Mendelian randomization and colocalization analyses reveal an association between diet consumption and altered...

Observational studies suggest dietary factors influence leukocyte telomere length (LTL), yet causality remains unproven. Using Mendelian randomization (MR) and colocalization analyses, we investigated causal relationships between 38 dietary phenotypes and LTL to clarify conflicting evidence on Mediterranean diet (MD) components (alcohol, nuts) and biological aging. Genetic instruments for dietary exposures were derived from genome-wide association studies data. Univariate MR analyses were conducted using inverse-variance weighted models, supplemented by sensitivity analyses (MR-Egger, weighted median) to address pleiotropy. Multivariable MR adjusted for correlated dietary factors, while colocalization analysis (posterior probability > 0.80) identified shared genetic variants. Reverse MR and analyses excluding pleiotropic single-nucleotide polymorphisms further validated robustness. Genetically predicted champagne/white wine and red wine intake were associated with shortened LTL, whereas nut consumption increased LTL. These associations persisted in multivariable MR (P < .05) and colocalization analyses, suggesting causal mechanisms independent of confounding. No other dietary phenotypes showed causal links to LTL. Sensitivity analyses confirmed minimal pleiotropic bias (MR-Egger intercept P > .05). This MR study provides genetic evidence that moderate alcohol consumption, including wine, accelerates telomere shortening, which contradicts previous observational claims regarding the benefits of the MD that often emphasize wine as a protective component. In contrast, nut intake aligns with dietary recommendations for anti-aging. These findings challenge the prevailing notion of the MD as a uniformly beneficial model for longevity (often promoted as a "holistic healthy pattern") by revealing heterogeneity and even antagonistic effects among its components (alcohol vs nuts) on aging. The study underscores the need to reassess the role of alcohol in longevity-promoting diets. Public health strategies should advocate reducing alcohol consumption and increasing nut intake to mitigate the risk of age-related diseases.