Mechanisms of early life programming: current knowledge and future directions.

It has been >20 y since epidemiologic studies showed a relation between patterns of early growth and subsequent risk of diseases, such as type 2 diabetes, cardiovascular disease, and the metabolic syndrome. 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 these relations. 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 on the metabolism of an organism many years later are only starting to emerge. These mechanisms include 1) permanent structural changes in an organ resulting from suboptimal concentrations of an important factor during a critical period of development, eg, the permanent reduction in β cell mass in the endocrine pancreas; 2) persistent alterations in epigenetic modifications (eg, DNA methylation and histone modifications) that lead to changes in gene expression (eg, several transcription factors are susceptible to programmed changes in gene expression through such mechanisms); and 3) permanent effects on the regulation of cellular aging (eg, increases in oxidative stress that lead to macromolecular damage, including that to DNA and specifically to telomeres, can contribute to such effects). Further understanding of such processes will enable the development of preventive and intervention strategies to combat the burden of common diseases such as type 2 diabetes and cardiovascular disease.