Genetic association of immunosenescence to immune decline.

Authors

Mohammad Y Alshahrani, Zahraa AlKhafaje, Uday Abdul-Reda Hussein, Zahraa Adel, Ola Kamal A Alkadir, Ahmed Aldulaimi, Rafid Kamal Jameel, Rafid Jihad Albadr, Mariem Alwan, Aseel Smerat

Published in

Immunogenetics. Volume 78. Issue 1. Jul 28, 2026. Epub Jul 28, 2026.

Abstract

Immunosenescence is a complex biological process characterized by progressive remodeling of immune function during aging, leading to increased susceptibility to infections, chronic inflammatory diseases, cancer, and reduced vaccine efficacy. While cumulative antigen exposure, infections, lifestyle factors, environmental exposures, and epigenetic influences contribute to immune decline, a growing body of evidence suggests that genetic predisposition also plays an important modulatory role in shaping the molecular trajectory of immune aging. This review discusses how inherited variation in cytokine-regulatory pathways may influence IL-6, TNF-α, interferon, and TGF-β signaling, thereby contributing to inflammatory set points that favor chronic immune activation and inflammaging. Inherited differences in innate and adaptive immune signaling, including KIR-HLA interactions, DNA-sensing pathways, and downstream JAK-STAT and NF-κB cascades, may alter activation thresholds and immune-cell differentiation. Variants affecting mitochondrial redox balance and autophagy may enhance reactive oxygen species accumulation and metabolic exhaustion, thereby potentially contributing to immune-cell senescence. Genetic factors affecting folate metabolism, epigenetics, telomeres, and DNA repair drive epigenetic drift, cellular aging, and clonal instability in immune cells. These mechanisms appear as measurable molecular and cellular biomarkers, including inflammatory signals, immune cell activation, oxidative stress, telomere shortening, and multi-omic indicators. Understanding this molecular architecture provides a foundation for identifying predictive biomarkers and developing precision strategies to preserve immune competence and promote healthy aging.

PMID:
42517957
Bibliographic data and abstract were imported from PubMed on 28 Jul 2026.

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