Mapping the immune-genetic architecture of aging: A single-cell causal framework for biomarker discovery and therapeutic targeting.

Yanggang Hong, Yi Wang, Wanyi Shu, Jiajun Li, Yuze Mi, Haolin Chen, Congde Chen

Key Laboratory of Structural Malformations in Children of Zhejiang Province, Department of Pediatric Urology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Children Genitourinary Diseases of Wenzhou City, Department of Pediatric, Urology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical, University, Wenzhou, Zhejiang, China; Wenzhou Medical University, Zhejiang, China. Electronic address: [email protected] Laboratory of Structural Malformations in Children of Zhejiang Province, Department of Pediatric Urology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Children Genitourinary Diseases of Wenzhou City, Department of Pediatric, Urology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical, University, Wenzhou, Zhejiang, China; Wenzhou Medical University, Zhejiang, China. Electronic address: [email protected]. · pubmed

Paper

Abstract

Aging is a complex biological process driven by genetic and immune-mediated mechanisms, yet the causal roles of immune-cell-specific gene regulation remain unclear. In this study, we integrate single-cell expression quantitative trait loci (sc-eQTL) data with Mendelian randomization (MR) and colocalization analyses to identify immune-mediated regulatory mechanisms and therapeutic targets for aging. Using data from 14 immune cell types, we systematically evaluated 8733 eGenes for causal effects on telomere length (TL), facial aging (FA), and frailty index (FI). We identified 27 immune-cell-specific eGenes with significant causal associations and strong colocalization evidence (posterior probability for a shared causal variant, PP.H4 > 50 %). Key regulators include FUBP1, TUFM, ATIC, and SLC22A5, with distinct effects across cell types and aging traits. Phenome-wide association studies (PheWAS) demonstrated minimal off-target associations for most genes, supporting their safety as therapeutic targets. Drug repurposing analysis revealed several approved or investigational compounds, such as Irofulven, zinc-based agents, and acetylcarnitine, with potential for aging-related interventions. Our findings provide new insights into the immune-genetic architecture of aging and establish a scalable framework for identifying cell-type-specific causal genes and repurposable drug targets. This approach enhances precision medicine strategies aimed at promoting healthy aging and delaying age-related decline.

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Research summary

The paper identifies immune-cell-specific eGenes that causally influence aging traits and suggests potential therapeutic targets for promoting healthy aging. This research is relevant as it addresses the genetic and immune mechanisms underlying aging, aiming to uncover root causes and therapeutic interventions rather than merely treating age-related symptoms.

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