PharmacoNutrition Reviewed

Source: Am. J. Physiol. Regul. Integr. Comp. Physiol. (2007) [Epub]
Article Type: Original Research
Authors: Martin-Gronert et al.

This is now the third time I am writing about the impact of in utero and early postnatal nutrition on fitness in later life.  Whereas before we learned some new insights in how changes in maternal dietary iron or fat might affect offspring life, the new paper by Martin-Gronert et al. addresses the question how dietary postnatal protein levels regulate key molecules believed to markedly control the aging process.

When pups of normally-fed dams were nursed by low-protein-fed (8% vs. 20% in the control group; iso-caloric diets) dams, dramatic biochemical changes (measured at day 21 post partum) occurred that might explain the earlier reported increased lifespan in these animals. The authors not only found that insulin sensitivity was improved but also a significant upregulation (measured in kidney tissue) of IRbeta, IGF1-R, Akt1, Akt2 as well as SIRT1. In addition, the expression of important antioxidant enzymes, i.e. catalase, CuZnSOD and GPx1, was elevated.

Martin-Gronert et al. conclude that “the findings of this study are in agreement with Hormesis Hypothesis, which has been proposed to explain the life-extending action of calorie restriciton. The hypothesis postulates that a low-intensity biological stressor exerts defence responses in the organism that help protect it against the causes of aging. The enhanced coping with intense stressors and restriction of senescent deterioration lead to retardation of age associated diseases and increased longevity. It seems that a similar process may underlie the association between early nutrition and the aging process.”

A candidate for the effect of restricted protein intake on lifespan has also been recently identified by Naudi et al.: methionine (whose restriction leads to upregulation of uncoupling proteins (UCP4) and an increase in mitochondrial biogenesis).

Poor mums-to-be: your burden of doing things right during pregnacy and nursing are certainly on the rise.

Image taken from: jupiterimages.com

Source: JBC 7 Jan 2008 (Epub)
Article Type: Original Research
Authors: Cuddihy et al.

For many people vitamin E supplementation is still the magic bullet for preventing the onset of chronic diseases and even the maladies of aging. Although vitamin E in its various forms is certainly important for cell and organ function, the present paper by Cuddihy et al. is a nice example that mother nature created the activity pattern of biomolecules not in a one-way fashion but somewhat chaotic. But read yourself…..

“Vitamin E is the major lipid soluble chain-breaking antioxidant in mammals and plays an important role in normal development and physiology. Deficiency (whether dietary or genetic) results in primarily nervous system pathology, including cerebellar neurodegeneration and progressive ataxia (abnormal gait). However, despite the widely acknowledged antioxidant properties of vitamin E, only a few studies have directly correlated levels of reactive oxygen species with vitamin E availability in animal models. We explored the relationship between vitamin E and reactive oxygen species in two mouse models of vitamin E deficiency; dietary deficiency, and a genetic model (tocopherol transfer protein, Ttp-/-, mice).

Both groups of mice developed near-complete depletion of alpha-tocopherol (the major tocopherol in vitamin E) in most organs, but not brain, which was relatively resistant to loss of alpha-tocopherol. F4-neuroprostanes, an index of lipid peroxidation, were unexpectedly lower in brain of deficient mice compared to controls. In vivo oxidation of dihydroethidium by superoxide radical was also significantly lower in brain of deficient animals. Superoxide production by brain mitochondria isolated from vitamin E deficient and Ttp-/- mice, measured by electron paramagnetic resonance spectroscopy, demonstrated a biphasic dependence on exogenously added alpha-tocopherol. At low concentrations, alpha-tocopherol enhanced superoxide flux from mitochondria, a response which was reversed at higher concentrations.

Here we propose a mechanism, supported by molecular modeling, to explain decreased superoxide production during alpha-tocopherol deficiency, and speculate that this could be a beneficial response under conditions of alpha-tocopherol deficiency.”

Image taken from: dopaminejewelery.com

Source: J. Pediatr. (152) 2008: 79-84
Article Type: Original Research
Authors: Aaltonen et al.

Alcohol consumption and smoking have long been the only concerns regarding the time we spend in utero. This, however, changed with the publication of the so-called Barker hypothesis in the 1980s. Barker postulated that maternal under-/malnutrition might have long-lasting effects on the susceptibility and occurrence of various diseases (especially cardiovascular disease) in the life of their children (’fetal or in utero programming‘).

Aaltonen et al. studied the effect of fat-modified diets consumed during pregnancy on the blood  pressure of 6-month old infants (n=256). After dividing the dietary intake into quartiles and correcting for various confounding variables, the authors found:

1) a U-shape association maternal mono-unsaturated fatty acid (MUFA) intake and infant diastolic blood pressure

2) a U-shape association between maternal carbohydrate intake and infant diastolic and systolic blood pressure

“One of the most interesting findings in our study was the complex interaction between maternal carbohydrate intake and infant blood pressure. This finding may be linked to the pathogenesis of gestational diabetes in which altered glucose metabolism in the mother exposes the fetus to high levels of blood glucose and subsequent hyperinsulinemia. Due to the anabolic properties of insulin, hyperglycemia (even in temporary peaks) may lead to cardiac hypertrophy and functional abnormalities. Therefore, a high maternal carbohydrate intake, particularly consumption of refined carbohydrates in the diet, could result in subclinical maternal hyperglycemia and mild fetal hyperinsulinemia, resulting in higher blood pressure in infancy. This concept is supported by the observation that the higher systolic blood pressure in the neonatal period is linked to increased umbilical cord insulin concentrations, which may be driven by even minor maternal hyperglycemia. In view of the adverse fetal metabolic programming of intrauterine hyperglycemia in gestational diabetes in combination with a postnatal nutritional imbalance manifesting itself in a clustering of the cardiovascular risk factors at even early ages, the long-term sequelae of our finding warrant further investigation.”

Taken together, this study again indicates that the environmental conditions (i.e. maternal diet, body weight, etc.) we are exposed to in utero might be a lot more important for our teenage and adult life than many of us previously thought.

Image taken from: pregnancy.about.com

Source: Am. J. Physiol. Heart Circ. Physiol. 04 JAN 2008 [Epub]
Article Type: Original Research

Authors: Angeloni et al.

The flavonoid quercetin (QU) is among the most common polyphenols found in the human diet. In the present study, Angeloni et al. assessed the in vitro effect of QU on the expression of more than 20.000 genes in cardiomyocytes.

The data, also this has not been directly discussed by the authors, suggest a hormetic effect of QU in this cell culture model, evident by the modulation of various phase II enzymes (such as HSP-32). These proteins, in turn, indirectly affect the cellular antioxidant defense system. i.e. render the cells better equipped for the occurrence of oxidative stress.

Although, in contrast to the authors, I think that the QU concentration tested (30 microM) is rather high (and certainly not in the physiological range), the article provides various interesting targets for the modulation of oxidative stress resistance of cardiomyocytes.

Let’s hope somebody dares to make the next step and assesses the impact of orally administered QU (and related flavonoids) and gene expression under in vivo conditions.

Image taken from: www.3dscience.com

When searching for some new interesting articles I came across a recent publication by Oben et al. which has been released online on September 05, 2007 in Lipids in Health and Disease (Biomed Central).
The article describes effects of ProAlgaZyme (PAZ), a novel algae infusion, on various CVD biomarkers in patients with metabolic syndrome. The product, though actually not that novel (PAZ has previously been marketed as Lebenszeit(TM), meaning “Lifetime” in German, in the 1980’s by Ponce de Leon Medical Development Corp. in the U.S., in reference to the legendary fountain of youth), recently received a lot of attention due to its supposedly tremendous effects in boosting and stabilizing the immune system, even in HIV patients.
Being traditionally sceptical, I searched for additional information on this product and below is what I found:

* Natural AIDS Cure Self Help Video
* HEPI Pharmaceuticals, Inc. Stops Trial of ProAlgaZyme(R) Due to Concerns Raised by Inconsistent Results
* Algae: False Claims and Hype

I am very curious whether the editors of the Lipids in Health and Disease are going to publish a comment on the above mentioned original research article by Oben et al.
What do you think???

Source: British Journal of Pharmacology 2007, Epub ahead of print
Article Type: Original Research
Authors: Schwedhelm et al.

Nitric oxide synthases (NOS) metabolize L-arginine (LA; semi-essential amino acid) to nitric oxide (NO) and L-citrulline (LC; non-essential amino acid). Due to its vasoactive activity, NO induces vasodilation of both arterial and venous blood vessels via activation of soluble guanylyl cyclase. Oral LA treatment in humans, however, is hampered by its extensive metabolism; furthermore LA’s efficiency is suggested to be influenced by its competition with the endogenous NOS inhibitor ADMA (asymmetric dimethylarginine), a phenomenon that has also been called the “arginine paradox”. Interestingly, LC, which does not undergo extensive presystemic and systemic elimination, can serve as an LA precursor. Following its uptake into the body, LA is converted to l-argininosuccinate by argininosuccinate synthase and subsequently to l-arginine by argininosuccinate lyase.
In their randomized, double-blind, placebo-controlled, cross-over study (n=20), Schwedhelm et al. assessed the pharmacokinetic and -dynamic properties of oral LC (and LA) intake. Major findings are:

* oral LC administration effectively increases plasma LA levels
* oral LC administration is well tolerated without side effects
* high dose LC treatment (3g) improves the LA:ADMA ratio
* only high dose LC treatment increases urinary nitrate and cGMP, thus indicating a modulation of NO metabolism

However, no significant effect of endothelial-dependant vasodilation (a secondary study goal) was found, possibly due to the good health status of the study subjects. The authors conclude that “our results provide a rationale for larger, prospective clinical studies with longer treatment periods to investigate the effects of oral l-citrulline supplementation on endothelial function in patients with endothelial dysfunction and vascular disease.”

Image taken from: student.ccbcmd.edu

Source: Science 317: 516-519
Article Type: Original Research
Authors: Outeiro et al.
As members of the histone deacetylase family of proteins, sirtuins play a prominent role in aging. Seven sirtuins, SIRT1 to SIRT7, have been identified in humans.
Most research on sirtuin-mediated modulation of life span focussed on the activation of sirtuins (especially SIRT1), e.g. via resveratrol, a stilbene present in red wine and other food plants.
In the July 27 issue of Science, Outeiro et al. now report on the rescue of alpha-synuclein-induced neurotoxicity in models (cell cuture and Drosophila m.) of Parkinson’s disease (PD) due to inactivation of SIRT2. The mechanism of action might be due to 1) alterations in alpha-synuclein aggregation and 2) microtubule stabilization. Whether SIRT2 inactivation also directly affects life span, however, has not been addressed in this article. Those interested in this aspect might want to have a look at a recent paper published by Wang et al. (Aging Cell 6(4), 2007), where the authors descibe elevated SIRT2 expression in response to caloric restriction, a classical ‘inducer’ of longevity.

If you are looking for more information on PD, have a look at the PD Blog Network.

Image taken from: www.pdmdcenter.com

Another conference on the advances of polyphenol research, though smaller in size than the one in Japan, will take place in Malta, 14-16 November 2007.

Here a summary of the conference features:
“After the great success of the Polyphenols 2006 conference, the International Society for Antioxidants in Nutrition and Health (ISANH) organizes the 4th international meeting to gather high level scientists and professionals to give an update of advances in polyphenols benefits and promising trends of their use in improvement of human health. The conference offers an excellent opportunity to exchange ideas and experiences between researchers and industrialists. (…)
* Latest advances in polyphenols benefits in human health
* Latest advances in the role of polyphenols in chronic diseases prevention and therapy with focus on promising role on diabetes, obesity and aging management
* New solutions to optimize polyphenols processing and to better evaluate and improve their bioeffeciency in finished products
* New sources, ingredients and technlogical solutions in polyphenols industrial application (food, beverage, cosmetic and pharmaceutical industries)
We look forward to welcome you in Malta for this particular event.” Pr Joseph Bannister and Dr Marvin Edeas

Image taken from: www.isanh.com

For all those interested in improving their daily diet, here some information on a book entitled “Personalized Nutrition: Principals and Applications” that is soon going to be published (August 2007) by CRC Press.

The content will cover the follwoing topics (taken from the CRC Press webpage):

From one person to the next, optimal health is governed by a huge array of minor genetic differences. When modulated by a variety of food bioiactives, these differences result in changes in gene expression and subsequent phenotypic expression. Combining biomedical and social science with contributions from leaders in both fields, Personalized Nutrition: Principles and Applications illustrates molecular, physiological, epidemiological, and public health aspects with examples from major diseases and discusses the behavioral, ethical, and consumer perspectives that will influence a successful introduction of personalized nutrition. Divided into three sections, the book answers pertinent questions crucial to the mainstream acceptance of personalized nutrition: to what extent is this personal diet-and-health relationship practically valid? how can nutrition science demonstrate this? And what is the proposition of stakeholders in society, including the consumer?The book begins with an overview of the state-of-the-science in nutrigenomic technologies including transcriptomics, proteomics, and metabolomics. It covers the use of genomics technology for a better understanding of the molecular mechanisms involved in major diet-related chronic disorders such as chronic inflammation, cardiovascular disease, diabetes, cancer, and obesity. Section two compares the practices and opinions of scientists, food companies, consumers, competitive athletes, and health care providers on the subject of personalized nutrition. It reviews marketing potential, consumer attitudes, and the ethical issues surrounding personalized advice.The final section focuses on humanitarian concerns related to developing countries and calls for international efforts to develop best practices, collaboration, and dataset sharing. The authors also consider ongoing innovations in food technology, nutrigenomics, and food delivery systems.Demonstrating scientific principles, varying opinions, and future perspectives, Personalized Nutrition, Principles and Applications presents a wealth of information on this revolutionary advancement in nutrition and health. 

For all those of you who are still thinking of submitting an abstract to the 3rd INTERNATIONAL CONFERENCE ON POLYPHENOLS AND HEALTH (ICPH 2007) taking place at the ICC Kyoto (Japan) from November 25-28, 2007, please be reminded that the deadline for abstract submission is June 30 !!!!

“(…) In recent years, much attention is internationally being denoted to polyphenols and health. Augustin Scalbert initiated International Conference on Polyphenols and Health in Vichy, France four years ago. It really stimulated and encouraged many people engaging in polyphenols on human health. The 2nd Conference at Davis, United States, was also a true success, and I would like to take this opportunity to thank Andrew Waterhouse and Cesar Fraga who organized this really fruitful conference. Nowadays, polyphenols are recognized as essential functional food factors and prevailed from the dining tables to medicinal uses. However, more scientific evidence should be required for understanding the optimal levels of their intake and the safety as well as the functionality. We believe 3rd Conference is necessary to discuss these subjects among the participants who are key contributors to the fields. (…)” Junji Terao, President of Organizing Committee.

Image taken from: ICPH 2007