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A total of 11,198 participants aged 40\u201379 years were included in the National Health and Nutrition Examination Survey (NHANES) spanning 2007\u20132016. Serum \u03b1-Klotho levels were quantified via enzyme-linked immunosorbent assays. CMDs comprised cardiovascular disease (CVD), and four metabolic disorders: type 2 diabetes (T2DM), obesity, chronic kidney disease (CKD), and non-alcoholic fatty liver disease (NAFLD). Weighted logistic regression analysis, subgroup analysis, mediation analysis, restricted cubic splines (RCS), and Cox proportional hazards regression analysis were used. \u03b1-Klotho exhibited negative associations with each single CMD except T2DM, and RCS showed U-shape and L-shape dose-response relationships of \u03b1-Klotho with risk of T2DM and CKD, respectively. Ordered logistic regression analysis revealed that higher levels of Klotho markedly reduced the cumulative number of metabolic comorbidities complicating CVD (OR 0.56 (0.35, 0.91)). Simple mediation analysis showed CKD may explain up to 20.42% of the association between Klotho and CVD. Notably, \u03b1-Klotho\u2019s association with cardiometabolic comorbidities was particularly evident among individuals who were widowed\/divorced\/separated, non-Hispanic Black, lower-income, or less educated, with hypertension, current smokers, lower leisure and commuting physical activity, but higher work-related physical activity. Regarding long-term effects, higher \u03b1-Klotho levels were associated with lower all-cause mortality among participants with CMDs, but not among those without CMDs. Higher \u03b1-Klotho levels were associated with lower CMD prevalence, particularly in high-risk cardiovascular populations with lower socioeconomic status and unfavorable lifestyles and reduced all-cause mortality risk among CMD patients.<\/jats:p>","DOI":"10.1038\/s41598-025-01580-4","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T07:23:24Z","timestamp":1747207404000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Anti-aging protein \u03b1-Klotho is potential for reducing comorbidity risk of cardiometabolic diseases in vulnerable populations and enhancing long-term prognosis"],"prefix":"10.1038","volume":"15","author":[{"given":"Kai","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8394-2743","authenticated-orcid":false,"given":"Jianing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"issue":"3","key":"1580_CR1","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/j.mayocpiqo.2021.05.005","volume":"5","author":"K ReFaey","year":"2021","unstructured":"ReFaey, K. et al. 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