Liver Aging Index: A Noninvasive Score for Liver Biological Aging and Liver‐Related Outcomes in Multicohorts

Biological aging is a key determinant of liver disease and mortality, but there is little evidence on noninvasive index for assessment of liver biological aging. We developed the Liver Aging Index (LAI) in the China Kadoorie Biobank (CKB, N = 21,629) using Cox-Gompertz proportional hazards model. The LAI incorporated three clinical factors (body mass index, systolic and diastolic blood pressure), eight plasma biomarkers (glucose, total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase), and two imaging biomarkers (fat attenuation parameter and liver stiffness measurement). External validation was conducted in the National Health and Nutrition Examination Survey (NHANES; N = 3412) and the VCTE-Prognosis cohort (N = 12,170, 16 global centers). Across all cohorts, the LAI demonstrated strong discrimination for all-cause mortality (AUROC: 0.764 in NHANES; 0.759 in VCTE-Prognosis), outperforming chronological age (p < 0.05). Liver aging acceleration (LAA), defined as the difference between LAI and chronological age, was associated with substantially elevated risks: each 1-SD increase in LAA conferred a 22%-85% higher risk of all-cause mortality and a 34%-170% higher risk of liver-related event or mortality. Using genetic instruments identified in CKB, we found genetic predisposition to accelerated liver aging was associated with higher risks of cirrhosis and liver cancer (HR = 3.94 [3.20-4.86] and 7.82 [2.05-29.80]), further validated in Biobank Japan. Integrating genetics and proteomics revealed novel pathophysiological involvement of amyloid-beta clearance pathway and amyloid precursor protein in liver aging. These findings demonstrate the feasibility of a noninvasive, liver-specific biological aging index and provide new insights into mechanisms underlying liver aging.

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Journal
Aging Cell
Published
2026-05-31
DOI
https://doi.org/10.1111/acel.70565
Primary Topic
Liver Disease Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
0.00

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article

Liver Aging Index: A Noninvasive Score for Liver Biological Aging and Liver‐Related Outcomes in Multicohorts

Shuyao Song, Robin Walters, X Y Zhou, C Q Yu et al.
Aging Cell
Liver Disease Diagnosis and Treatment
article

Liver Aging Index: A Noninvasive Score for Liver Biological Aging and Liver‐Related Outcomes in Multicohorts

Shuyao Song, Robin Walters, X Y Zhou, C Q Yu, Philip Noel Newsome, W K Chan, P Pei, H D Du, D J Y Sun, Y J Pang, J S Chen, Z M Chen, Iona Millwood, Jérôme Boursier, George Boon‐Bee Goh, Vincent Wai‐Sun Wong, Zhiyu Wu, Victor de Lédinghen, Manuel Romero‐Gomez, Emmanuel A. Tsochatzis, Laurent Castéra, Jun Lv, Arun J. Sanyal, Yiping Chen, the China Kadoorie Biobank Collaborative Group and VCTE‐Prognosis Study Group, Michelle Lai, José Luis Calleja, Ling Yang, Jian‐Gao Fan, Liming Li, Atsushi Nakajima, Hao Xu, Elisabetta Bugianesi, Yating Huang, Seung Up Kim, Shanshan Wu, Ming‐Hua Zheng, Salvatore Petta, Xiaoming Yang
article en

Abstract

Biological aging is a key determinant of liver disease and mortality, but there is little evidence on noninvasive index for assessment of liver biological aging. We developed the Liver Aging Index (LAI) in the China Kadoorie Biobank (CKB, N = 21,629) using Cox-Gompertz proportional hazards model. The LAI incorporated three clinical factors (body mass index, systolic and diastolic blood pressure), eight plasma biomarkers (glucose, total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase), and two imaging biomarkers (fat attenuation parameter and liver stiffness measurement). External validation was conducted in the National Health and Nutrition Examination Survey (NHANES; N = 3412) and the VCTE-Prognosis cohort (N = 12,170, 16 global centers). Across all cohorts, the LAI demonstrated strong discrimination for all-cause mortality (AUROC: 0.764 in NHANES; 0.759 in VCTE-Prognosis), outperforming chronological age (p < 0.05). Liver aging acceleration (LAA), defined as the difference between LAI and chronological age, was associated with substantially elevated risks: each 1-SD increase in LAA conferred a 22%-85% higher risk of all-cause mortality and a 34%-170% higher risk of liver-related event or mortality. Using genetic instruments identified in CKB, we found genetic predisposition to accelerated liver aging was associated with higher risks of cirrhosis and liver cancer (HR = 3.94 [3.20-4.86] and 7.82 [2.05-29.80]), further validated in Biobank Japan. Integrating genetics and proteomics revealed novel pathophysiological involvement of amyloid-beta clearance pathway and amyloid precursor protein in liver aging. These findings demonstrate the feasibility of a noninvasive, liver-specific biological aging index and provide new insights into mechanisms underlying liver aging.

Aging CellVol. 25(6)
Beth Israel Deaconess Medical Center (US), Inserm (FR), Chinese University of Hong Kong (HK), Shanghai Jiao Tong University (CN), Virginia Commonwealth University (US), Yonsei University (KR), Peking University (CN), Université Paris Cité (FR), Singapore General Hospital (SG), Wenzhou Medical University (CN), Hôpital Beaujon (FR), The Royal Free Hospital (GB), First Affiliated Hospital of Wenzhou Medical University (CN), University of Malaya (MY), University of Oxford (GB), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Xian Center for Disease Control and Prevention (CN), National Clinical Research Center for Digestive Diseases (CN), Sorbonne Paris Cité (FR), Ministry of Education (RO), Office of Readiness and Response (US), Hospital Universitario Puerta de Hierro Majadahonda (ES), Department of Medical Sciences (RU), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES), Instituto de Biomedicina de Sevilla (ES), China National Center for Food Safety Risk Assessment (CN), King's College Hospital (GB), University College London (GB), Université d'Angers (FR), Yokohama City University (JP), University of Palermo (IT)
Wellcome Trust, Cancer Research UK, British Heart Foundation, National Natural Science Foundation of China, Kadoorie Charitable Foundation, Medical Research Council, Beijing Nova Program, National Key Research and Development Program of China
Openalex Percentile: Top 6%
Liver Disease Diagnosis and Treatment
DOIOpen Access PDFOpenAlex
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