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Sustained immune youth risks autoimmune disease in the aging host

Nature Aging volume 5, pages 1404–1414 (2025)Cite this article

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Abstract

Immune responses underlying autoimmune diseases follow the same principles that protect individuals from infection and malignancies. However, while protective immunity wanes with progressive age, the risk for autoimmune disease steadily increases; incidence rates for many autoimmune diseases peak in later life. Here, we discuss whether aging predisposes to autoimmunity, arguing that disease progression in the autoimmune vasculitis giant cell arteritis is driven by age-inappropriate sustenance of immune competence. Stem-like memory CD4+ T cells (TSCM) that reside near the vasculitic lesions provide a continuous supply of pathogenic effector T cells. Antigen-presenting cells lacking inhibitory ligands further impede peripheral tolerance mechanisms. In the context of aging-associated accumulation of neoantigens, this incessant immune competence sets the stage for unopposed autoimmunity. We propose that sustained immune youthfulness can be detrimental to the aging host, while immune aging may be a beneficial adaptation to balance reactivity to self-antigens and non-self-antigens and thus protect from autoimmunity in aging.

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Fig. 1: Age as a risk factor of autoimmunity.
Fig. 2: Increase of the immunogenic antigen load with age.
Fig. 3: TSCM cells in autoimmune vasculitis.
Fig. 4: Youthfulness of peripheral T cell subset distribution in autoimmune vasculitis.
Fig. 5: The survival niche for stem-like CD4+ T cells in vasculitis.
Fig. 6: Non-inhibitory APCs and non-exhaustible CD4+ T cells in vasculitis.
Fig. 7: A disease model for autoimmunity in the older adult.
Fig. 8: Delayed immune aging predisposes to autoimmune disease.

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Acknowledgements

We thank the members of their research teams, the patients who donated research samples, the Encrantz Family Discovery Fund, the Southwell Family Discovery Fund and the Mary and Mark Davis Program in Autoimmunity. The work has received support from the National Institutes of Health (R01AR042527, R01AI108906, R01HL142068, U01AI179609, R01HL117913 to C.M.W. and R01AI108891, R01AG045779, R01AI129191, R01AI184360 to J.J.G.).

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Authors and Affiliations

  1. Department of Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN, USA

    Cornelia M. Weyand & Jörg J. Goronzy

  2. Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Cornelia M. Weyand & Jörg J. Goronzy

  3. Department of Cardiovascular Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN, USA

    Cornelia M. Weyand

  4. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Cornelia M. Weyand & Jörg J. Goronzy

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  1. Cornelia M. Weyand
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  2. Jörg J. Goronzy
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C.M.W. and J.J.G. conceptualized the manuscript. C.M.W. wrote the manuscript, and C.M.W. and J.J.G. edited the manuscript.

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Correspondence to Cornelia M. Weyand.

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C.M.W. has received consulting fees from AbbVie, Bristol Myers Squibb, Novartis, Ono Pharmaceutical, Boehringer Ingelheim and Sparrow Pharmaceuticals. J.J.G. has received consulting fees and stock options from Retro Biosciences.

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Weyand, C.M., Goronzy, J.J. Sustained immune youth risks autoimmune disease in the aging host. Nat Aging 5, 1404–1414 (2025). https://doi.org/10.1038/s43587-025-00919-w

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