Age-related diseases of the lung and brain represent a growing health burden, yet the immune mechanisms linking aging to tissue dysfunction remain incompletely understood. Here, we identify the pro-inflammatory cytokine interleukin-21 (IL-21) as a central mediator of age-associated immune dysregulation across organ systems. Using murine models and human samples, we demonstrate that IL-21 drives a pro-inflammatory state in the lung, characterized by increased expression of TNF-α, IL-6, IL-33, CXCL-10, and IL-18, along with induction of cellular senescence and expansion of KLRG1⁺ T cells. IL-21 also reprograms lung macrophages, promoting lipid accumulation and upregulation of TREM-2 and CD36, accompanied by increased TGF-β production, suggesting a mechanism linking inflammation to fibrosis. Additionally, IL-21 impairs antiviral immunity by reducing macrophage MHC-II expression and attenuating IFN-α responses. Notably, aged mice exhibit a lung phenotype closely resembling IL-21–treated young mice, and IL-21 expression is elevated in lungs of patients with idiopathic pulmonary fibrosis, supporting its relevance to human disease.

Extending these findings to the central nervous system, we show that IL-21 is elevated in the circulation of individuals with Alzheimer’s disease (AD), with increased IL-21 receptor expression in the hippocampi of AD patients and 5xFAD mice. Peripheral IL-21 administration exacerbates AD pathology, while systemic IL-21 exposure in young mice induces neuroinflammation, activates microglia and astrocytes, and promotes lipid droplet accumulation in microglia—features associated with neuronal injury. Importantly, IL-21 levels increase with age even in healthy individuals, with corresponding upregulation of IL-21R in aged brain tissue.

Collectively, these findings position IL-21 as a key link between immunosenescence and multi-organ dysfunction, driving inflammatory, senescent, and metabolic reprogramming in both lung and brain. Targeting IL-21 signaling may represent a promising therapeutic strategy for age-related pulmonary and neurodegenerative diseases.