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Mechanisms underlying the developmental origins of health and disease

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It is over twenty years since epidemiological studies revealed that there was a relationship between patterns of early growth and risk of developing metabolic diseases such as type 2 diabetes in later life. Studies of identical twins, individuals who were in utero during periods of famine and animal models have provided strong evidence that the early environment, including early nutrition, plays an important role in mediating this relationship. The concept of “early life programming” is therefore widely accepted. However the mechanisms by which a phenomenon that occurs in early life can have long-term effects on the function of a cell and therefore metabolism of an organism many years later are still emerging. These include: (1) Permanent structural changes in an organ due to exposure to suboptimal levels of essential hormones or nutrients (2) Permanent effects on regulation of cellular ageing through increases in oxidative stress and mitochondrial dysfunction leading to DNA damage and telomere shortening. (3) Persistent alterations in epigenetic modifications (including DNA methylation, histone modifications and miRNAs) leading to changes in gene expression. Several transcription factors have been shown to be susceptible to programmed changes in gene expression through such epigenetic mechanisms. These are conceptually attractive targets of programmed epigenetic regulation, as through regulation of their expression a network of other genes will be regulated. Further understanding of the extent and nature of these programming mechanisms could enable the development of preventative and intervention strategies to combat the burden of diseases such as type 2 diabetes.

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