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J Am Coll Nutr. 2000 Apr;19(2):242-55. OBJECTIVE: To examine associations of midlife tofu consumption with brain function and structural changes in late life. METHODS: The design utilized surviving participants of a longitudinal study established in 1965 for research on heart disease, stroke, and cancer. Information on consumption of selected foods was available from standardized interviews conducted 1965-1967 and 1971-1974. A 4-level composite intake index defined "low-low" consumption as fewer than two servings of tofu per week in 1965 and no tofu in the prior week in 1971. Men who reported two or more servings per week at both interviews were defined as "high-high" consumers. Intermediate or less consistent "low" and "high" consumption levels were also defined. Cognitive functioning was tested at the 1991-1993 examination, when participants were aged 71 to 93 years (n = 3734). Brain atrophy was assessed using neuroimage (n = 574) and autopsy (n = 290) information. Cognitive function data were also analyzed for wives of a sample of study participants (n = 502) who had been living with the participants at the time of their dietary interviews. RESULTS: Poor cognitive test performance, enlargement of ventricles and low brain weight were each significantly and independently associated with higher midlife tofu consumption. A similar association of midlife tofu intake with poor late life cognitive test scores was also observed among wives of cohort members, using the husband's answers to food frequency questions as proxy for the wife's consumption. Statistically significant associations were consistently demonstrated in linear and logistic multivariate regression models. Odds ratios comparing endpoints among "high-high" with "low-low" consumers were mostly in the range of 1.6 to 2.0. CONCLUSIONS: In this population, higher midlife tofu consumption was independently associated with indicators of cognitive impairment and brain atrophy in late life. From the full text article: [...] We began our analyses with the expectation that aculturation might be a risk factor for poor cognitive function in late life and that traditional Japanese lifestyle, culture and diet might be protective. Instead, we found that poorer cognitive test performance in later life was weakly associated with a more oriental midlife diet. As this finding was explored it became evident that the relationship with oriental diet could be attributed almost entirely to a single food item: tofu. [...] As shown in Fig. 2, an increase in the prevalence of cognitive impairment with greater tofu consumption (based on the 4-level 1965–1971 composite index) remained apparent after stratifying by age. The bars at the right side of the figure, summarizing prevalence levels for cognitive impairment after adjustment for single years of age, illustrate a statistically significant, increasing trend in total cognitive impairment with increasing mid-life tofu intake (p < 0.0001). [...] ... In this study population, 20% to 25% of the burden of cognitive impairment appears attributable to midlife tofu consumption — an effect size of enormous public health importance, yet not readily discernable in comparisons across populations of diverse education, occupation, age distribution and genetic composition, especially when studied using different methods. ... [...] Although low concentrations of isoflavone phytoestrogens are also found in sprouts, wheat, lentils, beans, chickpeas and other foods, soyfoods are the dominant human dietary source in the United States and most Asian nations [12–17]. Tofu is the major soyfood in Asian and in American vegetarian diets. Concentrations of isoflavones in the blood or urine of persons consuming soy foods have been shown to be substantial in persons consuming a tradition Asian diet [18,19]. Nonetheless, concentrations vary greatly among individuals, possibly reflecting differences in intestinal flora [20,21]. The pharmacologic properties of these molecules allow them to interact with estrogen receptors and with enzymes involved in estrogen metabolism. In some circumstances they act as weak estrogens; under other conditions their actions are anti-estrogenic [22,23]. Genistein, the most thoroughly studied soy phytoestrogen, is an inhibitor of aromatase, an enzyme found in the brain and other tissues that acts to convert androgenic hormones to estrogens [24,25]. Dietary phytoestrogens, including genistein and coumesterol, are potent inhibitors of estrogen-specific 17-beta-hydroxysteroid dehydrogenase and oxidoreductase type 1, enzymes involved in the biosynthesis and metabolism of endogenous estrogen [26]. Soy isoflavones have also been shown to inhibit tyrosine kinase [27] and to modulate topoisomerases I and II activities [28]. The physiologic impact of dietary phytoestrogens in a person who eats soyfoods regularly is not trivial, and nearly all studies reported to date confirm that regular consumption of a diet high in soyfoods results in pharmacologically significant blood levels of biologically active isoflavone phytoestrogens [12,29–31]. Although we have found no published information documenting an influence of dietary phytoestrogens on the central nervous system of adult humans, several studies have identified definite influences on endocrine, breast and gonadal tissues. Daily consumption of 60 grams of soy protein for one month was found to increase the follicular phase, lengthen the menstrual cycle and suppress the mid-cycle surges of luteinizing hormone and follicle-stimulating hormone in premenopausal women, thereby demonstrating effects similar to those reported for tamoxifen [32]. Recent studies suggest that premenopausal women consuming a diet high in isoflavone phytoestrogens may experience a drop in serum levels of endogenous estrogens in conjunction with alterations in the menstrual cycle [33,34]. In post-menopausal women, a six-week supplementation of the normal diet with soya flower (45 g daily), red clover sprouts and linseed induced modest changes in levels of follicle stimulating hormone and substantial vaginal cytology changes, indicating estrogenicity [35]. In other studies of post-menopausal women the effects of a high-phytoestrogen diet have been somewhat more variable [30,36,37]. Consumption of 38 grams of soy protein daily for five months was found to increase the secretion of breast fluid in women of childbearing age, with 29% of the women showing cytological evidence of epithelial hyperplasia [38]. The idea that phytoestrogens may affect late life brain structure and function rests in part on the role of endogenous (or replacement) estrogen as a modulator of brain aging. A growing body of information suggests that estrogens may be needed for optimal repair and replacement of neural structures eroded with aging, including synapses in the neocortex and hippocampus [39–42]. Chronic sub-optimal synaptic plasticity might be a factor in aging-related cognitive decline and could influence the clinical expression of dementing diseases, including Alzheimer’s disease [43]. Although there are certainly estrogen receptors in the neurons of males, the importance of estrogens or androgens as modulators of plasticity and synaptic connectivity in aging men has received little attention [44]. Adipose cells make substantial amounts of estrogen, and estrogen blood levels are strongly related to adiposity in men and in women [45]. While androgens may have a direct effect on plasticity, their influence could be mediated through an estrogen-dependent mechanism, since estrogens are generated in the brain by conversion of testosterone to estradiol-17 beta through the action of an enzyme complex comprised of cytochrome P450 aromatase and NADPH-dependent cytochrome P450 reductase [46]. Aromatase activity in the brain seems to be of two types, one that is modulated by sex hormone blood levels (localized to the hypothalamus) and a second that is uninfluenced by blood levels of sex hormones (in the amygdala, hippocampus and other areas of the neocortex), suggesting two separate neural functions [24,47]. Thus the male brain’s exposure to endogenous estrogen depends both on adiposity and the androgen-aromatase system. There are now several reports indicating that oral intake of soy isoflavones by experimental animals results in significant alterations in brain metabolism, including (1) alterations in 5 alpha reductase activity in the amygdala and hypothalamic-preoptic area of adult male rats [48], (2) marginally elevated levels of nerve growth factor message RNA in the hippocampus of young ovariectomized rats and significantly elevated choline acetyl transferase message RNA in the frontal cortex of ovariectomized retired breeder rats [49,50], (3) apparently permanent alterations of calbindin-D28k levels and in the hypothalamus and preoptic areas of male and female rats resulting from dietary phytoestrogen exposure during pregnancy [51] and (4) up regulation in estrogen receptor beta RNA expression (in contrast to down regulation with 17-beta estradiol) in the hypothalamus [52]. In addition to pharmacologic mechanisms involving modulation of estrogen-related metabolic processes, certain soy isoflavones are potent inhibitors of tyrosine kinase, an enzyme known to be involved in neuronal plasticity. In a study of the effects of five tyrosine kinase inhibitors on neuron electrophysiological functioning, genistein showed high specificity for hippocampal tyrosine kinase. Presumably by inhibiting the activity of this enzyme, genistein selectively blocked the induction of long-term potentiation (LPT) in post-synaptic cells [53]. LPT is widely viewed as centrally involved in learning and memory, particularly as they occur in the hippocampus and related brain areas, and normal postsynaptic LPT may be required for long-term synaptic plasticity in the hippocampus [54]. Genistein has also been shown to block voltage-sensitive sodium channels in cultured rat brain neurons, possibly by allosteric interaction with neurotoxin binding site 2 or possibly by virtue of its ability to inhibit tyrosine kinase [55]. Isoflavones might also effect plasticity by interfering with the regulation by tyrosine kinase of NMDA channels located at neuronal synapses [56]. The results presented here demonstrate an association of self-reported tofu consumption frequency in midlife with functional and structural indicators of brain aging. Because the effects were apparent at relatively modest levels of intake (two or more servings weekly), an adverse pharmacologic mechanism seems more likely than a nutritional pathogenesis. While our study cannot directly impune a specific constituent with certainty, isoflavone phytoestrogens are obvious candidates. We hypothesize that regular dietary exposure to soy isoflavones over many years during middle life may be associated with the appearance of accelerated brain aging in later life attributable to chronically sub-optimal neural plasticity. The specific means by which soy phytoestrogens might exert such influence could involve competition with endogenous estrogens for estrogen receptors in neurons and/or reduction in estrogen concentration in the brain by inhibition of the aromatization of androgens. Alternatively, isoflavones in tofu and other soyfoods might exert their influence through interference with tyrosine kinase dependent mechanisms required for optimal hippocampal function, structure and plasticity. Categories: 2000, Soy, Phytoestrogens, Endocrine, Hormone disruptors, Estrogen, Androgens, Brain, Plasticity, Cognitive, Cognitive impairment, Memory, Nutrition and diet, Vegetarian |