Association between perfluoroalkyl and polyfluoroalkyl internal exposure and serum α-Klotho levels in middle-old aged participants

Abstract

Purpose: Exposure to perfluoroalkyl and polyfluoroalkyl substances causes oxidative stress, which is strongly associated with adverse health effects. Klotho protein plays an anti-aging role via antioxidation activity.

Methods: We investigated the levels of serum α-Klotho and PFAS exposure in adults who participated in the National Health and Nutrition Examination Survey from 2013 to 2016. A nationally representative subsample of 1,499 adults aged 40-79 years was analyzed for the associations of serum α-Klotho levels with serum PFAS exposures by correlation analysis and multiple general linear models. Of note, the potential confounding factors including age and gender were adjusted. Quantile-based g-computation models were used to assess the effects of mixed PFAS exposure on serum α-Klotho levels.

Results: The weighted geometric mean of serum α-Klotho was 791.38 pg/mL for the subjects during 2013-2016. After adjusting for potential confounders, serum Klotho levels showed a statistically significant downward trend with increasing quartiles of PFOA and PFNA. Multivariate adjusted general linear regression analysis showed that increased exposure to PFNA was substantially associated with lower serum levels of α-Klotho, and each 1-unit increase in PFNA concentration was accompanied by a 20.23 pg/mL decrease in α-Klotho level; while no significant association was observed between other PFAS exposures and serum α-Klotho levels. It was negatively correlated between α-Klotho and Q4 for PFNA relative to the lowest quartile (Q1) of exposure (P = 0.025). It was found that the strongest negative correlation between PFNA exposure and serum α-Klotho levels was in the middle-aged (40-59 years) female participants. Furthermore, the mixture of the four PFAS substances showed an overall inverse association with serum α-Klotho concentrations, with PFNA being the major contributor.

Conclusions: Taken together, in a representative sample of the U.S. middle-aged and elderly populations, serum concentrations of PFAS, especially PFNA, have been negatively associated with serum levels of α-Klotho, which is strongly associated with cognition and aging. It was important to note that the majority of associations were limited to middle-aged women. It will be meaningful to clarify the causal relationship and the pathogenic mechanisms of PFAS exposure and α-Klotho levels, which is helpful to aging and aging-related diseases.

Keywords: NHANES; middle-aged women; perfluoroalkyl and polyfluoroalkyl substances (PFAS); perfluorononanoic acid (PFNA); α-Klotho.

Figure 1

Flow chart of the population included in the final analysis of this study. n = 1,499, NHANES, USA, 2013–2016.

Figure 2

The correlation between the four PFAS and α-Klotho levels. The test was Pearson's correlation coefficients among log-transformed indices.

Figure 3

All-adjusted geometric means (and 95% CIs) of serum α-Klotho by quartiles of serum PFAS. The all-adjusted model for serum PFAS were adjusted for age, gender, race, family income to poverty ratio, education, physical activity, BMI, smoking, alcohol consumption, diabetes, hypertension, uACR, and eGFR.

Figure 4

(A) The directions and magnitude of the assigned weights for each PFAS in relation to serum α-Klotho in quantile g-computation. (B) Mixed effects of four serum PFAS concentrations on serum α-Klotho. The model was adjusted for age, gender, race, family income to poverty ratio, education, physical activity, BMI, smoking, alcohol consumption, diabetes, hypertension, uACR, and eGFR.

Figure 5

Overview of the results of the association between PFAS exposure and serum α-Klotho levels in middle-old aged participants.