Understanding the molecular mechanisms by which maternal diet influences longevity

The diet of an individual has an important influence on the health of an individual at any stage of life. However there is evidence to suggest that the diet of a pregnant woman is particularly important as it has major long-term consequences on the health of her baby many years later when they themselves are adult. Babies that are not well nourished during pregnancy often have a low birth weight. It has been shown that individuals with a low birth weight are not only less likely to survive delivery but are also at substantially increased risk of developing various common diseases such as diabetes, high blood pressure and heart disease and are more likely to die at a younger age. The detrimental effect of having a low birth weight is exaggerated if rapid growth occurs during the postnatal period and the individual becomes fat. The molecular mechanisms linking poor fetal growth, long-term health and lifespan are not known. Many of our attempts to decipher mechanisms of human diseases both rely on and have benefited from studying animal models. We have shown that in a mouse model that if pregnant animals have too little protein during pregnancy their babies are small at birth. These animals growth very quickly during the lactation period if suckled by a normally fed mother and reach an apparently normal weight by weaning. However these patterns of growth have detrimental consequences for the animal and we have shown results in over a 25 % reduction in lifespan. We now plan to study these animals further to understand how a modest reduction in protein intake of the mother can have such a large effect on the lifespan of her offspring. We are particularly interested in proteins involved in insulin signalling as it is know that insulin has effects on growth and metabolism in mammals and more recently has been implicated in regulation of lifespan in simple organisms such as fruit flies. Once the underlying mechanisms linking maternal diet to the health and longevity of the offspring are understood, intervention strategies can then be developed to help improve the health of both pregnant women and their offspring.

A fetus responds to the nutrients it receives in a variety of ways including metabolic and endocrine changes that may lead to life-long changes in the function and structure of the body / a concept termed fetal programming. It is proposed that the baby receives from its mother a forecast of the nutritional environment it will receive after birth and modifies it metabolism to maximise chances of survival postnatally. These adaptations become detrimental if conditions after birth are not the same as those during fetal life. This Developmental Origins of Health and Disease hypothesis proposes that disorders such as heart disease and type 2 diabetes result from an imbalance between the environment experienced in utero and that experienced postnatally. This has been supported by human and animal studies. Furthermore human studies and our studies in rodents have shown that reduced fetal growth followed by rapid postnatal catch-up growth can lead to early death. There is emerging evidence to suggest that nutrition during early postnatal life also has long-term consequences on health. We showed that rodents that are suckled by low protein fed mums grow slowly during lactation, remain smaller and live longer than controls. Prior to these observations, the only known non-genetic way to increase life span in mammals was by permanent calorie restriction. Reducing the food intake of rodents can increase their life span by 40 %. A reproducible finding in such studies is that animals maintained on dietary restriction regimes exhibit reduced plasma insulin, enhanced glucose tolerance and reduced production of reactive oxygen species. This thus provides a direct association between food intake, plasma insulin concentrations and longevity. Our recent data suggests that nutritional restriction during critical periods of development is sufficient to influence longevity. This proposal addresses the possibility that this occurs through similar mechanisms as permanent calorie restriction.