Journal of Anti-Aging Medicine, 2003;6(4):335-6
New Findings May Support
In April 2000, Lon White and others reported a dose-dependent positive correlation between tofu consumption and brain atrophy in a large sample of men over several decades.  While correlation does not prove causation, study size and duration along with the robust dose-dependent relationship caused me, even as a vegetarian, to avoid tofu and other soy products.
Correlation-based hypotheses should be tested against the availability of possible causal mechanisms. In addition to possible causal mechanisms previously cited by this author,  recent findings significantly increase the case for a causal mechanism of soy-induced brain atrophy.
Atrophic Pharmacology Indicated
Brain-derived neurotrophic factor (BDNF) facilitates the survival and genesis of brain cells. [3,4] The neuroprotective effects of caloric restriction are attributed in part to increased BDNF.  On the other hand, reduced BDNF is known to cause brain-cell atrophy and is associated with Alzheimer’s disease. [6,7] Now, a study in "Neuroscience Letters" reports that soy significantly reduced BDNF in the hippocampus and cerebral cortex of male rats.  Since reduced BDNF can cause neural atrophy, these findings appear to provide compelling evidence for a causal mechanism that might explain the positive correlation between tofu (soy) consumption and brain atrophy reported by White et al. 
Bad For Boys, Good For Girls?
While soy appears to reduce BDNF in male rats, it has also been shown to increase BDNF in female rats.  In fact, soy appears to affect neurological parameters in a sex-defined fashion wherein females benefit and males suffer. [10-13] There is little doubt among researchers that this is because soy is high in phytoestrogens, which are plant-derived substances that act like the female hormone estrogen.
However, that sex-defined difference fails to explain the findings regarding the wives of male subjects in White et al., who reported: "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."  White et al. proposed that long-term consumption of weaker soy estrogens may displace the body’s own stronger estrogen along with its benefits.
Evidence Against Soy-Dementia Hypothesis?
A possible signal contrary to a soy-dementia link is the low prevalence of dementia  and high consumption of soy in Okinawa, Japan.  However, that negative correlation, like any correlation, does not prove causation. For example, perhaps soy does cause dementia but other factors in Okinawa offset the effect.
Also, White et al. explored correlations of a range of foods to neurological parameters, whereas this Okinawa analysis is a sweeping generalization of only tofu to all of Okinawa. In other words, it stands to reason that the study by White et al. finding a positive tofu-dementia correlation has the greater likelihood of providing the more accurate picture. Nevertheless, in my view this Okinawa data warrants further examination as a possible route to falsifying the soy-dementia hypotheses.
In closing, the findings of soy-induced BDNF reduction in male rat brain regions that are central to the onset of dementia, in addition to previous findings,  appear to provide compelling evidence of a possible causal mechanism that might explain the soy-dementia correlation reported by White et al.  Obviously further research is necessary before a clear picture emerges regarding the effects of long-term soy consumption on the brain. But in the meantime, my inclination is to play it safe and avoid soy.
Previous Soy Reports & Information
IS THERE REASON TO BELIEVE TOFU MAY CAUSE BRAIN ATROPHY? (c) 1999 Ian Williams Goddard The recent study suggesting a link between tofu and brain atrophy  calls to attention animal research showing that the soy-phytochemical genistein reduces DNA synthesis in the brain and inhibits the proliferation of brain cells.  That research tends to support the tofu study, for, since cell replication requires DNA synthesis, genistein-induced synthesis reduction leading to fewer new cells could manifest as atrophy. The only counter I've seen is that cell-proliferation physiology does not apply to adult brain cells, since they don't replicate. That claim, however, has been invalidated, for it has been shown that neurogenesis--the replication of new brain cells--appears to occur in the brain throughout life. As Dr. David Amaral told The Washington Post (11/21/99): "A decade ago, we still had the notion that you acquired all the neurons you would ever have by the sixth month of pregnancy... It turns out that nothing could be further from the truth." The Washington Post continued: "Last month, biologists at Princeton University demonstrated that monkey brains constantly produce thousands of new neurons which travel to the cerebral cortex, the center of higher intellectual functions. Earlier studies had documented other examples of neurogensis... The same process occurs in humans. ...researchers at the Salk Institute for Biological Studies in La Jolla, Calif., found evidence of recent cell division in a part of the brain called the hippocampus in every person studied."  Research in animals shows neurogenesis occurs in several areas of the adult brain.  Research also shows that reduced DNA synthesis decreases the number of new brain cells produced.  Based on the available data, I would dare to posit that IF in fact genistein inhibits DNA synthesis in the adult human brain as it has been shown to in developing rat brains  (and based on human/animal/soy studies, I see no reason to believe the rat/soy-to-human/soy extrapolation is unfounded), it stands to reason that soy products would reduce neurogensis and/or initiate apoptosis (programmed cell death) in the human brain, which could manifest itself as brain atrophy. In short, there's reason to believe the tofu study  may be accurate. Of course I hope the tofu study is not true, and that soy products ARE the healthy panacea I've always assumed! I've been a vegetarian since I was 13-years old because I believe we need to advance beyond the systematic mass murder sentient beings simply for pleasurable taste sensations. With my refrigerator full of soy stuff, I wish I could be sure now, but until the soy picture gets clearer, the evidence is enough for me to be inclined to err on the side of caution. However, it should be noted that the research indicating an anticancer potential for soy is consistent, and research shows that the cytotoxic properties of soy products are strongly specific, but apparently not entirely exclusive, to cancer cells. If I had terminal cancer, I would consider using soy products! ____________________________________________________________  Honolulu Star-Bulletin: Too much tofu induces ‘brain aging,’ study shows. By Helen Altonn, November 19, 1999  Experimental Neurology, 1999 Sep;159(1):164-76. Early effects of protein kinase modulators on DNA synthesis in rat cerebral cortex.  Brain Research, 1998 Jan 19;781(1-2):159-66. Transmural compression-induced proliferation and DNA synthesis through activation of a tyrosine kinase pathway in rat astrocytoma RCR-1 cells.  About glial cells: NeuroNews: Modulation of neuronal activity by glial cells. June 15, 1998  The Washington Post: The Brain's Power to Heal. D. Hales and R. Hales, Parade section, 11/21/99, page 10.  Science, 1999 Oct 15;286(5439):548-52. Neurogenesis in the neocortex of adult primates.  Proceedings of the National Academy of Science, 1999 Sep 28;96(20):11619-24. Regeneration of a germinal layer in the adult mammalian brain.  Journal of Comparative Neurology, 1999 Aug 30;411(3):495-502. Neurogenesis in the adult rat dentate gyrus is enhanced by vitamin E deficiency.  Brain Research. Developmental Brain Research, 1998 Jun 15;108(1-2):39-45. Developmental neurotoxicity of chlorpyrifos: delayed targeting of DNA synthesis after repeated administration. ------------------------------------------------------------ GODDARD'S JOURNAL: http://www.erols.com/igoddard/journal.htm ____________________________________________________________ Alternative theory about the tofu study. My Rebuttal ============================================================ Follow-up soy posts ============================================================ Date: Thu, 09 Dec 1999 02:33:39 -0500 From: Ian Goddard Subject: Tofu Study Update The following contains much information about the "tofu study" reported: http://starbulletin.com/1999/11/19/news/story4.html http://the.honoluluadvertiser.com/1999/Nov/20/localnews3.html I contacted Lon White, lead researcher in the tofu study to ask some questions. I asked him about the statistical significance of the findings in the study. He informed me that there were four major endpoints in the study: 1. cognitive impairment of men (number of men=3734) 2. cognitive impairment of sample of wives (n=502) 3. brain atrophy by weight of men who died (n=290) 4. brain atrophy by volume measured via MRI (n=574) The probability (p) value was less than .05 (significant) for a correlation between each endpoint and tofu intake (there was no significant correlation for other foods). In some cases the p value is less than .001 (if the p value is more than .05, it's not significant, if it's .05 or less, it's significant). Here's what this means: IF p = .05 there's 95% chance the correlation is true IF p = .01 there's 99% chance the correlation is true IF p = .001 there's 99.9% chance the correlation is true So the correlation between the four endpoints listed above and tofu consumption had an over 95% probably of being true, with a probability of truth as high as 99.9%. Of course this cannot be read as proof that tofu causes those problems, but at the least it signals the need for further investigation. What is perhaps most significant is that Dr White informed me that there is a dose-dependent relationship between tofu consumption and the endpoints, ie, the more tofu was eaten, the more impairment and/or atrophy is found. The odds that such findings would be chance are extremely low! ============================================================= Here are two papers Dr. White, et al., have had published: White, L., Petrovitch, H., Ross, G.W., & Masaki K.H. (1996) Association of mid-life consumption of tofu with late life cognitive impairment and dementia: The Honolulu-Asia Aging Study. The Neurobiology of Aging, 17 (suppl 4), S121. White, L., Petrovich, H., Ross, G. W., Masaki, K. H., Abbot RD, et al. (1996) Prevalence of dementia in older Japanese-American men in Hawaii. JAMA, 276, 955-960. ============================================================= More: http://www.soyonlineservice.co.nz/References/Brain.htm ============================================================= Here's a brief review of those two papers found in a letter to the FDA from Daniel Sheehan, PhD, Director of the Estrogen Base Program Division of Genetic and Reproductive Toxicology, and Daniel Doerge, PhD, Division of Biochemical Toxicology: ============================================================== On 02/18/99, Dr. Sheehan & Dr. Doerge comment on White's work ============================================================== Finally, initial data from a robust (7,000 men) long-term (30+ years) prospective epidemiological study in Hawaii showed that Alzheimer's disease prevalence in Hawaiian men was similar to European-ancestry Americans and to Japanese (White, et al, 1996a). In contrast, vascular dementia prevalence is similar in Hawaii and Japan and both are higher than in European- ancestry Americans. This suggests that common ancestry or environmental factors in Japan and Hawaii are responsible for the higher prevalence of vascular dementia in these locations. Subsequently, this same group showed a significant dose-dependent risk (up to 2.4 fold) for development of vascular dementia and brain atrophy from consumption of tofu, a soy product rich in isoflavones (White, et al, 1996b). This finding is consistent with the environmental causation suggested from the earlier analysis, and provides evidence that soy (tofu) phytoestrogens causes vascular dementia. Given that estrogens are important for maintenance of brain function in women; that the male brain contains aromatase, the enzyme that converts testosterone to estradiol; and that isoflavones inhibit this enzymatic activity (Irvine, 1998), there is a mechanistic basis for the human findings. ================================================================== Full Letter: http://www.soyonlineservice.co.nz/files/nctrpti.doc ================================================================== The following is the abstract to the recent study, which should be published by April. Below that is a memorandum sent out by Doctor White after the newspaper publications: =============================================================== ABSTRACT TO UPCOMING PUBLICATION OF TOFU STUDY =============================================================== Association of high midlife tofu consumption with accelerated brain aging . Lon White, MD, MPH (From the Pacific Health Research Institute, Honolulu, HI.) This investigation utilized the resources of the Honolulu Heart Program, a longitudinal study of Japanese-American men established in 1965 for research on heart disease and stroke. Questions regarding frequency of consumption of tofu and 26 other foods were asked at interviews in 1965-67 and again in 1971-74. Cognitive testing was done (n=3734) and cases of dementia identified (n=225) at the 1991-93 examination, when participants were aged 71-93 years. Atrophy was assessed by neuroimaging (n=574) or autopsy (n=290). Cognitive test data were also analyzed for wives of a sample of study participants (n=502) who had been living with the participants when their dietary interviews were done. Poor cognitive test performance in late life was associated with higher midlife tofu consumption. An independent association of similar magnitude and direction was apparent among wives of cohort members, using the husband's answers as proxy for the wife's consumption. Midlife tofu consumption was independently associated with low brain weight and with ventricular enlargement. Independent associations of more frequent midlife tofu consumption with clinically diagnosed Alzheimer's disease and with poor cognitive functioning among non-demented subjects were demonstrated. Associations generally followed a dose-response pattern, were statistically significant after controlling for all relevant and potentially confounding factors, and remained apparent after stratifying for age or obesity. These data suggest that regular consumption of tofu over many years in middle life may have an adverse influence on brain aging manifest as accelerated atrophy, cognitive decline, and a lowering of the threshold for the clinical manifestations of Alzheimer's disease. We speculate that these may reflect chronic sub-optimal neuronal plasticity caused by isoflavone inhibition of tyrosine kinase activity and/or by interference with estrogen-related mechanisms. ============================================================= MEMORANDUM TO: HHP/HAAS and PHRI Staff FROM: Lon White, M.D., M.P.H., Senior Neuroepidemiologist, HAAS and PHRI DATE: November 30, 1999 RE: Responding to questions about tofu The articles that recently appeared in the Star Bulletin and the Advertiser have caused a great deal of distress locally, and have elicited a number or requests for information. While we cannot give advice and no definitive statements are possible at this time, the following can be said: 1. We observed a consistent pattern of association between answers given by men interviewed in 1965 and in 1971 regarding the number of servings of tofu consumed per week - and their scores on a test of cognitive function when examined 1991-93. Higher frequencies of tofu consumption were associated with poorer test scores. This observation remained strong after controlling for all relevant factors (such as age, education, occupation, etc.) and no other foods or drink showed such an association. 2. Separately, we observed an association of high midlife tofu intake with low brain weight determined at autopsy, again after controlling for all other relevant factors. 3. Separately, we observed an association of high midlife tofu intake with enlarged ventricles identified by MRI. 4. Although we did not find an association of high midlife tofu intake with the brain lesions that characterize Alzheimer's disease in our autopsy study, we did find high midlife tofu intake to be a risk factor for the clinical diagnosis of Alzheimer's disease. Taken together, we interpret these as suggesting that consumption of tofu over many years during middle life is linked to a mild to moderate acceleration in brain aging, perhaps similar to that which might occur in a woman who did not receive hormone replacement therapy after menopause. We cannot be sure that the causal factor was really the tofu, but no other alternative is apparent at this time. We believe that the most reasonable mechanism would be an interference with the normal mechanisms in the brain that maintain the connections between neurons during aging (i.e., brain plasticity mechanisms), caused by the isoflavone phytoestrogens that are known to be present in pharmacologically significant concentrations in most soy foods. Although the findings are very consistent, it is never proper to draw definitive conclusions from a single study. It would be premature to advise anyone that they should change their diets based on a single research study. In addition, there is evidence that consumption of soy foods may have beneficial effects related to improving blood lipid levels, and reducing risks for breast cancer. Unfortunately it is likely that independent confirmation or refutation of our findings will require 1-3 years. In the meantime no definitive statements can be made. Individuals will have to weigh the evidence and make their own decisions concerning their consumption of soy foods and their isoflavone derivatives. LR White ================== End Of Forward Material ==================== =============================================================== IS SOY SAFE?: http://users.erols.com/igoddard/soy.htm =============================================================== MAYBE YES?: http://www.soy.com =============================================================== MAYBE NO?: http://www.soyonlineservice.co.nz =============================================================== --------------------------------------------------------------- GODDARD'S JOURNAL --> http://www.erols.com/igoddard/journal.htm _______________________________________________________________ Date: Sat, 04 Dec 1999 02:50:09 -0500 To: email@example.com From: Ian Goddard Subject: Soy Update A second article in another Hawaiian paper on the tofu study has been located. The papers published follow-ups that sought to allay concerns about tofu, raising points from the need for more research before coming to definitive conclusions (obviously) to harming local tofu businesses. Here are the articles I've found on the tofu study: http://starbulletin.com/1999/11/19/news/story4.html http://starbulletin.com/1999/11/22/news/story4.html http://starbulletin.com/1999/11/24/news/story5.html http://the.honoluluadvertiser.com/1999/Nov/20/localnews3.html http://the.honoluluadvertiser.com/1999/Nov/26/localnews3.html I contacted a researcher in a study I quoted showing that the soy phytochemical genistein killed testicular cells. I asked if those cells were normal or cancerous. He said they were altered, but in other studies he has and/or is working on, genistein is found to kill normal testicular cells, yet increase their proliferation at lower doses. While healthy folks may not need chemicals increasing or decreasing the number of their cells, that evidence suggests that if there's a toxic level, there may also be a safe and possibly beneficial level of soy. With respect to reducing rates of cancer and other major illness, research suggests that soy works. The FDA recently approved the use of a health claim on soy products.[*] PubMed searches find numerous studies (see: http://www.ncbi.nlm.nih.gov/PubMed) over the years that demonstrate an anti-cancer effect of soy phytochemicals, and their cytotoxic effect appears generally to be highly specific to cancer cells. Of course, the possibility of a risk of brain atrophy is not to be taken lightly. Of all organs, the brain is arguably the most valuable and important to preserve. [*] http://soy.com/Soy_Information/News/newfdaclaim/newfdaclaim.html IS SOY SAFE?: http://users.erols.com/igoddard/soy.htm ------------------------------------------------------------ GODDARD'S JOURNAL: http://www.erols.com/igoddard/journal.htm ____________________________________________________________ ============================================================ Initial soy-warning post ============================================================ Date: Sat, 27 Nov 1999 15:32:51 -0500 From: Ian Goddard Subject: SOY WARNING! SOYBEANS LINKED TO BRAIN ATROPHY AND CELL DEATH As a vegetarian, I present the following with great regret. Soy products like tofu have provided the staple alternative to eating murdered animals. Unfortunately the study reported here: http://starbulletin.com/1999/11/19/news/story4.html has found a significant link between eating tofu and brain aging and atrophy! My first reaction was to hope that the study was flawed. Unfortunately, a quick study of published research at the National Library of Medicine indicates that there is a STRONG physiological basis for the findings in that study. It seems that a main phytochemical in soybeans, genistein, reduces DNA synthesis in the brain, and reduced DNA synthesis promotes apoptosis, which is also known as "programmed cell death." Multiple studies I found indicate that drug-induced reduction of DNA synthesis is routinely assoicated with reduced cell proliferation and death. DNA synthesis is a critical part of the life cycle of a cell: http://www.geocities.com/CollegePark/Lab/1580/cycle2.gif http://www.geocities.com/CollegePark/Lab/1580/cycle.html It appears that the ability of genistein to reduce DNA synthesis may be why it is a promising anti-cancer agent, for research suggests genistein can kill cancer cells and other drugs that reduce DNA synthesis kill cancer cells. Unfortunately, genistein's cytotoxic properties appear to be nonspecific, ie, it doesn't only kill cancer cells. In the first abstract below, it was found that genistein "induced significant testicular cell death." Ouch! The second study finds that genistein reduced DNA synthesis in the brain. To get the full picture of what I've stated here, I recommend using the National Library of Medicine's search engine: http://www.ncbi.nlm.nih.gov/PubMed It is easily the most powerful tool on the Internet, accessing most of the published medical research since around 1965. Too much tofu induces ‘brain aging,’ study shows: http://starbulletin.com/1999/11/19/news/story4.html ================================================================= Soy-phytochemical genistein "induced significant testicular cell death." Biol Cell 1999 Sep;91(7):515-23 Cytotoxic potential of the phytochemical genistein isoflavone (4',5',7-trihydroxyisoflavone) and certain environmental chemical compounds on testicular cells. Kumi-Diaka J, Nguyen V, Butler A Florida Atlantic University, Department of Biology, College of Liberal Arts & Sciences, Davie 33314, USA. [Medline record in process] The effects of genistein (Gn), sodium azide (naz), and dexamethasone (dxm) on testicular cells TM3, TM4 and GC-1 spg were studied in vitro. First, a series of experiments were performed to assess the response of the cells to the exposure of Gn, naz, dxm, a combination of Gn with naz and Gn with dxm. Trypan blue exclusion assay was used to determine the percentage of viability, and LDH-cytotoxicity test was used to assess the degree of treatment-induced cytotoxicity on each cell type. A second series of experiments were performed to study cytomorphology and determine the type and percentage of treatment-induced cell death (apoptosis and necrosis) on each cell line, using fluorescent dye technique to detect apoptotic and necrotic cells, and tunnel assay to confirm apoptosis. The results from the data obtained demonstrated: i) that incubation of testis cells with each of the agents (Gn, dxm, naz) alone and in two combinations (Gn-dxm, and Gn-naz) induced significant testicular cell death; ii) that both genistein and dexamethasone mostly and significantly induced apoptotic cell death while sodium azide induced necrotic cell death; iii) that addition of dexamethasone to genistein demonstrated synergism in apoptosis on testis cells; and iv) that combination of naz with Gn demonstrated synergism in necrosis on testis cells even though Gn alone did not induce significant necrosis. It is concluded that the synergistic actions of genistein and dxm, and of genistein + sodium azide in induction of apoptosis and/or necrosis may be of clinical and pathophysiological research interest considering the chemopreventive and chemotherapeutic potential of genistein; and the clinico-pharmacological application of dexamethasone and sodium azide. http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=10572627&form=6&db=m&Dopt=b =============================================================== "Genistein decreased the DNA synthesis within less than 30 min." Exp Neurol 1999 Sep;159(1):164-76 Early effects of protein kinase modulators on DNA synthesis in rat cerebral cortex. Yakisich JS, Siden A, Vargas VI, Eneroth P, Cruz M Applied Biochemistry, Clinical Research Center, Karolinska Institute, Novum, Huddinge University Hospital, Huddinge, S-141 86, Sweden. By using tissue miniunits, protein kinase modulators, and topoisomerase inhibitors in short-term incubation (0-90 min) we studied (1) the role of protein phosphorylation in the immediate control of DNA replication in the developing rat cerebral cortex and (2) the mechanism of action for genistein- mediated DNA synthesis inhibition. Genistein decreased the DNA synthesis within less than 30 min. None of the other protein kinase inhibitors examined (herbimycin A, staurosporine, calphostin-C) or the protein phosphatase inhibitor sodium orthovanadate inhibited DNA synthesis and they did not affect the genistein-mediated inhibition. The selective topoisomerase inhibitors camptothecin and etoposide decreased the DNA synthesis to an extent similar to that of genistein and within less than 30 min. In addition, the effects of these substances on topoisomerase I and II were studied. Etoposide and genistein but not herbimycin A, staurosporine, or calphostin-C strongly inhibited the activity of topoisomerase II. Our results (1) strongly suggest that the net rate of DNA replication during the S phase of the cell cycle is independent of protein phosphorylation and (2) indicate that the early inhibitory effect of genistein on DNA synthesis is mediated by topoisomerase II inhibition rather than protein tyrosine kinase inhibition. Copyright 1999 Academic Press. http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=10486185&form=6&db=m&Dopt=b ============================================================ Reduce DNA synthesis associated with aging Acta Neuropathol (Berl) 1999 Jan;97(1):71-81 Age-related changes of DNA repair and mitochondrial DNA synthesis in the mouse brain. Schmitz C, Axmacher B, Zunker U, Korr H Department of Anatomy and Cell Biology, RWTH University of Aachen, Germany. firstname.lastname@example.org,de Using quantitative autoradiography, both nuclear DNA repair - measured as nuclear unscheduled DNA synthesis (UDS) - and mitochondrial (mt) DNA synthesis were evaluated in situ for several types of cells in the brains of untreated mice of various age. It was found that distinct types of neuronal cells showed a decline of both UDS and mtDNA synthesis with age, whereas - except for glial cells of the cerebral cortex - no glial or endothelial cells showed age-related alterations of UDS. Together with various data reported in the literature, these patterns of a cell type-specific decrease of UDS and mtDNA synthesis with age in the mouse brain lead to an improved understanding of the complex interrelationships between the molecular events associated with the phenomenon of aging as well as to a new idea regarding the cause of the specific distribution pattern of those cells in the human brain that are affected by the formation of paired helical filaments in Alzheimer's disease. http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=9930897&form=6&db=m&Dopt=b ========================================================= To get the full picture of what I stated above, I recommend using the National Library of Medicine's search engine: http://www.ncbi.nlm.nih.gov/PubMed The key words you choose make all the difference!