ANTIOXIDANT VITAMIN STUDIES: OXIDATIVE STRESS RECOMMENDED AS CLINICAL ENDPOINT

ANTIOXIDANT VITAMIN STUDIES: OXIDATIVE STRESS RECOMMENDED AS CLINICAL ENDPOINT instead of dietary deficiency by Jeffrey Blumberg, PhD, Tufts University, at an Oct. 11-13 symposium sponsored by Bristol Myers Squibb/Mead Johnson on nutrition research. Current recommended levels for vitamin E, vitamin C and beta carotene are designed to prevent deficiency diseases but are not based on levels which take into account their antioxidant activity, Blumberg explained. The symposium, convened to discuss the nutritional assessment of elderly populations, was hosted by the USDA Human Nutrition Research Center on Aging at Tufts University. Blumberg predicted that "when we begin to understand how free radical pathology leads to these chronic diseases, the model used to establish recommended dietary allowances associated with deficiency diseases may change a bit with respect to antioxidants." "When we look at vitamin C, we actually see . . . requirements as somewhat arbitrarily set to . . . prevent scurvy," Blumberg said. "These really are self-referential definitions as opposed to any kind of link with oxidative stress or with any other functional endpoint." Blumberg observed that a body of data has been growing that implicates oxidative stress and its generation of free radical activity to such chronic conditions as arteriosclerosis, cancer, cardiovascular disease and senile cataracts. In addition, he said that researchers are now speculating whether some age-related changes in the central nervous system associated with the development of senile dementia and Parkinson's disease are compounded by oxidative stress. Blumberg also urged the audience not to overlook the interaction of different antioxidants in studies. He noted that the scientific community is beginning to appreciate, "for example, that as vitamin E quenches free radicals generated from polyunsaturated fatty acids and cells become oxidized, that vitamin C becomes important in reducing the tocopherol radical back to its reduced state." He added: "It becomes increasingly naive of us to focus entirely on relationships between a single antioxidant and a process or particular chronic disease." Designs for prospective human studies have regularly included measurements of antioxidant intake and antioxidant status (plasma levels) but investigators have failed to include analysis of oxidative stress status and biomarkers of nonoxidant action, Blumberg said. Future antioxidant vitamin studies should examine all of these elements, he advised. In a separate session on water-soluble vitamins, Irwin Rosenberg, MD, Tufts University, delivered a presentation by proxy for John Lindenbaum, MD, Columbia University, on measures of function for vitamin B[12] and folate. Citing Lindenbaum's research, Rosenberg hypothesized that "we are going to have to have functional measures which go beyond some of the straight biochemical measures which have been traditional ways of assessing" vitamin B[12] and folate status. In a study of 40 individuals with mild neuropsychiatric disturbances, Lindenbaum found that while the majority of patients had normal or above normal ranges of vitamin B[12] and folate levels using standard criteria and did not have a "clinical presentation "of vitamin B[12] deficiency, they did have elevated homocysteine and methylmalanate levels. Elevated levels of these metabolites, associated with vitamin B[12] deficiency, have been linked to myocardial infarction ("The Tan Sheet" Oct. 4, p. 8). When the study participants were treated with vitamin B[12], "in spite of the fact that they would not have been clinically diagnosed as deficient, they experienced a drop almost uniformly" in their homocysteine and methylmalanate levels. "Perhaps more importantly," Rosenberg said, 39 out of the 40 "experienced clinical improvement with respect to neuropsychiatric observations." "We may have to reconsider what is a normal folate level based on these functional assessments," Rosenberg suggested. "If we look at that phenomenon plotted against folate . . . and B[12] intakes, I think we see evidence [that] the current Recommended Daily Allowances of 200 mcg per day for the elderly may not be enough to prevent these elevations" of homocysteine and methylmalanate. Using Lindenbaum's criteria, Rosenberg estimated that 20-25% of the "otherwise healthy elderly cohort" is subclinically deficient in either folate or vitamin B[12]. Addressing the call for higher RDAS, Catherine Wotecki, PhD, of the National Academy of Sciences' Food and Nutrition Board, alerted the group that she had been "looking for information in all of the sessions that would argue for a change in the present values" of the Recommended Dietary Allowances. "With respect to water-soluble vitamins," she reported, "this session . . . certainly has presented quite a bit of information that would argue for a change." However, Wotecki noted that most of the studies presented at the meeting "rely on relatively small numbers of observations and the people who are participating in those studies may not be representative of the group that we want to be making recommendations for." She suggested that more information is needed about the shape of the distribution curve, which she characterized as "extremely critical" for developing RDAs for the elderly.