History and impact of nutritional epidemiology.

The real and important role of epidemiology was discussed, noting heretofore unknown associations that led to improved understanding of the cause and prevention of individual nutritional deficiencies. However, epidemiology has been less successful in linking individual nutrients to the cause of chronic diseases, such as cancer and cardiovascular disease. Dietary changes, such as decreasing caloric intake to prevent cancer and the Mediterranean diet to prevent diabetes, were confirmed as successful approaches to modifying the incidence of chronic diseases. The role of the epidemiologist was confirmed as a collaborator, not an isolated expert of last resort. The challenge for the future is to decide which epidemiologic methods and study designs are most useful in studying chronic disease, then to determine which associations and the hypotheses derived from them are especially strong and worthy of pursuit, and finally to design randomized studies that are feasible, affordable, and likely to result in confirmation or refutation of these hypotheses.

Vitamin/trace mineral supplements for the elderly.

The fraction of population that is elderly has been increasing, as has the consumption of vitamin/trace mineral supplements, which is now a multibillion dollar industry. Yet the rationale for such supplement intake by the majority may be questioned. Some of the current recommendations for micronutrient intake by the elderly are extrapolations from recommendations made for younger adults, whereas other recommendations are based on measurements of biochemical indices not proven to reflect a deficient level in the elderly. Suggestions that the elderly need more than the recommended daily allowances largely rest on the assumption that they should have biochemical indices similar to younger adults despite decreased energy intake with decreased physical and metabolic activities of the elderly. Although some individuals require supplementation because of problems with intake, absorption, or metabolism, there is little or no proof that boosting micronutrient intake above what can be achieved in well-balanced diets, some of which already contain fortified foods, will lead to a healthier outcome for most elderly individuals. There is not only the potential for unnecessary and occasionally harmful excess administered to some, but there is a cost that now runs in the billions of dollars and adds to the costs of covering multiple chronic disease conditions. Hence, some caution should be exercised in public health promulgations concerning routine use of supplements for those in this age group (>65 y of age) and of both sexes until more research establishes clear connections between the need for micronutrients and nutrient-related health in the elderly.

Vitamin/mineral supplements: of questionable benefit for the general population.

In the United States today, there is a multibillion dollar industry in dietary supplements with at least a third sold as vitamin/mineral pills and drinks. Though everyone requires small amounts of these essential micronutrients, and supplements are of benefit to some within the population, the considerable majority of people can fulfill their needs with the intake of healthy diets of mixed foods. In addition, the fortification of some processed foods adds extra amounts of several micronutrients, especially those for which there is deemed to be a need in special segments of our population. In spite of this safe and adequate level of intake, there are many who have been led to believe that the frequent ingestion of supplements will be helpful in their efforts to maintain optimal health, live longer, and even prevent or cure non-deficiency diseases. It is the intent of this article to unravel the causes and misconceptions behind this practice and to emphasize that most of the money spent on unnecessary supplementation could be better used for other purposes.

On becoming a nutritional biochemist.

Much of the science underlying nutrition has come from biochemical studies. This certainly is true in our understanding of the metabolism and function of such micronutrient cofactors as vitamins and metal ions. My own interest stems from an early desire to understand the molecular events in an organism and ultimately to know the fate of those nutrients that are needed to maintain life. My training in chemistry, biochemistry, and nutrition was helpful in gaining knowledge about the interface among these disciplines. My interests followed an understandable trail, beginning with those factors that cause plant galls and continuing through carbohydrate metabolism to vitamins. After all, from studying such pentitols as ribitol with Professor Touster at Vanderbilt University through indoctrination with enzymes, vitamins, and coenzymes with Professor Snell at the University of California-Berkeley, it was rational to begin my independent academic life investigating the enzymes that convert a ribityl-containing vitamin, namely riboflavin, to its operational flavocoenzymes. While at Cornell University, I encountered Professor Wright, who shared an interest in biotin. My realization that there was a similar need to determine the metabolism of lipoate followed logically. Interactions with inorganic chemists such as Professor Sigel at Basel University, as well as inorganic chemists at Cornell, led to an interest in metal ions. As summarized in this article, my colleagues and I are pleased to have contributed to both basic knowledge about cofactors and to have utilized much of this information in extensions to applications. Along the way, I have served by teaching, researching, and administrating at the universities that provided my positions in academe, and I have worked to share the load of numerous public and professional duties that are summarized herein. Altogether it has been an enjoyable career to be a nutritional biochemist. I recommend it for those who follow.

Micronutrient cofactor research with extensions to applications.

Following identification of essential micronutrients, there has been a continuum of research aimed at revealing their absorption, transport, utilization as cofactors, and excretion and secretion. Among those cases that have received our attention are vitamin B6, riboflavin, biotin, lipoate, ascorbate, and certain metal ions. Circulatory transport and cellular uptake of the water-soluble vitamins exhibit relative specificity and facilitated mechanisms at physiological concentrations. Isolation of enzymes and metabolites from micro-organisms and mammals has provided information on pathways involved in cofactor formation and metabolism. Kinases catalysing phosphorylation of B6 and riboflavin have a preference for Zn2+ in stereospecific chelates with adenosine triphosphate. The synthetase for flavin adenine dinucleotide prefers Mg2+. The flavin mononucleotide-dependent oxidase that converts the 5'-phosphates of pyridoxine and of pyridoxamine to pyridoxal phosphate is a connection between B6 and riboflavin and is a primary control point for conversion of B6 to its coenzyme. Sequencing and cloning of a side-chain oxidase for riboflavin was achieved. Details on binding and function have been delineated for some cofactor systems, especially in several flavoproteins. There is both photochemical oxidation and oxidative catabolism of B6 and riboflavin. Both biotin and lipoate undergo oxidation of their acid side chains with redox cleavage of the rings. Applications from our findings include the development of affinity absorbents, enhanced drug delivery, delineation of residues in biopolymer modification, pathogen photoinactivation in blood components, and input into human dietary recommendations. Ongoing and future research in the cofactor arena can be expected to add to this panoply. At the molecular level, the way in which the same cofactor can participate in diverse catalytic reactions resides in interactions with surrounding enzyme structures that must be determined case by case. At the level of human intake, more knowledge is desirable for making micronutrient recommendations based on biochemical indicators, especially for the span between infancy and adulthood.