Associations of Dietary Nutrients with All-Cause and Disease-Specific Mortality: A Nutrient-Wide Analysis in Middle-Aged and Elderly Adults

Objective: To our knowledge, a systematic comparison of nutrients contribution to mortality in large scale cohort of middle-aged to elderly individuals has not yet been done. We aim to investigate the associations between most of the available nutrients and all-cause and disease-specific mortality, and explored their joint effect on mortality risk. Methods: A total of 208,312 participants from the UK Biobank (UKB) with baseline 24-hour dietary recall data were enrolled. Cox proportional hazards models were used for a nutrients-wide association analysis of all-cause mortality and disease-specific mortality. Mixed-effects analyses were further conducted to evaluate the combined effects of nutrients significantly associated with mortality risk by BKMR and Qgcomp regression models. Results: No significant associations were found between total energy, total protein, total lipid, or total carbohydrate intake and all-cause mortality risk. However, energy density was moderately and positively associated with all-cause mortality (HR=1.017, 95%CI: 1.004-1.030). Nutrient type and quality exhibited significant impacts: plant-derived protein (HR=0.995, 95%CI: 0.992-0.998), plant-derived lipids (HR=0.997, 95%CI: 0.995-0.999), were negatively associated with all-cause mortality. Among carbohydrates, starch, lactose, and intrinsic/milk sugars showed protective effects, while free sugars, non-milk extrinsic sugars, sucrose, and maltose were positively associated with increased mortality risk. For minerals and vitamins, copper, manganese, total iron, non-haem iron, vitamin E, riboflavin, biotin, and pantothenic acid exhibited inverse associations with all-cause mortality. Mixed-effects analyses revealed cumulative inverse trends of beneficial nutrients and positive trends of harmful nutrients on mortality risk, with manganese, maltose, biotin, and niacin being key contributors. Disease-specific analysis showed that energy density and certain sugars were positively associated with neoplasms mortality; multiple sugars were linked to nervous system disease mortality; and alcohol, maltose were positively associated with digestive system disease mortality, while most macronutrients, minerals, vitamins, and fibre had protective effects. Sodium and chloride were positively associated with circulatory system disease mortality. Conclusion: Total intake of major macronutrients was not significantly associated with mortality risk, but nutrient type and quality played critical roles. Plant-derived nutrients, specific minerals, vitamins, dietary fibre, and natural carbohydrates were protective against mortality, whereas refined sugars and high energy density were detrimental. These findings highlight the importance of dietary quality in reducing mortality risk and provide evidence for developing targeted dietary recommendations.