Introduction
Chronic liver disease—including alcoholic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and liver fibrosis/cirrhosis (LFC)—has emerged as a major global health challenge, accounting for over 2 million deaths annually1-2. Often progressing silently, chronic liver disease is frequently diagnosed at advanced stages, underscoring the urgent need for early identification of at-risk populations through reliable markers3. While recognized risk factors such as insulin resistance, alcohol overuse, and aging contribute to disease development, recent attention has focused on biological ageing acceleration (BioAgeAccel) as a comprehensive, integrative metric reflecting physiological decline, yet the utility in large populations remains underexplored4-6. In parallel, genetic susceptibility and phenotypic data hold promise for identifying individuals predisposed to chronic liver disease7.
Aims & Methods
We conducted research to explore the association between BioAgeAccel, the risk of chronic liver diseases, incorporating genetic susceptibility.
This study included participants from the UK Biobank (UKB) and the All of Us (AoU) two cohort databases. BioAgeAccel was defined as the deviation between an individual’s phenotypic age (PhenoAge) or Klemera-Doubal age (KDMAge) and chronological age. Cox proportional hazards models analyzed the associations between BioAgeAccel and the risk of MASLD, ALD, and LFC, with hazard ratios (HRs) and 95% confidence intervals (CIs), and combined polygenic risk scores (PRS) to quantify genetic predisposition to chronic liver diseases.
Results
In the UKB cohort, accelerated PhenoAge was associated with significantly higher risks of ALD (HR 2.29; 95% CI 2.03-2.58), MAFLD (1.10; 1.04-1.16), and LFC (2.22; 2.01-2.46). Similarly, in the AoU cohort, accelerated PhenoAge was associated with higher risks of ALD (1.97; 1.00-3.88), MAFLD (1.35; 1.15-1.58), and LFC (2.19; 1.48-3.22). Comparable trends were observed for KDMAgeAccel in the UKB. Greater BioAgeAccel was associated with progressively higher risks of ALD and LFC, with these trends consistently. In the UKB, accelerated biological ageing was associated with chronic liver diseases independently of genetic risk and remained significant across PRS levels. Furthermore, compared to individuals with biologically younger ages and low genetic risk, participants with high genetic risk and accelerated PhenoAgeAccel exhibited the highest risk of developing chronic liver diseases, and LDSC revealed a positive genetic correlation between ageing and ALD, with SMR identifying three shared genes.
Table 1: Association between biological ageing acceleration (PhenoAgeAccel) and incident of chronic liver diseases in two datasets
| PhenoAgeAccel | Non-accelerated ageing | Accelerated ageing | |
| | | HR (95% CI) | P value |
| UK Biobank | | | |
| ALD | 1 (Ref) | 2.29 (2.03-2.58) | <0.001 |
| MASLD | | 1.10 (1.04-1.16) | 0.001 |
| LFC | | 2.22 (2.01-2.46) | <0.001 |
| All of us | | | |
| ALD | 1 (Ref) | 1.97 (1.00-3.88) | 0.049 |
| MASLD | | 1.35 (1.15-1.58) | <0.001 |
| LFC | | 2.19 (1.48-3.22) | <0.001 |
Conclusion
Accelerated biological ageing was associated with increased risk of chronic liver diseases, independently of genetic risk. Identifying individuals with higher BioAgeAccel is crucial for predicting the risk of chronic liver diseases, and indicators related to the calculation of BioAgeAccel can serve as potential targets for interventions.
References
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Disclosure
The authors have declared no conflict of interest.
