Accelerated biological aging six decades after prenatal famine exposure

Abstract

To test the hypothesis that early-life adversity accelerates the pace of biological aging, we analyzed data from the Dutch Hunger Winter Families Study (DHWFS, N = 951). DHWFS is a natural-experiment birth-cohort study of survivors of in-utero exposure to famine conditions caused by the German occupation of the Western Netherlands in Winter 1944 to 1945, matched controls, and their siblings. We conducted DNA methylation analysis of blood samples collected when the survivors were aged 58 to quantify biological aging using the DunedinPACE, GrimAge, and PhenoAge epigenetic clocks. Famine survivors had faster DunedinPACE, as compared with controls. This effect was strongest among women. Results were similar for GrimAge, although effect-sizes were smaller. We observed no differences in PhenoAge between survivors and controls. Famine effects were not accounted for by blood-cell composition and were similar for individuals exposed early and later in gestation. Findings suggest in-utero undernutrition may accelerate biological aging in later life.

Keywords: Dutch famine; biological aging; epigenetic clock; fetal origins; natural experiment.

Fig. 1.

Differences in biological aging between survivors of in-utero famine exposure and unexposed control participants in the Dutch Hunger Winter Families Study. The figure shows effect-sizes of in-utero famine exposure associations with three DNA methylation (DNAm) measures of biological aging, DunedinPACE, PC GrimAge, and PC PhenoAge (N = 951). Panel (A) shows effect-sizes estimated in the full cohort. Panel (B) shows effect-sizes estimated for women and men separately. Effect-sizes were estimated from generalized estimating equation regressions with covariates for participant age, specified as a quadratic term, and sex, and are denominated in SD units of the aging measures, interpretable as Cohen’s d values. Error bars show 95% CIs.

Fig. 2.

Differences in biological aging between survivors of in-utero famine exposure and unexposed control participants in the Dutch Hunger Winter Families Study by gestational timing of famine exposure. The figure shows effect-sizes estimated for famine exposure during six gestational time windows. Famine-exposed participants were exposed during up to two periods. The developmental periods are ordered in the x-axis in chronological order relative to the famine. The left-most tick shows effect-sizes for late-gestational exposure (defined as exposure for the final 10 wk of gestation; N = 139 exposed). The second tick to the left shows effect-sizes for exposure during the penultimate 10 wk of gestation (N = 146 exposed). The third tick shows effect-sizes for exposure during the second 10 wk of gestation (N = 125 exposed). The fourth tick shows effect-sizes for exposure during the first 10 wk of gestation (N = 74 exposed). The fifth tick shows effect-sizes for early gestational exposure with duration <10 wk (N = 94 exposed). The right-most tick shows effect-sizes for preconceptual exposure, i.e., for exposure during the period preceding conception (N = 52 exposed). Numbers exposed do not add up to the total exposed sample because many participants were exposed in two adjacent periods (N = 143). Effect-sizes are reported for DunedinPACE, PC GrimAge, and PC PhenoAge. Effect-sizes were estimated from a multivariate regression in which indicator variables for each exposure window were included as predictor variables along with covariates for sex, age, and age-squared. Effect-sizes are denominated in SD units of the aging measures, interpretable as Cohen’s d values. Full results are reported in SI Appendix, Table S6. Effect-sizes are plotted separately for women (circles) and men (triangles). The figure shows a consistent sex-specific pattern in DunedinPACE and PC GrimAge effect-sizes. Women who survived in-utero famine exposure, whether at early or later gestation, tended to have faster pace of biological aging, as measured by DunedinPACE, and older biological age, as measured by PC GrimAge DNAm clock. In contrast, men who survived later-gestational famine exposure tended to have faster pace of biological aging and older biological age; whereas men who survived early-gestational famine exposure tended to have slower pace of biological aging and younger biological age, as measured by DunedinPACE and PC GrimAge DNAm clock, respectively. There was no consistent pattern in PC PhenoAge effect-sizes.

Fig. 3.

Flow diagram of the Dutch Hunger Winter Families Study. The figure shows how the analysis sample size was arrived at in each step for survivors of in-utero famine exposure, time controls, and same-sex sibling controls. N = 1,031 participants completed telephone interviews. Of this group, 971 participated in the clinic exam. DNA extracted from blood samples was analyzed to determine DNA methylation and data passed quality controls for N = 951 individuals. The figure illustrates the number of individuals in each exposure and control group included in the telephone interview, clinic examination, and analysis sample.

Fig. 4.

Gestational timing of exposure to famine in the Dutch Hunger Winter Families Study. The figure shows individual gestations of N = 547 famine-exposed participants (colored lines) and N = 176 time controls (gray lines). Each gestation is plotted as a single horizontal line. The start of the line is the date of the mother’s last menstrual period (LMP). The end of the line is the participant’s date of birth. Individual gestations are plotted from the top of the graph to the bottom, ordered by LMP date. For the famine-exposed participants, the segment of each line showing the first 10 wk of gestation is colored gold. The segment showing the second 10 wk is colored orange. The segment showing the third 10 wk is colored red. The segment showing the last 10 wk is colored purple. For the time controls, 10-wk gestational periods are colored in gray, with lighter shades for the earlier gestational periods. The x-axis shows the date. The vertical dashed lines show the start and end of the famine exposure period (November 26, 1944 to May 12, 1945).