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  • Perspective
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Aging reshapes the adaptive immune system from healer to saboteur

Nature Aging volume 5, pages 1393–1403 (2025)Cite this article

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Abstract

The classical role of adaptive immunity as a protector against external threats has expanded to include its functions in cancer surveillance, tissue repair and regeneration, and, more recently, it has emerged as a regulator of the aging process. In this Perspective, we discuss the mechanisms by which the deterioration of adaptive immunity contributes to inflammaging, cellular senescence and age-associated pathologies. We propose that age-related changes in lymphocytes contribute to aging through two distinct mechanisms. First, adaptive immune function worsens with age, impairing immunosurveillance of damaged or senescent cells and diminishing tissue regenerative potential, thereby indirectly disrupting tissue homeostasis. This disruption is particularly important in the gut, where maintaining tissue and microbiota homeostasis is crucial for overall health during aging. Second, adaptive immune cells often acquire pro-inflammatory and autoaggressive phenotypes with age, directly driving tissue damage, promoting senescence and exacerbating inflammaging. Finally, we explore the therapeutic potential of strategies aimed at enhancing the protective functions of lymphocytes or modulating their pathogenic phenotypes to promote healthy aging.

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Fig. 1: Hallmarks of adaptive immune aging.
Fig. 2: Loss of protective and regenerative functions.
Fig. 3: Acquisition of pathogenic features.
Fig. 4: Geroscience-based interventions to improve immune function.

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Acknowledgements

Funded by the European Union (M.M.). Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. This work was supported by the European Research Council (ERC-2021-CoG 101044248-Let T Be) (M.M.) and Spanish Ministerio de Ciencia e Innovación (PID2022-141169OB-I00) grants (M.M.), NIH grant R21AG087361 (M.J.Y.), a Nelson Family Transplant Innovation Award (M.J.Y.), pilot projects from the New York Nutrition and Obesity Research Center and the CALERIE study (M.J.Y.). S.D.-P. was supported by a PIPF grant (PIPF-2022/SAL-GL-25208) from the Comunidad de Madrid (Spain).

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Authors and Affiliations

  1. Tissue and Organ Homeostasis Program, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain

    Sandra Delgado-Pulido & Maria Mittelbrunn

  2. Columbia Center of Human Longevity, Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA

    Matthew J. Yousefzadeh & Maria Mittelbrunn

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  1. Sandra Delgado-Pulido
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  2. Matthew J. Yousefzadeh
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  3. Maria Mittelbrunn
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S.D.-P., M.J.Y. and M.M. contributed to the preparation of the Perspective.

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Delgado-Pulido, S., Yousefzadeh, M.J. & Mittelbrunn, M. Aging reshapes the adaptive immune system from healer to saboteur. Nat Aging 5, 1393–1403 (2025). https://doi.org/10.1038/s43587-025-00906-1

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