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

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.

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.

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 P < 0.01).

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.