Bruce Ames

Children's Hospital Oakland Research Institute | CHORI · Nutrition & Metabolism

Asthma in the obese is often severe, difficult to treat, and characterized by less eosinophilic inflammation than asthma in the nonobese. Obesity-associated metabolic dysregulation may be a causal factor. We previously reported that a nutrient- and fiber-dense bar [Children’s Hospital Oakland Research Institute (CHORI)-bar], which was designed to f...

Graft-versus-host disease (GVHD) is a common complication of allogeneic bone marrow transplantation (BMT). Upregulation of inflammatory cytokines precedes the clinical presentation of GVHD and predicts its severity. In this report, thiol/redox metabolomics was used to identify metabolic perturbations associated with early preclinical (Day+4) and cl...

This exploratory study assessed apoptosis in peripheral blood leucocytes (PBL) from β-thalassaemia patients receiving chronic transfusions and chelation therapy (deferasirox or deferoxamine) at baseline, 1, 6, and 12 months. At baseline, thalassaemic PBLs presented 50% greater levels of Bax (BAX), 75% higher caspase-3/7, 48% higher caspase-8 and 88...

4107 Graft-versus-host disease (GVHD) is characterized by cytokine and chemokine dysregulation that predicts and also contributes to disease severity. Intermediates in sulfur amino acid (SAA) metabolism are known to modulate cytokines implicated in GVHD, such as TNF-α and IL-2. In this report, a new redox metabolomics assay was used to simultaneous...

Eotaxin-3 (CCL-26), a potent chemokine for eosinophil recruitment and contributing significantly to the pathogenesis of asthma, is secreted by lung epithelial cells in response to T helper 2 cytokines including interleukin 13 (IL-13). Here we showed that vitamin E forms, but not their metabolites, differentially inhibited IL-13-stimulated generatio...

The triage theory proposes that modest deficiency of any vitamin or mineral (V/M) could increase age-related diseases. V/M-dependent proteins required for short-term survival and/or reproduction (i.e., "essential") are predicted to be protected on V/M deficiency over other "nonessential" V/M-dependent proteins needed only for long-term health. The...

Epidemiological studies reveal strong association between micronutrient deficiencies and development of cancer. Since chromosome breaks and abnormal chromosome segregation, identified as micronuclei (MN), are central to malignant transformation, the influence of micronutrient status upon MN frequency has been the subject of intense research. Motiva...

I review three of our research efforts which suggest that optimizing micronutrient intake will in turn optimize metabolism, resulting in decreased DNA damage and less cancer as well as other degenerative diseases of aging. (1) Research on delay of the mitochondrial decay of aging, including release of mutagenic oxidants, by supplementing rats with...

Three of our research efforts are reviewed, which suggest that optimizing metabolism will delay aging and the diseases of aging in humans. (1) Research on delay of the mitochondrial decay of aging by supplementing rats with lipoic acid and acetyl carnitine. (2) The triage theory, which posits that modest micronutrient deficiencies (common in much o...

4065 Poster Board III-1000 Background Oxidative stress in β-thalassemia major is a well documented problem thought in part to be due to transfusional iron overload. Sulfur amino acid (SAA)-derived metabolites, chiefly glutathione (GSH), are critical components of cellular antioxidant defense. Inability to adequately regulate endogenous antioxidant...

The triage theory posits that some functions of micronutrients (the approximately 40 essential vitamins, minerals, fatty acids, and amino acids) are restricted during shortage and that functions required for short-term survival take precedence over those that are less essential. Insidious changes accumulate as a consequence of restriction, which in...

The total concentrations of four sulfur amino acid (SAA) metabolite redox couples (reduced and oxidized forms of homocysteine, cysteine, glutathione, and cysteinylglycine) in human blood are assayed with a simple and sensitive method by liquid chromatography-electrospray positive ionization-tandem mass spectrometry. To prevent ex vivo thiol oxidati...

GENERAL PRINCIPLES Molecular Mechanisms of Cancer Induction and Chemoprevention (Bartsch and Gerhauser) Types and Consequences of DNA Damage (Shaughnessy and DeMarini) Induction of DNA Damage and Cancer by Dietary Factors (Parzefall, Kager and Knasmuller) Mechanisms of Chemoprevention, Antimutagenesis, and Anticarcinogenesis: An Overview (De Flora,...

Compared to healthy subjects, individuals with allergic airway disease (e.g., asthma, allergic rhinitis) have enhanced inflammatory responses to inhaled ozone. We created a rodent model of ozone-enhanced allergic nasal responses in Brown Norway rats to test the therapeutic effects of the dietary supplement gamma-tocopherol (gammaT). Ovalbumin (OVA)...

We measured age-dependent effects of human ApoE4 on cerebral blood flow (CBF) using ApoE4 transgenic mice compared to age-matched wild-type (WT) mice by use of [(14)C] iodoantipyrene autoradiography. ApoE4 associated factors reduce CBF gradually to create brain hypoperfusion when compared to WT, and the differences in CBF are greatest as animals ag...

Iron overload has been shown to induce DNA damage and may be implicated in leukocyte apoptosis. Previously we have shown that indirect markers of apoptosis such as caspase activity and Bax levels were higher in leukocytes of thalassemia patients. We have now assessed whether nucleosomal DNA fragmentation, a hallmark of apoptosis, is higher in leuko...

Iron overload has been shown to induce DNA damage and may be implicated in leukocyte apoptosis. Previously we have shown that indirect markers of apoptosis such as caspase activity and Bax levels were higher in leukocytes of thalassemia patients. We have now assessed whether nucleosomal DNA fragmentation, a hallmark of apoptosis, is higher in leuko...

To investigate the mitochondrial decay and oxidative damage resulting from aging, the activities/kinetics of the mitochondrial complexes were examined in the brains of young and old rats as well as in old rats fed R-alpha-lipoic acid plus acetyl-L-carnitine (LA/ALC). The brain mitochondria of old rats, compared with young rats, had significantly de...

A simple statistical method is described to test whether data are consistent with minimum statistical variability expected in a biological experi- ment. The method is applied to data presented in data tables in a subset of 84 articles among more than 200 published by 3 investigators in a small medical biochemistry department at a major university i...

A simple statistical method is described to test whether data are consistent with minimum statistical variability expected in a biological experiment. The method is applied to data presented in data tables in a subset of 84 articles among more than 200 published by 3 investigators in a small medical biochemistry department at a major university in...

Nonsteroidal anti-inflammatory drugs such as aspirin are used for pain relief and chemoprevention against cancer, but frequently cause gastric mucosal injury. We examined whether combinations of aspirin and alpha-tocopherol (alphaT) or aspirin and gamma-tocopherol (gammaT), with alphaT and gammaT being the two major forms of vitamin E, are better a...

The aim of this study was to determine whether women with low iron stores (plasma ferritin <or= 20 microg/L) receiving a daily iron supplement for 8 wks at a level commonly used to treat poor iron status develop increased lipid peroxidation as measured by ethane exhalation rates and plasma malondialdehyde. The women served as their own control as p...

Background and aims: The diagnosis of autosomal dominant hyperc-holesterolemia (ADH) in Greece has primarily been based on clinical characteristics. In fact, only a limited number of Greek patients have been screened for LDLR mutations. Over the past three years, in an attempt to enhance our limited knowledge of the molecular basis of ADH in Greece...

Magnesium inadequacy affects more than half of the U.S. population and is associated with increased risk for many age-related diseases, yet the underlying mechanisms are unknown. Altered cellular physiology has been demonstrated after acute exposure to severe magnesium deficiency, but few reports have addressed the consequences of long-term exposur...

Vitamin D insufficiency is common in the United States; the elderly and African-Americans are at particularly high risk of deficiency. This review, written for a broad scientific readership, presents a critical overview of scientific evidence relevant to a possible causal relationship between vitamin D deficiency and adverse cognitive or behavioral...

Brain function declines with age and is associated with diminishing mitochondrial integrity. The neuronal mitochondrial ultrastructural changes of young (4 months) and old (21 months) F344 rats supplemented with two mitochondrial metabolites, acetyl-L-carnitine (ALCAR, 0.2%[wt/vol] in the drinking water) and R-alpha-lipoic acid (LA, 0.1%[wt/wt] in...

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...

Airway epithelial cells release eotaxins (CCLll, CCL24, CCL26) upon being stimulated by IL‐13, a cytokine generated from Th2 cells. Eotaxins are potent chemotactic agents for eosinophils, which play an important role in the pathogenesis of allergic airway diseases. The goal in the current study is to investigate the potential effect of vitamin E fo...

We examined whether combinations of aspirin and alpha‐tocopherol (aT) or gamma‐tocopherol (gT), two major forms of vitamin E, can alleviate aspirin‐caused stomach lesion and may be better anti‐inflammatories than aspirin alone. In carrageenan‐induced inflammation air‐pouch model, aspirin at 150mg/kg inhibited inflammation‐associated increase of pro...

We studied the cellular and subcellular features of vascular lesions, immunoreactivity of vasoactive substances, and mitochondria in brain vascular wall cells and hippocampal neurons from human Alzheimer disease (AD) and animal models that mimic AD. Lesioned vessels with immunopositive staining for AbPP and iNOS, and large, lipid‐laden vacuoles in...

Methylene blue (MB) has been used clinically for about a century to treat numerous ailments. We show that MB and other diaminophenothiazines extend the life span of human IMR90 fibroblasts in tissue culture by >20 population doubling (PDLs). MB delays senescence at nM levels in IMR90 by enhancing mitochondrial function. MB increases mitochondrial c...

Autism Spectrum Disorder (ASD) is a behaviorally defined neurodevelopmental disorder whose etiology is poorly understood. Recent studies have shown that autistic children may be experiencing increased inflammation and oxidative stress. Altered immune regulation may be one contributing factor to inflammation and oxidative stress in autistic children...

Iron overload occurs frequently in thalassemia and other disorders that require regular blood transfusions. Excess iron is toxic owing to the generation of free radicals that lead to oxidation of biomolecules and tissue damage. In order to identify compounds that reduce oxidative injury from iron, we evaluated alpha-lipoic acid (LA), a multifunctio...

Improvements are made to our gas-chromatography-mass-spectrometry-based assay for quantifying low levels of DNA-uracil. Folate deficiency leads to increased deoxyuridine monophosphate/thymidylate (dUMP/dTMP) ratios and uracil misincorporation into DNA, which may increase cancer risk. Vitamin B6 (B6) deficiency might also result in increased DNA-ura...

Erythrocyte glutathione depletion has been linked to hemolysis and oxidative stress. Glutamine plays an additional antioxidant role through preservation of intracellular nicotinamide adenine dinucleotide phosphate (NADPH) levels, required for glutathione recycling. Decreased nitric oxide (NO) bioavailability, which occurs in the setting of increase...

Age-related macular degeneration (AMD) is the leading cause of severe visual impairment in the elderly in developed countries. AMD patients have elevated levels of iron within the retinal pigment epithelia (RPE), which may lead to oxidative damage to mitochondria, disruption of retinal metabolism, and vision impairment or loss. As a possible model...

Iron overload has been shown to increase mitochondrial dysfunction and apoptosis and may be implicated in leukocyte apoptosis. We assessed whether markers of leukocyte apoptosis and mitochondrial dysfunction are higher in iron-overloaded thalassemia patients compared with control subjects and whether improvement in the control of iron overload with...

Oxidative stress is integral to pathophysiology of sickle cell disease and thalassemia. Precipitated globin chains in thalassemia generate free radicals, while increased superoxide, vaso-occlusive crises (VOC) and depletion of NO contribute to pro-oxidant state in SCD. To combat oxidative stress in hemoglobinopathies, potent antioxidant compounds a...

The erythrocyte redox environment may contribute to increased hemolysis and decreased nitric oxide (NO) bioavailability in pulmonary hypertension (PH) of sickle cell disease (SCD). Glutathione (GSH) is the principal thiol redox buffer in erythocytes and its depletion has been linked to hemolysis. Glutamine plays an additional anti-oxidant role thro...

Ozone is a commonly encountered environmental oxidant which has been linked to asthma exacerbation in epidemiological studies. Ozone induces airway inflammation and enhances response to inhaled allergen. It has been suggested that antioxidant therapy may minimize the adverse effects of ozone in asthma. We have previously shown that the antioxidant...

The known functions of folate are to support one-carbon metabolism and to serve as photoreceptors for cryptochromes and photolyases. We demonstrate that 5-methyltetrahydrofolate (5-MTHF, the predominant folate in plasma) is also a potent, near diffusion limited, scavenger of singlet oxygen and quencher of excited photosensitizers. Both pathways res...

We studied the cellular and subcellular features of vascular lesions, immunoreactivity of vasoactive substances, and mitochondria in brain vascular wall cells and hippocampal neurons from human Alzheimer disease (AD) and animal models that mimic AD. Lesioned vessels with immunopositive staining for AbPP and iNOS, and large, lipid-laden vacuoles in...

This review, intended for a broad scientific readership, summarizes evidence relevant to whether a causal relation exists between dietary iron deficiency with (ID+A) or without (ID-A) anemia during development and deficits in subsequent cognitive or behavioral performance. An overview of expert opinion and major evidence in humans and animals is pr...

Although alcoholism causes changes in hepatic folate metabolism that are aggravated by folate deficiency, male reproductive effects have never been studied. We evaluated changes in folate metabolism in the male reproductive system following chronic ethanol consumption and folate deficiency. Twenty-four juvenile micropigs received folate-sufficient...

To understand better the cell and molecular basis for the epidemiologic association between cigarette smoke, oxidant injury, and age-associated macular degeneration, the authors examined the effects of acrolein, a major toxicant in cigarette smoke, on oxidative mitochondrial damage in retinal pigment epithelial (RPE) cells and the reduction of this...

Four of the 5 biotin-dependent carboxylases (BDC) are in the mitochondria. BDC replace intermediates in the Krebs [tricarboxylic acid (TCA)] cycle that are regularly removed for the synthesis of key metabolites such as heme or amino acids. Heme, unlike amino acids, is not recycled to regenerate these intermediates, is not utilized from the diet, an...

Inadequate dietary intakes of vitamins and minerals are widespread, most likely due to excessive consumption of energy-rich, micronutrient-poor, refined food. Inadequate intakes may result in chronic metabolic disruption, including mitochondrial decay. Deficiencies in many micronutrients cause DNA damage, such as chromosome breaks, in cultured huma...

Background: Pulmonary hypertension (PHT) is a strong predictor of mortality in sickle cell disease (SCD), and is associated with dysregulation of the arginine-nitric oxide (NO) pathway. This is in part the consequence of hemolysis, as erythrocyte release of plasma hemoglobin consumes NO, while simultaneous release of arginase consumes arginine, the...

Background: Glutathione (GSH) is the most abundant intracellular non-protein thiol and is an anti-oxidant present in high millimolar concentration in erythrocytes. Additionally, GSH plays an important role in signal transduction, gene expression, apoptosis, protein glutathionylation, nitric oxide metabolism, and is the principal thiol redox buffer...

In our recent paper,'') we called attention to some of the points raised by Wlupple and by Zeise, Crouch, and Wilson. Our interest in this subject developed as we began analyzing our database of animal carcinogenesis bioas~ays.(*~~)In our analyses, we used as a measure of carcinogenic potency, the TD,,, defined as the dose rate (in mg/kg/body wt/da...

IntroductionRemediation by High B Vitamin Intake of Variant Enzymes with Poor Binding Affinity (Km) for CoenzymesDeformation of Proteins in Mitochondria with AgingNonmitochondrial Enzymes that are Deformed with AgeConclusion AcknowledgmentsReferences

Interest in the role of mitochondria in aging has intensified in recent years. This focus on mitochondria originated in part from the free radical theory of aging, which argues that oxidative damage plays a key role in degenerative senescence. Among the numerous mechanisms known to generate oxidants, leakage of the superoxide anion and hydrogen per...

This review is part of a series intended for non-specialists that will provide an overview of evidence for causal relationships between micronutrient deficiencies and brain function. Here, we review 34 studies in rodents linking the availability of choline during gestation and perinatal development to neurological function or performance of offspri...

Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alte...

To determine whether (R)-alpha-lipoic acid (LA) protects cultured human fetal retinal pigment epithelial (hfRPE) cells against oxidative injury and identify the pathways that may mediate protection. Cultured hfRPE cells were pretreated with various concentrations of LA for 14 to 16 hours followed by treatment with a chemical oxidant, tert-butylhydr...

Objective: We examined whether oxidant-stress and inflammation in β-thalassemia can be controlled by deferasirox as effectively as by deferoxamine (DFO) through analysis of body iron burden and biomarkers of lipid peroxidation and inflammation. Methods: Thalassemia Clinical Research Network patients participating in the Novartis CICL670A0107 trial...

Antioxidant supplementation could reduce organ damage and premature death in patients with iron overload. We evaluated the improvement in iron-induced oxidative stress with α-Lipoic acid (LA), a multifunctional thiol antioxidant and inducer of phase II enzymes, and compared it with benzylhydroxylamine (BH), a reducing agent that protects against fr...

Double-stranded DNA breaks are serious lesions that contribute to the pathogenesis of cancer and chronic illnesses. Free radical injury is an important mechanism for the production of DNA modifications that eventually lead to chromosomal breaks. The generation of free radicals is increased in sickle cell disease (SCD) owing to the presence of the r...

This review is part of a series intended for nonspecialists that will summarize evidence relevant to the question of whether causal relations exist between micronutrient deficiencies and brain function. Here, we focus on experiments that used cognitive or behavioral tests as outcome measures in experimental designs that were known to or were likely...

This review is part of a series intended for nonspecialists that will summarize evidence relevant to the question of whether causal relations exist between micronutrient deficiencies and brain function. Here, we focus on experiments that used cognitive or behavioral tests as outcome measures in experimental designs that were known to or were likely...

Mitochondrial oxidative decay, which is a major contributor to aging, is accelerated by many common micronutrient deficiencies. One major mechanism is inhibition of the pathway of heme biosynthesis in mitochondria, which causes a deficit of heme-a. Heme-a, only found in Complex IV, is selectively diminished, resulting in oxidant leakage and acceler...

Mitochondrial decay due to oxidative damage is a contributor to brain aging and age-related neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). One type of mitochondrial decay is oxidative modification of key mitochondrial enzymes. Enzyme dysfunction, that is due to poor binding of substrates and coenzymes may...

Exposure to environmental stress, such as radiation, poor nutrition, or smoking, can cause hazardous lesions in DNA, including double-strand breaks. In red blood cells, a DNA fragment or lagging chromosome forms a micronucleus when left behind after the main nucleus is extruded to form the mature reticulocyte during erythropoiesis. Reticulocytes wi...

Iron-mediated oxidative stress plays an important role in the pathophysiology of thalassemia. Oxidative stress can cause lesions in DNA, including double-strand breaks. DNA damage, which is a cause of cancer (although not the only one), is recognized as deleterious. Unlike cancer, DNA damage can be assayed easily and relatively inexpensively in hum...

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 cel...

γ-Tocopherol (γT), the predominant form of vitamin E in diets, but not α-tocopherol, the major vitamin E form in tissues and supplements, inhibits proliferation of prostate cancer cells (LNCaP and PC-3) and lung cancer cells (A549). In contrast, at similar concentrations, γT has no effect on normal prostate epithelial cells. Combinations of some vi...

Oxidative mitochondrial decay is a major contributor to aging. Some of this decay can be reversed in old rats by feeding them normal mitochondrial metabolites, acetylcarnitine (ALC) and lipoic acid (LA), at high levels. Feeding the substrate ALC with LA, a mitochondrial antioxidant, restores the velocity of the reaction (K(m)) for ALC transferase a...

L-carnitine and acetyl-L-carnitine (ALC) are both used to improve mitochondrial function. Although it has been argued that ALC is better than l-carnitine in absorption and activity, there has been no experiment to compare the two compounds at the same dose. In the present experiment, the effects of ALC and L-carnitine on the levels of free, acyl, a...

Folate is required for one-carbon transfer reactions and the formation of purines and pyrimidines for DNA and RNA synthesis. Deficiency of folate can lead to many clinical abnormalities, including macrocytic anemia, cardiovascular diseases, birth defects, and carcinogenesis. The nucleotide imbalance due to folate deficiency causes cell cycle arrest...

Iron accumulates as a function of age and is associated with the pathology of numerous age-related diseases. These changes may be caused by altered iron homeostasis at the cellular level, yet this is poorly understood. Therefore, changes in iron content in primary human fibroblasts were studied in culture models of cellular senescence. Total iron c...

Folate deficiency leads to increased dUMP/dTMP ratios and uracil misincorporation into DNA, which may increase cancer risk. We improved a previously described gas chromatography-mass spectrometry (GC-MS) assay for uracil in DNA and validated the assay by analyzing the DNA-uracil content of normal, primary human lymphocytes that were cultured in 0-3...

Mitochondrial dysfunction may be a principal underlying event in aging, including the degenerative diseases of aging such as brain degeneration. Mitochondria provide energy for basic metabolic processes, and their decay with age impairs cellular metabolism and leads to cellular decline. Progress over the last decade in delaying the mitochondrial de...

Mitochondrial decay due to oxidant byproducts is a principal underlying contributor to aging, including the degenerative diseases of aging such as brain degeneration [15,23,32]. The energy for basic metabolic processes comes from mitochondria, and their decay with age impairs cellular metabolism and leads to cellular decline. Our progress over the...