Pathways linking the early environment to long-term health and lifespan.

The intrauterine environment is a major contributor to normal physiological growth and development of an individual. Disturbances at this critical time can affect the long-term health of the offspring. Low birth weight individuals have strong correlations with increased susceptibility to type 2 diabetes and cardiovascular disease in later-life. These observations led to the Thrifty Phenotype Hypothesis which suggested that these associations arose because of the response of a growing fetus to a suboptimal environment such as poor nutrition. Animal models have shown that environmentally induced intrauterine growth restriction increases the risk of a variety of diseases later in life. These detrimental features are also observed in high birth weight offspring from mothers who were obese or consumed a high fat diet during gestation. Recent advances in our understanding of the mechanisms underlying this phenomenon have elucidated several potential candidates for the long-term effects of the early environment on the function and metabolism of a cell. These include: (1) Epigenetic alterations (e.g. DNA methylation and histone modifications), which regulate specific gene expression and can be influenced by the environment, both during gestation and early postnatal life and (2) Oxidative stress that changes the balance between reactive oxygen species generation (e.g. through mitochondrial dysfunction) and antioxidant defense capacity. This has permanent effects on cellular ageing such as regulation of telomere length. Further understanding of these processes will help in the development of therapeutic strategies to increase healthspan and reduced the burden of age-associated diseases. Crown