Life Extension Magazine®

Issue: Aug 2009


Guidelines for the early detection of osteoporosis and prediction of fracture risk. Council of the National Osteoporosis Foundation.

OBJECTIVE: To assess methods available in clinical practice for the early detection of osteoporosis and prediction of fracture risk, and to set guidelines for their use. To make recommendations regarding cost-effective screening of asymptomatic subjects by physicians. OPTIONS: Three methods to predict fracture risk are considered: (i) clinical risk factor analysis; (ii) biochemical tests; and (iii) techniques to measure bone mass. Mass (unselected) screening is compared with screening only those at risk of sustaining a fracture. The optimal age/time of screening and therapeutic intervention thresholds are also considered. OUTCOMES: The main potential outcomes considered are the morbidity and mortality of advanced osteoporosis and fracture; the accuracy, precision, safety and costs of screening tests; and treatment for those at risk. EVIDENCE: Based on the results of published recommendations of international osteoporosis societies, World Health Organisation guidelines and expert opinion. VALUES: The guidelines were developed by the National Osteoporosis Foundation in conjunction with other specialists and societies. A workshop attended by all the osteodensitometrists in the country was held in August 1994 to obtain consensus on recommendations. There were no major disputes about the content. The guidelines are intended to optimise health care of society as a whole and are not geared to individual patients. BENEFITS, HARMS AND COSTS: Up to 20% of victims of hip fracture die within 1 year and less than 50% ever regain the functional capability to lead an independent life. The cost of acute fracture care in the USA exceeded $10 billion in 1990. Early intervention has been shown to reduce the rate of vertebral and hip fractures by 50 - 70%. The cost of fracture care and of selected screening has not been measured in this country. Measurement of bone mass is safe, accurate and precise. RECOMMENDATIONS: (i) Measurement of bone mass employing dual-energy X-ray absorptiometry (DEXA) is at present the method of choice to predict hip and vertebral fracture risk. A single measurement can correctly identify the majority of those at risk. (ii) Densitometric screening of all (asymptomatic) women cannot be recommended, and selective screening according to specific indications is suggested. Densitometry is indicated at any age if the indication is valid. (iii) Guidelines for the interpretation of bone mass data, including therapeutic intervention thresholds, are suggested.

S Afr Med J. 1996 Sep;86(9):1113-6

Detection of coronary artery disease in asymptomatic patients with type 2 diabetes mellitus.

In type 2 diabetes mellitus (DM2) patients, coronary artery disease (CAD) generally is detected in an advanced stage, whereas an asymptomatic stage is commonly missed. Abnormal myocardial perfusion during stress myocardial contrast echocardiography (MCE) and significant CAD were similar, irrespective of risk factor (RF) profile in our patients, but coronary anatomy differed. An “aggressive” diagnostic approach, requiring coronary angiography in asymptomatic DM2 patients with < or = 1 associated RF for CAD and abnormal MCE, identified silent CAD, characterized by a more favorable angiographic anatomy. The criterion of > or = 2 RFs did not help to identify patients with a higher prevalence of CAD and is only related to a more severe coronary atherosclerosis with unfavorable anatomy.OBJECTIVES: We sought to verify the effectiveness of current American Diabetes Association screening guidelines in identifying asymptomatic patients with coronary artery disease (CAD) in type 2 diabetes mellitus (DM2). BACKGROUND: In DM2 patients, CAD generally is detected in an advanced stage with an extensive atherosclerosis and poor outcome, whereas CAD in an asymptomatic stage is commonly missed. METHODS: This study included 1,899 asymptomatic DM2 patients (age < or = 60 years). Of these, 1,121 had > or = 2 associated risk factors (RFs), group A, and the remaining 778 had < or = 1 RF, group B, for CAD. All patients underwent dipyridamole myocardial contrast echocardiography (MCE), and in those with myocardial perfusion defects, the anatomy of coronary vessels was analyzed by selective coronary angiography. RESULTS: In the two study groups, the prevalence of abnormal MCE (59.4% vs. 60%, p = 0.96) and of a significant CAD (64.6% vs. 65.5%, p = 0.92) was similar, irrespective of RF profile. But coronary anatomy differed: group B had a lower prevalence of three-vessel disease (7.6% vs. 33.3%, p < 0.001), of diffuse disease (18.0% vs. 54.9%, p < 0.001), and of vessel occlusion (3.8% vs. 31.2%, p < 0.001), whereas one-vessel disease was more frequent (70.6% vs. 46.3%, p < 0.001). Coronary anatomy did not allow any revascularization procedure in 45% of group A patients. CONCLUSIONS: An “aggressive” diagnostic approach, requiring coronary angiography in asymptomatic DM2 patients with < or =1 associated RF for CAD and abnormal MCE, identified patients with a subclinical CAD characterized by a more favorable angiographic anatomy. The criterion of > or =2 RFs did not help to identify asymptomatic patients with a higher prevalence of CAD and is only related to a more severe CAD with unfavorable coronary anatomy.

J Am Coll Cardiol. 2006 Jan 3;47(1):65-71

Electrophysiological markers of rapid cognitive decline in mild cognitive impairment.

Electroencephalography (EEG) is an easily accessible and low-cost modality that might prove to be a particularly powerful tool for the identification of subtle functional changes preceding structural or metabolic deficits in progressive mild cognitive impairment (PMCI). Most previous contributions in this field assessed quantitative EEG differences between healthy controls, MCI and Alzheimer’s disease(AD) cases leading to contradictory data. In terms of MCI conversion to AD, certain longitudinal studies proposed various quantitative EEG parameters for an a priori distinction between PMCI and stable MCI. However, cross-sectional comparisons revealed a substantial overlap in these parameters between MCI patients and elderly controls. Methodological differences including variable clinical definition of MCI cases and substantial interindividual differences within the MCI group could partly explain these discrepancies. Most importantly, EEG measurements without cognitive demand in both cross-sectional and longitudinal designs have demonstrated limited sensitivity and generally do not produce significant group differences in spectral EEG parameters. Since the evolution of AD is characterized by the progressive loss of functional connectivity within neocortical association areas, event-modulated EEG dynamic analysis which makes it possible to investigate the functional activation of neocortical circuits may represent a more sensitive method to identify early alterations of neuronal networks predictive of AD development among MCI cases. The present review summarizes clinically significant results of EEG activation studies in this field and discusses future perspectives of research aiming to reach an early and individual prediction of cognitive decline in healthy elderly controls.

Front Neurol Neurosci. 2009;24:39-46

Quantitative EEG in early Alzheimer’s disease patients - power spectrum and complexity features.

The goal of this study was to investigate the EEG signs of early stage Alzheimer’s disease (AD) by conventional analyses and by methods quantifying linear and nonlinear EEG-complexity. The EEG was recorded in 12 mild AD patients and in an age-matched healthy control group (24 subjects) in both eyes open and eyes closed conditions. Frequency spectra, Omega-complexity and Synchronization likelihood were calculated on the data. In the patients a significant decrease of the relative alpha and increase of the theta power were found. Remarkably increased Omega-complexity and lower Synchronization likelihood were observed in AD in the 0.5-25 Hz frequency ranges. It is concluded that both spectral- and EEG-complexity changes can be found already in the early stage of AD in a wide frequency range. Application of conventional EEG analysis methods in combination with quantification of EEG-complexity may improve the chances of early diagnosis of AD.

Int J Psychophysiol. 2008 Apr;68(1):75-80

Abnormal EEG complexity in patients with schizophrenia and depression.

OBJECTIVE: Schizophrenics are usually unable to perform well on cognitive tasks due to disturbances in cortical information processing that are observable as abnormalities in electroencephalogram (EEG) signals. However, whether such cortical disturbances can be assessed by quantitative EEG analysis remains unclear. The purpose of this study was to characterize EEG disturbances, using the Lempel-Ziv complexity (LZC), in the subjects with schizophrenia at rest or while performing mental arithmetic tasks. The results were compared to those from the subjects with depression and with healthy controls. METHODS: The subjects included 62 schizophrenia patients, 48 depression patients and 26 age-matched healthy controls. EEG was recorded under two conditions: (i) resting with eyes closed, and (ii) a mentally active condition wherein the subjects were asked to subtract 7 from 100 iteratively with their eyes closed. EEG signals were analyzed by LZC and conventional spectral methods. RESULTS: In all the groups, LZC of EEG decreased during the mental arithmetic compared with those under the resting conditions. Both the schizophrenia and the depression groups had a higher LZC (p<0.05) than the controls. Also, the schizophrenia group had a lower LZC (p<0.05) than the depression group during the mental arithmetic task as well as during the resting state. Significant differences in LZC, at some symmetrically located loci (FP1/FP2, F7/F8), between the two hemispheres were found in all the patient groups only during the arithmetic task. CONCLUSIONS: Compared with conventional spectral analysis, LZC was more sensitive to both the power spectrum and the temporal amplitude distribution. LZC was associated with the ability to attend to the task and adapt the information processing system to the cognitive challenge. Thus, it would be useful in studying the disturbances in the cortical information processing patients with depression or schizophrenia. SIGNIFICANCE: LZC of EEG is associated with mental activity. Thus, LZC analysis can be an important tool in understanding the pathophysiology of schizophrenia and depression in future studies.

Clin Neurophysiol. 2008 Jun;119(6):1232-41

Application of electroencephalography to the study of cognitive and brain functions in schizophrenia.

The electroencephalogram (EEG) recorded from the human scalp is widely used to study cognitive and brain functions in schizophrenia. Current research efforts are primarily devoted to the assessment of event-related potentials (ERPs) and event-related oscillations (EROs), extracted from the ongoing EEG, in patients with schizophrenia and in clinically unaffected individuals who, due to their family history and current mental status, are at high risk for developing schizophrenia. In this article, we discuss the potential usefulness of ERPs and EROs as genetic vulnerability markers, as pathophysiological markers, and as markers of possible ongoing progressive cognitive and cortical deterioration in schizophrenia. Our main purpose is to illustrate that these neurophysiological measures can offer valuable quantitative biological markers of basic pathophysiological mechanisms and cognitive dysfunctions in schizophrenia, yet they may not be specific to current psychiatry’s diagnosis and classification. These biological markers can provide unique information on the nature and extent of cognitive and brain dysfunction in schizophrenia. Moreover, they can be utilized to gain deeper theoretical insights into illness etiology and pathophysiology and may lead to improvements in early detection and more effective and targeted treatment of schizophrenia. We conclude by addressing several key methodological, conceptual, and interpretative issues involved in this research field and by suggesting future research directions.

Schizophr Bull. 2007 Jul;33(4):955-70

The value of quantitative electroencephalography in clinical psychiatry: a report by the Committee on Research of the American Neuropsychiatric Association.

The authors evaluate quantitative electroencephalography (qEEG) as a laboratory test in clinical psychiatry and describe specific techniques, including visual analysis, spectral analysis, univariate comparisons to normative healthy databases, multivariate comparisons to normative healthy and clinical databases, and advanced techniques that hold clinical promise. Controversial aspects of each technique are discussed, as are broader areas of criticism, such as commercial interests and standards of evidence. The published literature is selectively reviewed, and qEEG’s applicability is assessed for disorders of childhood (learning and attentional disorders), dementia, mood disorders, anxiety, panic, obsessive-compulsive disorder, and schizophrenia. Emphasis is placed primarily on studies that use qEEG to aid in clinical diagnosis, and secondarily on studies that use qEEG to predict medication response or clinical course. Methodological problems are highlighted, the availability of large databases is discussed, and specific recommendations are made for further research and development. As a clinical laboratory test, qEEG’s cautious use is recommended in attentional and learning disabilities of childhood, and in mood and dementing disorders of adulthood.

J Neuropsychiatry Clin Neurosci. 2006 Fall;18(4):460-500

Is C-reactive protein specific for vascular disease in women?

BACKGROUND: C-reactive protein (CRP) predicts risk for future cardiovascular events in asymptomatic individuals. However, because CRP also predicts total mortality, its specificity for vascular disease is uncertain. OBJECTIVE: To compare the predictive value of CRP for cancer and cardiovascular disease, the major determinants of mortality. DESIGN: Prospective, nested case-control study. SETTING: The Women’s Health Study, an ongoing prospective cohort study involving 2,8345 US women 45 years of age and older who were healthy at the time of enrollment. PARTICIPANTS: 643 women who subsequently developed cancer or had cardiovascular events; 643 age- and smoking-matched women who remained free of either disease during 58-month follow-up. MEASUREMENTS: Baseline CRP levels. RESULTS: Little evidence showed that increasing quartiles of baseline CRP predicted incident cancer (adjusted relative risks, 1.0, 1.2, 1.1, and 1.3; P for trend > 0.2). In contrast, increasing quartiles of baseline CRP were a strong marker of risk for future cardiovascular disease (adjusted relative risks, 1.0, 2.9, 3.4, and 5.6; P for trend < 0.001). CONCLUSION: C-reactive protein appears to independently predict cardiovascular events but not cancer.

Ann Intern Med. 2002 Apr 2;136(7):529-33

Abdominal obesity: a health threat

Abdominal obesity is often associated with a constellation of comorbidities that include central adiposity, insulin resistance, dyslipidemia, and hypertension. Clinical evaluations should include a measurement of waist circumference, which is a good marker of abdominal obesity. Abdominal obesity is closely associated with an elevated outflow of free fatty acids from the visceral fat compartment and dysregulation of adipokine expression, accompanied by increased inflammation. The most serious consequences of abdominal obesity are coronary heart disease and stroke. It is also associated, however, with polycystic ovary syndrome and hepatic steatosis. Weight reduction and increased physical activity should be recommended to patients with a high waist circumference. Patients with abdominal obesity and other classic risk factors are at high cardiovascular risk and require strict monitoring of their blood pressure, LDL-c, and blood glucose. New pharmacological strategies might help manage both abdominal obesity and its metabolic consequences.

Presse Med. 2008 Oct;37(10):1407-14

Testosterone and coronary artery disease.

The strongest independent risk factors for coronary artery disease (CAD) are increasing age and male gender. Whilst a wide variation in CAD mortality exists between countries, a male to female ratio of approximately 2:1 is consistently observed. These observations have led to the assumption that testosterone may exert a detrimental influence on the cardiovascular system. Despite this, coronary atherosclerosis increases with age, whilst a marked fall in serum bioavailable testosterone levels is observed. Similarly, low testosterone levels are also associated with other cardiovascular risk factors and increased expression of mediators of the atherosclerotic process. This in itself suggests that testosterone does not promote atheroma formation. Moreover, epidemiological studies show an inverse relationship between testosterone levels and surrogate markers of atherosclerosis, which suggests that it may be a testosterone deficient state, rather than male sex which is associated with CAD. In cholesterol-fed animal models, atherosclerosis is accelerated by castration and reduced after testosterone replacement therapy. Testosterone has also been shown to improve myocardial ischemia in men with angina pectoris. Consequently, increasing evidence suggests that the process of atherosclerosis is beneficially modulated by testosterone. These studies are the focus of this chapter.

Front Horm Res. 2009;37:91-107

Serum DHEA-S level is associated with the presence of atherosclerosis in postmenopausal women with type 2 diabetes mellitus.

We investigated the relationship between serum dehydroepiandrosterone-sulfate (DHEA-S) and insulin-like growth factor-I (IGF-I) to various parameters for atherosclerosis in type 2 diabetes. The levels of DHEA-S and IGF-I are known to decrease with aging and thereby might be associated with an increased risk of cardiovascular disease. One hundred forty-eight men and 106 postmenopausal women with type 2 diabetes were assessed in a cross-sectional study. Serum DHEA-S and IGF-I concentrations were measured and brachial-ankle pulse wave velocity (baPWV) and ultrasonographically-evaluated intima-media thickness (IMT) were assessed. Although simple regression analysis showed that log(DHEA-S) and IGF-I in men and log(DHEA-S) in women were significantly and inversely correlated with baPWV and IMT, only log(DHEA-S) in women was still significantly and inversely correlated with these atherosclerotic parameters after multiple regression analysis was adjusted for age, duration of diabetes, BMI, HbA(1C), systolic blood pressure, LDL-Cholesterol (C), serum creatinine, and smoking (Brinkman index). Serum DHEA-S level seemed to be associated with atherosclerosis in diabetic postmenopausal women independent of age, body stature, diabetic status, and other atherosclerotic risk factors, and might be a useful addition to other parameters for assessing the risk of atherosclerosis in this population.

Endocr J. 2008 Aug;55(4):667-75

Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival.

BACKGROUND: The age-related decline of circulating anabolic hormones in men is associated with increased morbidity and mortality. We studied the prevalence and prognostic consequences of deficiencies in circulating total testosterone (TT) and free testosterone, dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor-1 (IGF-1) in men with chronic heart failure (CHF). METHODS AND RESULTS: Serum levels of TT, DHEAS, and IGF-1 were measured with immunoassays in 208 men with CHF (median age 63 years; median left ventricular ejection fraction 33%; New York Heart Association class I/II/III/IV, 19/102/70/17) and in 366 healthy men. Serum levels of free testosterone were estimated (eFT) from levels of TT and sex hormone binding globulin. Deficiencies in DHEAS, TT, eFT, and IGF-1, defined as serum levels at or below the 10th percentile of healthy peers, were seen across all age categories in men with CHF. DHEAS, TT, and eFT were inversely related to New York Heart Association class irrespective of cause (all P<0.01). DHEAS correlated positively with left ventricular ejection fraction and inversely with N-terminal pro-brain natriuretic peptide (both P<0.01). Circulating TT, eFT, DHEAS, and IGF-1 levels were prognostic markers in multivariable models when adjusted for established prognostic factors (all P<0.05). Men with CHF and normal levels of all anabolic hormones had the best 3-year survival rate (83%, 95% CI 67% to 98%) compared with those with deficiencies in 1 (74% survival rate, 95% CI 65% to 84%), 2 (55% survival rate, 95% CI 45% to 66%), or all 3 (27% survival rate, 95% CI 5% to 49%) anabolic endocrine axes (P<0.0001). CONCLUSIONS: In male CHF patients, anabolic hormone depletion is common, and a deficiency of each anabolic hormone is an independent marker of poor prognosis. Deficiency of >1 anabolic hormone identifies groups with a higher mortality.

Circulation. 2006 Oct 24;114(17):1829-37

Niacin for stroke prevention: evidence and rationale.

Low levels of high-density lipoprotein (HDL) cholesterol are associated with increased atherothrombotic events, including stroke. Niacin is a safe and effective means of raising HDL, yet its role in stroke prevention is not well characterized. The purpose of the study is to determine the role of niacin in stroke prevention. A search of the PUBMED database using the keywords niacin, stroke, atherosclerosis, and/or carotid artery was undertaken to identify studies for review. National guidelines from the American Heart Association and National Cholesterol Education Program were reviewed. Treatment of low serum HDL (<40 mg/dL) is an identified goal of dyslipidemic therapy. Niacin is effective in raising HDL levels and reducing cardiovascular events in individuals with high vascular risk and can be used for treatment of stroke patients with low serum HDL. Niacin can be used safely in combination with statins, the first-line dyslipidemic treatment for secondary stroke risk reduction, with increased efficacy. Studies are needed to better define the role for niacin in secondary stroke prevention. Treatment of stroke patients with extended-release (ER) of niacin, alone or in combination with statins, should be considered in stroke patients with atherosclerotic mechanisms with low serum HDL-C levels.

CNS Neurosci Ther. 2008 Winter;14(4):287-94

Taurine depletion caused by knocking out the taurine transporter gene leads to cardiomyopathy with cardiac atrophy.

The sulfur-containing beta-amino acid, taurine, is the most abundant free amino acid in cardiac and skeletal muscle. Although its physiological function has not been established, it is thought to play an important role in ion movement, calcium handling, osmoregulation and cytoprotection. To begin examining the physiological function of taurine, we generated taurine transporter- (TauT-) knockout mice (TauTKO), which exhibited a deficiency in myocardial and skeletal muscle taurine content compared with their wild-type littermates. The TauTKO heart underwent ventricular remodeling, characterized by reductions in ventricular wall thickness and cardiac atrophy accompanied with the smaller cardiomyocytes. Associated with the structural changes in the heart was a reduction in cardiac output and increased expression of heart cardiac failure (fetal) marker genes, such as ANP, BNP and beta-MHC. Moreover, ultrastructural damage to the myofilaments and mitochondria was observed. Further, the skeletal muscle of the TauTKO mice also exhibited decreased cell volume, structural defects and a reduction of exercise endurance capacity. Importantly, the expression of Hsp70, ATA2 and S100A4, which are upregulated by osmotic stress, was elevated in both heart and skeletal muscle of the TauTKO mice. Taurine depletion causes cardiomyocyte atrophy, mitochondrial and myofiber damage and cardiac dysfunction, effects likely related to the actions of taurine. Our data suggest that multiple actions of taurine, including osmoregulation, regulation of mitochondrial protein expression and inhibition of apoptosis, collectively ensure proper maintenance of cardiac and skeletal muscular structure and function.

J Mol Cell Cardiol. 2008 May;44(5):927-37

Melatonin in combined therapy of patients with stable angina and arterial hypertension

Study of 2 randomized groups of patients with coronary heart disease, stable exertional angina combined with arterial hypertension, receiving traditional treatment and combined therapy with inclusion of melatonin, was performed. All patients (43 persons at the age from 44 to 69 years) before and after treatment underwent daily monitoring of arterial pressure (AP) by system “BR-102 Schiller”, Switzerland. As a result of study, in the group of traditional treatment positive dynamics such as significant decrease in average daily values of systolic arterial pressure (SAP) from 159.7 +/- 3.4 to 146.1 +/- 4.6 (p = 0.02), diastolic arterial pressure (DAP) from 92.7 +/- 1.2 to 88.6 +/- 1.3 (p = 0.03), average daytime AP indices, average nighttime SAP indices, was noticed. SAP and DAP variability was significantly decreased only at daytime from 23.1 +/- 1.7 to 18.8 +/- 1.4 (p = 0.05) and from 18.1 +/- 0.5 to 16.5 +/- 0.4 respectively. Insufficient decrease in SAP and DAP at nighttime was detected. Inclusion of melatonin in traditional therapy leaded to more expressed decrease in average daily, daytime and nighttime AP indices and significant decrease in load by pressure value (SAP and DAP time indices were significantly reduced both at daytime and at nighttime). Degree of SAP and DAP nighttime decrease initially was upon the average 8.1 +/- 1.1% and 7.0 +/- 1.0% respectively (non-dippers), and after combined treatment was 13.4 +/- 0.9% (p = 0.003) and 11.0 +/- 1.1% (dippers), which proved recovery of normal daily AP profile. Significant decrease in SAP variability at daytime from 22.3 +/- 1.8 to 15.1 +/- 1.2 (p = 0.003), at nighttime from 16.1 +/- 1.4 to 12.7 +/- 1.0 (p = 0.05) in DAP variability at daytime from 17.5 +/- 0.4 to 14.5 +/- 0.4 (p < 0.001), at nighttime from 13.1 +/- 0.7 to 11.1 +/- 0.7 (p = 0.05).

Klin Med (Mosk). 2008;86(9):64-7

The mediterranean lecture: wine and thrombosis—from epidemiology to physiology and back.

The protective effect of moderate alcohol consumption on the risk of cardiovascular disease has been consistently shown in many epidemiological studies. Antiatherogenic alterations in plasma lipoproteins, particularly increase in high-density lipoprotein (HDL) cholesterol, are considered as the most plausible mechanism of the protective effect of alcohol consumption on coronary artery disease (CHD). Other potential mechanisms contributing to the cardio-protective effects of moderate alcohol consumption include anti-thrombotic down regulation of blood platelet function, as well as of the coagulation and fibrinolysis balance. Since the proposal of a “French paradox” in the early Nineties, the possibility that consuming alcohol in the form of wine might confer a protection against CHD above that expected from its alcohol content, has made the topic “wine and health” increasingly popular. Many epidemiological studies have explored such a possibility, by comparing specific alcoholic beverage types (wine,beer, liqueur) in respect to their relative capacity to reduce the risk of CHD. In parallel, experimental studies have been done, in which wine and wine-derived products have been tested for their capacity to interfere with molecular and cellular mechanisms relevant to the pathogenesis of CHD. Wine might indeed conceivably have other ethanol unrelated beneficial effects. The biological rationale for such a hypothesis has been linked to the enrichment in grape-derived, non-alcoholic components, that possibly make it peculiar in respect to other alcoholic beverages. In fact, while the mechanisms underlying the effects of alcohol on cardiovascular disease have been limited to lipid metabolism and the haemostatic system, those related to wine consumption have also been extended to specific anti-inflammatory, antioxidant and nitric oxide related vaso-relaxant properties of its polyphenolic constituents. The effect of wine consumption has been carefully investigated to account for potential confounding of several conditions (inappropriate use of abstainers as control population, correlation between wine or total alcohol consumption and markers of healthy lifestyle and socioeconomic factors, diet, etc.). Strong evidence indicates that moderate wine consumption rather than confounders reduces both fatal and non fatal CHD events. In spite of the fact that the healthy effect of moderate intake of wine is by now well accepted, important issues remain to be resolved about the relationship between wine, alcohol and alcoholic beverages, the (possibly different) optimal amount of alcohol intake in men and women, the individual or environmental modulation of the alcohol related effect and the pattern of drinking. Some of these issues have been recently addressed in a large meta-analysis, in which the relationship between wine or beer consumption and CHD risk was quantitatively evaluated. We shall summarize here the experimental and epidemiological studies with wine or wine-derived products aimed at finding biological explanations for the supposed superior cardio-protective effects of wine consumption and to discuss some open questions about wine and vascular disease as approached in epidemiological studies.

Pathophysiol Haemost Thromb. 2003 Sep-2004 Dec;33(5-6):466-71

Resveratrol improves health and survival of mice on a high-calorie diet.

Resveratrol (3,5,4’-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.

Nature. 2006 Nov 16;444(7117):337-42

Cellular stress response: a novel target for chemoprevention and nutritional neuroprotection in aging, neurodegenerative disorders and longevity.

The predominant molecular symptom of aging is the accumulation of altered gene products. Moreover, several conditions including protein, lipid or glucose oxidation disrupt redox homeostasis and lead to accumulation of unfolded or misfolded proteins in the aging brain. Alzheimer’s and Parkinson’s diseases or Friedreich ataxia are neurological diseases sharing, as a common denominator, production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis of these so called “protein conformational diseases.” The central nervous system has evolved the conserved mechanism of unfolded protein response to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Thus, the impact of dietary factors on health and longevity is an increasingly appreciated area of research. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against disease.Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin, a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Recent findings suggest that several phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of vitagenes encoding survival proteins, as in the case of the Keap1/Nrf2/ARE pathway activated by curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Consistently, the neuroprotective roles of dietary antioxidants including curcumin, acetyl-L-carnitine and carnosine have been demonstrated through the activation of these redox-sensitive intracellular pathways. Although the notion that stress proteins are neuroprotective is broadly accepted, still much work needs to be done in order to associate neuroprotection with specific pattern of stress responses. In this review the importance of vitagenes in the cellular stress response and the potential use of dietary antioxidants in the prevention and treatment of neurodegenerative disorders is discussed.

Neurochem Res. 2008 Dec;33(12):2444-71

Trans-resveratrol: a magical elixir of eternal youth?

Trans-resveratrol or (E)-resve-ratrol [3,4’,5 trihydroxy-trans-stilbene, t-RESV or (E)-RESV] is a natural component of Vitis vinifera L. (Vitaceae), abundant in the skin of grapes (but not in the flesh) and in the leaf epidermis and present in wines (especially red wines). In in vitro, ex vivo and in vivo experiments, t-RESV exhibits a number of biological activities, including anti inflammatory, antioxidant, platelet antiaggregatory and anticarcinogenic properties, and modulation of lipoprotein metabolism. Some of these activities have been implicated in the cardiovascular protective effects attributed to t-RESV and to red wine. Prior to 2002 there had been no previous studies describing the potential effects of t-RESV on the lifespan extension. However, in the last 5 years, several researchers have reported that t-RESV is a potent activator of sirtuin enzymatic activity, mimics the beneficial effects of caloric restriction (CR), retards the aging process and increases longevity in a number of organisms from different phyla such as yeasts, worms, flies and short-lived fish. In addition, t-RESV seems to be effective in delaying the onset of a variety of age-related diseases in mammals (e.g.: rodents). Therefore, this review will basically focus on the possible role of t-RESV to extend life duration and on some of the mechanisms by which t-RESV may act as an anti-aging agent.

Curr Med Chem. 2008;15(19):1887-98

Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span.

A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.

Cell Metab. 2008 Aug;8(2):157-68

Sirtuins in mammals: insights into their biological function.

Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.

Biochem J. 2007 May 15;404(1):1-13

Sirtuins: a conserved key unlocking AceCS activity.

Bacterial acetyl-coenzyme A (acetyl-CoA) synthetase (AceCS), an evolutionarily conserved enzyme that converts acetate to acetyl-CoA, is activated by sirtuin-mediated deacetylation. Two recent studies show that this mechanism of regulation is also crucial for mammalian AceCS activity, indicating that control of metabolism at the step of converting acetate to acetyl-CoA is conserved. These findings highlight a metabolic regulatory network controlled by sirtuins that has implications for the mechanisms of calorie restriction and modulation of mammalian life span.

Trends Biochem Sci. 2007 Jan;32(1):1-4

Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations.

The dietary polyphenolic compound resveratrol, by activating the protein deacetylase enzyme silent information regulator 2/sirtuin 1 (SIRT1), prolongs life span in evolutionarily distant organisms and may mimic the cytoprotective effects of dietary restriction. The present study was designed to elucidate the effects of resveratrol on cigarette smoke-induced vascular oxidative stress and inflammation, which is a clinically highly relevant model of accelerated vascular aging. Cigarette smoke exposure of rats impaired the acetylcholine-induced relaxation of carotid arteries, which could be prevented by resveratrol treatment. Smoking and in vitro treatment with cigarette smoke extract (CSE) increased reactive oxygen species production in rat arteries and cultured coronary arterial endothelial cells (CAECs), respectively, which was attenuated by resveratrol treatment. The smoking-induced upregulation of inflammatory markers (ICAM-1, inducible nitric oxide synthase, IL-6, and TNF-alpha) in rat arteries was also abrogated by resveratrol treatment. Resveratrol also inhibited CSE-induced NF-kappaB activation and inflammatory gene expression in CAECs. In CAECs, the aforementioned protective effects of resveratrol were abolished by knockdown of SIRT1, whereas the overexpression of SIRT1 mimicked the effects of resveratrol. Resveratrol treatment of rats protected aortic endothelial cells against cigarette smoking-induced apoptotic cell death. Resveratrol also exerted antiapoptotic effects in CSE-treated CAECs, which could be abrogated by knockdown of SIRT1. Resveratrol treatment also attenuated CSE-induced DNA damage in CAECs (comet assay). Thus resveratrol and SIRT1 exert antioxidant, anti-inflammatory, and antiapoptotic effects, which protect the endothelial cells against the adverse effects of cigarette smoking-induced oxidative stress. The vasoprotective effects of resveratrol will likely contribute to its antiaging action in mammals and may be especially beneficial in pathophysiological conditions associated with accelerated vascular aging.

Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2721-3

Beneficial effects of resveratrol on atherosclerosis.

Atherosclerosis, a progressive disease characterized by the accumulation of lipids and fibrous elements in the arteries, is a most important contributor to cardiovascular diseases. Resveratrol is a naturally occurring phytopolyphenol compound and shows the ability to reduce the risk of cardiovascular diseases. In this review, beneficial effects of resveratrol on the initiation and progression of atherosclerosis, including regulation of vasodilator and vasoconstrictor production, inhibition of oxidative stress/reactive oxygen species generation, anti-inflammation, inhibition of modification of low-density lipoproteins, anti-platelet aggregation, and its abilities to impede progression and modulate complications of atherosclerosis, are discussed.

J Med Food. 2008 Dec;11(4):610-4

Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production.

The mechanisms through which moderate wine consumption reduces ischemic cardiovascular events are not yet fully unraveled. Grape extracts or a mixture of the polyphenols contained in wine were previously shown to increase nitric oxide (NO); however, little information is available on the effect of resveratrol, one of the main polyphenols of wine, on platelet NO production. We assessed the effects of resveratrol, at the concentrations attainable after moderate wine intake, on platelet NO production and the mechanism of this activity. Twenty healthy volunteers were studied before and after 15 d of controlled white or red wine intake (300 mL/d). After wine intake, plasma resveratrol and the release of NO by stimulated platelets increased significantly. Resveratrol, at the concentrations detected in plasma after wine intake, was incubated in vitro with washed platelets and several variables related to NO production and to signal transduction were measured. Resveratrol in vitro enhanced significantly the production of NO by stimulated platelets, the activity of platelet NO synthase (NOS), phosphorylation of protein kinase B, an activator of the endothelial NOS (eNOS), and phosphorylation of vasodilator-activated protein (VASP), an expression of the biologic activity of NO in platelets. Simultaneously, we observed decreased phosphorylation of P38 mitogen-activated protein kinase (p38MAPK), a proinflammatory pathway in human platelets, a reduction of the activity of NADPH oxidase, a major source of reactive oxygen species (ROS) and of the generation of O(2)(-) radicals, as detected by cytochrome C reduction. In conclusion, resveratrol, at concentrations attainable after moderate wine intake, activates platelet eNOS and in this way blunts the proinflammatory pathway linked to p38MAPK, thus inhibiting ROS production and ultimately platelet function. This activity may contribute to the beneficial effects of moderate wine intake on ischemic cardiovascular disease.

J Nutr. 2008 Sep;138(9):1602-8

Cardioprotective actions of grape polyphenols.

The aim of this review is to discuss the accumulating evidence that suggests that grape extracts and purified grape polyphenols possess a diverse array of biological actions and may be beneficial in the prevention of some inflammatory-mediated diseases including cardiovascular disease. The active components from grape extracts, which include the grape seed, grape skin, and grape juice, that have been identified thus far include polyphenols such as resveratrol, phenolic acids, anthocyanins, and flavonoids. All possess potent antioxidant properties and have been shown to decrease low-density lipoprotein-cholesterol oxidation and platelet aggregation. These compounds also possess a range of additional cardioprotective and vasoprotective properties including antiatherosclerotic, antiarrhythmic, and vasorelaxation actions. Although not exclusive, antioxidant properties of grape polyphenols are likely to be central to their mechanism(s) of action, which also include cellular signaling mechanisms and interactions at the genomic level. This review discusses some of the evidence favoring the consumption of grape extracts rich in polyphenols in the prevention of cardiovascular disease. Consumption of grape and grape extracts and/or grape products such as red wine may be beneficial in preventing the development of chronic degenerative diseases such as cardiovascular disease.

Nutr Res. 2008 Nov;28(11):729-37

Long-term effects of resveratrol supplementation on suppression of atherogenic lesion formation and cholesterol synthesis in apo E-deficient mice.

Atherosclerosis is a chronic inflammatory disease of the arteries resulting from interactions between lipids, monocytes, and arterial wall cells. The effects of resveratrol supplements (RV, 0.02% and 0.06% each, w/w) with regard to the modulation of lipid profiles, cholesterol synthesis, and anti-atherogenesis were examined in apo E-deficient (apo E(-/-)) mice fed a normal diet. The concentration of total-cholesterol (total-C) and LDL-cholesterol (LDL-C) in plasma was significantly lower in the resveratrol-supplemented groups compare to the control group over the entire experimental period. The plasma HDL-C concentration was significantly elevated, and the ratio of HDL-C/total-C was significantly higher in the CF and RV groups than in the control group. Plasma paraoxonase (PON) activity was significantly higher in the 0.06% resveratrol group. The hepatic HMG-CoA reductase (HMGR) activity was significantly lower in the clofibrate and resveratrol groups than in the control group. Resveratrol supplements attenuated the presence of atherosclerotic lesions and periarterial fat deposition in the apo E(-/-) mice. The presence of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in atherosclerotic vessels was diminished in the resveratrol-supplemented apo E(-/-) mice. These results provide new insight into the anti-atherogenic and hypocholesterolemic properties of resveratrol in apo E(-/-) mice that were fed a normal diet.

Biochem Biophys Res Commun. 2008 Sep 12;374(1):55-9

The cardiac microvasculature in hypertension, cardiac hypertrophy and diastolic heart failure.

Recent studies revealed an exceedingly high mortality with diastolic heart failure that was previously regarded as relatively benign compared to systolic heart failure. Prominent risk factors for diastolic heart failure are increasing age, hypertension and diabetes. These risk factors are associated with coronary microvascular rarefaction and resultant decreased coronary flow reserve, thereby rendering the myocardium vulnerable to ischemia. We discuss the importance of angiogenic gene programming in preserving the coronary microvasculature, preserving cardiac function and altering disease course. Further, we discuss the possible utility of therapies that activate hypoxia inducible factor-1 in preventing rarefaction of the coronary microvasculature and maintaining cardiac diastolic function.

Curr Vasc Pharmacol. 2008 Oct;6(4):292-300

Diastolic dysfunction: a link between hypertension and heart failure.

Diastolic heart failure is characterized by the symptoms and signs of heart failure, a preserved ejection fraction and abnormal left ventricular (LV) diastolic function caused by a decreased LV compliance and relaxation. The signs and symptoms of diastolic heart failure are indistinguishable from those of heart failure related to systolic dysfunction; therefore, the diagnosis of diastolic heart failure is often one of exclusion. The majority of patients with heart failure and preserved ejection fraction have a history of hypertension. Hypertension induces a compensatory thickening of the ventricular wall in an attempt to normalize wall stress, which results in LV concentric hypertrophy, which in turn decreases LV compliance and LV diastolic filling. There is an abnormal accumulation of fibrillar collagen accompanying the hypertension-induced LV hypertrophy, which is also associated with decreased compliance and LV diastolic dysfunction. There are no specific guidelines for treating diastolic heart failure, but pharmacological treatment should be directed at normalizing blood pressure, promoting regression of LV hypertrophy, preventing tachycardia and treating symptoms of congestion. Preventive strategies directed toward an early and aggressive blood pressure control are likely to offer the greatest promise for reducing the incidence of diastolic heart failure.

Drugs Today (Barc). 2008 Jul;44(7):503-13

Resveratrol inhibits cardiac hypertrophy via AMP-activated protein kinase and Akt.

Whereas studies involving animal models of cardiovascular disease demonstrated that resveratrol is able to inhibit hypertrophic growth, the mechanisms involved have not been elucidated. Because studies in cells other than cardiomyocytes revealed that AMP-activated protein kinase (AMPK) and Akt are affected by resveratrol, we hypothesized that resveratrol prevents cardiac myocyte hypertrophy via these two kinase systems. Herein, we demonstrate that resveratrol reduces phenylephrine-induced protein synthesis and cell growth in rat cardiac myocytes via alterations of intracellular pathways involved in controlling protein synthesis (p70S6 kinase and eukaryotic elongation factor-2). Additionally, we demonstrate that resveratrol negatively regulates the calcineurin-nuclear factor of activated T cells pathway thus modifying a critical component of the transcriptional mechanism involved in pathological cardiac hypertrophy. Our data also indicate that these effects of resveratrol are mediated via AMPK activation and Akt inhibition, and in the case of AMPK, is dependent on the presence of the AMPK kinase, LKB1. Taken together, our data suggest that resveratrol exerts anti-hypertrophic effects by activating AMPK via LKB1 and inhibiting Akt, thus suppressing protein synthesis and gene transcription.

J Biol Chem. 2008 Aug 29;283(35):24194-201

Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac muscle cells.

Resveratrol, one of polyphenols derived from red wine, has been shown to protect against cell death, possibly through the association with several signaling pathways. Currently numerous studies indicate that cardiovascular diseases are linked to the release of intracellular reactive oxygen species (ROS) often generated in states such as ischemia/reperfusion injury. In the present study, we investigated whether resveratrol has the capability to control intracellular survival signaling cascades involving AMP-activated kinase (AMPK) in the inhibitory process of cardiac injury. We hypothesized that resveratrol may exert a protective effect on damage to heart muscle through modulating of the AMPK signaling pathway. We mimicked ischemic conditions by inducing cell death with H(2)O(2) in H9c2 muscle cells. In this experiment, resveratrol induced strong activation of AMPK and inhibited the occurrence of cell death caused by treatment with H(2)O(2). Under the same conditions, inhibition of AMPK using dominant negative AMPK constructs dramatically abolished the effect of resveratrol on cell survival in H(2)O(2)-treated cardiac muscle cells. These results indicate that resveratrol-induced cell survival is mediated by AMPK in H9c2 cells and may exert a novel therapeutic effect on oxidative stress induced in cardiac disorders.

Genes Nutr. 2008 Feb;2(4):323-6

Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese.

BACKGROUND: To date, no prospective studies have examined the association between serum homocysteine levels and the risk of stroke and stroke subtypes in Asian populations. METHODS AND RESULTS: A prospective, nested, case-control study of Japanese subjects 40 to 85 years of age was conducted by using frozen serum samples from 11,846 participants in cardiovascular risk surveys collected from 1984 to 1995 for one community and 1989 to 1995 for the other two communities. By the end of 2000, we identified 150 incident strokes, the subtypes of which were confirmed by imaging studies. Three control subjects per case were selected by matching for sex, age, community, year of serum storage, and fasting status. Serum total homocysteine levels were measured by high-performance liquid chromatography. Compared with control subjects, total (n=150), hemorrhagic (n=52), and ischemic (n=98) strokes had higher geometric mean values of total homocysteine and higher proportions of homocysteine > or =11.0 micromol/L. The multivariate odds ratios (95% CI) for highest (> or =11.0 micromol/L) versus lowest quartiles (<7.0 micromol/L) of homocysteine after adjustment for body mass index, smoking, alcohol intake, hypertension, serum total cholesterol, and other cardiovascular risk factors were 2.99 (1.51 to 5.93) for total stroke, 3.89 (1.60 to 9.46) for ischemic stroke, 3.36 (1.27 to 8.90) for lacunar infarction, and 1.63 (0.44 to 6.00) for hemorrhagic stroke. The respective multivariate odds ratios associated with a 5-micromol/L increase in homocysteine were 1.40 (1.09 to 1.80), 1.52 (1.07 to 2.14), 1.48 (1.01 to 2.18), and 1.10 (0.76 to 1.59). The excess risk of total and ischemic strokes did not vary significantly according to sex, age, smoking status, or hypertensive status. CONCLUSIONS: High total homocysteine concentrations were associated with the increased risk of total stroke, more specifically ischemic stroke and lacunar infarction, among Japanese men and women.

Circulation. 2004 Jun 8;109(22):2766-72

The methylation, neurotransmitter, and antioxidant connections between folate and depression.

Depression is common - one-fourth of the US population will have a depressive episode sometime in life. Folate deficiency is also relatively common in depressed people, with approximately one-third of depressed individuals having an outright deficiency. Folate is a water-soluble B-vitamin necessary for the proper biosynthesis of the monoamine neurotransmitters serotonin, epinephrine, and dopamine. The active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF, L-methylfolate), participates in re-methylation of the amino acid metabolite homocysteine, creating methionine. S-adenosylmethionine (SAMe), the downstream metabolite of methionine, is involved in numerous biochemical methyl donation reactions, including reactions forming monoamine neurotransmitters. Without the participation of 5-MTHF in this process, SAMe and neurotransmitter levels decrease in the cerebrospinal fluid, contributing to the disease process of depression. SAMe supplementation was shown to improve depressive symptoms. 5-MTHF also appears to stabilize, enhance production of, or possibly act as a substitute for, tetrahydrobiopterin (BH4), an essential cofactor in monoamine neurotransmitter biosynthesis. There are few intervention studies of folic acid or 5-MTHF as a stand-alone treatment for depression related to folate deficiency; however, the studies that have been conducted are promising. Depressed individuals with low serum folate also tend to not respond well to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Correcting the insufficiency by dosing folate along with the SSRI results in a significantly better antidepressant response.

Altern Med Rev. 2008 Sep;13(3):216-26

Homocysteine levels and risk of hip fracture in postmenopausal women.

BACKGROUND: Recent studies suggest that high homocysteine levels are associated with an increased risk of fractures. Homocysteine levels are known to be influenced by vitamin B and folate supply or status, and poor renal function can result in higher levels independent of nutritional adequacy. OBJECTIVE: The aim of the study was to determine the associations between fasting homocysteine levels and incident hip fractures, and the effects of other factors on hip fracture risk. DESIGN: We conducted a case-control study in the Women’s Health Initiative Observational Study, a study of postmenopausal women (n = 93,676) recruited in the United States. We selected 400 incident cases of hip fracture and 400 controls matched on age, ethnicity, and blood draw date among women not on osteoporosis therapies. Outcome measures included physician-adjudicated, incident hip fractures. Baseline lifestyle and nutritional questionnaires were performed. RESULTS: The risk of hip fracture increased 1.38-fold [95% confidence interval (CI), 1.14, 1.66] for each sd increase in serum homocysteine level after adjustment for fracture risk factors. This association was not affected by adjustment for dietary folate, B6, or B12 intake, but it diminished after adjustment for cystatin-C level (odds ratio, 1.08; 95% CI, 0.66-1.79), a measure of renal function not affected by muscle mass. Among women in the highest quartile of homocysteine and cystatin-C compared to those without elevations in either biomarker, the risk of hip fracture was substantially elevated (odds ratio, 2.8; 95% CI, 1.61-4.87). CONCLUSIONS: This study indicates that high homocysteine levels are associated with an increased risk of hip fracture, which could be accounted for by poor renal function.

J Clin Endocrinol Metab. 2009 Apr;94(4):1207-13

B vitamins, homocysteine, and bone disease: epidemiology and pathophysiology.

Observational studies indicate that mildly elevated homocysteine is a strong risk factor for osteoporotic fracture, yet there is no clear biologic mechanism for an effect of homocysteine on bone. The association could instead be attributed to B vitamins (folate, vitamin B(12), vitamin B(6)), as low levels of these nutrients are the primary determinants of homocysteine and may be associated with lower bone quality. Discovery of a direct effect of homocysteine or B vitamins on bone would be important in terms of interventions, as these factors can be modified with changes in diet or supplementation. This article reviews the connections of homocysteine and B vitamins to measures of bone quality and osteoporotic fracture. Although the literature suggests that these factors may be associated with bone health, most of the epidemiologic studies are observational, limiting conclusions regarding causality. More controlled trials are needed to determine whether treatment with B vitamins would reduce fracture rates among community-dwelling cohorts.

Curr Osteoporos Rep. 2007 Sep;5(3):112-9

Elevated serum homocysteine, low serum vitamin B12, folate, and age-related macular degeneration: the Blue Mountains Eye Study.

PURPOSE: To assess associations between increased serum homocysteine, low vitamin B12, low folate, and age-related macular degeneration (AMD). DESIGN: Population-based, cross-sectional analysis. METHODS: Serum homocysteine, vitamin B12, and folate were measured in 2,335 participants of the Blue Mountains Eye Study second survey. AMD detected from retinal photographs included atrophic or neovascular lesions. RESULTS: After adjusting for age, gender, and smoking in logistic regression models, homocysteine >15 micromol/l was associated with an increased likelihood of AMD in participants aged <75 years (odds ratio [OR] 3.21, 95% confidence interval [95% CI] 1.09 to 9.43). A similar association was found for vitamin B12 <125 pmol/l (OR 2.30, 95% CI 1.08 to 4.89) among all participants. In participants with homocysteine < or =15 micromol/l, low serum B12 was associated with nearly four-fold higher odds of AMD (OR 3.74, 95% CI 1.06 to 13.24). Folate was not statistically significantly associated with AMD. CONCLUSIONS: Increased homocysteine and low vitamin B12 were independently associated with an increased risk of AMD in this study population.

Am J Ophthalmol. 2007 Feb;143(2):344-6

Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women’s Antioxidant and Folic Acid Cardiovascular Study.

BACKGROUND: Observational epidemiologic studies indicate a direct association between homocysteine concentration in the blood and the risk of age-related macular degeneration (AMD), but randomized trial data to examine the effect of therapy to lower homocysteine levels in AMD are lacking. Our objective was to examine the incidence of AMD in a trial of combined folic acid, pyridoxine hydrochloride (vitamin B(6)), and cyanocobalamin (vitamin B(12)) therapy. METHODS: We conducted a randomized, double-blind, placebo-controlled trial including 5,442 female health care professionals 40 years or older with preexisting cardiovascular disease or 3 or more cardiovascular disease risk factors. A total of 5,205 of these women did not have a diagnosis of AMD at baseline and were included in this analysis. Participants were randomly assigned to receive a combination of folic acid (2.5 mg/d), pyridoxine hydrochloride (50 mg/d), and cyanocobalamin (1 mg/d) or placebo. Our main outcome measures included total AMD, defined as a self-report documented by medical record evidence of an initial diagnosis after randomization, and visually significant AMD, defined as confirmed incident AMD with visual acuity of 20/30 or worse attributable to this condition. RESULTS: After an average of 7.3 years of treatment and follow-up, there were 55 cases of AMD in the combination treatment group and 82 in the placebo group (relative risk, 0.66; 95% confidence interval, 0.47-0.93 [P = .02]). For visually significant AMD, there were 26 cases in the combination treatment group and 44 in the placebo group (relative risk, 0.59; 95% confidence interval, 0.36-0.95 [P = .03]). CONCLUSIONS: These randomized trial data from a large cohort of women at high risk of cardiovascular disease indicate that daily supplementation with folic acid, pyridoxine, and cyanocobalamin may reduce the risk of AMD.

Arch Intern Med. 2009 Feb 23;169(4):335-41

Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.

CONTEXT: It has been suggested that total blood homocysteine concentrations are associated with the risk of ischemic heart disease (IHD) and stroke. OBJECTIVE: To assess the relationship of homocysteine concentrations with vascular disease risk. DATA SOURCES: MEDLINE was searched for articles published from January 1966 to January 1999. Relevant studies were identified by systematic searches of the literature for all reported observational studies of associations between IHD or stroke risk and homocysteine concentrations. Additional studies were identified by a hand search of references of original articles or review articles and by personal communication with relevant investigators. STUDY SELECTION: Studies were included if they had data available by January 1999 on total blood homocysteine concentrations, sex, and age at event. Studies were excluded if they measured only blood concentrations of free homocysteine or of homocysteine after a methionine-loading test or if relevant clinical data were unavailable or incomplete. DATA EXTRACTION: Data from 30 prospective or retrospective studies involving a total of 5,073 IHD events and 1,113 stroke events were included in a meta-analysis of individual participant data, with allowance made for differences between studies, for confounding by known cardiovascular risk factors, and for regression dilution bias. Combined odds ratios (ORs) for the association of IHD and stroke with blood homocysteine concentrations were obtained by using conditional logistic regression. DATA SYNTHESIS: Stronger associations were observed in retrospective studies of homocysteine measured in blood collected after the onset of disease than in prospective studies among individuals who had no history of cardiovascular disease when blood was collected. After adjustment for known cardiovascular risk factors and regression dilution bias in the prospective studies, a 25% lower usual (corrected for regression dilution bias) homocysteine level (about 3 micromol/L [0.41 mg/L]) was associated with an 11% (OR, 0.89; 95% confidence interval [CI], 0.83-0.96) lower IHD risk and 19% (OR, 0.81; 95% CI, 0.69-0.95) lower stroke risk. CONCLUSIONS: This meta-analysis of observational studies suggests that elevated homocysteine is at most a modest independent predictor of IHD and stroke risk in healthy populations. Studies of the impact on disease risk of genetic variants that affect blood homocysteine concentrations will help determine whether homocysteine is causally related to vascular disease, as may large randomized trials of the effects on IHD and stroke of vitamin supplementation to lower blood homocysteine concentrations.

JAMA. 2002 Oct 23-30;288(16):2015-22

In pregnant women who smoke, caffeine consumption is associated with an increased level of homocysteine.

AIM. To investigate whether maternal caffeine consumption is associated with increased maternal homocysteine (Hcy) levels in uncomplicated pregnancies. METHODS. Ninety-two pregnant women were randomly selected, and maternal serum levels of folate, vitamin B(12), and Hcy at gestational weeks 17 and 33 were measured. Caffeine consumption was estimated from dietary records collected at the same gestational ages. RESULTS. In women who smoked, Hcy levels were associated with caffeine consumption both in gestational weeks 17 and 33 and with folate at week 33. Consumption of one cup of coffee was associated with an increase in maternal Hcy of 0.26 micromol/l at week 17 and 0.69 micromol/l at week 33, indicating that one extra cup (150 ml) of coffee per day may increase Hcy by 5--10% in pregnant smokers. In non-smokers, caffeine consumption was not associated with Hcy levels. CONCLUSIONS. In uncomplicated pregnancies, maternal caffeine consumption early in the second and in the third trimester is associated with increased maternal Hcy levels in women who smoked, but not in non-smokers.

Acta Obstet Gynecol Scand. 2005 Nov;84(11):1049-54

Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study.

OBJECTIVE—To estimate the relations between established cardiovascular risk factors and total homocysteine (tHcy) in plasma. DESIGN—Health examination survey by the Norwegian Health Screening Service in 1992 and 1993. SETTING—General community, Hordaland County of Western Norway. PARTICIPANTS—A total of 7,591 men and 8,585 women, 40 to 67 years of age, with no history of hypertension, diabetes, coronary heart disease, or cerebrovascular disease were included. MAIN OUTCOME MEASURE—Plasma tHcy level. RESULTS—The level of plasma tHcy was higher in men than in women and increased with age. In subjects 40 to 42 years old, geometric means were 10.8 mumol/L for 5918 men and 9.1 mumol/L for 6,348 women. At age 65 to 67 years, the corresponding tHcy values were 12.3 mumol/L (1,386 men) and 11.0 mumol/L (1,932 women). Plasma tHcy level increased markedly with the daily number of cigarettes smoked in all age groups. Its relation to smoking was particularly strong in women. The combined effect of age, sex, and smoking was striking. Heavy-smoking men aged 65 to 67 years had a mean tHcy level 4.8 mumol/L higher than never-smoking women aged 40 to 42 years. Plasma tHcy level also was positively related to total cholesterol level, blood pressure, and heart rate and inversely related to physical activity. The relations were not substantially changed by multivariate adjustment, including intake of vitamin supplements, fruits, and vegetables. CONCLUSIONS—Elevated plasma tHcy level was associated with major components of the cardiovascular risk profile, ie, male sex, old age, smoking, high blood pressure, elevated cholesterol level, and lack of exercise. These findings should influence future studies on the etiology and pathogenesis of cardiovascular disease.

JAMA. 1995 Nov 15;274(19):1526-33

Homocysteine, B-vitamins and CVD.

There is considerable interest in plasma homocysteine (tHcy) as a CVD risk factor. Although the secondary prevention trials published to date have been inconclusive in confirming a benefit of tHcy-lowering treatment with B-vitamins on CVD events generally, such studies are widely recognised to have been insufficiently powered to detect a significant effect for the predicted magnitude of association between tHcy and heart disease risk, and therefore cannot be interpreted as evidence that no relationship exists. In fact, a recent meta-analysis of clinical trials has confirmed that folic acid supplementation reduces the risk of stroke, particularly in individuals without a history of stroke. Evidence supporting a causal relationship between elevated tHcy and heart disease also comes from genetic studies. The most important genetic determinant of tHcy in the general population is the common C677T variant in methylenetetrahydrofolate reductase (MTHFR) that results in higher tHcy. Individuals with the homozygous mutant (TT) genotype have a significantly higher (14-21%) risk of heart disease. Plasma tHcy is very responsive to intervention with the B-vitamins required for its metabolism, in particular folic acid, and to a lesser extent vitamins B12 and B6. Thus, although primarily aimed at reducing neural-tube defects, folic acid fortification may have an important role in the primary prevention of CVD via tHcy lowering. Besides folate, riboflavin is required as a cofactor for MTHFR and enhanced riboflavin status results in a marked lowering in tHcy specifically in individuals with the TT genotype, presumably by neutralising the variant form of the enzyme. About 10% of the UK and Irish populations have the TT genotype. In the present paper the potential role of folate and related B-vitamins in the primary prevention of CVD and the implications for nutrition policy are explored.

Proc Nutr Soc. 2008 May;67(2):232-7

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