PharmacoNutrition Reviewed

The facts stated in the current editorial of Nature (Vol. 454) on the bad shape of global nutrition & dietary habits are certainly not new to most of us; nonetheless, I very much liked the comment on the state of current funding practices in the field of nutrition as it - at least for me - is the cause of nutrition still being considered mainly as a soft science.

The latest issue of PNAS contains a collection of more than a dozen articles on reactive oxygen species (ROS):

“(…) The contents of this Special Feature on Reactive Oxygen Species in Chemistry and Biology represents a sampling of the excellent work that is being carried out at this important interface of chemistry and biology by using a wide range of chemical, kinetic, spectroscopic, and biological approaches. The authors come from several different fields and use a wide diversity of techniques and experimental systems; nevertheless, their studies all relate to the fundamental chemical reactivity of dioxygen and species derived from it.”
  

For the last couple of days I have been digging myself through I don’t know how many webpages and articles in search of the truth: to fear cholesterol or not to fear.

What a mess!
And what a shame to be part of the biomedical research field.
Whenever I thought that I had a somewhat clear picture it got rapdily destroyed by opening the next webpage or article PDF.
It seems that the whole field of pharmaco-nutritional medicine has gone crazy.
And that’s a terrible pity because nutrition - at least that’s what almost everone agrees on - can help to maintain your health. If we only would know how!

Coming back to the topic of this blog entry: if you are interested to obtain some critical information on the importance of cholesterol for human health and the impact & efficiency of cholesterol-lowering interventions (e.g. statins), I recommend you have a look at the THINCS webpage.

“For decades, enormous human and financial resources have been wasted on the cholesterol campaign, more promising research areas have been neglected, producers and manufacturers of animal food all over the world have suffered economically, and millions of healthy people have been frightened and badgered into eating a tedious and flavorless diet or into taking potentially dangerous drugs for the rest of their lives. As the scientific evidence in support of the cholesterol campaign is non-existent, we consider it important to stop it as soon as possible.
The International Network of Cholesterol Skeptics (THINCS) is a steadily growing group of scientists, physicians, other academicians and science writers from various countries. Members of this group represent different views about the causation of atherosclerosis and cardiovascular disease, some of them are in conflict with others, but this is a normal part of science. What we all oppose is that animal fat and high cholesterol play a role. The aim with this website is to inform our colleagues and the public that this idea is not supported by scientific evidence; in fact, for many years a huge number of scientific studies have directly contradicted it.”

If you are now interested in a critical analysis of Thincs’ critical view, read Robert Todd Carroll’s comment here.

Last but not least, a very interesting re-assessment of the current evidence regarding the cholesterol/heart link can be found at Science-Based Medicine.org (including more than 300 comments on this subject).

And I still insist, the whole discussion of whether cholesterol is good or bad for your heart and brain and I don’t know what else caused a terrible mess, especially for those who are confronted with a diagnosis that requires some kind of action.

It seems that there’s still a long way to go before we can move on from believing to knowing what cholesterol actually does or does not to our human body.

Source: Neuroscience Letters 439 (2008): 208-211
Article Type: Original Research
Authors: Kushida S et al.

In their latest paper, Kushida and colleagues examined in Amyloid beta-infused rats the effect of soft-diet feeding on two parameters which are typically affected in Alzheimer’s Disease (AD) patients

a) the release of the neurotransmitter dopamine
b) the learning ability and memory performance

Rats were fed either a hard (standard) or soft diet for 3 weeks days. During the last 2 weeks, rat brains were continuously infused with Abeta, the putative main culprit in AD.

“We found no significant differences in the basal level of dopamine release in the hippocampus between soft- and hard-diet-fed groups; however, the dopamine release evoked by high-K Ringer’s solution was significantly different between the soft- and hard-diet-fed groups. The increase of dopamine release in the hard-diet-fed group reached 420%; however, that in the soft-diet-fed group reached only 260%. In AD model rats, dopamine release in the soft-diet-fed group was significantly less than that of the hard-diet-fed group.”

After assessing the rats in the co-called step-through passive avoidance test, the authors conclude that:

“Our results also suggest that soft-diet feeding impairs learning ability and memory in AD rats; however, the underlying mechanism is unknown. One possible explanation is that the present results may be caused by the changes of activity in sensori-motor pathways of soft-diet-fed rats.”

How does this now relate to AD patients?

“Elderly people lose many teeth as they age. The loss of teeth not only forces them to eat soft foods, but also correlates to the development of senile dementia and Alzheimer’s disease (AD).”

So might one speculate that a rather early move in life towards the consumption of soft food triggers the onset of AD? An interesting idea – although much research is needed to establish this link of cause and consequence.

More on AD and diet (i.e. coffee intake) can be found here.

I don’t know whether many of you already read this article. As it is not (yet?) listed in the PubMed and has been published in a rather new journal (Current Aging Science) most probably not.
Anyway, I very much liked reading the review by Alberto Sanz and Rhoda Stefanatos (University of Tampere, Finland) which again deals with the pros and cons of the Mitochondrial Free Radical Theory of Aging (MFRTA).

“The Mitochondrial Free Radical Theory of Aging (MFRTA) proposes that mitochondrial free radicals, produced as by-products during normal metabolism, cause oxidative damage. According to MFRTA, the accumulation of this oxidative damage is the main driving force in the aging process. Although widely accepted, this theory remains unproven, because the evidence supporting it is largely correlative. For example, long-lived animals produce fewer free radicals and have lower oxidative damage levels in their tissues. However, this does not prove that free radical generation determines life span. In fact, the longest-living rodent -Heterocephalus glaber- produces high levels of free radicals and has significant oxidative damage levels in proteins, lipids and DNA.

In summary, available data concerning the role of free radicals in longevity control are contradictory, and do not prove MFRTA. In fact, the only way to test this theory is by specifically decreasing mitochondrial free radical production without altering other physiological parameters (e.g. insulin signalling). If MFRTA is true animals producing fewer mtROS must have the ability to live much longer than their experimental controls.”

The full text article is available here.

For the past almost 20 years my body weight remains constant – no matter what I eat. Bad metabolizer is what most people (and maybe textbooks) would say. Another explanation I once heard from a colleague is that people like him and me would ‘suffer’ from a reduced gut surface to body size ratio, i.e. in comparison to same size, ‘normal’ weighed people, the capacity to absorb the ‘right’ amount of nutrients is reduced in us lean ones.

But there’s more: what happens if you transfer the gut microbiota of a normal weighed mouse to a germ-free mouse? The mouse will develop a normal body weight. And how will a germ-free mouse look like after receiving the gut microbiota of an obese mouse? Overweighed! And this despite the fact that the two mouse models ingested the same amount of food.

If you want to know more about the details of the study (which has been published in Nature in 2006 already), I recommend you take 15 minutes and watch the Nature movie featuring the work of JI Gordan’s group at Washington University.

A special article by DiBaise et al. summarizes the advances in understanding “Gut microbiota and its possible relationship with obesity”, Mayo Clin Proc 2008;83:460-469

Sorry for my long absence, but the arrival of the young lady shown below kept me considerably busy during the last few weeks; now I hope to be back on track….if & when Mia allows….

Today I would like to introduce a new category which I wanted to add for quite some time already, i.e. book reviews. Not necessarily of brand new releases only, but also of those (older) publications that hopefully will provide you with same enlightenment and diversion I experienced while reading these books.

A couple of days ago I borrowed a rather small book (just about 200 pages) written by Adrian Woolfson and published in 2004, which carries the interesting title “An Intelligent Person’s Guide to Genetics”.

Let me cite from its preface:
“ (…) We are at the cusp of a new Enlightenment, defined by the accumulated genetic knowledge that enables us to entertain the possibility of modifying our own nature and of creating artificial life. The tremendous power for change is unprecedented. (…) My view is slightly different: the creation of synthetic life is an inevitability.”

Such a statement might invite to indulge in all too fantastic speculations about the future of (human) life on earth.
Instead, Woolfson takes you on a thrilling voyage though the origins, key principles and recent developments of genetics. For me, the book has been a real page-turner, especially due to the myriads of papers he cites (many of which I – sadly - haven’t heard about before) and anecdotes from the life of scientists whose groundbreaking work will change our life, maybe forever.

So, if you want to learn something about smart genes, the N-value paradox, how to make creatures from scratch, the Fibonacci pattern in plants, the hypothetical organism LUCA, the trade-off between olfaction and vision, why humans are natural-born dualists and how the one-by-one study of over one million fruit fly embryos can pave the way to the Nobel prize, than the books is just right for you.

In his last chapter ‘A Manifesto for Life’, Woolfson asks “Should we attempt to remodel ourselves?”

An absurd question.

Because “it is inevitable that someone somewhere will eventually create advanced synthetic life and modify human nature beyond all recognition. The intervening ethical and philosophical issues are important details – perhaps the most important that mankind will ever have to consider – but they are details nonetheless. (…) we are intrinsically curious, because we have utopian desires: these are inalienably human characteristics. (…) We may need to accept that humans and all other DNA-based life are not an end point in themselves, but contingent beginnings (…).“

Well said.

Source: J Neuroinflammation (2008), 5: 12 (open access)
Article Type: Original Research
Authors: X Chen et al.

A morning without coffee is unthinkable for me. And especially during the day in the lab I need the regular ‘perfusion’ with the black gold. A habit, which - based on the latest publication by Chen et al. - might not be that bad at all for me.

One of the earliest symptoms experienced by Alzheimer’s disease (AD) patients is olfactory dysfunction. The olfactory bulb is characterized by an intact blood brain barrier (BBB) that can get disrupted, e.g., when ingesting a high-cholesterol diet.
When testing such a diet (2% cholesterol) in rabbits, Chen et al. found that the daily administration of 3mg caffeine in the drinking water for 12 weeks “blocked high cholesterol diet-induced
* increases in extravasation of IgG and fibrinogen,
* increases in leakage of Evan’s blue dye
* decreases in levels of the tight junction proteins occludin and ZO-1
* increases in astrocytes activation and microglia density where IgG extravasation was present.”

“Our observations that caffeine had no effects on plasma levels of total cholesterol and HDL indicate that caffeine protects against high cholesterol diet-induced disruption of BBB downstream of cholesterol.”

“The protective effects of caffeine against high cholesterol diet-induced increases in BBB disruption might happen at the BBB per se, and the protective effects of caffeine against high cholesterol diet-induced increases in the density of astrocytes and microglia could be an indirect consequence of its protective effects against BBB disruption. On the other hand, it has been shown that caffeine (and adenosine) can regulate neuroinflammation in in vitro models devoid of BBB. Therefore, the protective effects of caffeine against high cholesterol diet induced increases in astrocyte activation and increases in density of microglia might parallel its protective effects against BBB disruption.”

From a practical point of view it is interesting to note that “the dose of caffeine (3 mg/day) used in this study for 3 to 4 kg rabbits is equivalent to an adult human weighing 70-80 kg consuming a single cup of coffee and is far less than the average caffeine consumption in the USA and Canada that is about 200 mg per person per day.”

The provisional PDF can be downloaded here.

Source: Journal of Gerontology (Biol. Sci.) 63A (2008): 242-252
Article Type: Original Research
Authors: I Lenaerts et al.

When working with C. elegans myself (limited times though) I didn’t break my head too much about the pros and cons of feeding them with heat-inactivated E. coli as long as each plate contained the same amount of food.
Well, I maybe should have given it another thought, at least based on the latest article by Isabel Lenaerts and colleagues.

Here, the authors “…describe convenient ways to exert DR (dietary restriction) by culture on agar plates containing axenic (i.e., there is no microbial food source) medium. We used these to explore whether effects of axenic culture really reflect DR. Our results imply that major nutrient components of axenic medium, and overall caloric content, are not limiting for life span. However, adding growth-arrested Escherichia coli as an additional food source rescued the effects of axenic culture. We then sought to identify the component of E. coli that is critical for normal C. elegans nutrition using add-back experiments. Our results suggest that C. elegans has a nutritional requirement for live, metabolically active microbes or, possibly, an unidentified, heat-labile, nonsoluble component present in live microbes.”

Of note also, the addition of Daucus carota and Pisum sativum extracts to axenic medium, e.g., increased fecundity without affecting lifespan. In contrast, increasing concentrations of autoclaved or sonicated E. coli had no effect on offspring number.
Also, radiation-arrested but metabolically active E. coli rescued the effect of axenic medium. This, however, was just seen for low-dose radiated E.coli, indicating that “…as long as some metabolically active E. coli remained, rescue was possible. This finding suggests the surprising conclusion that metabolic activity in its microbial food source is a nutritional requirement for C. elegans.”

Almost everything known regarding C. elegans can be found here: wormbook.org