Eating window duration follows a U-shaped mortality curve — a counterintuitive finding that challenges the blanket enthusiasm for aggressive time-restricted eating. Observational data flagged in this review reveal that windows of ≤8 hours carry elevated mortality and biological aging risk, even as preclinical and clinical trial data show 4–12 hour time-restricted eating improves cardiometabolic markers. Alternate-day fasting and 5:2 protocols show similar healthspan benefits in controlled settings. Circadian alignment of specific macronutrients — front-loading carbohydrates and proteins earlier in the day, timing antioxidant intake to circadian phase — appears to compound benefits beyond window duration alone. Irregular meal patterns, breakfast skipping, and late-evening eating independently associate with aging-related disease risk.
The U-shaped risk curve is the most clinically consequential signal here. Millions of adults practicing aggressive 6- or 7-hour windows may be trading one risk profile for another — particularly for cardiovascular mortality, as suggested by recent AHA data on 8-hour TRE. This review synthesizes cross-sectional, cohort, and animal evidence, but that methodological mix limits causal inference; confounding (who skips breakfast, who eats late) is difficult to disentangle. The gut microbiota and nutrient-sensing pathways like mTOR and AMPK are implicated mechanistically but remain under-characterized in humans. For longevity-focused adults, the practical takeaway is nuanced: a 10–12 hour eating window aligned with daylight hours, with carbohydrate-heavier meals earlier, likely optimizes the benefit-to-risk ratio better than extreme restriction.