Life Extension Magazine®

Issue: Mar 2012

Vitamin E

Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer.

BACKGROUND: Selenium and alpha-tocopherol, the major form of vitamin E in supplements, appear to have a protective effect against prostate cancer. However, little attention has been paid to the possible role of gamma-tocopherol, a major component of vitamin E in the US diet and the second most common tocopherol in human serum. A nested case-control study was conducted to examine the associations of alpha-tocopherol, gamma-tocopherol, and selenium with incident prostate cancer. METHODS: In 1989, a total of 10,456 male residents of Washington County, MD, donated blood for a specimen bank. A total of 117 of 145 men who developed prostate cancer and 233 matched control subjects had toenail and plasma samples available for assays of selenium, alpha-tocopherol, and gamma-tocopherol. The association between the micronutrient concentrations and the development of prostate cancer was assessed by conditional logistic regression analysis. All statistical tests were two-sided. RESULTS: The risk of prostate cancer declined, but not linearly, with increasing concentrations of alpha-tocopherol (odds ratio (highest versus lowest fifth) = 0.65; 95% confidence interval = 0.32--1.32; P(trend) =.28). For gamma-tocopherol, men in the highest fifth of the distribution had a fivefold reduction in the risk of developing prostate cancer than men in the lowest fifth (P:(trend) =.002). The association between selenium and prostate cancer risk was in the protective direction with individuals in the top four fifths of the distribution having a reduced risk of prostate cancer compared with individuals in the bottom fifth (P(trend) =.27). Statistically significant protective associations for high levels of selenium and alpha-tocopherol were observed only when gamma-tocopherol concentrations were high. CONCLUSIONS: The use of combined alpha- and gamma- tocopherol supplements should be considered in upcoming prostate cancer prevention trials, given the observed interaction between alpha-tocopherol, gamma-tocopherol, and selenium.

J Natl Cancer Inst. 2000 Dec 20;92(24):2018-23

Gamma-tocopherol induces apoptosis in androgen-responsive LNCaP prostate cancer cells via caspase-dependent and independent mechanisms.

We found that gamma-tocopherol, the predominant vitamin E form in diets, but not alpha-tocopherol, which is the exclusive form of vitamin E in most supplements, exhibited antiproliferation effect on prostate (PC-3, LNCaP) and lung (A549) cancer cells. gamma-Tocopherol induced apoptosis in androgen-sensitive LNCaP but not androgen-resistant PC-3 cells. Consequently, gamma-tocopherol treatment caused cytochrome c release and caspase-9, -3 and -7 activation. However, the apoptosis could not be completely reversed by an irreversible pancaspase inhibitor, indicating that an alternative caspase-independent pathway may also be involved. Our study suggests that gamma-tocopherol may be valuable in the prevention and therapy for certain types of cancer.

Ann N Y Acad Sci. 2004 Dec;1031:399-400

Gamma-tocopherol-enriched mixed tocopherol diet inhibits prostate carcinogenesis in TRAMP mice.

Gamma-tocopherol (gamma-T) alone or in combination with alpha-tocopherol has been shown to suppress biomarkers of oxidative stress in asthamatics and human subjects with metabolic syndrome. Oxidative stress has been implicated as a key event in prostate carcinogenesis. Hence, the purpose of this study was to examine the effects of gamma-tocopherol-enriched mixed tocopherol diet on prostate carcinogenesis in a murine prostate cancer model (TRAMP). 8 week old TRAMP males were fed 0.1% gamma-T-enriched mixed tocopherol diet that contained 20-fold higher levels of gamma-tocopherol, and roughly 3-fold higher levels of alpha-tocopherol. The effect of such diet on tumor and PIN development was observed. The expression of phase II detoxifying, antioxidant enzymes and Nrf2 mRNA and protein were determined by RT-PCR, immunohistochemistry and western blotting techniques. Treatment with gamma-T-enriched mixed tocopherols significantly suppressed the incidence of palpable tumor and Prostate Intraepithelial Neoplasia (PIN) development without affecting the expression of the transgene (SV-40). Tumor progression occurred with a significant suppression of antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase, heme-oxygenase-1 and phase II detoxifying enzymes. Treatment with gamma-T-enriched mixed tocopherol diet upregulated the expression of most detoxifying and antioxidant enzymes. Nrf2-a redox sensitive transcription factor known to mediate the expression of phase II detoxifying enzymes, was also significantly upregulated following treatment with gamma-T-enriched mixed tocopherol diet. Gamma-T-enriched mixed tocopherols significantly up-regulated the expression of Nrf2 and its related detoxifying and antioxidant enzymes thereby suppressing PIN and tumor development.

Int J Cancer. 2009 Apr 1;124(7):1693-9

RRR-gamma-tocopherol induces human breast cancer cells to undergo apoptosis via death receptor 5 (DR5)-mediated apoptotic signaling.

Goal of this study was to investigate the pro-apoptotic properties of RRR-gamma-tocopherol (gammaT) in human breast cancer cells. gammaT was shown to induce cancer cells but not normal cells to undergo apoptosis, sensitize cancer cells to Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL)-induced apoptosis, and increase death receptor 5 (DR5) mRNA, protein and cell surface expression. Knockdown of DR5 attenuated gammaT-induced apoptosis. Investigations of post-receptor signaling showed: caspase-8, Bid and Bax activation, increases in mitochondria permeability, cytochrome c release and caspase-9 activation. Thus, gammaT is a potent pro-apoptotic agent for human breast cancer cells inducing apoptosis via activation of DR5-mediated apoptotic pathway.

Cancer Lett. 2008 Feb 8;259(2):165-76

Gamma-tocopherol detoxification of nitrogen dioxide: superiority to alpha-tocopherol.

In the vitamin E group, alpha-tocopherol is generally considered to be the most potent antioxidant with the highest vitamin bioactivity, yet gamma-tocopherol is produced in greater amounts by many plants and is the principal tocopherol in the United States diet. This report describes a fundamental difference in the chemical reactivities of alpha-tocopherol and gamma-tocopherol with nitrogen dioxide (NO2), which leads to the formation of a nitrosating agent from alpha-tocopherol, but not from gamma-tocopherol. Nitric oxide (NO) is a major product of the reaction of gamma-tocopherol with NO2, while alpha-tocopherol reacts with NO2 to form an intermediate tocopheroxide analogue. The biological significance of gamma-tocopherol is suggested by limited epidemiological data as well as the observation that it is a more potent inhibitor than alpha-tocopherol of neoplastic transformation during the postinitiation phase in 3-methylcholanthrene-treated C3H/10T1/2 murine fibroblasts. This latter property suggests the superiority of gamma-tocopherol in a mammalian biological assay and a role for endogenous NO production in promotion of neoplastic transformation.

Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1771-5

gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications.

Peroxynitrite, a powerful mutagenic oxidant and nitrating species, is formed by the near diffusion-limited reaction of .NO and O2.- during activation of phagocytes. Chronic inflammation induced by phagocytes is a major contributor to cancer and other degenerative diseases. We examined how gamma-tocopherol (gammaT), the principal form of vitamin E in the United States diet, and alpha-tocopherol (alphaT), the major form in supplements, protect against peroxynitrite-induced lipid oxidation. Lipid hydroperoxide formation in liposomes (but not isolated low-density lipoprotein) exposed to peroxynitrite or the .NO and O2.- generator SIN-1 (3-morpholinosydnonimine) was inhibited more effectively by gammaT than alphaT. More importantly, nitration of gammaT at the nucleophilic 5-position, which proceeded in both liposomes and human low density lipoprotein at yields of approximately 50% and approximately 75%, respectively, was not affected by the presence of alphaT. These results suggest that despite alphaT’s action as an antioxidant gammaT is required to effectively remove the peroxynitrite-derived nitrating species. We postulate that gammaT acts in vivo as a trap for membrane-soluble electrophilic nitrogen oxides and other electrophilic mutagens, forming stable carbon-centered adducts through the nucleophilic 5-position, which is blocked in alphaT. Because large doses of dietary alphaT displace gammaT in plasma and other tissues, the current wisdom of vitamin E supplementation with primarily alphaT should be reconsidered.

Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3217-22

Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

CONTEXT: The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer. OBJECTIVE: To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men. DESIGN, SETTING, AND PARTICIPANTS: A total of 35,533 men from 427 study sites in the United States, Canada, and Puerto Rico were randomized between August 22, 2001, and June 24, 2004. Eligibility criteria included a prostate-specific antigen (PSA) of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older for black men and 55 years or older for all others. The primary analysis included 34,887 men who were randomly assigned to 1 of 4 treatment groups: 8,752 to receive selenium; 8,737, vitamin E; 8,702, both agents, and 8,696, placebo. Analysis reflect the final data collected by the study sites on their participants through July 5, 2011. INTERVENTIONS: Oral selenium (200 µg/d from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-a-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years. MAIN OUTCOME MEASURES: Prostate cancer incidence. RESULTS: This report includes 54,464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary report. Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR], 1.17; 99% CI, 1.004-1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P = .18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination. CONCLUSION: Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men.

JAMA. 2011 Oct 12;306(14):1549-56

Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

CONTEXT: Secondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer. OBJECTIVE: To determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer. INTERVENTIONS: Oral selenium (200 microg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years. MAIN OUTCOME MEASURES: Prostate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer. RESULTS: As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group. CONCLUSION: Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men.

JAMA. 2009 Jan 7;301(1):39-51

Gamma tocopherol upregulates the expression of 15-S-HETE and induces growth arrest through a PPAR gamma-dependent mechanism in PC-3 human prostate cancer cells.

Chronic inflammation and dietary fat consumption correlates with an increase in prostate cancer. Our previous studies in the colon have demonstrated that gamma-tocopherol treatment could upregulate the expression of peroxisome proliferator-activated preceptors (PPAR) gamma, a nuclear receptor involved in fatty acid metabolism as well modulation of cell proliferation and differentiation. In this study, we explored the possibility that gamma-tocopherol could induce growth arrest in PC-3 prostate cancer cells through the regulation of fatty acid metabolism. Growth arrest (40%) and PPAR gamma mRNA and protein upregulation was achieved with gamma-tocopherol within 6 h. gamma-Tocopherol-mediated growth arrest was demonstrated to be PPAR gamma dependent using the agonist GW9662 and a PPAR gamma dominant negative vector. gamma-tocopherol was shown not to be a direct PPAR gamma ligand, but rather 15-S-HETE (an endogenous PPAR gamma ligand) was upregulated by gamma-tocopherol treatment. 15-Lipoxygenase-2, a tumor suppressor and the enzyme that converts arachidonic acid to 15-S-HETE, was upregulated at 3 h following gamma-tocopherol treatment. Expression of proteins downstream of the PPAR gamma pathway were examined. Cyclin D1, cyclin D3, bcl-2, and NFkappa B proteins were found to be downregulated following gamma-tocopherol treatment. These data demonstrate that the growth arrest mediated by gamma-tocopherol follows a PPAR-gamma-dependent mechanism.

Nutr Cancer. 2009;61(5):649-62

Gamma-tocopherol supplementation alone and in combination with alpha-tocopherol alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome.

Metabolic syndrome (MetS) is associated with increased incidence of diabetes and cardiovascular disease (CVD). Prospective clinical trials with alpha-tocopherol (AT) have not yielded positive results. Because AT supplementation decreases circulating gamma-tocopherol (GT), we evaluated supplementation with GT (800 mg/day), AT (800 mg/day), the combination or placebo for 6 weeks alone AT and GT concentrations, biomarkers of oxidative stress, and inflammation in subjects with MetS (n=20/group). Plasma AT and GT levels increased following supplementation with AT alone or GT alone or in combination. AT supplementation significantly decreased GT levels. Urinary alpha- and gamma-CEHC, metabolites of the respective Ts, also increased correspondingly, i.e., alpha-CEHC with AT and gamma-CEHC with GT supplementation, compared to placebo. HsCRP levels significantly decreased in the combined AT+GT group. LPS-activated whole blood release of IL-1 and IL-6 did not change. There was a significant decrease in TNF with AT alone or in combination with GT. Plasma MDA/HNE and lipid peroxides were significantly decreased with AT, GT, or in combination. Nitrotyrosine levels were significantly decreased only with GT or GT+AT but not with AT compared to placebo. Thus, the combination of AT and GT supplementation appears to be superior to either supplementation alone on biomarkers of oxidative stress and inflammation and needs to be tested in prospective clinical trials to elucidate its utility in CVD prevention.

Free Radic Biol Med. 2008 Mar 15;44(6):1203-8

Effects of high-dose vitamin E supplementation on oxidative stress and microalbuminuria in young adult patients with childhood onset type 1 diabetes mellitus.

INTRODUCTION: The aim of this study was to evaluate the effects of high-dose vitamin E supplementation (1,200 mg/day) on reducing both microalbuminuria (MA) and oxidative stress in patients with type 1 diabetes mellitus (T1DM) and persistent MA. METHODS: We performed a 12-month, randomized, placebo-controlled, double-blind cross-over trial in ten Caucasian young adults (7m/3f; mean age 18.87 +/- 2.91 years) with T1DM and persistent MA. At baseline and at end of the treatment period, determination of albumin excretion rate (AER) and HbA(1c) and evaluation of the oxidant/antioxidant status were performed. RESULTS: At the beginning of the study, AER and HbA(1c) were not significantly different between the vitamin E and placebo group. No differences in terms of oxidant and antioxidant status were found between the two groups. This was associated with no significantly different urinary VEGF and TGF-beta levels. After 6 months, no significant differences in AER were observed between the two groups (p = 0.59). However, plasma and LDL-vitamin E content were significantly higher in the vitamin E group compared to the placebo group (p = 0.0001 and p = 0.004, respectively). This was associated with a significantly longer lag phase (p = 0.002) and lower MDA (p = 0.049). However, no statistically significant differences were detected in terms of VEGF and TGF-beta urinary levels. CONCLUSION: These data demonstrate that high-dose vitamin E supplementation reduces markers of oxidative stress and improves antioxidant defence in young patients with T1DM. However, although it positively affects the oxidant/antioxidant status, vitamin E supplementation does not reduce AER in patients with T1DM and persistent MA.

Diabetes Metab Res Rev. 2007 Oct;23(7):539-46

g-Tocopherol abolishes postprandial increases in plasma methylglyoxal following an oral dose of glucose in healthy, college-aged men.

Postprandial hyperglycemia contributes to the risk of cardiovascular disease in part by increasing concentrations of the reactive dicarbonyl methylglyoxal (MGO), a byproduct of glucose metabolism. Oxidative stress increases MGO formation from glucose in vitro and decreases its glutathione-dependent detoxification to lactate. We hypothesized that the antioxidant g-tocopherol, a form of vitamin E, would decrease hyperglycemia-mediated postprandial increases in plasma MGO in healthy, normoglycemic, college-aged men. Participants (n=12 men; 22.3±1.0 years; 29.3±2.4 kg/m(2)) received an oral dose of glucose (75 g) in the fasted state prior to and following 5-day ingestion of a vitamin E supplement enriched in g-tocopherol (500 mg/day). g-Tocopherol supplementation increased (P<.0001) plasma g-tocopherol from 2.22±0.32 to 7.06±0.71 µmol/l. Baseline MGO concentrations and postprandial hyperglycemic responses were unaffected by g-tocopherol supplementation (P>.05). Postprandial MGO concentrations increased in the absence of supplemental g-tocopherol (P<.05), but not following g-tocopherol supplementation (P>.05). Area under the curve for plasma MGO was significantly (P<.05) smaller with the supplementation of g-tocopherol than without (area under the curve (0-180 min), -778±1010 vs. 2277±705). Plasma concentrations of g-carboxyethyl-hydroxychroman, reduced glutathione and markers of total antioxidant capacity increased after supplementation, and these markers and plasma g-tocopherol were inversely correlated with plasma MGO (r=-0.48 to -0.67, P<.05). These data suggest that short-term supplementation of g-tocopherol abolishes the oral glucose-mediated increases in postprandial MGO through its direct and indirect antioxidant properties and may reduce hyperglycemia-mediated cardiovascular disease risk.

J Nutr Biochem. 2011 May 2

Anti-inflammatory properties of alpha- and gamma-tocopherol.

Natural vitamin E consists of four different tocopherol and four different tocotrienol homologues (alpha,beta, gamma, delta) that all have antioxidant activity. However, recent data indicate that the different vitamin E homologues also have biological activity unrelated to their antioxidant activity. In this review, we discuss the anti-inflammatory properties of the two major forms of vitamin E, alpha-tocopherol (alphaT) and gamma-tocopherol (gammaT), and discuss the potential molecular mechanisms involved in these effects. While both tocopherols exhibit anti-inflammatory activity in vitro and in vivo, supplementation with mixed (gammaT-enriched) tocopherols seems to be more potent than supplementation with alphaT alone. This may explain the mostly negative outcomes of the recent large-scale interventional chronic disease prevention trials with alphaT only and thus warrants further investigation.

Mol Aspects Med. 2007 Oct-Dec;28(5-6):668-91

Effects of gamma-tocopherol supplementation on thrombotic risk factors.

OBJECTIVE: The antioxidant activity of vitamin E is derived primarily from alpha-tocopherol (alpha-T) and gamma-tocopherol (gamma-T). Results of epidemiological studies have demonstrated an inverse relationship between vitamin E intake and coronary disease. However, the results of clinical trials using alpha-T are equivocal. We determined the effect of 5 weeks of 100 mg/d or 200 mg/d gamma-T supplementation on thrombotic markers such as platelet reactivity, lipid profile and the inflammation marker C-reactive protein (CRP). METHODS AND RESULTS: Fourteen healthy subjects consumed 100 mg/day while 13 consumed 200 mg/d of gamma-T and 12 received placebo (soybean capsules with less than 5 mg/d gamma-T) in a double-blinded parallel study design. Fasting pre and post dose blood samples were analysed. Blood gamma-T concentrations increased significantly (p<0.05) relative to dose during the intervention period. Both groups receiving active ingredients showed significantly lower platelet activation after supplementation (p<0.05). Subjects consuming 100 mg/d gamma-T had significantly decreased LDL cholesterol, platelet aggregation and mean platelet volume (MPV) (p<0.05). Little effect of gamma-T was observed on other parameters. CONCLUSIONS: These data suggest that gamma-T supplementation may have a permissive role in decreasing the risk of thrombotic events by improving lipid profile and reducing platelet activity.

Asia Pac J Clin Nutr. 2007;16(3):422-8

Gamma-tocopherol prevents airway eosinophilia and mucous cell hyperplasia in experimentally induced allergic rhinitis and asthma.

BACKGROUND: Traditional therapies for asthma and allergic rhinitis (AR) such as corticosteroids and antihistamines are not without limitations and side effects. The use of complementary and alternative approaches to treat allergic airways disease, including the use of herbal and dietary supplements, is increasing but their efficacy and safety are relatively understudied. Previously, we have demonstrated that gamma-tocopherol (gammaT), the primary form of dietary vitamin E, is more effective than alpha-tocopherol, the primary form found in supplements and tissue, in reducing systemic inflammation induced by non-immunogenic stimuli. OBJECTIVE: We used allergic Brown Norway rats to test the hypothesis that a dietary supplement with gammaT would protect from adverse nasal and pulmonary responses to airway allergen provocation. METHODS: Ovalbumin (OVA)-sensitized Brown Norway rats were treated orally with gammaT before intranasal provocation with OVA. Twenty-four hours after two challenges, histopathological changes in the nose, sinus and pulmonary airways were compared with gene expression and cytokine production in bronchoalveolar lavage fluid and plasma. RESULTS: We found that acute dosing for 4 days with gammaT was sufficient to provide broad protection from inflammatory cell recruitment and epithelial cell alterations induced by allergen challenge. Eosinophil infiltration into airspaces and tissues of the lung, nose, sinus and nasolacrimal duct was blocked in allergic rats treated with gammaT. Pulmonary production of soluble mediators PGE(2), LTB(4) and cysteinyl leukotrienes, and nasal expression of IL-4, -5, -13 and IFN-gamma were also inhibited by gammaT. Mucous cell metaplasia, the increase in the number of goblet cells and amounts of intraepithelial mucus storage, was induced by allergen in both pulmonary and nasal airways and decreased by treatment with gammaT. CONCLUSIONS: Acute treatment with gammaT inhibits important inflammatory pathways that underlie the pathogenesis of both AR and asthma. Supplementation with gammaT may be a novel complementary therapy for allergic airways disease.

Clin Exp Allergy. 2008 Mar;38(3):501-11

Blood pressure in early adulthood, hypertension in middle age, and future cardiovascular disease mortality: HAHS (Harvard Alumni Health Study).

OBJECTIVES: We sought to examine the association of early adulthood blood pressure with cardiovascular disease (CVD) mortality, while accounting for middle-age hypertension. BACKGROUND: Elevated blood pressure in middle age is an established CVD risk factor, but evidence for association with measurements earlier in life is sparse. METHODS: The HAHS (Harvard Alumni Health Study) is a cohort study of 18,881 male university students who had their blood pressure measured at university entry (1,914 to 1,952; mean age 18.3 years) and who responded to a questionnaire mailed in either 1962 or 1966 (mean age 45.8 years) in which physician-diagnosed hypertension status was reported. Study members were subsequently followed for mortality until the end of 1998. RESULTS: Following adjustment for age, body mass index, smoking, and physical activity at college entry, compared with men who were normotensive according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure criteria (<120/<80 mm Hg), there was an elevated risk of coronary heart disease (CHD) mortality (1,917 deaths) in those who were pre-hypertensive (120 to 139/80 to 89 mm Hg) (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.07 to 1.36), stage 1 (140 to 159/90 to 99 mm Hg) (HR: 1.46; 95% CI: 1.25 to 1.70), and stage 2 hypertensive (≥160/≥100 mm Hg) (HR: 1.89; 95% CI: 1.46 to 2.45), incremental across categories (p(trend) < 0.001). After additionally accounting for middle-age hypertension, estimates were somewhat attenuated, but the pattern remained. Similar associations were apparent for total and CVD mortality, but not stroke mortality. CONCLUSIONS: Higher blood pressure in early adulthood was associated with elevated risk of all-cause mortality, CVD, and CHD, but not stroke, several decades later. Effects largely persisted after taking into account mediation by middle-age hypertension. Thus, the long-term benefits of blood pressure lowering in early adulthood are promising, but supporting trial data are required.

J Am Coll Cardiol. 2011 Nov 29;58(23):2396-403

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.

“The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure” provides a new guideline for hypertension prevention and management. The following are the key messages(1) In persons older than 50 years, systolic blood pressure (BP) of more than 140 mm Hg is a much more important cardiovascular disease (CVD) risk factor than diastolic BP; (2) The risk of CVD, beginning at 115/75 mm Hg, doubles with each increment of 20/10 mm Hg; individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hypertension; (3) Individuals with a systolic BP of 120 to 139 mm Hg or a diastolic BP of 80 to 89 mm Hg should be considered as prehypertensive and require health-promoting lifestyle modifications to prevent CVD; (4) Thiazide-type diuretics should be used in drug treatment for most patients with uncomplicated hypertension, either alone or combined with drugs from other classes. Certain high-risk conditions are compelling indications for the initial use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers); (5) Most patients with hypertension will require 2 or more antihypertensive medications to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease); (6) If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy with 2 agents, 1 of which usually should be a thiazide-type diuretic; and (7) The most effective therapy prescribed by the most careful clinician will control hypertension only if patients are motivated. Motivation improves when patients have positive experiences with and trust in the clinician. Empathy builds trust and is a potent motivator. Finally, in presenting these guidelines, the committee recognizes that the responsible physician’s judgment remains paramount.

JAMA. 2003 May 21;289(19):2560-72

Olive (Olea europaea) leaf extract effective in patients with stage-1 hypertension: comparison with Captopril.

A double-blind, randomized, parallel and active-controlled clinical study was conducted to evaluate the anti-hypertensive effect as well as the tolerability of Olive leaf extract in comparison with Captopril in patients with stage-1 hypertension. Additionally, this study also investigated the hypolipidemic effects of Olive leaf extract in such patients. It consisted of a run-in period of 4 weeks continued subsequently by an 8-week treatment period. Olive (Olea europaea L.) leaf extract (EFLA® 943) was given orally at the dose of 500 mg twice daily in a flat-dose manner throughout the 8 weeks. Captopril was given at the dosage regimen of 12.5 mg twice daily at start. After 2 weeks, if necessary, the dose of Captopril would be titrated to 25 mg twice daily, based on subject’s response to treatment. The primary efficacy endpoint was reduction in systolic blood pressure (SBP) from baseline to week-8 of treatment. The secondary efficacy endpoints were SBP as well as diastolic blood pressure (DBP) changes at every time-point evaluation and lipid profile improvement. Evaluation of BP was performed every week for 8 weeks of treatment; while of lipid profile at a 4-week interval. Mean SBP at baseline was 149.3±5.58 mmHg in Olive group and 148.4±5.56 mmHg in Captopril group; and mean DBPs were 93.9±4.51 and 93.8±4.88 mmHg, respectively. After 8 weeks of treatment, both groups experienced a significant reduction of SBP as well as DBP from baseline; while such reductions were not significantly different between groups. Means of SBP reduction from baseline to the end of study were -11.5±8.5 and -13.7±7.6 mmHg in Olive and Captopril groups, respectively; and those of DBP were -4.8±5.5 and -6.4±5.2 mmHg, respectively. A significant reduction of triglyceride level was observed in Olive group, but not in Captopril group. In conclusion, Olive (Olea europaea) leaf extract, at the dosage regimen of 500 mg twice daily, was similarly effective in lowering systolic and diastolic blood pressures in subjects with stage-1 hypertension as Captopril, given at its effective dose of 12.5-25 mg twice daily.

Phytomedicine. 2011 Feb 15;18(4):251-8

Food supplementation with an olive (Olea europaea L.) leaf extract reduces blood pressure in borderline hypertensive monozygotic twins.

Hypertension is a harmful disease factor that develops unnoticed over time. The treatment of hypertension is aimed at an early diagnosis followed by adequate lifestyle changes rather than pharmacological treatment. The olive leaf extract EFLA943, having antihypertensive actions in rats, was tested as a food supplement in an open study including 40 borderline hypertensive monozygotic twins. Twins of each pair were assigned to different groups receiving 500 or 1,000 mg/day EFLA943 for 8 weeks, or advice on a favourable lifestyle. Body weight, heart rate, blood pressure, glucose and lipids were measured fortnightly. Blood pressure changed significantly within pairs, depending on the dose, with mean systolic differences of < or =6 mmHg (500 mg vs control) and < or =13 mmHg (1,000 vs 500 mg), and diastolic differences of < or =5 mmHg. After 8 weeks, mean blood pressure remained unchanged from baseline in controls (systolic/diastolic: 133 +/- 5/77 +/- 6 vs 135 +/- 11/80 +/- 7 mmHg) and the low-dose group (136 +/- 7/77 +/- 7 vs 133 +/- 10/76 +/- 7), but had significantly decreased for the high dose group (137 +/- 10/80 +/- 10 vs 126 +/- 9/76 +/- 6). Cholesterol levels decreased for all treatments with significant dose-dependent within-pair differences for LDL-cholesterol. None of the other parameters showed significant changes or consistent trends. Concluding, the study confirmed the antihypertensive and cholesterol-lowering action of EFLA943 in humans.

Phytother Res. 2008 Sep;22(9):1239-42

Olea europaea leaf extract exerts L-type Ca(2+) channel antagonistic effects.

ETHNOPHARMACOLOGICAL RELEVANCE: In Southern Europe Olea europaea leafs are known as a folk remedy for hypertension. Cardiovascular diseases are still the leading causes of morbidity and mortality in industrialized countries with hypertension being one of the main risk factors. AIM OF THE STUDY: We investigated effects of a commercial Olea europaea leaf extract (OLE) on isolated hearts and cultured cardiomyocytes. MATERIALS AND METHODS: Isolated rabbit hearts were perfused according to the Langendorff technique and connected to a 256-channel epicardial mapping system. Voltage clamp experiments were performed in cultured neonatal rat cardiomyocytes using a perforated-patch technique. RESULTS: OLE caused a concentration-depended decrease in systolic left ventricular pressure and heart rate as well as an increase in relative coronary flow and a slight, but not significant prolongation of PQ-time. There were no significant changes between the groups in the activation-recovery interval and its dispersion, total activation time, peak-to-peak amplitude, percentage of identical breakthrough-points and similar vectors of local activation. Voltage clamp experiments in cultured neonatal rat cardiomyocytes showed a significant decrease in maximum I(Ca,L) by OLE which was reversible upon wash-out. CONCLUSIONS: OLE suppresses the L-type calcium channel directly and reversibly. Our findings might help to understand the traditional use of OLE in the treatment of cardiovascular disease.

J Ethnopharmacol. 2008 Nov 20;120(2):233-40

Blood pressure lowering effect of olive is mediated through calcium channel blockade.

Olive (Olea europea) is used in traditional medicine as a remedy for hypertension. The aqueous-methanolic crude extract of O. europea fruit (OeF.Cr) was studied in anaesthetized rats and its possible mechanism was elucidated using isolated cardiovascular preparations. Intravenous administration of OeF.Cr produced a dose-dependent (30-100 mg/kg) fall in arterial blood pressure in normotensive anaesthetized rats. This effect remained unaltered in atropinized animals. In the in vitro studies OeF.Cr (0.1-3.0 mg/ml) inhibited spontaneously beating guinea-pig atria. Moreover, it relaxed K+ and/or phenylephrine-induced contractions of rabbit aortic preparations over a dose range of 0.1-3.0 mg/ml, suggesting calcium channel blockade (CCB). The CCB effect was confirmed when pretreatment of the vascular preparations with OeF.Cr produced a dose-dependent rightward shift of the Ca2+ dose-response curves, similar to verapamil. These results suggest that the blood pressure lowering effect of olive is mediated through CCB, justifying its use in hypertension.

Int J Food Sci Nutr. 2005 Dec;56(8):613-20

Oleuropein, the bitter principle of olives, enhances nitric oxide production by mouse macrophages.

The Mediterranean diet, rich in fresh fruits and vegetables, has been associated with a lower incidence of cardiovascular disease and cancer, partly because of its high proportion of bioactive compounds such as vitamins, flavonoids and polyphenols. The major lipid component of such diet is the drupe-derived olive oil, that can be distinguished from other seed oils for the peculiar composition of its non-triglyceride fraction. In fact, several minor components, including polyphenols, grant the oil its particular taste and aroma. Oleuropein, the most abundant among these components, has been shown to be a potent antioxidant endowed with antiinflammatory properties. We investigated the effects of oleuropein on NO release in cell culture and its activity toward nitric oxide synthase (iNOS) expression. The results show that oleuropein dose-dependently enhance nitrite production in LPS-challenged mouse macrophages. This effect was blocked by the iNOS inhibitor L-NAME, indicating increased iNOS activity. Also, Western blot analysis of cell homogenates show that oleuropein increases iNOS expression in such cells. Taken together, our data suggest that, during endotoxin challenge, oleuropein potentiates the macrophage-mediated response, resulting in higher NO production, currently believed to be beneficial for cellular and organismal protection.

Life Sci. 1998;62(6):541-6

Iron-induced oxidant stress leads to irreversible mitochondrial dysfunctions and fibrosis in the liver of chronic iron-dosed gerbils. The effect of silybin.

Hepatic iron toxicity because of iron overload seems to be mediated by lipid peroxidation of biological membranes and the associated organelle dysfunctions. However, the basic mechanisms underlying this process in vivo are still little understood. Gerbils were dosed with weekly injections of iron-dextran alone or in combination with sylibin, a well-known antioxidant, by gavage for 8 weeks. A strict correlation was found between lipid peroxidation and the level of desferrioxamine chelatable iron pool. A consequent derangement in the mitochondrial energy-transducing capability, resulting from a reduction in the respiratory chain enzyme activities, occurred. These irreversible oxidative anomalies brought about a dramatic drop in tissue ATP level. The mitochondrial oxidative derangement was associated with the development of fibrosis in the hepatic tissue. Silybin administration significantly reduced both functional anomalies and the fibrotic process by chelating desferrioxamine chelatable iron.

J Bioenerg Biomembr. 2000 Apr;32(2):175-82

Iron accumulation during cellular senescence in human fibroblasts in vitro.

Iron accumulates as a function of age in several tissues in vivo and is associated with the pathology of numerous age-related diseases. The molecular basis of this change may be due to a loss of iron homeostasis at the cellular level. Therefore, changes in iron content in primary human fibroblast cells (IMR-90) were studied in vitro as a model of cellular senescence. Total iron content increased exponentially during cellular senescence, resulting in 10-fold higher levels of iron compared with young cells. Low-dose hydrogen peroxide (H2O2) induced early senescence in IMR-90s and concomitantly accelerated iron accumulation. Furthermore, senescence-related and H2O2-stimulated iron accumulation was attenuated by N-tert-butylhydroxylamine (NtBHA), a mitochondrial antioxidant that delays senescence in vitro. However, SV40-transformed, immortalized IMR-90s showed no time-dependent changes in metal content in culture or when treated with H2O2 and/or NtBHA. These data indicate that iron accumulation occurs during normal cellular senescence in vitro. This accumulation of iron may contribute to the increased oxidative stress and cellular dysfunction seen in senescent cells.

Antioxid Redox Signal. 2003 Oct;5(5):507-16

Iron toxicity in diseases of aging: Alzheimer’s disease, Parkinson’s disease and atherosclerosis.

Excess free iron generates oxidative stress that hallmarks diseases of aging. The observation that patients with Alzheimer’s disease or Parkinson’s disease show a dramatic increase in their brain iron content has opened the possibility that disturbances in brain iron homeostasis may contribute to the pathogenesis of these disorders. While the reason for iron accumulation is unknown, iron localization correlates with the production of reactive oxygen species in those areas of the brain that are prone to neurodegeneration. A role for iron is also proposed in atherosclerosis, a further frequent disorder of aging. We will review experimental evidences for an involvement of iron in these diseases and discuss some mouse models with impairment in iron-related genes that may be useful to study the role of iron in these disorders.

J Alzheimers Dis. 2009;16(4):879-95

MRI evaluation of brain iron in earlier- and later-onset Parkinson’s disease and normal subjects.

Tissue iron levels in the extrapyramidal system of earlier- and later-onset Parkinson’s disease (PD) subjects were evaluated in vivo using a magnetic resonance imaging (MRI) method. The method involves scanning subjects in both high- and low-field MRI instruments, measuring tissue relaxation rate (R2), and calculating the field-dependent R2 increase (FDRI) which is the difference between the R2 measured with the two MRI instruments. In tissue, only ferritin iron is known to increase R2 in a field-dependent manner and the FDRI measure is a specific measure of this tissue iron pool. Two groups of male subjects with PD and two age-matched groups of normal control males were studied. The two groups of six subjects with PD consisted of subjects with earlier- or later-onset (before or after age 60) PD. FDRI was measured in five subcortical structures: the substantia nigra reticulata (SNR), substantia nigra compacta (SNC), globus pallidus, putamen, and caudate nucleus, and in one comparison region; the frontal white matter. Earlier-onset PD subjects had significant (p < 0.05) increases in FDRI in the SNR, SNC, putamen, and globus pallidus, while later-onset PD subjects had significantly decreased FDRI in the SNR when compared to their respective age-matched controls. Controlling for illness duration or structure size did not meaningfully alter the results. Published post-mortem studies on SN iron levels indicate decreased ferritin levels and increased free iron levels in the SN of older PD subjects, consistent with the decreased FDRI observed in our later-onset PD sample, which was closely matched in age to the post-mortem PD samples. The FDRI results suggest that disregulation of iron metabolism occurs in PD and that this disregulation may differ in earlier- versus later-onset PD.

Magn Reson Imaging. 1999 Feb;17(2):213-22

In vivo MR evaluation of age- related increases in brain iron.

PURPOSE: To assess the validity of an MR method of evaluating tissue iron. METHODS: The difference between the transverse relaxation rate (R2) measured with a high-field MR instrument and the R2 measured with a lower field instrument defines a measure termed the field-dependent R2 increase (FDRI). Previous in vivo and in vitro studies indicated that FDRI is a specific measure of tissue iron stores (ferritin). T2 relaxation times were obtained using two clinical MR instruments operating at 0.5 T and 1.5 T. T2 relaxation times were measured in the frontal white matter, caudate nucleus, putamen, and globus pallidus of 20 healthy adult male volunteers with an age range of 20 to 81 years. R2 was calculated as the reciprocal of T2 relaxation time. These in vivo MR results were correlated with previously published postmortem data on age-related increases of nonheme iron levels. RESULTS: The FDRI was very highly correlated with published brain iron levels for the four regions examined. In the age range examined, robust and highly significant age-related increases in FDRI were observed in the caudate and putamen. The correlations of age and FDRI in the globus pallidus and white matter were significantly lower and did not have statistical significance. CONCLUSIONS: The data provide additional evidence that FDRI is a specific measure of tissue iron stores. The data also show that age-related increases in tissue iron stores can be quantified in vivo despite significant age-related processes that oppose the increase in R2 caused by iron. These results are relevant to the investigation of neurodegenerative processes in which iron may catalyze toxic free-radical reactions.

AJNR Am J Neuroradiol. 1994 Jun;15(6):1129-38

In vivo evaluation of brain iron in Alzheimer’s disease and normal subjects using MRI.

Magnetic resonance imaging (MRI) can measure transverse relaxation rate (R2) of tissues. Although R2 is increased by tissue iron levels, R2 is not a specific measure of iron. A new method, based on the fact that ferritin (the primary tissue iron storage protein) affects R2 in a field-dependent manner, can quantify tissue iron with specificity by measuring the Field Dependent R2 Increase (FDRI). Using the FDRI method, we compared brain iron stores in frontal white matter, caudate nucleus, putamen, and globus pallidus of five male patients with Alzheimer disease (AD) and eight age and gender-matched normal controls. FDRI values were significantly higher among AD patients in the caudate and globus pallidus. The data suggest that AD may involve disturbances in brain iron metabolism and that the involvement of iron in the pathophysiology of age-related neurodegenerative disorders can be investigated in vivo using MRI.

Biol Psychiatry. 1994 Apr 1;35(7):480-7

MRI evaluation of basal ganglia ferritin iron and neurotoxicity in Alzheimer’s and Huntingon’s disease.

BACKGROUND: The basal ganglia contain the highest levels of iron in the brain and post-mortem studies indicate a disruption of iron metabolism in the basal ganglia of patients with neurodegenerative disorders such as Alzheimer’s disease (AD) and Huntington’s disease (HD). Iron can catalyze free radical reactions and may contribute to oxidative damage observed in AD and HD brain. Magnetic resonance imaging (MRI) can quantify transverse relaxation rates, which can be used to quantify tissue iron stores as well as evaluate increases in MR-visible water (an indicator of tissue damage). METHODS: A magnetic resonance imaging (MRI) method termed the field dependent relaxation rate increase (FDRI) was employed which quantifies the iron content of ferritin molecules (ferritin iron) with specificity through the combined use of high and low field-strength MRI instruments. Three basal ganglia structures (caudate, putamen and globus pallidus) and one comparison region (frontal lobe white matter) were evaluated. Thirty-one patients with AD and a group of 68 older control subjects, and 11 patients with HD and a group of 27 adult controls participated (4 subjects overlap between AD and HD controls). RESULTS: Compared to their respective normal control groups, increases in basal ganglia FDRI levels were seen in both AD and HD. FDRI levels were significantly increased in the caudate (p = 0.007) and putamen (p = 0.008) of patients with AD with a trend toward an increase in the globus pallidus (p = 0.13). In the patients with HD, all three basal ganglia regions showed highly significant FDRI increases (p<0.001) and the magnitude of the increases were 2 to 3 times larger than those observed in AD versus control group comparison. For both HD andAD subjects, the basal ganglia FDRI increase was not a generalized phenomenon, as frontal lobe white matter FDRI levels were decreased in HD (p = 0.015) and remained unchanged in AD. Significant low field relaxation rate decreases (suggestive of increased MR-visible water and indicative of tissue damage) were seen in the frontal lobe white matter of both HD and AD but only the HD basal ganglia showed such decreases. CONCLUSIONS: The data suggest that basal ganglia ferritin iron is increased in HD and AD. Furthermore, the increased iron levels do not appear to be a byproduct of the illness itself since they seem to be present at the onset of the diseases, and thus may be considered a putative risk factor. Published post-mortem studies suggest that the increase in basal ganglia ferritin iron may occur through different mechanisms in HD and AD. Consistent with the known severe basal ganglia damage, only HD basal ganglia demonstrated significant decreases in low field relaxation rates. MRI can be used to dissect differences in tissue characteristics, such as ferritin iron and MR-visible water, and thus could help clarify neuropathologic processes in vivo. Interventions aimed at decreasing brain iron levels, as well as reducing the oxidative stress associated with increased iron levels, may offer novel ways to delay the rate of progression and possibly defer the onset of AD and HD.

Cell Mol Biol (Noisy-le-grand). 2000 Jun;46(4):821-33

MR evaluation of age-related increase of brain iron in young adult and older normal males.

The purposes of this study were to extend the investigation of age-related increases in brain iron to a younger age group, replicate previously published results, and further evaluate the validity of a novel noninvasive magnetic resonance (MR) method for measuring tissue iron (ferritin) levels with specificity. The method consists of measuring the dependence of tissue transverse relaxation rates (R2) on the field strength of MR instruments. Two MR instruments operating at 1.5 and 0.5 T were used to measure the field-dependent R2 increase (FDRI) in the frontal white matter, caudate, putamen, and globus pallidus. A group of 13 normal adult males (ages 21-77), with seven subjects below and six above age 35, was examined. As expected from postmortem and prior FDRI data, robust and significant age-related increases in FDRI were observed in the caudate, putamen, and globus pallidus, with the globus pallidus FDRI increasing sharply in the second decade and reaching a plateau after age 30. In addition, we replicated previous reports showing very high correlations between FDRI and published brain iron levels for the four regions examined. The data replicate and extend previous FDRI observations on brain aging and are consistent with postmortem data on age-related increases in brain iron. These results are relevant to the investigation of age-related neurodegenerative diseases in which iron may catalyze toxic free radical reactions.

Magn Reson Imaging. 1997;15(1):29-35

Brain ferritin iron as a risk factor for age at onset in neurodegenerative diseases.

Tissue iron can promote oxidative damage. Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Higher iron levels in males may contribute to higher risk for younger-onset PD and recent studies have linked the presence of the hemochromatosis gene with a younger age at onset of AD. We examined whether age at onset of PD and AD was associated with increased brain ferritin iron. Ferritin iron can be measured with specificity in vivo with MRI utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in three basal ganglia regions (caudate, putamen, and globus pallidus) and frontal lobe white matter for younger- and older-onset male PD and AD patients and healthy controls. Significant increases in basal ganglia FDRI levels were observed in the younger-onset groups of both diseases compared to their respective control groups, but were absent in the older-onset patients. The results support the suggestion that elevated ferritin iron and its associated toxicity is a risk factor for age at onset of neurodegenerative diseases such as AD and PD. Clinical phenomena such as gender-associated risk of developing neurodegenerative diseases and the age at onset of such diseases may be associated with brain iron levels. In vivo MRI can measure and track brain ferritin iron levels and provides an opportunity to design therapeutic interventions that target high-risk populations early in the course of illness, possibly even before symptoms appear.

Ann N Y Acad Sci. 2004 Mar;1012:224-36

Gender and iron genes may modify associations between brain iron and memory in healthy aging.

Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimer’s disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON+) vs noncarrier (IRON-) status (for HFE H63D/TfC2) modify the associations. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON+ vs IRON- status was determined in a cohort of 63 healthy older individuals. Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r=-0.50, p=0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRON- group (r=-0.49, p=0.005) but not in the IRON+ group. Between-group interactions (p=0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups.

Neuropsychopharmacology. 2011 Jun;36(7):1375-84

Brain ferritin iron may influence age- and gender-related risks of neurodegeneration.

BACKGROUND: Brain iron promotes oxidative damage and protein oligomerization that result in highly prevalent age-related proteinopathies such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Dementia with Lewy Bodies (DLB). Men are more likely to develop such diseases at earlier ages than women but brain iron levels increase with age in both genders. We hypothesized that brain iron may influence both the age- and gender-related risks of developing these diseases. METHODS: The amount of iron in ferritin molecules (ferritin iron) was measured in vivo with MRI by utilizing the field dependent relaxation rate increase (FDRI) method. Ferritin iron was measured in four subcortical nuclei [caudate (C), putamen (P), globus pallidus (G), thalamus (T)], three white matter regions [frontal lobe (Fwm), genu and splenium of the corpus callosum (Gwm, Swm)] and hippocampus (Hipp) in 165 healthy adults aged 19-82. RESULTS: There was a high correlation (r>0.99) between published post-mortem brain iron levels and FDRI. There were significant age-related changes in ferritin iron (increases in Hipp, C, P, G, and decreases in Fwm). Women had significantly lower ferritin iron than men in five regions (C, T, Fwm, Gwm, Swm). CONCLUSIONS: This is the first demonstration of gender differences in brain ferritin iron levels. It is possible that brain iron accumulation is a risk factor that can be modified. MRI provides the opportunity to assess brain iron levels in vivo and may be useful in targeting individuals or groups for preventive therapeutic interventions.

Neurobiol Aging. 2007 Mar;28(3):414-23

Premenopausal hysterectomy is associated with increased brain ferritin iron.

Iron is essential for triggering oligodendrocytes to myelinate, however, in gray matter (GM) iron increases with age and is associated with age-related degenerative brain diseases. Women have lower iron levels than men, both in the periphery and in the brain, particularly in white matter (WM), possibly due to iron loss through menstruation. We tested the hypothesis that hysterectomy could increase WM iron levels. We assessed 3 WM and 5 gray matter regions in 39 postmenopausal women, of whom 15 had premenopausal hysterectomy, utilizing a validated magnetic resonance imaging technique called field-dependent R2 increase (FDRI) that quantifies ferritin iron. A group of 54 matched male subjects was included for comparison. Amongst women, hysterectomy was associated with significantly higher frontal lobe WM iron. Men had higher iron levels than women without hysterectomy in 3 brain regions but did not differ from women with hysterectomy in any region. The results suggest that menstruation-associated blood loss is a source of gender differences in brain iron. It is possible that brain iron can be influenced by peripheral iron levels and may thus be a modifiable risk factor for age-related degenerative diseases.

Neurobiol Aging. 2011 Sep 16