis induced by unilateral ureteral obstruction. Iran J Kidney Dis 9, (2015). google scholar
- 56. Miao, J. et al. Wnt/p-catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction. Aging Cell 18, (2019). google scholar
- 57. Zhang, D. Y et al. Wnt/p-catenin signaling induces the aging of mesenchymal stem cells through promoting the ROS production. Mol Cell Biochem 374, (2013). google scholar
- 58. Tan RJ, Zhou D, Zhou L, Liu Y Wnt/p-catenin signaling and kidney fibrosis. Kidney Int Suppl (2011). 2014 Nov;4(1):84-90. google scholar
- 59. Bian A, Neyra JA, Zhan M, Hu MC. Klotho, stem cells, and aging. Clin Interv Aging. 2015 Aug 4;10:1233-43. google scholar
- 60. Speeckaert MM, Vanfraechem C, Speeckaert R, Delanghe JR. Peroxisome proliferator-activated receptor agonists in a battle against the aging kidney. Ageing Res Rev. 2014 Mar;14:1-18. google scholar
- 61. A.K., G., S.E., Q. & D.E., V. Molecular basis of organ fibrosis: Potential therapeutic approaches. Exp Biol Med 238, (2013). google scholar
- 62. Briganti, S., Flori, E., Bellei, B. & Picardo, M. Modulation of PPARy provides new insights in a stress induced premature senescence model. PLoS One 9, (2014). google scholar
- 63. Deng, Y. L., Xiong, X. Z. & Cheng, N. S. Organ fibrosis inhibited by blocking transforming growth factor-p signaling via peroxisome proliferator-activated receptor y agonists. Hepatobiliary and Pancreatic Diseases International 11, (2012). google scholar
- 64. Lim, H. A. et al. PPARy activation by baicalin suppresses NF-KB-mediated inflammation in aged rat kidney. Biogerontology 13, (2012). google scholar
- 65. Wang, P. et al. Activation of PPAR-y by pioglitazone attenuates oxidative stress in aging rat cerebral arteries through upregulating UCP2. J Cardiovasc Pharmacol 64, (2014). google scholar
- 66. Yoon HE, Choi BS. The renin-angiotensin system and aging in the kidney. Korean J Intern Med. 2014 May;29(3):291-5. google scholar
- 67. Sangaralingham, S. J. et al. Cardiorenal fibrosis and dysfunction in aging: Imbalance in mediators and regulators of collagen. Peptides (N.Y.) 76, (2016). google scholar
- 68. Fogo, A. B. The role of angiotensin II and plasminogen activator inhibitor-1 in progressive glomerulosc-lerosis. American Journal of Kidney Diseases 35, (2000). google scholar
- 69. Vajapey R, Rini D, Walston J, Abadir P. The impact of age-related dysregulation of the angiotensin system on mitochondrial redox balance. Front Physiol. 2014 Nov 24;5:439. google scholar
- 70. Benigni A, Cassis P, Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med. 2010 Jul;2(7):247-57. google scholar
- 71. Cuevas, C. A., Gonzalez, A. A., Inestrosa, N. C., Vio, C. P. & Prieto, M. C. Angiotensin II increases fibronectin and collagen I through the p-catenin-dependent signaling in mouse collecting duct cells. Am J Physiol Renal Physiol 308, (2015). google scholar
- 72. Ruiztorres, P., Bosch, J., Moral, G. D. E. L. & Iglesias, C. Age-Related Kidney : Increase Relationship in Expression to Morphologic of TGF-1 Changes in the Rat. Journal of the American Society of Nephrology 9, (1998). google scholar
- 73. Rodriguez-Puyol, M. Age-related progressive renal fibrosis in rats and its prevention with ACE inhibitors and taurine. American Journal of Physiology - Renal Fluid and Electrolyte Physiology 278, (2000). google scholar
- 74. de Cavanagh EM, Piotrkowski B, Basso N, Stella I, Inserra F, Ferder L, Fraga CG. Enalapril and losartan attenuate mitochondrial dysfunction in aged rats. FASEB J. 2003 Jun;17(9):1096-8. google scholar
- 75. Panickar KS, Jewell DE. The beneficial role of anti-inflammatory dietary ingredients in attenuating markers of chronic low-grade inflammation in aging. Horm Mol Biol Clin Investig. 2015 Aug;23(2):59-70. google scholar
- 76. Vlassara H, Torreggiani M, Post JB, Zheng F, Uribarri J, Striker GE. Role of oxidants/inflammation in dec-lining renal function in chronic kidney disease and normal aging. Kidney Int Suppl. 2009 Dec;(114):S3-11. google scholar
- 77. Pole, A., Dimri, M. & P. Dimri, G. Oxidative stress, cellular senescence and ageing. AIMS Mol Sci 3, 300-324 (2016). google scholar
- 78. Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science (1979) 279, (1998). google scholar
- 79. Melk, A. et al. Telomere shortening in kidneys with age. Journal of the American Society of Nephrology 11, (2000). google scholar
- 80. Raschenberger, J. et al. Association of relative telomere length with progression of chronic kidney disease in two cohorts: Effect modification by smoking and diabetes. Sci Rep 5, (2015). google scholar
- 81. Raschenberger J, Kollerits B, Titze S, Köttgen A, Barthlein B, Ekici AB, at al. ; GCKD study Investigators. Association of relative telomere length with cardiovascular disease in a large chronic kidney disease cohort: the GCKD study. Atherosclerosis. 2015 Oct;242(2):529-34. google scholar
- 82. Boxall MC, Goodship TH, Brown AL, Ward MC, von Zglinicki T. Telomere shortening and haemodialysis. Blood Purif. 2006;24(2):185-9. google scholar
- 83. Sturmlechner I, Durik M, Sieben CJ, Baker DJ, van Deursen JM. Cellular senescence in renal ageing and disease. Nat Rev Nephrol. 2017 Feb;13(2):77-89. google scholar
- 84. Wen, J. et al. Aging increases the susceptibility of cisplatin-induced nephrotoxicity. Age (Omaha) 37, (2015). google scholar
- 85. Wolstein, J. M. et al. INK4a knockout mice exhibit increased fibrosis under normal conditions and in response to unilateral ureteral obstruction. Am J Physiol Renal Physiol 299, (2010). google scholar
- 86. van Deursen JM. The role of senescent cells in ageing. Nature. 2014 May 22;509(7501):439-46. google scholar
- 87. Baker, D. J. et al. Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. Nature 530, (2016). google scholar
- 88. Schmitt R, Susnik N, Melk A. Molecular aspects of renal senescence. Curr Opin Organ Transplant. 2015 Aug;20(4):412-6. google scholar
- 89. von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002 Jul;27(7):339-44. google scholar
- 90. Sedelnikova, O. A. et al. Senescing human cells and ageing mice accumulate DNA lesions with unrepai-rable double-strand breaks. Nat Cell Biol 6, (2004). google scholar
- 91. Wiley, C. D. et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab 23, (2016). google scholar
- 92. Westhoff JH, Hilgers KF, Steinbach MP, Hartner A, Klanke B, Amann K, Melk A. Hypertension induces somatic cellular senescence in rats and humans by induction of cell cycle inhibitor p16INK4a. Hyperten-sion. 2008 Jul;52(1):123-9. google scholar
- 93. Epstein FH, Prasad P. Effects of furosemide on medullary oxygenation in younger and older subjects. Kidney Int. 2000 May;57(5):2080-3. google scholar
- 94. Kasiske BL. Relationship between vascular disease and age-associated changes in the human kidney. Kidney Int. 1987 May;31(5):1153-9. google scholar
- 95. Costello-White R, Ryff CD, Coe CL. Aging and low-grade inflammation reduce renal function in midd-le-aged and older adults in Japan and the USA. Age (Dordr). 2015 Aug;37(4):9808. google scholar
- 96. Sarkar D, Fisher PB. Molecular mechanisms of aging-associated inflammation. Cancer Lett. 2006 May 8;236(1):13-23. google scholar
- 97. Asanuma K, Mundel P. The role of podocytes in glomerular pathobiology. Clin Exp Nephrol. 2003 Dec;7(4):255-9. google scholar
- 98. Ziyadeh FN, Wolf G. Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev. 2008 Feb;4(1):39-45. google scholar
- 99. Hodgin, J. B. et al. Glomerular aging and focal global glomerulosclerosis: A podometric perspective. Journal of the American Society of Nephrology 26, (2015). google scholar
- 100. Jin, H. et al. Epithelial innate immunity mediates tubular cell senescence after kidney injury. JCI Insight 4, (2019). google scholar
- 101. Luo, C. et al. Wnt9a promotes renal fibrosis by accelerating cellular senescence in tubular epithelial cells. Journal of the American Society of Nephrology 29, (2018). google scholar
- 102. Saran R, Robinson B, Abbott KC, Agodoa LYC, Bhave N, Bragg-Gresham J, at al. US Renal Data System 2017 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis. 2018 Mar;71(3 Suppl 1):A7. doi: 10.1053/j.ajkd.2018.01.002. google scholar
- 103. Hsu, R. K., McCulloch, C. E., Dudley, R. A., Lo, L. J. & Hsu, C. Y. Temporal changes in incidence of dialysis-requiring AKI. Journal of the American Society of Nephrology 24, (2013). google scholar
- 104. Minutolo, R., Borrelli, S. & de Nicola, L. CKD in the Elderly: Kidney Senescence or Blood Pressure-Re-lated Nephropathy? American Journal of Kidney Diseases vol. 66 Preprint at https://doi.org/10.1053/j. ajkd.2015.05.004 (2015). google scholar
- 105. Zhang, L. et al. Prevalence of chronic kidney disease in China: A cross-sectional survey. The Lancet 379, (2012). google scholar
- 106. Tonelli M, Riella MC. World Kidney Day 2014: CKD and the aging population. Am J Kidney Dis. 2014 Mar;63(3):349-53. google scholar
- 107. Silva FG. The aging kidney: a review--part II. Int Urol Nephrol. 2005;37(2):419-32. google scholar
- 108. Sis, B. et al. Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease. Kidney Int 71, (2007). google scholar
- 109. Macrae, J., Friedman, A. L., Friedman, E. A. & Eggers, P. Live and deceased donor kidney transplantation in patients aged 75 years and older in the United States. Int Urol Nephrol 37, (2005). google scholar
- 110. Molnar, M. Z. et al. Age and the associations of living donor and expanded criteria donor kidneys with kidney transplant outcomes. American Journal of Kidney Diseases 59, (2012). google scholar
- 111. Tullius, S. G. et al. The combination of donor and recipient age is critical in determining host immuno-responsiveness and renal transplant outcome. Ann Surg 252, (2010). google scholar
- 112. Zhou, X. J. et al. The aging kidney. Kidney Int 74, 710-720 (2008). google scholar
- 113. Peters-Sengers, H. et al. Stretching the limits of renal transplantation in elderly recipients of grafts from elderly deceased donors. Journal of the American Society of Nephrology 28, (2017). google scholar
- 114. Massie, A. B. et al. Quantifying postdonation risk of ESRD in living kidney donors. Journal of the American Society of Nephrology 28, (2017). google scholar
- 115. McCay, C. M., Crowell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition 5, (1989). google scholar
- 116. Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science (1979) 325, (2009). google scholar
- 117. Weindruch, R. & Sohal, R. S. Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. N Engl J Med 337, (1997). google scholar
- 118. Calvo-Rubio, M. et al. Dietary fat composition influences glomerular and proximal convoluted tubule cell structure and autophagic processes in kidneys from calorie-restricted mice. Aging Cell 15, (2016). google scholar
- 119. Walford, R. L., Mock, D., Verdery, R. & MacCallum, T. Calorie restriction in biosphere 2: Alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. Journals of Gerontology - Series A Biological Sciences and Medical Sciences 57, (2002). google scholar
- 120. Benigni, A. et al. Disruption of the Ang II type 1 receptor promotes longevity in mice. Journal of Clinical Investigation 119, (2009). google scholar
- 121. Yang, H. C. et al. The PPARgamma agonist pioglitazone ameliorates aging-related progressive renal injury. J Am Soc Nephrol 20, 2380-2388 (2009). google scholar
- 122. Wanner, C. et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. New England Journal of Medicine 375, (2016). google scholar
- 123. Kitada, K. et al. Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy. J Diabetes Complications 28, (2014). google scholar
- 124. Kawai, M., Kinoshita, S., Ozono, K. & Michigami, T. Inorganic phosphate activates the AKT/mTORC1 pathway and shortens the life span of an a?klotho-deficient model. Journal of the American Society of Nephrology 27, (2016). google scholar
- 125. Iglesias-Bartolome, R. et al. MTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis. Cell Stem Cell 11, (2012). google scholar
- 126. Li J, Gui Y, Ren J, Liu X, Feng Y, Zeng Z, He W, Yang J, Dai C. Metformin Protects Against Cisplatin-In-duced Tubular Cell Apoptosis and Acute Kidney Injury via AMPKa-regulated Autophagy Induction. Sci Rep. 2016 Apr 7;6:23975. google scholar