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

## TL;DR

This paper reviews how aging disrupts immune system networks, leading to chronic inflammation and age-related diseases, and explores potential therapies to restore immune balance.

## Contribution

The paper provides a systems-level perspective on immune aging, emphasizing network rewiring and its role in inflammaging and age-related pathologies.

## Key findings

- Aging disrupts immune networks, causing chronic inflammation and impaired tissue repair.
- Defective efferocytosis and reduced responsiveness to pro-resolving signals contribute to persistent inflammation.
- Altered innate and adaptive immunity, immunometabolism, and senescence drive age-related diseases.

## Abstract

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.