Serum alpha-Klotho has been recognized as a surrogate of the Klotho family that acts as a marker of the aging process. Our study first highlighted the associations between gender and serum Klotho protein concentrations, and gender-specific associations between Klotho and metabolic syndrome. Generally, serum Klotho levels had gender disparities regardless of age and renal function in middle-aged and older adults. Various laboratory parameters may be associated with Klotho levels, however, after adjustment for these confounders as well as sex hormones, MetS components still had gender-specific associations with Klotho levels, i.e., HDL in men and TG in women.
The general function of serum Klotho
Serum Klotho is an antiaging protein with essential protective activity for the proper function of many organs. Klotho downregulation has been recognized as an early biomarker for aging and several diseases [12]. The reduction of Klotho with advanced age was apparent in the cohort. Also, as reported in the literature, Klotho expressions were significantly lower in people who were overweight and current smokers [13,14,15]. Notably, people who have experienced heart arrest had reduced serum Klotho concentrations. One explanation may come from the study by Takeshita, K., et al., who found that Klotho protein is present in the pacemaker cells of the mouse sinoatrial node and sinus arrest in Klotho-deficient mice [16]. Given the known association between Klotho deficiency and renal dysfunction [17], we found that Klotho was negatively correlated with creatinine, uric acid, and urea nitrogen. Triglycerides were inversely correlated with Klotho, which is consistent with previous studies [18]. One explanation may be that Klotho interferes with insulin-mediated phosphorylation, blocks insulin-stimulated glucose uptake, and reduces malonyl-CoA, thereby promoting fatty acid oxidation, and preventing intracellular lipid overload and lipotoxicity, a proposed mechanism of the life-shortening metabolic syndrome [19]. Since inflammation is one of the pathological mechanisms of hyperlipidemia, we also found that CRP and WBC were negatively correlated with Klotho concentrations, which was also in consist with the anti-inflammatory properties of Klotho. Similar to a previous study, Klotho was correlated with the level of estradiol and sex hormone-binding globulin (SHBG), which may physiologically decrease with aging [20].
Gender-specific differences in Klotho and MetS
Generally, female participants had a higher Klotho level when compared with male participants, after adjusting for ethnicity, age, BMI, and tobacco intake. One possible reason could be that Klotho expressions were inversely associated with cigarette smoke—an aging accelerator, which is more common in men, another reason may come from the estradiol, which was found positively correlated with soluble Klotho concentration. Therefore, estrogen and gender-specific lifestyles may lead to different aging processes in men and women. The overall (non-gender specific) expression of Klotho was negatively associated with triglyceride levels, and the correlation was particularly significant in women, who, as a cohort, also had a higher proportion of individuals with high waist circumference. This finding suggested that central obesity and hyperlipidemia may be the major MetS factors associated with reduced Klotho concentrations, and therefore impact aging in women. Furthermore, the adjusted multivariate regression model showed that HDL should be a pivotal MetS component affecting male aging. These findings may provide therapeutic implications for future anti-aging management targeting abnormal lipid profiles in different genders.
Gender-specific risk factors associated with aging
Hu et al. have proposed that Klotho acts as an autocrine enzyme in the renal proximal tubule [21]. Klotho deficiency has been known associated with renal interstitial fibrosis and chronic kidney disease, which is also a known risk factor for cardiovascular disease and mortality [22]. In multiple regression analysis, serum Klotho was correlated with renal function biomarkers such as creatinine and uric acid independent of age and gender. Tobacco use was another factor associated with reduced Klotho levels, which may result from the effect of smoking on chronic inflammation (elevated CRP, fibrinogen, IL-6, and CEA levels), immune disorders, and blood cell composition [23]. Consistently, we found tobacco use and CRP were independent factors that were negatively associated with Klotho levels in men, owing to men’s higher frequency of smoking and tobacco-associated chronic inflammation. Estradiol and SHBG were positively correlated with Klotho in men, which may stem from their potentially correlated changes during aging. Interestingly, a previous meta-analysis found that lower SHBG levels were associated with MetS but not gender-specific [24]. In women, WBC count was seen as a factor negatively associated with Klotho independent of renal function, age, smoking, and TG. It is well known that the endothelial function of human arteries may deteriorate with age and cigarette intake, leading to inflammatory atherosclerosis, lipid disorder, and obesity, and increasing the risk of metabolic disorders. Therefore, postmenopausal women may be more fragile than their counterparts owing to impaired endothelial function, resulting in an increased risk of inflammatory status and MetS. Notably, adjusted multivariate regression analysis showed that estradiol was not independently associated with Klotho in women. Therefore, the mechanism underlying the complex gender-specific association between Klotho and MetS may be related to inflammation. Although the anti-inflammatory and lipid-lowering effects of Klotho have been widely discussed [25], gender differences in anti-aging treatments require more attention.
Limitations
Due to its retrospective nature, the current study has some intrinsic limitations. Although the data were collected in a random sample set of the US population willing to participate in the NHANES study, there may still be some selection bias. The gender-specific pathological context of the association between Klotho and MetS remains unclear. For the potential inflammatory background of these associations, we currently only had hs-CRP and WBC counts, which may have some limitations in interpreting these findings.
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