α-Klotho is an anti-aging protein linked to various age-related diseases. Environmental metal exposure has been associated with oxidative stress and aging, but its effect on α-Klotho levels remains unclear. This study investigated the relationship between urinary metal concentrations and serum α-Klotho levels using data from the National Health and Nutrition Examination Survey (NHANES) 2007-2016 cycles. A total of 4071 adults aged 40 to 79 years were included in the analysis. After adjusting for potential confounders, positive associations were found between serum α-Klotho levels and barium (Ba), cesium (Cs), and molybdenum (Mo), while tungsten (W) and uranium (U) were negatively correlated with α-Klotho levels. The combined effects of multiple metals were further analyzed using the qgcomp model, which demonstrated a negative correlation between increased metal mixtures and serum α-Klotho levels. Specifically, U, total arsenic (t-As), W, cadmium (Cd), antimony (Sb), and lead (Pb) contributed to the reduction of α-Klotho levels, while Ba, Cs, dimethylarsinic acid (DMA), Mo, thallium (Tl), and cobalt (Co) were positively associated with α-Klotho levels. These findings suggest that exposure to certain metals, particularly in combination, may reduce serum α-Klotho levels, potentially accelerating aging processes. Further studies should investigate the underlying mechanisms responsible for these associations.

Cadmium (Cd) is one of the most polluting heavy metal in the environment. Cd exposure has been elucidated to cause dysfunction of the glomerular filtration barrier (GFB). However, the underlying mechanism remains unclear. C57BL/6J male mice were administered with 2.28 mg/kg cadmium chloride (CdCl2) dissolved in distilled water by oral gavage for 14 days. The expression of SDC4 in the kidney tissues was detected. Human renal glomerular endothelial cells (HRGECs) were exposed to varying concentrations of CdCl2 for 24 h. The mRNA levels of SDC4, along with matrix metalloproteinase (MMP)-2 and 9, were analyzed by quantitative PCR. Additionally, the protein expression levels of SDC4, MMP-2/9, and both total and phosphorylated forms of Smad2/3 (P-Smad2/3) were detected by western blot. The extravasation rate of fluorescein isothiocyanate-dextran through the Transwell was used to evaluate the permeability of HRGECs. SB431542 was used as an inhibitor of transforming growth factor (TGF)-β signaling pathway to further investigate the role of TGF-β. Cd reduced SDC4 expression in both mouse kidney tissues and HRGECs. In addition, Cd exposure increased permeability and upregulated P-Smad2/3 levels in HRGECs. SB431542 treatment inhibited the phosphorylation of Smad2/3, Cd-induced SDC4 downregulation, and hyperpermeability. MMP-2/9 levels increased by Cd exposure was also blocked by SB431542, demonstrating the involvement of TGF-β/Smad pathway in low-dose Cd-induced SDC4 reduction in HRGECs. Given that SDC4 is an essential component of glycocalyx, protection or repair of endothelial glycocalyx is a potential strategy for preventing or treating kidney diseases associated with environmental Cd exposure.

For the first time, the associations between urinary concentrations of oxidant polycyclic aromatic hydrocarbon (PAH) metabolites and serum concentrations of anti-oxidant α-klotho were estimated for US adults aged 40-79 years. Multivariate regression models with α-klotho as dependent variable and one of the urinary metabolite of PAH as independent variables were fitted. In the absence of albuminuria and normal (eGFR > 90 mL/min/1.73 m²) kidney function, 10% increases in concentrations of 2-hydroxynaphthalene, 9-hydroxyfluorene, and ∑PAH were associated with 0.25%, 0.32%, and 0.19% decreases in serum α-klotho concentrations. In the absence of albuminuria and near normal (60 <  = eGFR < 90 mL/min/1.73 m²) kidney function, 10% increases in concentrations of 1-hydroxynaphthalene, 9-hydroxyfluorene, 1-hydroxyphenanthrene, and ∑PAH were associated with 0.17%, 0.38%, 0.34%, and 0.18% decreases in serum α-klotho concentrations. To what degree, these mild decreases in α-klotho are a matter of concern, is a subject ripe for discussion and additional investigations. When kidney function was normal or near normal but albuminuria was present, the associations between α-klotho and different metabolites of PAH were, more or less, randomly positive or negative and none reached statistical significance. To conclude, exposure to polycyclic aromatic hydrocarbons may result in reduced concentrations of α-klotho, an antiaging protein.

Exposures to per- and polyfluoroalkyl substances (PFAS) cause oxidative stress, a risk factor for tissue damage leading to kidney and cardiovascular diseases. The antiaging protein klotho is known to act as an anti-oxidative agent, and how klotho homeostasis interacts with PFAS has not been reported. This study among 3981 US adults aged 40-79 years old evaluated relationships of internal PFAS contamination to α-klotho across stages of estimated glomerular filtration rate or eGFR-based kidney function and albuminuria defined as urinary albumin creatinine ratio of >30 mg/g creatinine. In the absence of albuminuria and when eGFR based kidney function was in stage GF-1 (eGFR ≥ 90 mL/min/1.73 m2), statistically significant inverse associations between α-klotho and PFNA (β = -0.04930, p < 0.01), PFDA (β = -0.03307, p = 0.02), and PFUnDA (β = -0.03451, p = 0.01), PFHxS (β = -0.03011, p = 0.04) and PFOS (β = -0.03126, p = 0.03) were noted. No associations between α-klotho and PFAS were observed when kidney function was in stages GF-2 (60 ≤ eGFR < 90 mL/min/1.73 m2) or GF-3A (45 ≤ eGFR < 60 mL/min/1.73 m2) in the presence or absence of albuminuria. Unexpectedly, however, in the absence of albuminuria, with kidney function in stage GF-3B/4 (15 ≤ eGFR < 45 mL/min/1.73 m2), associations were positive between α-klotho and PFOA (β = 0.20989, p < 0.01), PFNA (β = 0.18373, p < 0.1), PFDA (β = 0.20413, p < 0.01), PFUnDA (β = 0.17660, p < 0.01), and PFOS (β = 0.14267, p < 0.01). The inverse relationship of PFAS to the antioxidant protein α-klotho in those with healthy kidney function has not been previously reported and should be evaluated in other populations.