The association between dietary total, animal and plant protein and macronutrient substitution; and the risk of all-cause, cardiovascular or cancer mortality in the Golestan cohort study

Dietary protein is essential for health, yet its association with mortality risk across various causes remains unclear. This study examines the associations between total, animal-, and plant-based dietary protein intake and macronutrient substitution, as well as all-cause, cardiovascular (CVD), and cancer-related mortality. We used data from the Golestan Cohort Study (GCS), a population-based prospective study initiated in 2004 in Golestan Province, Iran, comprising 43,050 adults aged 40–75 years. Dietary intakes were assessed using validated Food Frequency Questionnaires (FFQ). Mortality outcomes were tracked annually over a mean follow-up period of 15.05 years. Cox proportional hazard regression models adjusted for demographic, lifestyle, and clinical factors were employed. Substitution analysis and restricted cubic spline functions explored the association between different ranges of protein intake and substitution with carbohydrates or fats and mortality risks. During follow-up, 9,309 deaths were documented, including 3,707 from CVD and 1,917 from cancer. Higher total protein intake was associated with increased all-cause (HR for 10 g intake 1.02, 95% CI 1.01–1.03) and CVD mortality (HR for 10 g intake 1.02, 95% CI 1.00–1.03), while animal protein showed similar associations (HR for 10 g intake 1.01, 95% CI 1.01–1.02 for all-cause mortality; HR for 10 g intake 1.02, 95% CI 1.00–1.03 for CVD mortality), plant protein intake was associated with a reduced risk of all-cause mortality in the total population (HR for 10 g intake 0.97, 95% CI 0.95–1.00). The associations were slightly more significant in female and rural participants. Substituting total protein or animal protein with carbohydrates or fat was associated with a lower risk of total and CVD mortality. Protein intake showed a non-linear association with mortality. Balanced protein intake, comprising an appropriate mix of animal and plant sources, appears to support longevity and reduce mortality risk, particularly from cardiovascular causes. This study evaluates the associations between animal and vegetable protein intakes and their substitution with other macronutrients and mortality. Higher intakes of total and animal protein were associated with increased risk of all-cause and cardiovascular disease mortality. The association between protein intake and mortality showed a nonlinear pattern. Substituting total or animal protein with carbohydrates or fats was associated with lower all-cause and CVD mortality.