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• Research Paper Volume 12, Issue 4 pp 3828-3847

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

  Relevance score: 12.598237

  Mirela Ambeskovic, Yaroslav Ilnytskyy, Douglas Kiss, Cheryl Currie, Tony Montina, Igor Kovalchuk, Gerlinde A.S. Metz

  Keywords: sexual dimorphism, epigenetic regulation, prenatal stress, longevity, non-communicable disease

  Published in Aging on February 22, 2020

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  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.

  

  MPS modifies the emotional and sensorimotor phenotype across the lifespan. (A–C) MPS increased anxiety-like behaviours in young and aged males, but not in females. (D–F) MPS exacerbated the age-associated reduction in learned helplessness. (G–I) MPS induced sex- and age-specific effects in fore- and hindlimb skilled limb use. (J) Females showed higher locomotor activity than males at all ages. Asterisks indicate significances: *p<0.05. “b” indicates MPS effect. All data are presented as mean ± SEM.

  
  
  

  

  MPS determines physiological health trajectories. Plasma corticosterone and blood glucose levels and body weight in male and female rats revealed an effect of MPS across the lifespan. (A, B) MPS induced sex- and age-specific modifications in the stress response as indicated by reduced plasma corticosterone levels in young and aged males (A), and middle-aged females (B). (C, D) MPS elevated non-fasting blood glucose levels especially in young females. (E, F) MPS diminished body weight in young and increased it in old males (E). Body weight in males and females increased with age, while males weighed twice as much as females. Asterisks indicate significances: *p<0.05, **p<0.01, ***p<0.001; “b” indicates MPS effect.

  
  
  

  

  MPS determines sex-specific morbidity and mortality. (A) MPS males were more likely to die prematurely than any other group (at 14-15 months). (B) Midlife premature death in MPS males was linked to higher disease risk for renal failure, heart and respiratory disease and tumors. (C) Life expectancy with 530 days maximum endpoint. Asterisks indicate significances: *p<0.05, **p<0.01, ***p<0.001, “c” indicates survival probability of MPS males vs. MPS females age 14-15 (*), 16 (**) and 17-18 months (**). Male CONTROL n=10, male MPS n=12, female CONTROL n=14, female MPS n=14.

  
  
  

  

  MPS alters disease incidence across the lifespan. (A) Diagram illustrating the colour code of organ pathophysiological changes. (B) Disease incidences as represented by respective colours. The relative risk (RR) in white letters indicates diseases prevalence in relation to CONTROLs. (C) Photographs of disease pathology in MPS animals, illustrating enlarged spleen, alveoli changes in lung disease (yellow arrow), abdominal tumor, and kidneys linked to renal failure (red arrow).

  
  
  

  

  MPS raises age-associated stress vulnerability via sex-specific miRNA and mRNA expression. Fold change of miRNA and mRNA expression as determined by deep sequencing of prefrontal cortex. (A) Expression of miR-34a, (B) miR-150 and miR-181a, (C) miR-124, (D) miR-29b indicate MPS-programming of aging trajectories. Biological processes and miRNA targets are shown for (E) miR-34a, (F) miR-150, (G) miR-124, and (H) miR-21. (I) Sex-specific changes in the expression of pre-B-cell leukemia transcription factor 3 (pbx3) and doublecortin (dcx) genes as a function of age. (J) Phenotype overview of pbx3 and dcx as per MDB database. All data are represented as log change relative to CONTROL levels. Blue, dashed line indicates age-specific CONTROL levels. Asterisks indicate significances: *p<0.05, **p<0.01. All data are presented as mean ± SEM, “b” indicates MPS effect, n=3 per age/sex/group.

  
  
  

  

  MPS defines cellular homeodynamics as reflected by deep learning metabolomics analysis. (A) Given their disease vulnerability, males revealed a characteristic metabolic signature in urine ¹H-NMR spectra based on VIAVC testing. Individual metabolite changes are indicated; bars indicate % change from CONTROLS. (B) Pathway topology analysis showing all matched pathways according to p-values and pathway impact values in young males. This figure was created using the lists of metabolites identified in A. n=7 CONTROL and n=6 MPS rats; 1-MN 1-methylnicotinamide.

  
  
  

  

  MPS rat lineages and experimental design. (A) The MPS lineage was generated by stressing pregnant dams over four consecutive generations (F0, F1, F2, F3) to produce multigenerationally stressed (MPS) F4 offspring. Yoked non-stress CONTROL F4 offspring were generated in parallel. (B) Behavioural phenotype was assessed in open field exploratory behaviour, forced swim task learned helplessness, and ladder rung skilled walking. (C) MPS and CONTROL F4 generations were used for a mixed longitudinal experiment with tests at 6, 12 and 18 months of age.