CONGRESS ABSTRACT

Background: Baseline folate status is an under-recognized measure of individual health.  Folate metabolism is thought to be a metabolic cornerstone in eucaryotic cells and it is committed to ensure proper functioning across a wide spectrum of task encompassing myelinization, endothelial function via 1-carbon-unit metabolism,embryogenesis. It is commonly accepted that folates-deficiency leads to an higher risk of stroke and death this supporting folate fortification. On the other side there is no knowledge of higher folate-status as a risk factor for death.  Objective: We investigated association between high folate status and mortality risk, by conducting a meta-analysis of  studies expressing quartiles of folates. We explored the relationship between folate levels and mortality, focusing on the highest quartile of folate with respect to the sum of second and third quartiles concentrations. Due to significant heterogeneity of involved studies, a meta-regression analysis was performed to evaluate age as a covariate. Methods: We included 9 studies in our meta-analysis, encompassing 439,052 person-year, with 7,195 -years events reported. Using a random-effects models, risk ratios (RR) were calculated. Heterogeneity was quantified using tau², I², and Q statistics, while meta-regression was applied to determine whether age influenced the relationship between folate and mortality. Results: The random-effect model indicated a statistically significant reduction in mortality risk for intermediate folate status levels with respect to the higher quartile (RR = 0.7575, 95% CI: 0.6167–0.9305, p = 0.0081 – Graph 1.). Nonetheless, a significant heterogeneity across studies (I² = 93.9%, tau² = 0.0797) was found. A meta-regression with age was assessed. Notably, in the meta-regression, age did not emerge as a significant moderator (estimate = 0.0100, p = 0.5875 – Graph.2 ). Conclusions: Our findings highlight a relationship between high folate levels and mortality risk. While moderate folate concentrations appear protective. The lack of moderation by age underscores the need to explore subgroup, to explain such heterogeneity. These results have significant public health implications, warranting a reevaluation of folic acid fortification policies and reconsidering baseline higher folate-status as a risk factor for death from any cause. Future research should prioritize identifying subgroups at risk and clarifying the biological mechanisms underlaid.