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

IF 12.4 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews Pub Date : 2025-07-12 DOI:10.1016/j.arr.2025.102835

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

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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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绘制衰老的免疫遗传结构：生物标志物发现和治疗靶向的单细胞因果框架。

衰老是一个复杂的生物学过程，由遗传和免疫介导机制驱动，但免疫细胞特异性基因调控的因果作用尚不清楚。在这项研究中，我们将单细胞表达数量性状位点（sc-eQTL）数据与孟德尔随机化（MR）和共定位分析相结合，以确定免疫介导的衰老调节机制和治疗靶点。使用来自14种免疫细胞类型的数据，我们系统地评估了8,733个eGenes对端粒长度（TL）、面部衰老（FA）和脆弱指数（FI）的因果影响。我们确定了27个具有显著因果关系和强共定位证据的免疫细胞特异性eGenes（共同因果变异的后验概率，PP.H4 > 50%）。关键的调节因子包括FUBP1、TUFM、ATIC和SLC22A5，它们在不同的细胞类型和衰老性状中具有不同的作用。全现象关联研究（PheWAS）显示大多数基因的脱靶关联最小，支持其作为治疗靶点的安全性。药物再利用分析显示，一些已批准或正在研究的化合物，如Irofulven、锌基药物和乙酰肉碱，具有潜在的衰老相关干预作用。我们的发现为衰老的免疫遗传结构提供了新的见解，并建立了一个可扩展的框架，用于识别细胞类型特异性的因果基因和可重复利用的药物靶点。这种方法增强了旨在促进健康老龄化和延缓年龄相关衰退的精准医学策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Ageing Research Reviews 医学-老年医学

CiteScore

19.80

自引率

2.30%

发文量

216

审稿时长

55 days

期刊介绍： With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends. ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research. The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.