Association of serum Klotho with tinnitus prevalence, duration and severity: A cross-sectional study in middle-aged and older adults

Abstract

Background: As an anti-aging protein, although studies increasingly suggest that the Klotho plays a role in the auditory system, the link between serum Klotho levels and tinnitus remains poorly characterized. The aim of this study was to investigate the associations between serum Klotho levels and tinnitus focusing on prevalence, duration and severity in middle-aged and older adults.

Methods: We performed a population-based cross-sectional study of individuals in the National Health and Nutrition Examination Survey (NHANES) 2009-2012 and 2015-2016. Univariable and multivariable logistic regression was used to evaluate the relationship between serum Klotho levels and tinnitus, with adjustment for potential confounders and further age-stratified analyses. Restricted cubic splines were applied to assess potential non-linearity in the dose-response relationship. Furthermore, Subgroup and interaction analyses were conducted to assess the consistency of this association.

Results: In this research of 3280 individuals aged 40-79 years with a median age of 55 (IQR: 48, 62) and 48% male participants, the median serum Klotho level was 779.80pg/mL. Multivariable logistic regression uncovered consistent inverse associations between serum Klotho levels and tinnitus incidence across progressively adjusted models (ORs: 0.68-0.70, p = 0.009-0.01). Age-based stratified analyses suggested the strongest effect was observed in individuals aged 50-59 years (full model ORs: 0.55, p = 0.046). A marginally significant protective effect was observed in the 60-69 age group (unadjusted OR=0.62, 95% CI: 0.39-1.00, p = 0.050). Serum Klotho levels showed no significant correlation with tinnitus severity, while a potential association with the duration of tinnitus was observed (p = 0.058). Additionally, restricted cubic spline analysis revealed a linear inverse association between Klotho and tinnitus risk stratified by age (all p for nonlinear >0.15). Finally, subgroup and interaction analyses revealed no significant effect modification (all p-interaction >0.1).

Conclusion: Serum Klotho concentrations showed a consistent inverse association with tinnitus prevalence in US adults, with the strongest effect observed in individuals aged 50-69 years.

Fig 1. Participant screening flowchart.

Fig 2. Dose–response relationship between serum Klotho and tinnitus prevalence stratified by age.

Restricted cubic spline (RCS) with 3 knots was applied to the flexible regression model stratified by age: A. 40–49years, B. 50–59years, C. 60–69years, D. 70–79years. The red dotted line indicates the reference line (OR=1), The blue solid lines and light-blue shaded areas were the ORs for tinnitus and 95% CI, respectively.

Fig 3. Subgroup analyses of the association between serum Klotho level and tinnitus.

Odds ratios (ORs) were adjusted for age, gender, ethnic origin, educational status, marital status, PIR, BMI, smoking, diabetes, hypertension, cardiovascular disease, total cholesterol, PTA, PHQ-9 and noise exposure. For all subgroup analyses, the stratification variable was excluded from adjusted models. Interaction p-values were derived from likelihood ratio tests (LRT). All estimates were weighted to be nationally representative. Abbreviations: OR: odds ratio; CI: confidence interval; BMI: body mass index; PIR: poverty income ratio; PHQ-9: Patient Health Questionnaire-9; PTA: Pure-tone average.