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Immunology of the ageing kidney

Abstract

Immunosenescence involves a series of ageing-induced alterations in the immune system and is characterized by two opposing hallmarks: defective immune responses and increased systemic inflammation. The immune system is modulated by intrinsic and extrinsic factors and undergoes profound changes in response to the ageing process. Immune responses are therefore highly age-dependent. Emerging data show that immunosenescence underlies common mechanisms responsible for several age-related diseases and is a plastic state that can be modified and accelerated by non-heritable environmental factors and pharmacological intervention. In the kidney, resident macrophages and fibroblasts are continuously exposed to components of the external environment, and the effects of cellular reprogramming induced by local immune responses, which accumulate with age, might have a role in the increased susceptibility to kidney disease among elderly individuals. Additionally, because chronic kidney disease, especially end-stage renal disease, is often accompanied by immunosenescence, which affects these patients independently of age, and many kidney diseases are strongly age-associated, treatment approaches that target immunosenescence might be particularly clinically relevant.

Key points

  • Ageing affects the composition and function of the immune system and leads to immunosenescence, which is characterized by defective immune responses and increased systemic inflammation (also termed inflammageing).

  • Inflammageing is maladaptive and results from multiple mechanisms, including aberrant inflammasome activation, microbial dysbiosis, accumulation of senescent cells and primary dysregulation of immune cells.

  • The causes and consequences of immunosenescence overlap, thus forming a vicious cycle that exacerbates immunosenescence.

  • Immunosenescence is a risk factor for the development of a wide spectrum of age-related diseases and therefore targeting immunosenescence might represent a novel therapeutic strategy for preventing them.

  • The immune status of patients with chronic kidney disease mimics that of elderly individuals, which underlies shared clinical characteristics such as an increased risk of infection and atherosclerosis.

  • The immune system has crucial roles in the pathophysiology of kidney disease and the effects of immunosenescence on kidney diseases are therefore also widespread and substantial.

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Fig. 1: Immunosenescence in elderly individuals and patients with CKD.
Fig. 2: Age-associated changes in the immune system and the kidney.
Fig. 3: Causes and consequences of senescent T cell accumulation in the elderly.
Fig. 4: Age-related alterations in multiple lymphoid organs contribute to immunosenescence.
Fig. 5: Tertiary lymphoid tissue in aged, injured kidneys.

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Acknowledgements

The authors’ work is supported by the Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP18gm5010002 and JP18gm0610011; as well as grants from the TMK Project, KAKENHI Grant-in-Aid for Scientific Research B (17H04187), Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science (JSPS), Grant-in-Aid on Innovative Areas (17H05642, 18H04673), Grant-in-Aid for Exploratory Research (17K19677), the Translational Research Program, and the Strategic Promotion for Practical Application of Innovative Medical Technology (TR-SPRINT) from AMED, and grants from the Uehara Memorial Foundation, Takeda Science Foundation, Yukiko Ishibashi Foundation and the Sumitomo Foundation.

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Both authors contributed equally to all aspects of article preparation.

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Correspondence to Yuki Sato or Motoko Yanagita.

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Y.S. is employed by the TMK Project. M.Y. receives research grants from Astellas, Chugai, Daiichi Sankyo, Fujiyakuhin, Kyowa Hakko Kirin, Mitsubishi Tanabe, MSD, Nippon Boehringer Ingelheim and Torii.

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Nature Reviews Nephrology thanks M. Attanasio and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Replicative senescence

Senescence that occurs as a result of repeated cell division, which is accompanied by gradual telomere shortening.

Premature senescence

Senescence that occurs as a result of various stress stimuli such as DNA damage, oxidative stress and oncogenic insults.

Induction therapy

Short-term intensive immunosuppressive therapy administered in the perioperative period to reduce the risk of acute allograft rejection.

Sarcopenia

Degenerative loss of skeletal muscle strength and mass with ageing.

Kaede mice

Transgenic mice that ubiquitously express the photoconvertible Kaede protein, which permanently changes its fluorescence emission from green to red on photoactivation with near-UV light.

Heterologous immunity

Previous immunity to one pathogen can alter the outcome of a subsequent infection with a different pathogen by modulating the immune response.

Exhausted T cells

T cells with impaired effector functions such as cytokine production and cytotoxicity due to chronic antigen stimulation.

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Sato, Y., Yanagita, M. Immunology of the ageing kidney. Nat Rev Nephrol 15, 625–640 (2019). https://doi.org/10.1038/s41581-019-0185-9

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