Molecular mechanisms of renal aging

Schmitt, Roland; Melk, Anette

doi:10.1016/j.kint.2017.02.036

Cited by 235Chronic Kidney Disease and DiabetesAcute Kidney Injury ResearchRenal Diseases and Glomerulopathies

Molecular mechanisms of renal aging

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Schmitt, Roland, Melk, Anette·2017·Kidney International

DOI 10.1016/j.kint.2017.02.036

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Abstract

Epidemiologic, clinical, and molecular evidence suggest that aging is a major contributor to the increasing incidence of acute kidney injury and chronic kidney disease. The aging kidney undergoes complex changes that predispose to renal pathology. The underlying molecular mechanisms could be the target of therapeutic strategies in the future. Here, we summarize recent insight into cellular and molecular processes that have been shown to contribute to the renal aging phenotype.The main clinical finding of renal aging is the decrease in glomerular filtration rate, and its structural correlate is the loss of functioning nephrons. Mechanistically, this has been linked to different processes, such as podocyte hypertrophy, glomerulosclerosis, tubular atrophy, and gradual microvascular rarefaction. Renal functional recovery after an episode of acute kidney injury is significantly worse in elderly patients. This decreased regenerative potential, which is a hallmark of the aging process, may be caused by cellular senescence. Accumulation of senescent cells could explain insufficient repair and functional loss, a view that has been strengthened by recent studies showing that removal of senescent cells results in attenuation of renal aging. Other potential mechanisms are alterations in autophagy as an important component of a disturbed renal stress response and functional differences in the inflammatory system. Promising therapeutic measures to counteract these age-related problems include mimetics of caloric restriction, pharmacologic renin-angiotensin-aldosterone system inhibition, and novel strategies of senotherapy with the goal of reducing the number of senescent cells to decrease aging-related disease in the kidney.

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From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [146]

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Regression of sclerosis in aging by an angiotensin inhibition-induced decrease in PAI-1
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Telomere Shortening Reduces Regenerative Capacity after Acute Kidney Injury
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Self-citation
Time-dependent dysregulation of autophagy: Implications in aging and mitochondrial homeostasis in the kidney proximal tubule
Yamamoto, T., Takabatake, Y., Kimura, T., Takahashi, A., Namba, T., Matsuda, J., Minami, S., Kaimori, J.-Y., Matsui, I., Kitamura, H., et al. (2016) · Autophagy · doi:10.1080/15548627.2016.1159376 · Cited by 135 · see citing works
The aging kidney: increased susceptibility to nephrotoxicity
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“Inflammaging” as a druggable target: a senescence-associated secretory phenotype-centered view of type 2 diabetes
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CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury
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From Mitochondria to Disease: Role of the Renin-Angiotensin System
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Markers of cellular senescence in zero hour biopsies predict outcome in renal transplantation
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Increased Cellular Senescence and Vascular Rarefaction Exacerbate the Progression of Kidney Fibrosis in Aged Mice Following Transient Ischemic Injury
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Mitochondrial Biogenesis in Kidney Disease
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Peritubular capillary rarefaction: a new therapeutic target in chronic kidney disease
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Klotho Gene Deficiency Causes Salt-Sensitive Hypertension via Monocyte Chemotactic Protein-1/CC Chemokine Receptor 2–Mediated Inflammation
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Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions
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Effects of Donor Age and Cell Senescence on Kidney Allograft Survival
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Cellular senescence in pretransplant renal biopsies predicts postoperative organ function
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Zag Expression during Aging Suppresses Proliferation after Kidney Injury
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Nephron Hypertrophy and Glomerulosclerosis and Their Association with Kidney Function and Risk Factors among Living Kidney Donors
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A comparison of rat chronic progressive nephropathy with human renal disease—implications for human risk assessment
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Primary proximal tubule injury leads to epithelial cell cycle arrest, fibrosis, vascular rarefaction, and glomerulosclerosis
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Cell Senescence and Its Implications for Nephrology
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Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments
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Changes in renal hemodynamics and structure in the aging kidney; sexual dimorphism and the nitric oxide system
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Senescence of renal cells: molecular basis and clinical implications
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Short-term calorie restriction protects against renal senescence of aged rats by increasing autophagic activity and reducing oxidative damage
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Autophagy and the kidney: health and disease
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Telomerase deficiency delays renal recovery in mice after ischemia–reperfusion injury by impairing autophagy
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Obesity-induced chronic inflammation in high fat diet challenged C57BL/6J mice is associated with acceleration of age-dependent renal amyloidosis
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Ablation of the p16INK4a tumour suppressor reverses ageing phenotypes of klotho mice
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Reliability of Transcutaneous Measurement of Renal Function in Various Strains of Conscious Mice
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Aging-related renal injury and inflammation are associated with downregulation of Klotho and induction of RIG-I/NF-κB signaling pathway in senescence-accelerated mice
Zeng, Y., Wang, P.-H., Zhang, M., & Du, J. (2015) · Aging Clinical and Experimental Research · doi:10.1007/s40520-015-0371-y · Cited by 68 · see citing works
Donor age intensifies the early immune response after transplantation
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Aging in the Glomerulus
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Adult-onset calorie restriction delays the accumulation of mitochondrial enzyme abnormalities in aging rat kidney tubular epithelial cells
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Glomerular Function, Structure, and Number in Renal Allografts from Older Deceased Donors
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In Vivo and In Vitro Analysis of Age-Associated Changes and Somatic Cellular Senescence in Renal Epithelial Cells
Berkenkamp, B., Susnik, N., Baisantry, A., Kuznetsova, I., Jacobi, C., Sörensen-Zender, I., Broecker, V., Haller, H. G., Melk, A., & Schmitt, R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0088071 · Cited by 59 · see citing works
Self-citation
Endostatin and transglutaminase 2 are involved in fibrosis of the aging kidney
Lin, C. H. S., Chen, J., Zhang, Z., Johnson, G. V. W., Cooper, A. J. L., Feola, J., Bank, A., Shein, J., Ruotsalainen, H. J., Pihlajaniemi, T. A., et al. (2016) · Kidney International · doi:10.1016/j.kint.2016.01.030 · Cited by 59 · see citing works
Aging and endothelin: Determinants of disease
Barton, M. (2014) · Life Sciences · doi:10.1016/j.lfs.2014.09.009 · Cited by 58 · see citing works
Renal tubular Notch signaling triggers a prosenescent state after acute kidney injury
Sörensen-Zender, I., Rong, S., Susnik, N., Zender, S., Pennekamp, P., Melk, A., Haller, H. G., & Schmitt, R. (2014) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00030.2014 · Cited by 58 · see citing works
Self-citation
GDF11 improves tubular regeneration after acute kidney injury in elderly mice
Zhang, Y., Li, Q., Liu, D., Huang, Q., Cai, G., Cui, S., Sun, X., & Chen, X. (2016) · Scientific Reports · doi:10.1038/srep34624 · Cited by 58 · see citing works
Epidemiology and outcomes of acute kidney injury in elderly chinese patients: a subgroup analysis from the EACH study
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Zinc-α2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart
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Interstitial pericytes decrease in aged mouse kidneys
Stefańska, A., Eng, D. G., Kaverina, N. V., Duffield, J. S., Pippin, J. W., Rabinovitch, P. S., & Shankland, S. J. (2015) · Aging · doi:10.18632/aging.100756 · Cited by 45 · see citing works
Replicative senescence in kidney aging, renal disease, and renal transplantation.
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Aging-associated renal disease in mice is fructokinase dependent
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Sexual Dimorphism: The Aging Kidney, Involvement of Nitric Oxide Deficiency, and Angiotensin II Overactivity
Baylis, C. (2012) · The Journals of Gerontology Series A · doi:10.1093/gerona/gls171 · Cited by 44 · see citing works
p21 and mTERT are novel markers for determining different ischemic time periods in renal ischemia-reperfusion injury
Hochegger, K., Koppelstaetter, C., Tagwerker, A., Huber, J., Heininger, D., Mayer, G. J., & Rosenkranz, A. R. (2006) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00084.2006 · Cited by 41 · see citing works
Age-dependent renal cortical microvascular loss in female mice
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New Insights on Molecular Mechanisms of Renal Aging
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Immunosenescence in renal transplantation
Seyda, M., Quante, M., Uehara, H., Slegtenhorst, B. R., Elkhal, A., & Tullius, S. G. (2015) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0000000000000210 · Cited by 35 · see citing works
Anti-Inflamm-Aging Effects of Long-Term Caloric Restriction via Overexpression of SIGIRR to Inhibit NF-κB Signaling Pathway
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Unmasking Silent Endothelial Activation in the Cardiovascular System Using Molecular Magnetic Resonance Imaging
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Identification of Novel Genes Associated with Renal Tertiary Lymphoid Organ Formation in Aging Mice
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Quantitative podocyte parameters predict human native kidney and allograft half-lives
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Telomere length, cardiovascular risk and arteriosclerosis in human kidneys: an observational cohort study
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Aging aggravates long-term renal ischemia-reperfusion injury in a rat model
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Genetic Suppression of GH-IGF-1 Activity, Combined with Lifelong Caloric Restriction, Prevents Age-Related Renal Damage and Prolongs the Life Span in Rats
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Protective role of female gender in programmed accelerated renal aging in the rat
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Dietary fat composition influences glomerular and proximal convoluted tubule cell structure and autophagic processes in kidneys from calorie-restricted mice
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Ageing mouse kidney—not always the SAME old story
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Reducing mTOR augments parietal epithelial cell density in a model of acute podocyte depletion and in aged kidneys
McNicholas, B., Eng, D. G., Lichtnekert, J., Rabinowitz, P. S., Pippin, J. W., & Shankland, S. J. (2016) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00196.2016 · Cited by 25 · see citing works
The impact of autophagy on the development of senescence in primary tubular epithelial cells
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Grafts from elderly donors elicit a stronger immune response in the early period posttransplantation: A study in a rat model
Reutzel‐Selke, A., Filatenkov, A., Jurisch, A., Denecke, C., Martins, P. N. A., Pascher, A., Jonas, S., Pratschke, J., Neuhaus, P., & Tullius, S. G. (2005) · Transplantation Proceedings · doi:10.1016/j.transproceed.2005.01.005 · Cited by 19 · see citing works
Aging and Age-Related Disorders
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Renal phenotype of young and old telomerase-deficient mice
Schildhorn, C., Jacobi, C., Weißbrodt, A., Hermstedt, C., Westhoff, J. H., Hömme, M., Bhayadia, R., Gretz, N., Falk, C. S., Schmitt, R., et al. (2015) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2015.08.004 · Cited by 16 · see citing works
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Cell aging and kidney repair
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Protein Redox-Regulation Mechanisms in Aging
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Age-Related Renal Microvascular Changes: Evaluation by Three-Dimensional Digital Imaging of the Human Renal Microcirculation Using Virtual Microscopy
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Effects of age and caloric restriction in the vascular response of renal arteries to endothelin-1 in rats
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Autophagy in kidney transplants of sirolimus treated recipients
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Inflammation and aging: signaling pathways and intervention therapies
Li, X., Li, C., Zhang, W., Wang, Y., Qian, P., & Huang, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01502-8 · Cited by 1,443 · see citing works
Biomarkers of aging
Bao, H., Cao, J., Chen, M., Min, C., Chen, W., Chen, X., Chen, Y., Chen, Y., Chen, Y., Chen, Z., et al. (2023) · Science China Life Sciences · doi:10.1007/s11427-023-2305-0 · Cited by 389 · see citing works
Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment
Chen, L., Yang, T., Lu, D., Zhao, H., Feng, Y., Chen, H., Chen, D., Vaziri, N. D., & Zhao, Y. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.02.090 · Cited by 363 · see citing works
Sirt3-mediated mitophagy regulates AGEs-induced BMSCs senescence and senile osteoporosis
Guo, Y., Jia, X., Cui, Y., Song, Y., Wang, S., Geng, Y., Li, R., Gao, W., & Fu, D. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101915 · Cited by 300 · see citing works
Immune cells and inflammation in AKI to CKD progression
Sato, Y., & Yanagita, M. (2018) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00195.2018 · Cited by 273 · see citing works
“Functional and structural impairment in aged kidneys as well as chronic inflammatory traits contribute to increased risk for AKI to CKD progression and developing AKI in the elderly (37, 121, 142).”
Background
The ageing kidney: Molecular mechanisms and clinical implications
Fang, Y., Gong, A. Y., Haller, S. T., Dworkin, L. D., Liu, Z., & Gong, R. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101151 · Cited by 211 · see citing works
“donors have declined function, higher risk of graft failure and functional loss, reduced repair capacity after acute rejection, greater susceptibility to ischemia and drug toxicity, and higher incidence of immunogenicity (Li and Wang, 2018; Schmitt and Melk, 2017).”
Influential
Autophagy in Chronic Kidney Diseases
Lin, T., Wu, V. C., & Wang, C. (2019) · Cells · doi:10.3390/cells8010061 · Cited by 185 · see citing works
“Therefore, a balanced caloric restriction strategy taking into consideration of the autophagy activation is one of the therapeutic options to delay the progression of CKD among elderly patients [100].”
Background
Homocysteine and age-associated disorders
Ostrakhovitch, E. A., & TABIBZADEH, S. S. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.10.010 · Cited by 182 · see citing works
Pathophysiology of AKI to CKD progression
Sato, Y., Takahashi, M., & Yanagita, M. (2020) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2020.01.011 · Cited by 181 · see citing works
Prevalence of undiagnosed stage 3 chronic kidney disease in France, Germany, Italy, Japan and the USA: results from the multinational observational REVEAL-CKD study
Tangri, N., Moriyama, T., Schneider, M. P., Virgitti, J. B. J., Nicola, L. D., Arnold, M., Barone, S., Peach, E. J., Wittbrodt, E. T., Chen, H., et al. (2023) · BMJ Open · doi:10.1136/bmjopen-2022-067386 · Cited by 142 · see citing works
Targeting angiogenesis and lymphangiogenesis in kidney disease
Tanabe, K., Wada, J., & Sato, Y. (2020) · Nature Reviews Nephrology · doi:10.1038/s41581-020-0260-2 · Cited by 131 · see citing works
Role of hypoxia in cellular senescence
Gao, H., Nepovimová, E., Heger, Z., Valko, M., Wu, Q., Kuča, K., & Adam, V. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106841 · Cited by 130 · see citing works
Immunology of the ageing kidney
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Distribution of estimated glomerular filtration rate and determinants of its age dependent loss in a German population-based study
Waas, T., Schulz, A., Lotz, J., Rossmann, H., Pfeiffer, N., Beutel, M. E., Schmidtmann, I. M., Münzel, T. F., Wild, P. S., & Lackner, K. J. (2021) · Scientific Reports · doi:10.1038/s41598-021-89442-7 · Cited by 114 · see citing works
Curcumin as Prospective Anti-Aging Natural Compound: Focus on Brain
Tarek, B., Soleti, R., Panaro, M. A., Torre, M. E. L., Monda, V., Messina, G., & Porro, C. (2021) · Molecules · doi:10.3390/molecules26164794 · Cited by 100 · see citing works
Cellular senescence is associated with reorganization of the microtubule cytoskeleton
Moujaber, O., Fishbein, F., Omran, N., Liang, Y., Colmegna, I., Presley, J. F., & Stochaj, U. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2999-1 · Cited by 95 · see citing works
Accelerated Kidney Aging in Diabetes Mellitus
Guo, J., Zheng, H., Zhang, W., Lou, W., Xia, C., Han, X. T., Huang, W. J., Zhang, F., Wang, Y., & Liu, W. J. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/1234059 · Cited by 99 · see citing works
“The similarities of SASP and the CKD-associated secretory phenotype (CASP) have been compared with one another and may present a link between CKD and renal cellular senescence [67].”
BackgroundInfluential
Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage
Franzin, R., Stasi, A., Fiorentino, M., Stallone, G., Cantaluppi, V., Gesualdo, L., & Castellano, G. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00734 · Cited by 93 · see citing works
“Mechanisms of Renal Inflammaging The term renal senescence reflects the complex interplay between genetics, immunological, and hormonal factors able to lead to structural and functional changes observed in aged kidneys (138).”
Background
Peritubular Capillary Rarefaction: An Underappreciated Regulator of CKD Progression
Kida, Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218255 · Cited by 89 · see citing works
“Interestingly, the aging process itself accelerates PTC rarefaction [14].”
Background
Reversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression
Al‐Dabet, M. M., Shahzad, K., Elwakiel, A., Sulaj, A., Kopf, S., Bock, F. M., Gadi, I., Zimmermann, S., Rana, R., Krishnan, S., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32477-9 · Cited by 87 · see citing works
Age-related GSK3β overexpression drives podocyte senescence and glomerular aging
Fang, Y., Chen, B., Liu, Z., Gong, A. Y., Gunning, W. T., Ge, Y., Malhotra, D., Gohara, A. F., Dworkin, L. D., & Gong, R. (2022) · Journal of Clinical Investigation · doi:10.1172/jci141848 · Cited by 92 · see citing works
“Some senescence signaling mediators may also regulate the cell cycle (5).”
BackgroundInfluential
Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide
Andrikopoulos, P., Aron‐Wisnewsky, J., Chakaroun, R., Myridakis, A., Forslund, S. K., Nielsen, T., Adriouch, S., Holmes, B., Chilloux, J., Vieira‐Silva, S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39824-4 · Cited by 86 · see citing works
“In page 22, line#216, R2=0.009, is not consistent to that was shown in page 24 Fig 2, R2=0.0082.”
Influential
Acute kidney injury and aging
Chang-Panesso, M. (2021) · Pediatric Nephrology · doi:10.1007/s00467-020-04849-0 · Cited by 86 · see citing works
Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease
Pippin, J. W., Kaverina, N. V., Wang, Y., Eng, D. G., Zeng, Y., Tran, U., Loretz, C. J., Chang, A., Akilesh, S., Poudel, C., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci156250 · Cited by 79 · see citing works
“As expected, when compared with their young counterparts (Figure 3, A and D), staining for senescence-associated β-galactosidase (SA-β-gal) (9) was higher in both glomerular and tubular epithelial cells in aged mice (Figure 3, B and E).”
Cellular senescence and kidney aging
Rex, N., Melk, A., & Schmitt, R. (2023) · Clinical Science · doi:10.1042/cs20230140 · Cited by 83 · see citing works
“Age-associated, very common health conditions such as hypertension, diabetes, cardiovascular disease, and potential exposure to nephrotoxic medications cumulatively increase the risk for AKI and contribute to the transition from AKI to CKD [4,26–28].”
BackgroundSelf-citation
Hyperoside attenuates renal aging and injury induced by D-galactose via inhibiting AMPK-ULK1 signaling-mediated autophagy
Liu, B.-H., Tu, Y., He, W., Liu, Y., Wu, W., Fang, Q., Tang, H., Tang, R., Wan, Z.-Y., Sun, W., et al. (2018) · Aging · doi:10.18632/aging.101723 · Cited by 79 · see citing works
“com 4198 AGING secretory phenotype, SASP) and renal interstitial fibrosis/tubular atrophy (IF/TA) [3-6].”
Background
The impact of senescence on muscle wasting in chronic kidney disease
Huang, Y., Wang, B., Hassounah, F., Price, S. R., Klein, J. D., Mohamed, T., Wang, Y., Park, J., Cai, H., Zhang, X., et al. (2022) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13112 · Cited by 70 · see citing works
“For example, p16 cells have been observed in kidney in different types of kidney diseases, including membranous nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, and in transplanted kidneys.(13,14) SA-β-gal and p16 were also increased in kidney epithelial cells of patients with diabetic nephropathy.”
Background
Structural and Functional Changes in Aging Kidneys
Dybiec, J., Szlagor, M., Młynarska, E., Rysz, J., & Franczyk, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315435 · Cited by 71 · see citing works
“The activity of p16INK4a, as a senescence mediator, may also be induced by oxidative stress, oncogenic Ras expression, and epigenetic alterations [33].”
Background
Klotho and calciprotein particles as therapeutic targets against accelerated ageing
Kuro‐o, M. (2021) · Clinical Science · doi:10.1042/cs20201453 · Cited by 68 · see citing works
Treatment of chronic kidney disease in older populations
Kishi, S., Kadoya, H., & Kashihara, N. (2024) · Nature Reviews Nephrology · doi:10.1038/s41581-024-00854-w · Cited by 66 · see citing works
“Mechanistically, processes such as glomerulosclerosis, podocyte hypertrophy, interstitial fibrosis and tubular atrophy, and progressive microvascular rarefaction are involved 27 , exacerbated by factors such as diabetes, obesity and hypertension.”
Podocyte Aging: Why and How Getting Old Matters
Shankland, S. J., Wang, Y., Shaw, A. S., Vaughan, J. C., Pippin, J. W., & Wessely, O. (2021) · Journal of the American Society of Nephrology · doi:10.1681/asn.2021050614 · Cited by 59 · see citing works
Evolution, kidney development, and chronic kidney disease
Chevalier, R. L. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.05.024 · Cited by 58 · see citing works
Decoy receptor 2 mediation of the senescent phenotype of tubular cells by interacting with peroxiredoxin 1 presents a novel mechanism of renal fibrosis in diabetic nephropathy
Chen, J., Chen, K., Xiao, F., Dai, H., Yang, J. W., Li-ming, W., Wang, X., Jian-guo, Z., & He, Y. (2020) · Kidney International · doi:10.1016/j.kint.2020.03.026 · Cited by 57 · see citing works
“Previous published studies have shown that cell senescence mainly relies on the p16-retinoblastoma and alternative reading frame–p53–p21 signaling pathways.(8,9) Cell senescence plays an important role not only in embryonic development, but also in the progression of major diseases such as diabetes mellitus, cancer, a…”
Background
Molecular Mechanisms of Cellular Injury and Role of Toxic Heavy Metals in Chronic Kidney Disease
Mishra, M., Nichols, L., Dave, A. A., Pittman, E. H., Cheek, J. P., Caroland, A. J. V., Lotwala, P., Drummond, J., & Bridges, C. C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911105 · Cited by 55 · see citing works
“Senescent cells accumulate in the renal parenchyma, leading to tissue deterioration, fibrosis, and aberrant signaling in different types of cell populations [29,69,78].”
Background
Macrophage iron dyshomeostasis promotes aging‐related renal fibrosis
Wu, L., Lin, H., Li, S., Huang, Y., Sun, Y., Shu, S., Luo, T., Liang, T., Lai, W., Rao, J., et al. (2024) · Aging Cell · doi:10.1111/acel.14275 · Cited by 55 · see citing works
“An aging kidney often exhibits diminished filtration function, leading to an elevated prevalence of chronic kidney disease (Fang et al., 2022 ; Luo et al., 2018; Schmitt & Melk, 2017 ).”
C/EBPα deficiency in podocytes aggravates podocyte senescence and kidney injury in aging mice
Zhang, L., Zhou, F., Yu, X., Zhu, Y., Zhou, Y., Liu, J., Liu, Y., Ma, Q., Zhang, Y., Wang, W., et al. (2019) · Cell Death & Disease · doi:10.1038/s41419-019-1933-2 · Cited by 48 · see citing works
Induction of ferroptosis selectively eliminates senescent tubular cells
Liao, C. M., Wulfmeyer, V. C., Chen, R., Erlangga, Z., Sinning, J., von Mäßenhausen, A., Sörensen-Zender, I., Beer, K., von Vietinghoff, S., Haller, H. G., et al. (2022) · American Journal of Transplantation · doi:10.1111/ajt.17102 · Cited by 51 · see citing works
Self-citation
A chimeric peptide promotes immune surveillance of senescent cells in injury, fibrosis, tumorigenesis and aging
Ming, X., Yang, Z. R., Huang, Y., Wang, Z., Zhang, Q., Lu, C., Sun, Y., Chen, Y., Zhang, L., Wu, J., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00750-9 · Cited by 54 · see citing works
“Natural aging leads to organ dysfunction, associated diseases or motor dysfunction 52–54 .”
Global transcriptomic changes occur in aged mouse podocytes
Wang, Y., Eng, D. G., Kaverina, N. V., Loretz, C. J., Koirala, A., Akilesh, S., Pippin, J. W., & Shankland, S. J. (2020) · Kidney International · doi:10.1016/j.kint.2020.05.052 · Cited by 50 · see citing works
Alginate Oligosaccharide Ameliorates D‐Galactose‐Induced Kidney Aging in Mice through Activation of the Nrf2 Signaling Pathway
Pan, H., Feng, W., Chen, M., Luan, H., Hu, Y., Zheng, X., Wang, S., & Mao, Y. (2021) · BioMed Research International · doi:10.1155/2021/6623328 · Cited by 50 · see citing works
“According to the free radical aging theory that was first proposed by Hamann, oxidative stress damage caused by reactive oxygen species (ROS) and free radicals plays an important role in the aging process [3].”
Background
Effect of renin–angiotensin system on senescence
Mogi, M. (2020) · Geriatrics & Gerontology International · doi:10.1111/ggi.13927 · Cited by 48 · see citing works
Deciphering the role of lipoproteins and lipid metabolic alterations in ageing and ageing-associated renal fibrosis
Liu, H.-J., Miao, H., Yang, J.-Z., Liu, F., Cao, G., & Zhao, Y. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101861 · Cited by 49 · see citing works
Prospective Pharmacological Potential of Resveratrol in Delaying Kidney Aging
Uddin, M. J., Farjana, M., Moni, A., Hossain, K. S., Hannan, M. A., & Ha, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158258 · Cited by 47 · see citing works
“The stable transformation of the kidney structure and its functions in the elderly exhibits a significant reduction in the number of glomeruli (responsible for nephrosclerosis), cortical volume, glomerular filtration rate (GFR), and manifold kidney cysts [3,5,6].”
Background
Stiffening Matrix Induces Age‐Mediated Microvascular Phenotype Through Increased Cell Contractility and Destabilization of Adherens Junctions
Schnellmann, R., Ntekoumes, D., Choudhury, M. I., Sun, S. X., Zhao, W., & Gerecht, S. (2022) · Advanced Science · doi:10.1002/advs.202201483 · Cited by 45 · see citing works
Cardiovascular Consequences of Uremic Metabolites: an Overview of the Involved Signaling Pathways
Curaj, A., Vanholder, R. C., Loscalzo, J., Quach, K., Wu, Z., Jankowski, V., & Jankowski, J. (2024) · Circulation Research · doi:10.1161/circresaha.123.324001 · Cited by 46 · see citing works
Biomarkers of ageing of humans and non-human primates
Wu, Z., Qu, J. T., Zhang, W., Bao, Z., Bi, Y., Cai, J.-P., Cai, S.-Q., Cao, C.-M., Cao, F., Cao, Z., et al. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00883-8 · Cited by 49 · see citing works
“At the cellular level, aged kidneys primarily demonstrate decreased density and hypertrophy of podocytes 327,329,330 (Supplementary Table 3).”
SerpinB2 Regulates Immune Response in Kidney Injury and Aging
Sen, P., Helmke, A., Liao, C. M., Sörensen-Zender, I., Rong, S., Bräsen, J. H., Melk, A., Haller, H. G., von Vietinghoff, S., & Schmitt, R. (2020) · Journal of the American Society of Nephrology · doi:10.1681/asn.2019101085 · Cited by 45 · see citing works
Self-citation
Youthful systemic milieu alleviates renal ischemia-reperfusion injury in elderly mice
Liu, D., Lun, L., Huang, Q., Ning, Y., Zhang, Y., Wang, L., Yin, Z., Zhang, Y., Xia, L., Yin, Z., et al. (2018) · Kidney International · doi:10.1016/j.kint.2018.03.019 · Cited by 44 · see citing works
Sex-Based Differences in Risk Factors and Complications of Chronic Kidney Disease
Wyld, M. L. R., Mata, N. L. D. L., Viecelli, A. K., Swaminathan, R., O’Sullivan, K. M., O’Lone, E., Rowlandson, M., Francis, A., Wyburn, K., & Webster, A. C. (2022) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2022.04.006 · Cited by 44 · see citing works
Dexmedetomidine attenuates renal fibrosis via α2-adrenergic receptor-dependent inhibition of cellular senescence after renal ischemia/reperfusion
Li, Q., Chen, C., Chen, X., Han, M., & Li, J. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.05.003 · Cited by 42 · see citing works
Targeting Premature Renal Aging: from Molecular Mechanisms of Cellular Senescence to Senolytic Trials
Franzin, R., Stasi, A., Ranieri, E., Netti, G. S., Cantaluppi, V., Gesualdo, L., Stallone, G., & Castellano, G. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.630419 · Cited by 40 · see citing works
Kidney function and dementia risk in community-dwelling older adults: the Shanghai Aging Study
Wang, M., Ding, D., Zhao, Q., Wu, W., Xiao, Z., Liang, X., Luo, J., & Chen, J. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00729-9 · Cited by 38 · see citing works
Implication of cellular senescence in the progression of chronic kidney disease and the treatment potencies
Wang, Y., Wang, Y., Yang, M., & Ma, X. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.111191 · Cited by 37 · see citing works
Ellagic acid ameliorates aging-induced renal oxidative damage through upregulating SIRT1 and NRF2
Naghibi, N., Sadeghi, A., Movahedinia, S., Naiini, M. R., Rajizadeh, M. A., Bahri, F., & Nazari‐Robati, M. (2023) · BMC Complementary Medicine and Therapies · doi:10.1186/s12906-023-03907-y · Cited by 36 · see citing works
“The aging process is closely connected to enhanced mitochondrial dysfunction and reduced antioxidant capacity leading to redox signaling disruption and a wide range of phenotypic changes, including altered gene expression, arrested cell proliferation and growth, and cellular senescence [3, 4].”
Background
The role of STAT3/mTOR-regulated autophagy in angiotensin II-induced senescence of human glomerular mesangial cells
Yang, S., Sun, D., Wang, L., Wang, X., Shi, M., Jiang, X., & Gao, X. (2018) · Cellular Signalling · doi:10.1016/j.cellsig.2018.10.021 · Cited by 34 · see citing works
14-3-3 proteins: an important regulator of autophagy in diseases.
Jia, H., Liang, Z., Zhang, X., Wang, J., Xu, W., & Qian, H. (2017) · Europe PMC (PubMed Central) · Cited by 34 · see citing works
Protective effects of berberine on various kidney diseases: Emphasis on the promising effects and the underlined molecular mechanisms
Hassanein, E. H. M., Ibrahim, I. M., Abd‐alhameed, E. K., Mohamed, N. M., & Ross, S. A. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.120697 · Cited by 31 · see citing works
Design and methodology of the screening for CKD among older patients across Europe (SCOPE) study: a multicenter cohort observational study
on behalf of SCOPE investigators, Corsonello, A., Tap, L., Roller‐Wirnsberger, R., Wirnsberger, G. H., Zoccali, C., Kostka, T., Guligowska, A., Mattace-Raso, F. U. S., Gil, P., et al. (2018) · BMC Nephrology · doi:10.1186/s12882-018-1030-2 · Cited by 31 · see citing works
“suggests that ageing contributes to the incidence of reduced renal filtration capacity [1].”
Background
Chronic Kidney Disease
Goligorsky, M. S. (2020) · American Journal Of Pathology · doi:10.1016/j.ajpath.2020.01.016 · Cited by 31 · see citing works
Structural and physiological changes of the kidney with age and its impact on chronic conditions and COVID-19
Ray, N., & Reddy, P. H. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101932 · Cited by 30 · see citing works
Sirtuin 3 in renal diseases and aging: From mechanisms to potential therapies
Xuan, P., Ni, H., Kuang, B., Wang, Z., Hou, S., Gu, S., & Gong, N. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107261 · Cited by 30 · see citing works
The Role of SIRT3 in the Osteoporosis
Hu, S., & Wang, S. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.893678 · Cited by 30 · see citing works
“Osteoporosis is a prevalent aging-related disease, which is usually accompanied by changes in metabolic processes and mitochondrial dysfunction (8, 9).”
Background
Associations between nephron number and podometrics in human kidneys
Haruhara, K., Kanzaki, G., Sasaki, T., Hatanaka, S., Okabayashi, Y., Puelles, V. G., Harper, I. S., Shimizu, A., Cullen‐McEwen, L. A., Tsuboi, N., et al. (2022) · Kidney International · doi:10.1016/j.kint.2022.07.028 · Cited by 29 · see citing works
Detrimental Effects of Chronic L-Arginine Rich Food on Aging Kidney
Huang, J., Ladeiras, D., Yu, Y., Ming, X., & Yang, Z. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.582155 · Cited by 29 · see citing works
Recent Advances in Epigenetics of Age-Related Kidney Diseases
Liu, F., Chen, J., Li, Z., & Meng, X. (2022) · Genes · doi:10.3390/genes13050796 · Cited by 29 · see citing works
“The main pathological characteristics of the aged kidney include arteriosclerosis, glomerulosclerosis, tubular atrophy, and interstitial fibrosis [7].”
Background
Renal inflamm-aging provokes intra-graft inflammation following experimental kidney transplantation
He, A., Sarwar, A., Thole, L. M. L., Siegle, J., Sattler, A., Ashraf, M., Proß, V., Stahl, C., Dornieden, T., Bergmann, Y., et al. (2022) · American Journal of Transplantation · doi:10.1111/ajt.17154 · Cited by 30 · see citing works
Endothelial dysfunction in the aging kidney
Borri, M., Jacobs, M. E., Carmeliet, P., Rabelink, T. J., & Dumas, S. J. (2025) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00287.2024 · Cited by 30 · see citing works
Resveratrol Pretreatment Ameliorates Concanavalin A-Induced Advanced Renal Glomerulosclerosis in Aged Mice through Upregulation of Sirtuin 1-Mediated Klotho Expression
Chen, C.-C., Chang, Z., Tsai, F., & Chen, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186766 · Cited by 28 · see citing works
“This renal aging results in reduced capacities for adaption to stress and structural repair [25].”
Background
Proteasome activator PA200 maintains stability of histone marks during transcription and aging
Jiang, T.-X., Ma, S., Han, X., Luo, Z.-Y., Zhu, Q., Chiba, T., Xie, W., Chen, S., Lin, K., & Qiu, X. (2020) · Theranostics · doi:10.7150/thno.48744 · Cited by 27 · see citing works
Anti-senescence therapies: a new concept to address cardiovascular disease
Stojanović, S. D., Thum, T., & Bauersachs, J. K. (2025) · Cardiovascular Research · doi:10.1093/cvr/cvaf030 · Cited by 28 · see citing works
Mitochondrial calcium uniporter promotes kidney aging in mice through inducing mitochondrial calcium-mediated renal tubular cell senescence
Xiong, Y., Huang, W., Ling, X., Zhou, S. Y., Wang, X., Li, X., & Zhou, L. (2024) · Acta Pharmacologica Sinica · doi:10.1038/s41401-024-01298-5 · Cited by 28 · see citing works
“Currently, there are a bunch of theories suggesting the mechanisms of aging, such as oxidative stress [12], telomere shortening [13], protein homeostasis imbalance [14], epigenetic changes, DNA damage, and persistent in ﬂ ammation [15].”
Accelerated Glomerular Cell Senescence in Experimental Lupus Nephritis
Yang, C., Xue, J., An, N., Huang, X.-J., Wu, Z., Ye, L., Li, Z., Wang, S., Pan, Q., Liang, D., et al. (2018) · Medical Science Monitor · doi:10.12659/msm.909353 · Cited by 26 · see citing works
“Recently, cellular senescence has been reported to play a causal role in the pathogenesis of glomerular diseases [19].”
Background
Incidence, severity, risk factors and outcomes of acute kidney injury in older adults: systematic review and meta-analysis
Stille, K., Kribben, A., & Herget‐Rosenthal, S. (2022) · Journal of Nephrology · doi:10.1007/s40620-022-01381-2 · Cited by 26 · see citing works
Berberine ameliorates renal injury in a rat model of D‐galactose-induced aging through a PTEN/Akt-dependent mechanism
El‐Horany, H. E., Gaballah, H. H., & Helal, D. S. (2018) · Archives of Physiology and Biochemistry · doi:10.1080/13813455.2018.1499117 · Cited by 24 · see citing works
“In renal aging, a complex interplay of genetics, environmental change, and cellular dysfunction leads to characteristic structural and functional changes (Schmitt and Melk 2017).”
Background
Genetic susceptibility to diabetic kidney disease is linked to promoter variants of XOR
Wang, Q., Qi, H., Wu, Y., Yu, L., Bouchareb, R., Li, S., Lassén, E., Casalena, G., Stadler, K., Ebefors, K., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00776-0 · Cited by 26 · see citing works
Deciphering the whale's secrets to have a long life
Lagunas‐Rangel, F. A. (2021) · Experimental Gerontology · doi:10.1016/j.exger.2021.111425 · Cited by 23 · see citing works
The interaction between cellular senescence and chronic kidney disease as a therapeutic opportunity
Zhao, J.-L., Qiao, X.-H., Mao, J., Liu, F., & Fu, H. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.974361 · Cited by 23 · see citing works
“, 2019), and the autophagic flux induced by calorie restriction (CR) (Schmitt and Melk, 2017) can slow down the process of renal tubular atrophy and interstitial fibrosis.”
Background
Combating chronic kidney disease-associated cachexia: A literature review of recent therapeutic approaches
Saadat, Y. R., Abbasi, A., Hejazian, S. S., Hekmatshoar, Y., Ardalan, M., Farnood, F., & Vahed, S. Z. (2025) · BMC Nephrology · doi:10.1186/s12882-025-04057-8 · Cited by 22 · see citing works
“…across many renal pathologies, notably IgA nephropathy, focal segmental glomerulosclerosis, membranous nephropathy, and in transplanted kidneys [58, 59]. p16 INK4a and senescence-associated beta-galactosidase (SA-β-gal) were likewise elevated in the kidney epithelium of individuals with…”
Podocyte FFAR4 deficiency aggravated glomerular diseases and aging
Yin, T., Yang, L., Tang, L., Li, J., Liu, D., Guo, F., Mu, Y., Wu, Q., Feng, Y., Tan, Z., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.05.035 · Cited by 21 · see citing works
PPARα/β Activation Alleviates Age-Associated Renal Fibrosis in Sprague Dawley Rats
Chung, K. W., Ha, S., Kim, S. M., Kim, D. H., An, H. J., Lee, E. K., Moon, H. R., & Chung, H. Y. (2019) · The Journals of Gerontology Series A · doi:10.1093/gerona/glz083 · Cited by 21 · see citing works
RETRACTED ARTICLE: Cinnamaldehyde attenuates kidney senescence and injury through PI3K/Akt pathway-mediated autophagy via downregulating miR-155
Xiao, Q. (2022) · Renal Failure · doi:10.1080/0886022x.2022.2056485 · Cited by 21 · see citing works
Retracted
Long-term lithium therapy and risk of chronic kidney disease, hyperparathyroidism and hypercalcemia: a cohort study
Boivin, E., Daré, B. L., Bellay, R., Vigneau, C. M., Mercerolle, M., & Bacle, A. (2023) · International Journal of Bipolar Disorders · doi:10.1186/s40345-023-00286-8 · Cited by 21 · see citing works
“3 times more rapid compared to the general population where mean annual GFR loss is estimated at approximately 1 mL/min/1.73 m2 (Glassock and Rule 2016; Nankivell 2001; Schmitt and Melk 2017).”
BackgroundInfluential
SGLT2 inhibition to target kidney aging
Russo, E., Zanetti, V., Macciò, L., Benizzelli, G., Carbone, F., Porta, E. L., Esposito, P. B., Verzola, D., Garibotto, G., & Viazzi, F. C. (2024) · Clinical Kidney Journal · doi:10.1093/ckj/sfae133 · Cited by 22 · see citing works
“Physiologic kidney aging and several kidney diseases share common biologic processes and molecular pathways [1 ], including cellular senescence, inflammation, fibrosis, vascular rarefaction, loss of glomeruli and tubular dysfunction, which lead to glomerulosclerosis and tubulointerstitial fibrosis…”
Background
Complement C3 deficiency ameliorates aging related changes in the kidney
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Complex Pathophysiology of Acute Kidney Injury (AKI) in Aging: Epigenetic Regulation, Matrix Remodeling, and the Healing Effects of H2S
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Authors: Schmitt, R., & Melk, A.
Affiliations: Medizinische Hochschule Hannover (DE)
ORCID: Schmitt, Roland
Melk, Anette
Venue: Kidney International
Publisher: Elsevier BV
Published: 2017-09
Volume: 92
Issue: 3
Pages: 569-579
ISSN: 0085-2538 (ISSN-L)
DOI: 10.1016/j.kint.2017.02.036
OpenAlex: W2737090018
Cited by: 235
References: 149
Citations by year: 2026: 18 · 2025: 27 · 2024: 31 · 2023: 32 · 2022: 30 · 2021: 32 · 2020: 29 · 2019: 19 · 2018: 15 · 2017: 2
FWCI: 2.37
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1461 d)
Locations: Kidney International (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
Keywords: kidney aging, acute kidney injury, chronic kidney disease, glomerular filtration rate decline, nephron loss, podocyte hypertrophy, glomerulosclerosis, tubular atrophy, microvascular rarefaction, cellular senescence, senolytics, autophagy, renal inflammation, caloric restriction mimetics, renin-angiotensin-aldosterone system inhibition, kidney regeneration
MeSH terms: Aging, Angiotensin-Converting Enzyme Inhibitors, Animals, Autophagy, Disease Models, Animal, Disease Susceptibility, Glomerular Filtration Rate, Humans, Kidney, Renin-Angiotensin System, Cellular Senescence, Caloric Restriction, Acute Kidney Injury

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