Research Paper Volume 12, Issue 4 pp 3828—3847

Ancestral stress programs sex-specific biological aging trajectories and non-communicable disease risk

Mirela Ambeskovic1, , Yaroslav Ilnytskyy2, , Douglas Kiss1, , Cheryl Currie3, , Tony Montina4, , Igor Kovalchuk2, , Gerlinde A.S. Metz1, ,

  • 1 Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge T1K 3M4, Alberta, Canada
  • 2 Department of Biological Sciences, University of Lethbridge, Lethbridge T1K 3M4, Alberta, Canada
  • 3 Faculty of Health Sciences, University of Lethbridge, Lethbridge T1K 3M4, Alberta, Canada
  • 4 Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge T1K 3M4, Alberta, Canada

Received: December 13, 2019       Accepted: February 5, 2020       Published: February 22, 2020
How to Cite

Copyright © 2020 Ambeskovic et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


The incidence of non-communicable diseases (NCDs) is rising globally but their causes are generally not understood. Here we show that cumulative ancestral stress leads to premature aging and raises NCD risk in a rat population. This longitudinal study revealed that cumulative multigenerational prenatal stress (MPS) across four generations (F0-F3) raises age- and sex-dependent adverse health outcomes in F4 offspring. MPS accelerated biological aging processes and exacerbated sex-specific incidences of respiratory and kidney diseases, inflammatory processes and tumors. Unbiased deep sequencing of frontal cortex revealed that MPS altered expression of microRNAs and their target genes involved in synaptic plasticity, stress regulation, immune function and longevity. Multi-layer top-down deep learning metabolite enrichment analysis of urine markers revealed altered metabolic homeodynamics in MPS males. Thus, peripheral metabolic signatures may provide sensitive biomarkers of stress vulnerability and disease risk. Programming by MPS appears to be a significant determinant of lifetime mental health trajectories, physical wellbeing and vulnerability to NCDs through altered epigenetic regulation.


ANOVA: analysis of variance; CI: Confidence interval; CORT: corticosterone; DOHaD: Developmental origins of health and disease; FL: Forelimb; FST: Forced swim test; GD: gestational day; HL: Hindlimb; HPA: hypothalamic-pituitary-adrenal; mRNA: Messenger RNA; miRNA: microRNA; MPS: Multigenerational prenatal stress; NCD: Non-communicable disease; NMR: Nuclear magnetic resonance; PTSD: Post-traumatic stress disorder; RR: Relative risk; VIAVC: Variable importance analysis based on random variable combination.