Phenotypic age acceleration: a novel biomarker associated with increased risk of metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease (MAFLD) poses a growing public health challenge, but traditional metabolic markers may not fully capture individual risk, especially in individuals with normal metabolic phenotypes. Phenotypic age acceleration (PhenoAgeAccel), a composite biomarker reflecting systemic aging burden, may offer additional value for risk stratification. We conducted a two-stage study involving a case-control analysis (6,343 MAFLD cases vs. 6,343 chronological age- and sex-matched controls) and a prospective cohort analysis (7,997 participants initially free of fatty liver disease). PhenoAgeAccel was derived from chronological age and nine clinical biomarkers. Associations between PhenoAgeAccel and MAFLD were assessed using conditional logistic regression and competing risk models, with adjustments for lifestyle factors, comorbidities and medication histories. In the case-control analysis, each 5-year increase in PhenoAgeAccel was associated with 66% higher odds of MAFLD after multivariable adjustment (OR = 1.66, 95% CI: 1.56–1.77). In the prospective cohort, PhenoAgeAccel remained significantly associated with incident MAFLD (HR = 1.45, 95% CI: 1.32–1.59). While the main analyses estimated the overall association, subgroup analyses examined whether this association varied across different populations. These suggested stronger associations in females (vs. males), individuals with younger chronological age (vs. older age), and those without hypertension or diabetes (vs. those with hypertension or diabetes, respectively). PhenoAgeAccel demonstrated better discriminative ability (AUC = 0.622) than traditional fibrosis scores (FIB-4, NFS, BARD), with a high negative predictive value (88.8%). PhenoAgeAccel was associated with MAFLD risk in a Chinese health examination population, providing information beyond chronological age and common metabolic factors. It may serve as a useful indicator for identifying individuals with normal metabolic phenotypes but accelerated biological aging, particularly in those without overt metabolic risk factors. This study, through a two-stage design (case-control and prospective cohort), found that phenotypic age acceleration (PhenoAgeAccel) was significantly associated with the risk of metabolic dysfunction-associated fatty liver disease in a Chinese health examination population. This association was more pronounced in females (vs. males), individuals with younger chronological age (vs. older age), and those without hypertension or diabetes (vs. those with hypertension or diabetes, respectively). Compared with commonly used liver fibrosis scores, PhenoAgeAccel had better discriminative ability, especially showing outstanding performance in a high negative predictive value. It may serve as a potential auxiliary marker for identifying individuals with normal metabolism but accelerated biological aging.