Assessing Association Between Circulating Bilirubin Levels and the Risk of Frailty: An Observational and Mendelian Randomization Study

Background: Bilirubin is a by-product of haemoglobin breakdown and has been reported to be a potent antioxidant recently. While elevated levels of bilirubin have been linked to a reduced risk of various diseases, their role remains unknown in frailty. This study aims to explore the relationship between serum bilirubin levels and the risk of frailty.

Methods: This cohort study included 442 223 White British participants (aged 39 to 73 years) with an available frailty index at baseline (2006 to 2010) from the UK Biobank. The associations of total/direct bilirubin levels with the continuous frailty index were analysed by multivariable linear regression, and multivariable logistic regression was used after classifying frailty outcomes into non-frailty, pre-frailty and frailty. A Mendelian randomization (MR) analysis was applied to evaluate the association of genetically predicted bilirubin levels with frailty risk.

Results: The prevalence rates of both pre-frailty and frailty were 46.17% and 12.49%, respectively, with higher rates observed in women than in men (pre-frailty: 47.33% vs. 44.79%, frailty: 13.64% vs. 11.13%, respectively). There was a non-linear negative association between total bilirubin levels and frailty indexes (p < 0.0001). Mildly elevated total bilirubin levels had protective effects against pre-frailty (OR = 0.863, 95% CI: 0.849 to 0.879, p < 0.001) and frailty (OR = 0.660, 95% CI: 0.641 to 0.679, p < 0.001). Increased total bilirubin levels were more beneficial for women with frailty risk (percent changes per SD μmol/L = -0.37%, 95% CI: -0.40% to -0.34%). The MR analysis revealed a negative association between genetically predicted total/direct bilirubin levels and frailty risk (both p < 0.0001).

Conclusions: Circulating total/direct bilirubin levels were negatively associated with frailty risk in White British individuals. Mildly elevated total bilirubin levels were more beneficial for women subpopulation.