The womb as the cradle of longevity: Perinatal origins of biological aging.

Abstract

The perinatal period is increasingly recognized as an important determinant of biological aging trajectories and disease susceptibility across the lifespan. This narrative review synthesizes current evidence linking intrauterine exposures to adult health outcomes across three biological dimensions: fetal programming, maternal influences, and placental mediation. Evidence from the Dutch Hunger Winter suggests that the timing of gestational exposure-not birth weight alone-might govern programming outcomes. Modern epigenetic clock studies have since reported accelerated biological aging at midlife in famine-exposed individuals. Preterm birth and fetal growth restriction (FGR) are independently associated with reduced nephron endowment, impaired cardiac and pulmonary development, and metabolic dysfunction, and with a 30%-50% increase in all-cause mortality risk in early-to-mid adulthood in observational cohorts. Maternal factors, including advanced biological age, preeclampsia, gestational diabetes, and nutritional deficiencies, further shape the intrauterine milieu and are associated with increased offspring risk across multiple organ systems, although residual confounding by shared genetic and postnatal factors cannot be excluded. Emerging evidence implicates placental senescence and maternal microbiome dysbiosis as additional candidate mediators linking perinatal adversity to long-term health trajectories. These findings support a role for lifetime risk stratification for individuals born preterm or with FGR, structured postpartum surveillance for women with pregnancy complications, and primary prevention strategies targeting the intrauterine environment, alongside continued efforts to strengthen the underlying evidence base. Reframing the perinatal period as a potential determinant of the pace of biological aging, and not merely a risk window for specific diseases, identifies it as a priority domain for longevity-focused obstetric research.