Early-Life Sugar Restriction, Multi-omics Architecture, and Multisystem Resilience: A Natural Experiment

Summary Background The systemic long-term health effects and underlying biological mechanisms of early-life sugar restriction remain poorly defined. Methods We exploited a natural experiment created by the abrupt end of UK postwar sugar rationing (September 1953), including 60,768 UK Biobank participants born between October 1951 and March 1956. Exposure to early-life sugar restriction was defined by birth date relative to the policy end. We assessed 27 incident disease outcomes and all-cause mortality. In subsets, we performed plasma proteomic and metabolomic profiling, evaluated 81 adult phenotypes, and applied formal mediation analysis. Findings Of 60,768 participants (mean age 54.6 years; 56.2% female), 38,453 (63.3%) were exposed to early-life sugar restriction. Longer exposure was associated with dose-dependent risk reductions for infections, cancer, mental and behavioural disorders, nervous system, digestive, musculoskeletal, genitourinary, and skin disorders (adjusted HRs 0.83–0.93), and with lower all-cause mortality (adjusted HR 0.79; 95% CI 0.73–0.87). The exposure was associated with a distinct molecular signature and an adult phenotype marked by higher fat-free mass and lower basal metabolic rate, with no difference in BMI. Mediation analyses identified a modest “molecular memory” pathway (3–9% of effect) and a dominant “physiological programming” pathway (4–13% of effect). Interpretation Sugar restriction in the first 1,000 days programs multisystem resilience that substantially reduces risk of chronic diseases and later-life mortality. This protection operates through a hierarchical biological architecture dominated by a metabolically efficient physiological phenotype, providing mechanistic support for stricter regulation of added sugars in infant foods. Fundings National Natural Science Foundation of China and other funding sources. Research in Context Evidence before this study We searched PubMed, Web of Science, and medRxiv up to January 31, 2026, using “sugar rationing”, “natural experiment”, and “UK Biobank”. Studies using the 1953 end of UK sugar rationing as a natural experiment have reported reduced risks of type 2 diabetes, hypertension, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease, respiratory conditions, heart failure, and anxiety. All previous studies examined single disease outcomes in isolation; none tested for coordinated protection across organ systems or examined underlying biological mechanisms with multi-omics profiling. Added value of this study This study demonstrates that early-life sugar restriction confers dose-dependent protection across 27 incident outcomes spanning multiple organ systems—including infections, cancer, mental and behavioural disorders, nervous system, digestive, musculoskeletal, and genitourinary diseases—and reduces all-cause mortality, establishing a pattern of multisystem resilience. Through proteomic and metabolomic profiling, it identifies a molecular signature of early-life sugar restriction and a corresponding adult physiological phenotype characterized by higher fat-free mass and lower basal metabolic rate, with no difference in BMI. Formal mediation analysis reveals a hierarchical dual-pathway mechanism: a modest molecular memory (3–9% of total effect) and a dominant physiological programming pathway mediated by fat-free mass and basal metabolic rate (4–13%). Conventional risk traits, including visceral adiposity and dysglycemia, showed no significant mediation. Implications of all the available evidence Early-life nutrition programs lifelong multisystem resilience through a hierarchical biological architecture dominated by physiological reprogramming. These findings provide a mechanistic mandate for stricter regulation of added sugars in infant and toddler foods as primary prevention of non-communicable diseases, and highlight fat-free mass and basal metabolic rate as physiological pathways for future risk assessment and intervention.