Frailty and tertiary lymphoid structures in immunosenescence: Emerging associations, mechanistic clues and future perspectives

Abstract

Frailty, a geriatric syndrome marked by multisystem functional decline and heightened vulnerability, threatens older adults’ health span. Immunosenescence and chronic low-grade inflammation are increasingly recognized as core drivers, with age-related impairments in cellular, humoral, and innate immunity disrupting immune homeostasis. Tertiary lymphoid structures (TLS), ectopic immune aggregates that orchestrate local immune responses, have emerged as candidate regulators in chronic disease, yet their role in frailty remains largely unexplored. Here, we propose a conceptual framework for frailty pathogenesis in which immunosenescence and chronic low-grade inflammation (inflammaging) may act as upstream biological drivers associated with systemic lymphatic dysfunction, potentially contributing to the structural and functional dysregulation of TLS, a candidate intermediate tissue-level histological link. TLS dysfunction may subsequently contribute to multi-organ functional decline and the progression of frailty. We synthesize current evidence on the dynamic characteristics of TLS in aging, discuss TLS as candidate biomarkers and putative therapeutic targets for frailty, and highlight intervention strategies including molecular modulation, lymphatic function enhancement, immunotherapy, and lifestyle modifications. This tissue-level perspective highlights TLS as a potential histological link connecting immunosenescence, lymphatic dysfunction, and frailty, offering novel avenues for geriatric precision medicine and the development of immune-targeted interventions to delay frailty progression.

Keywords

Frailty / immune aging / tertiary lymphoid structure / chronic inflammation / immune regulation

Acknowledgements

The authors would like to thank all the researchers whose work is included in this review. We acknowledge the use of AI-assisted tools, including ChatGPT (OpenAI, USA) for language editing and polishing of the manuscript, and BioRender.com for the creation and optimization of the schematic figures. All authors have full control over the content of the manuscript, have thoroughly reviewed and revised all parts of the manuscript, and take full responsibility for all content of the manuscript.

Authors contribution

Zheng L, Wen S: Conceptualization, supervision.

Lin Z: Investigation, formal analysis.

Chen J, Liu S: Writing-review & editing.

Conflicts of interest

Shaodi Wen is a Youth Editorial Board of Ageing and Cancer Research & Treatment. The other authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

None.

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