Associations between klotho levels and mortality risk among middle-aged and older adults taking prescription opioids.

Objective: Prescription opioids are widely recognized as the most commonly used and effective analgesics for the management of moderate to severe pain. Klotho protein has been indicated to show a nonlinear relationship with mortality, but findings are inconsistent across populations. The present study investigated the association between Klotho levels and mortality in middle-aged and older adults who use prescription opioids, with the aim of identifying potential therapeutic targets.

Methods: This study included participants aged ≥40 years from the National Health and Nutrition Examination Survey (2007-2018) with complete data. Mortality data were obtained from the 2019 public use-linked mortality files released by the National Center for Health Statistics in May 2022. Covariates included demographics, lifestyle habits, and disease history. Survey-weighted Cox regression assessed the relationship between Klotho levels and mortality risk.

Results: Among the 898 participants (mean age 56 years; 43.3 % men) followed up for a median of 88 months, 13.5 % died. Participants in the third Klotho quartile had a lower risk of all-cause mortality compared to the first quartile. Higher Klotho levels were associated with lower cancer mortality, but cardiovascular mortality did not differ significantly. Restricted cubic spline analysis revealed a significant nonlinear association between Klotho levels and all-cause mortality (nonlinear  < 0.01).

Conclusions: A significant nonlinear relationship exists between Klotho levels and all-cause mortality among middle-aged and older adults taking prescription opioids. Future research should explore mechanisms underlying this relationship and develop Klotho-targeted therapies.