Plasma proteomic signatures of biological aging and metabolic dysfunction-associated steatotic liver disease risk: a prospective cohort study
Hepatology International, 2026
Cao T., Wu L., Yang X., Fan N., Ding J., Gong M., Feng X., Li Y., Yan Y.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Metabolic Diseases Hepatology Aging | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
Background
Biological aging is associated with incident metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying proteomic mechanisms remain largely unknown. This study aimed to systematically characterize the plasma proteomic landscape and identify specific biomarkers that mediate the aging-MASLD axis.
Methods
We analyzed the associations between four multi-dimensional biological aging indicators (telomere length, frailty index, Klemera-Doubal method biological age, and phenotypic age), 2911 plasma proteins, and incident MASLD among 52,131 UK Biobank participants. A rigorous two-stage analytical pipeline, integrating multivariable linear and elastic net regression, was applied to screen robust aging-related proteins. Cox proportional hazard regression models and mediation analyses were employed to assess their roles in MASLD risk, followed by comprehensive tissue and functional enrichment analyses to elucidate underlying biological mechanisms.
Results
During a median follow-up of 13.60 years, 762 participants developed MASLD. All biological aging indicators were significantly linked to MASLD incidence. We identified distinct proteomic signatures for these biological aging indicators. Furthermore, multiple proteins significantly mediated the corresponding association, explaining 0.5 to 50.7% of the risk. Notably, 769 unique mediators were identified, anchored by a core signature of five shared proteins (AXL, CCL19, CPM, REN, and TNFRSF11B) across all four indicators. Enrichment analyses revealed a multi-organ origin (predominantly lung, adipose tissue, and arteries), highlighting the dominance of immune-inflammatory pathways.
Conclusions
Plasma proteins partially mediate the increased MASLD risk driven by biological aging. These findings underscore the roles of systemic immune-inflammatory signaling, providing biomarkers for early risk stratification and potential novel therapeutic targets for aging-associated hepatic pathology.