Network Rewiring in the Aging Immune System: From Chronic Inflammation to Age-Related Pathologies

Mar 14, 2026Cells

Changes in Immune System Networks with Aging Linked to Long-Term Inflammation and Age-Related Diseases

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Aging is associated with profound alterations in immune function that increase susceptibility to infection and age-related diseases.

Immunosenescence and inflammaging coexist, indicating a systems-level reprogramming of immune networks rather than isolated cellular defects.
Aging is linked to impaired resolution of inflammation and defective clearance of dead cells, contributing to persistent inflammation and tissue damage.
Chronic inflammation, failed resolution, and defective repair mechanisms may reinforce each other in aging individuals.
Alterations in both innate and adaptive immunity, as well as immune-tissue interactions, contribute to age-related diseases such as cancer and neurodegenerative disorders.
Emerging therapeutic strategies aim to restore immune balance and enhance resolution processes to promote healthy aging.

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Aging is accompanied by profound alterations in immune function that collectively drive increased susceptibility to infection, reduced vaccine efficacy, impaired tissue repair, and heightened risk of age-related diseases (ARDs). These alterations are characterized by the coexistence of immunosenescence and inflammaging. Rather than reflecting isolated cellular defects, immune aging emerges as a systems-level reprogramming of immune networks that disrupts the initiation, resolution, and regenerative phases of inflammatory responses. In particular, aging is associated with impaired resolution of inflammation, defective efferocytosis, reduced responsiveness to pro-resolving signals, and diminished regenerative capacity, leading to persistent inflammatory milieus and tissue damage. This review summarizes recent advances in the mechanisms underlying immune dysfunction in aging, with a focus on how chronic inflammation, failed resolution, and defective repair reinforce one another. We discuss how alterations in innate and adaptive immunity, immunometabolism, cellular senescence, and immune-tissue interactions drive inflammaging and contribute to major ARDs, including cancer, neurodegenerative, and cardiometabolic diseases. Finally, we highlight emerging therapeutic strategies aimed at restoring immune balance and resolution. By adopting a systems-level and network-based perspective, this review underscores immune aging as a modifiable driver of ARDs and identifies key knowledge gaps and future directions toward interventions that promote healthy aging and extended healthspan.

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Network Rewiring in the Aging Immune System: From Chronic Inflammation to Age-Related Pathologies

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