The Early Life Origins of Non-Communicable Diseases: An Overview of Recent Advances

Field: Medicine (Health Sciences)

Non-communicable diseases (NCDs) represent a major global health burden in that they account for approximately 63% of all deaths, 80% of which occur in low and middle income countries.There is compelling evidence that a proportion of the risk of NCDs originates during prenatal and postnatal development as a consequence of environmental challenges which is captured by the early life origins of disease hypothesis.This talk will focus on interrelated NCDs that are driven by obesity, primarily cardiovascular disease and type 2 diabetes mellitus; cardiometabolic disease (CMD) and will review recent developments in research on the early life origins of CMD.The main topics will include evidence from epidemiological studies, the findings of studies of animal models, the passage of induced traits between generations, recent insights into underlying mechanisms, and the potential for translation of these findings for health benefit.Epidemiological studies have provided pivotal insights into the early life origins of disease.The older cohort studies highlighted the causal association between environmental constraint, such as nutritional scarcity, and increased risk of CMD.However, the driving factors for CMD in more contemporary populations are over-nutrition and obesity.Studies of more recent cohorts have shown that infants born to obese mothers, including those who develop gestational diabetes, are at increased risk of CMD.Furthermore, infants who exhibit rapid growth in infancy or early childhood have greater risk of developing CMD as adults, which is exacerbated if they were born at the lower end of the range of birthweights.Studies of animal models have confirmed the findings of epidemiological studies and have facilitated mechanistic insights that are not possible in humans.In alignment with the shift towards epidemiological studies of the effects of over nutrition, there is a progressive paradigm shift towards using animal models of maternal obesity.These studies have demonstrated clearly that over-nutrition or maternal obesity can induce persistent changes in the offspring including hypertension, structural changes in the heart, increased adiposity, impaired lipid homeostasis and hepatosteatosis.Importantly, these studies have shown persistent changes in key processes including mitochondrial function, cell signaling and membrane lipid composition.There is increasing evidence from both epidemiology studies and from studies of animal models that induced traits can be passed to more than one generation through maternal and paternal lines.Nutrition of grandparents during their pre-pubertal slow growth period has been associated with mortality risk in the grandchildren, contingent on sex.Grand maternal smoking has been shown to influence anthropometric outcomes in their granddaughters.In rodents, paternal or maternal diet in an F0 generation has been shown to influence a number of phenotypic outcomes in subsequent generations, although at least in some studies such effects diminished with increasing number of generations.However, a rat model of persistent nutritional challenge over three generations suggested metabolic adjustment to the altered environment over three generations.Studies of the role of epigenetic processes in the early life origins of CMD have led to a paradigm shift in the field.These have primarily been carried out in small animal models of maternal under nutrition.The key findings are that environmental challenge during pregnancy can induce persistent epigenetic changes in the offspring.The majority of studies have focused on DNA methylation, although there is rapidly emerging evidence for effects on histone modifications and non-coding RNAs.To date there have been a smaller number of studies in humans, which have tended to show relatively modest epigenetic changes compared to those in animals models, and the experiments have yet to be done that test whether such changes alter biological outcomes.Recent studies have shown that differentially methylated CpG loci in fetal tissue or blood from children may have utility as biomarkers of CMD risk.Such epigenetic biomarkers may facilitate targeted therapeutic interventions in early life before the development of CMD.There are also emerging findings which show that in DNA methylation can be modified in a targeted manner by dietary supplementation in adult humans, although rodent studies indicate that development of interventions to ameliorate or reverse adverse effects of the early life environment must proceed cautiously.Research into the early life origins of disease is undergoing a transition from characterising the phenomena to understand the underlying mechanisms and translating this knowledge for human benefit.However, delivery of the potential benefit will require substantial effort and financial commitment.