Premature brain aging in humans exposed to maternal nutrient restriction during early gestation

Abstract

Background: Prenatal exposure to undernutrition is widespread in both developing and industrialized countries, causing irreversible damage to the developing brain, resulting in altered brain structure and decreased cognitive function during adulthood. The Dutch famine in 1944/45 was a humanitarian disaster, now enabling studies of the effects of prenatal undernutrition during gestation on brain aging in late adulthood.

Methods: We hypothesized that study participants prenatally exposed to maternal nutrient restriction (MNR) would demonstrate altered brain structure resembling premature brain aging in late adulthood, expecting the effect being stronger in men. Utilizing the Dutch famine birth cohort (n = 118; mean age: 67.5 ± 0.9 years), this study implements an innovative biomarker for individual brain aging, using structural neuroimaging. BrainAGE was calculated using state-of-the-art pattern recognition methods, trained on an independent healthy reference sample, then applied to the Dutch famine MRI sample, to evaluate the effects of prenatal undernutrition during early gestation on individual brain aging in late adulthood.

Results: Exposure to famine in early gestation was associated with BrainAGE scores indicative of an older-appearing brain in the male sample (mean difference to subjects born before famine: 4.3 years, p < 0.05). Furthermore, in explaining the observed variance in individual BrainAGE scores in the male sample, maternal age at birth, head circumference at birth, medical treatment of hypertension, history of cerebral incidences, actual heart rate, and current alcohol intake emerged to be the most influential variables (adjusted R² = 0.63, p < 0.01).

Interpretation: The findings of our study on exposure to prenatal undernutrition being associated with a status of premature brain aging during late adulthood, as well as individual brain structure being shaped by birth- and late-life health characteristics, are strongly supporting the critical importance of sufficient nutrient supply during pregnancy. Interestingly, the status of premature brain aging in participants exposed to the Dutch famine during early gestation occurred in the absence of fetal growth restriction at birth as well as vascular pathology in late-life. Additionally, the neuroimaging brain aging biomarker presented in this study will further enable tracking effects of environmental influences or (preventive) treatments on individual brain maturation and aging in epidemiological and clinical studies.

Keywords: Aging; BrainAGE; Dutch famine; Epigenetics; Magnetic resonance imaging (MRI); Undernutrition; Voxel-based morphometry (VBM).