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Pathological mechanisms of kidney disease in ageing

Nature Reviews Nephrology volume 20, pages 603–615 (2024)Cite this article

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Abstract

The kidney is a metabolically active organ that requires energy to drive processes such as tubular reabsorption and secretion, and shows a decline in function with advancing age. Various molecular mechanisms, including genomic instability, telomere attrition, inflammation, autophagy, mitochondrial function, and changes to the sirtuin and Klotho signalling pathways, are recognized regulators of individual lifespan and pivotal factors that govern kidney ageing. Thus, mechanisms that contribute to ageing not only dictate renal outcomes but also exert a substantial influence over life expectancy. Conversely, kidney dysfunction, in the context of chronic kidney disease (CKD), precipitates an expedited ageing trajectory in individuals, leading to premature ageing and a disconnect between biological and chronological age. As CKD advances, age-related manifestations such as frailty become increasingly conspicuous. Hence, the pursuit of healthy ageing necessitates not only the management of age-related complications but also a comprehensive understanding of the processes and markers that underlie systemic ageing. Here, we examine the hallmarks of ageing, focusing on the mechanisms by which they affect kidney health and contribute to premature organ ageing. We also review diagnostic methodologies and interventions for premature ageing, with special consideration given to the potential of emerging therapeutic avenues to target age-related kidney diseases.

Key points

  • The kidney is a metabolically active organ that requires energy for processes such as tubular reabsorption and secretion; however, kidney function declines with age.

  • Various molecular mechanisms, including cellular senescence, inflammation, mitochondrial function, changes to the sirtuin and Klotho signalling pathways, and the autophagy–lysosome system, are recognized as regulators of individual lifespan and are important factors that govern kidney ageing.

  • Chronic kidney disease (CKD) and premature ageing share several common features and pathophysiological mechanisms; CKD is therefore considered a disease associated with accelerated or premature ageing.

  • The accelerated ageing phenotype of the kidney in the context of CKD results in a disconnect between the biological age of the kidney and the chronological age of the individual, known as the ‘age gap’.

  • Emerging technologies and biomarkers hold promise for improving the early detection, diagnosis and management of age-related kidney diseases and premature ageing.

  • Targeting the pathways associated with inflammation, mitochondrial function, oxidative stress, senescence and the autophagy–lysosome system holds promise for developing therapeutic interventions to prevent, delay or attenuate age-related kidney diseases and promote healthy ageing.

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Fig. 1: The hallmarks of kidney ageing.
Fig. 2: Molecular mechanisms of autophagy dysregulation in ageing.
Fig. 3: The concept of biological age versus chronological age.
Fig. 4: Interactions between premature ageing, frailty and CKD.

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Acknowledgements

The authors’ work is supported by Japan Society for the Promotion of Science (21K16163, 23K07671 to T.Y. and 21H02935 to Y.I.), Japan Agency for Medical Research and Development (JP23ek0310022 to T.Y. and JP22gm1410014 to Y.I.), the Astellas Foundation for Research on Metabolic Disorders, Naito Foundation, Kato Memorial Bioscience Foundation, Salt Science Research Foundation, Sumitomo Insurance Welfare Foundation, G-7 Scholarship Foundation, and Takeda Medical Research Foundation (to T. Y.).

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    Takeshi Yamamoto & Yoshitaka Isaka

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Yamamoto, T., Isaka, Y. Pathological mechanisms of kidney disease in ageing. Nat Rev Nephrol 20, 603–615 (2024). https://doi.org/10.1038/s41581-024-00868-4

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