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<p>Aging exhibits both systemic and organ-specific components, yet existing models struggle to disentangle their shared versus distinct biological determinants at the population level. We present a structural decomposition framework that partitions seven organ-based biological age gaps (BAGs) into a Common BAG (CBAG) and seven Organ-Specific BAGs (OSBAGs) in 501,388 UK Biobank participants. This dual-axis model outperforms undecomposed body/organ BAG approaches in predicting lifespan, healthspan, and organ-specific disease risk. A large-scale aging GWAS identifies 747 novel loci, complemented by integrative proteomic and metabolomic analyses that reveal causal and druggable targets, including CST1. Pathway-guided multi-omics demonstrates a modular aging architecture, with CBAG reflecting cross-tissue regulators (e.g., FOXO3) and OSBAGs capturing organ-restricted effectors (e.g., UMOD). Drug-aging profiling uncovers organ-specific pro-aging effects consistent with known toxicities that are largely missed by undecomposed models. Sex-stratified analyses further reveal divergent molecular trajectories between males and females. All findings are integrated into HONOR, the first open-access atlas for structural aging and multi-omics translation.</p>

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Structural decomposition enables multi-omics dissection of common and organ-specific aging

  • 期刊论文

  • 发表日期：

    2026年5月8日

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  • He Huang,
  • Yi Li,
  • Qinglin Song,
  • Liyun Yuan,
  • Yuqi Yang,
  • Minwei Zhu,
  • Renliang Sun,
  • Yue Hu,
  • Chenyihang Xiong,
  • Ting Ni,
  • Yun Liu,
  • Andrés Ruiz-Linares,
  • Guoqing Zhang,
  • Fan Liu,
  • Qianqian Peng,
  • Sijia Wang

摘要

Aging exhibits both systemic and organ-specific components, yet existing models struggle to disentangle their shared versus distinct biological determinants at the population level. We present a structural decomposition framework that partitions seven organ-based biological age gaps (BAGs) into a Common BAG (CBAG) and seven Organ-Specific BAGs (OSBAGs) in 501,388 UK Biobank participants. This dual-axis model outperforms undecomposed body/organ BAG approaches in predicting lifespan, healthspan, and organ-specific disease risk. A large-scale aging GWAS identifies 747 novel loci, complemented by integrative proteomic and metabolomic analyses that reveal causal and druggable targets, including CST1. Pathway-guided multi-omics demonstrates a modular aging architecture, with CBAG reflecting cross-tissue regulators (e.g., FOXO3) and OSBAGs capturing organ-restricted effectors (e.g., UMOD). Drug-aging profiling uncovers organ-specific pro-aging effects consistent with known toxicities that are largely missed by undecomposed models. Sex-stratified analyses further reveal divergent molecular trajectories between males and females. All findings are integrated into HONOR, the first open-access atlas for structural aging and multi-omics translation.