Early determinants of the ageing trajectory.

Over the past 250 years, human life expectancy has increased dramatically and continues to do so in most countries worldwide. Genetic factors account for about one third of variation in life expectancy so that most inter-individual variation in lifespan is explained by stochastic and environmental factors. The ageing process is plastic and is driven by the accumulation of molecular damage causing the changes in cell and tissue function which characterise the ageing phenotype. Early life exposures mark the developing embryo, foetus and child with potentially profound implications for the individual's ageing trajectory. Maternal factors including age, smoking, socioeconomic status, infections, nutritional status and season of birth influence offspring life expectancy and the development of age-related diseases. Although the mechanistic processes responsible are poorly understood, many of these factors appear to affect foetal growth directly or via effects on placental development. Those born relatively small i.e. which did not achieve their genetic potential in utero, appear to be at greatest disadvantage especially if they become overweight or obese in childhood. Early life events and exposures which enhance ageing are likely to contribute to molecular damage and/or reduce the repair of such damage. Such molecular damage may produce immediate defects in cellular or tissue function that are retained into later life. In addition, there is growing evidence that early life exposures produce aberrant patterns of epigenetic marks that are sustained across the life-course and result in down-regulation of cell defence mechanisms.