From the First 1000 Days to the First 100 Years: Early-Life Biological Programming, Sentinel Phenotypes, and Healthy Aging

The first 1000 days of life, spanning from conception to approximately two years of age, represent a period of exceptional biological plasticity during which nutritional, metabolic, inflammatory, psychosocial, microbial, and environmental exposures may shape developmental trajectories across the life course. For this narrative review, PubMed/MEDLINE, Scopus, and Web of Science were searched from inception to June 2026, focusing primarily on human cohorts, systematic reviews, meta-analyses, guidelines, and consensus documents, with selected experimental studies included for mechanistic evidence. Within the framework of the Developmental Origins of Health and Disease (DOHaD), we examine the epigenetic, oxidative, inflammatory, mitochondrial, and telomere-related mechanisms proposed to link early-life exposures with lifelong health and biological aging. Because most human evidence in this field is observational, whereas much of the mechanistic evidence derives from experimental models, these relationships are presented as associations and biologically plausible hypotheses rather than as demonstrated causal pathways. We then consider how these processes may become clinically apparent during childhood through four illustrative “sentinel phenotypes”—allergic and atopic disease, respiratory vulnerability, renal–cardiovascular risk, and altered metabolic growth—proposed here as a conceptual framework rather than as an established classification. We also review preventive opportunities during pregnancy, infancy, and early childhood. Overall, the first 1000 days should be viewed as a critical window for developmental health, while the specific contribution of this review is to integrate early-life biological mechanisms with clinically observable pediatric sentinel phenotypes within the broader framework of biological and healthy aging.