The relationships of Klotho levels with cognition and dementia are poorly understood. This study aimed to investigate the association between Klotho levels and cognitive function and to determine causality between Klotho and dementia using Mendelian randomization (MR). Based on data from the National Health and Nutrition Survey (NHANES) 2011–2014, this study consisted of 1875 older adults aged 60–79 years. Cognitive function was assessed by the digit symbol substitution test (DSST). We performed weighted multivariable-adjusted linear regression to assess the association between Klotho concentrations and cognitive function. Then, 2-sample MR was conducted to assess the causal relationship between Klotho and dementia. The inverse variance weighted (IVW) method was used as the primary analysis. We observed a positive association between serum Klotho concentrations and the results of the Digit Symbol Substitution test (DSST) (T2: β 2.16, 95% CI: 0.30–4.01, P = 0.03, T3: β 2.48, 95% CI: 0.38–4.57, P = 0.02) after adjusting for the covariates. Moreover, there was also a potential nonlinear relationship between Klotho and DSST. The IVW method showed that genetically predicted high Klotho levels were not significantly associate with any type of dementia, including Alzheimer’s disease (OR = 1.03, 95% CI: 0.96–1.10, P = 0.46), vascular dementia (OR = 1.04, 95% CI: 0.87–1.25, P = 0.66), frontotemporal dementia (OR = 0.73, 95% CI: 0.47–1.14, P = 0.16), or dementia with Lewy bodies (OR = 1.03, 95% CI: 0.87–1.23, P = 0.73). In the cross-sectional observational study, Klotho and cognitive function were significantly correlated; however, findings from MR studies did not indicate a causal relationship between Klotho and dementia.

Background: There is growing evidence that an antioxidant diet is a protective factor against frailty. However, few studies have examined the effect of comprehensive dietary antioxidants on frailty symptoms. The aim of this study was to examine the relationships between the composite dietary antioxidant index (CDAI) and frailty and the underlying mechanisms involved. Methods: Based on the National Health and Nutrition Survey (NHANES) 2003– 2018, this study included 11,277 older persons aged ≥ 60 years. In this study, frailty was defined as having a total score > 0.21 on the 49-item frailty index. Six dietary antioxidants were selected for use in calculating the CDAI. A weighted multiple logistic regression model with subgroup analysis and restricted cubic splines (RCSs) were used to examine the association between the CDAI and frailty. To examine the role of oxidative stress, mediation analyses were also conducted. Results: The association between the CDAI score and frailty risk was significant according to the multivariate model. Compared with participants in tertile 1, participants in both tertile 2 and tertile 3 had lower odds of developing frailty symptoms (OR=0.86; 95% CI=0.75– 0.97; P=0.02; and OR=0.81; 95% CI=0.70– 0.93; P=0.003). According to the subgroup analyses, the differences in interactions were not statistically significant. There was also a potential nonlinear relationship between the CDAI score and frailty risk. The serum albumin concentration and uric acid concentration had significant mediating effects on the association between the CDAI score and frailty index, with 19.25% (P=0.002) and 21.26% (P < 0.001) of the total, respectively. Conclusion: Frailty is negatively associated with the CDAI score, which may be partially mediated by oxidative stress.