Stress During Pregnancy Accelerates Measures of Aging Across Generations in Rats
It was discovered comparatively recently that laboratory species exhibit a plasticity of life span that is passed across generations. This can be epigenetic, in which the offspring of calorie restricted parents exhibit some of the same metabolic responses to calorie restriction even in its absence. In the other direction, stresses in a parent during pregnancy can lead to an acceleration of degenerative aging in offspring.
Researchers here demonstrate this second class of mechanism across four generations of rats, in which the final generation exhibits measurably accelerated manifestations of aging. One question that springs to mind is the degree to which differences in the gestational environment can explain the natural variation in aging within a mammalian species. How much of the distribution of life spans is this, versus later environmental circumstances such as exposure to pathogens?
Experiences in early life may lay the foundation for age-related non-communicable disease (NCD) suseptibility. The developmental origins of health and disease (DOHaD) hypothesis postulates that many common NCDs originate in utero by re-programming fetal physiological and metabolic responses with lifelong consequences on organ and tissue function. The biological signatures linked to early life adversity are also transmitted across generations. Natural disaster and nutritional birth cohorts as well as experimental studies have demonstrated that remote ancestral adverse experiences increase the risk of metabolic, cardiac, and renal disease, and mental illness with a sex-specific bias. These adverse health outcomes are linked to epigenetic regulation, including altered microRNA (miRNA) expression.
Here, we performed a longitudinal rat cohort study to examine the impact of recurrent stress reaching back across four generations (F0-F3) on lifetime health trajectories. We hypothesized that multigenerational prenatal stress (MPS) in the F4 generation would lead to a behavioural phenotype of sex-specific stress vulnerability and resilience at young and old age. Moreover, we proposed particular vulnerability to NCDs in old age in association with up-stream epigenetic and down-stream metabolic biomarker signatures.
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.