This topic is most often raised in response to the question: ''What—if any—are the fetal origins of individual differences in aging and the incidence of age-related diseases?'' During pregnancy, dietary requirements change because a mother must consume or synthesize all that is required for the growth and development of her baby. Factors like poverty, moral or religious taboos, or poor education are major influences on dietary habits in pregnancy. If, for reason of poor diet or placental insufficiency, a fetus fails to receive necessary calories and nutrients required for development, the risks increase of several age-related diseases. The importance of maternal nutrition and the consequences of low birth weight are now widely recognized in studies of aging and age-related disease.
Fetal nutritional programming is defined as ''a stimulus (nutrient) or insult (absence of essential nutrient) to the fetus at a critical or sensitive period in intrauterine life with lasting effects on body structure, physiology and metabolism'' (Godfrey and Barker, 2001). This concept underpins the ''fetal origins of adult disease hypothesis.'' The hypothesis rests on the facts that, although genes determine optimum growth potential, the intra-uterine environment and nutrient availability determine the extent of fetal growth attained.
Neonatal body weights, sizes, and proportions are gauges of the intrauterine growth and nutritional status. These provide useful proxies in population-based studies of nutritional status and growth. But these are less than ideal. Research methods to improve on this are in development and are likely to derive from the following. Fetal nutrition depends on the concentration of nutrients in the maternal circulation, on uteroplacental blood flow, and on the efficiency of transfer of nutrients across the placenta. Nutrient concentration in maternal blood essentially is determined by the mother's body composition, activity, metabolism, and diet. Recent studies have developed noninvasive techniques to measure relevant parameters (e.g., functional magnetic resonance imaging of placental function). Although these are certainly feasible in population-based studies, at present it is not possible to obtain large-scale normative data on the healthy fetus.
The general hypothesis that fetal growth is an important influence on late-onset diseases has been developed further. The Barker Hypothesis proposes that the fetal nutritional environment programs offspring for the likely availability of calories/nutrients during later development. Infants who have experienced a poor nutritional environment in utero are programmed to anticipate poor nutritional conditions in later life. Consequently, their metabolism is primed to conserve calories and nutrients as these become available. Their phenotype is small, and in poor conditions their health remains good. Conversely, infants whose intrauterine nutritional supplies were good will develop an optimal phenotype and enjoy corresponding good health. Problems for health and aging arise when intrauterine nutrition is mismatched with the adult nutritional environment (McMillen and Robinson, 2005). When the poorly nourished fetus encounters abundant foods in adulthood, programs to retain calories/nutrients are inappropriate; obesity, hyper-lipidemia, hypertension, and abnormal glucose metabolism arise. Research methods to analyze the mechanisms initially relied on human ecological studies that exploit historical databases with high standards of clinical follow-up (in survivors born during the Dutch famine of 1944/1945; Roseboom et al., 2001) and, increasingly, on animal models. The term metabolic imprinting was recently introduced to promote studies to unravel associations between early nutrition and increased susceptibility to late-onset diseases. This term implies the persistence of an adaptive genomic change in response to a nutritional stimulus that occurs during a critical period of development. The phenomenon of imprinting describes the effect on the single allele of a gene, which is expressed in a parent-of-origin dependent manner. Genetic mechanisms to explain these processes are now described. These do not involve alterations to DNA sequences, but rather to epigenetic gene regulation (Waterland and Jirtle, 2004). DNA methylation is highly dependent on the availability of dietary methyl donors (e.g., methionine) and cofactors (e.g., vitamin B12). Early in embryogenesis, continuous cycles of cytosine methylation are established. Under- or overavailability of methyl donors can cause lasting effects on specific genes. It is now a subject of great interest in the study of the role of nutrients in aging and susceptibility to age-related diseases to identify the classes of genes that may be involved. Imprinted genes might be one such class of gene, and studies are now underway to determine if one or more of these genes is associated with individual differences in rates of aging and disease incidence.
Research into aging will remain a priority for the foreseeable future. Whatever is achieved seems likely always to fall short of a human craving for a long and healthy life. The key outcome variable from a public perspective is a decrease in age-dependent mortality with the hope that for most, these added years will be comfortable and productive. There are without doubt major genetic and environmental contributions to aging and, of these, the environmental contribution seems most open to effective intervention. In broad terms, there is a popular view that lifestyle issues are the most important and the one over which an individual can exercise most control. When this rather imprecise term is analyzed, the spotlight falls on nutrition holding center stage in aging research.
This chapter has set out some of the pitfalls—and more than one elephant trap—for the researcher new to this field. The scene was set by looking first from an historical perspective and seeing that aging populations comprise diverse groups of people so much so that differences between the young-old and the old-old attributed to aging might sometimes be better understood in terms of major differences in dietary histories. This point recurred in the final sections on gene-nutrient interactions and the importance of nutritional programming. Here, full knowledge of the maternal, neonatal, and adult nutritional histories of people is necessary to unravel the basic biology in human studies. More likely, promising animal models will be developed to explore the ways aging processes are influenced by the early nutritional environment.
Although this chapter has emphasized the role of nutritional studies in aging human populations, there is an important place for animal studies. Much of this is outside the competence of this reviewer, being found in journals concerning animal husbandry and in nutritional biochemistry. Although the case is strong to focus on human studies, when there is little commercial interest in old animals, this should not be understood as making light of the possible contributions to human health such animal studies might make.
Emphasis was placed on the need in nutritional studies to devise and implement effective methods to estimate the validity and reliability of nutritional intake methods. None of those summarized earlier are perfect, and there is great scope for novel improvements. In step with this, there are also opportunities to introduce advanced statistical models into studies on nutrients and human aging. The exponential growth witnessed in the molecular epidemiology of nutrition and the huge interest shown in understanding the role of specific genes makes this one of the most stimulating areas in which to start research. These are exciting times.
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