Wednesday, June 12, 2013

Nutrigenomics - "Let Food be Thy Medicine and Medicine Be Thy Food." An Ancient Truth in Light of Fancy DNA Analyses

Researchers working in the field of nutrigenomics prioritize berries over pills and individuality over "one-size-fits-it-all approaches" - can they also tell us how to "eat away cancer"?
"Live longer, live stronger"... rings any bells? Anyone? Of course. That's the motto of Super Human Radio. So anyone, who has been listening to the Science Roundup over the past couple of weeks will  have heard it at least once. Now, while the "stronger" part of Carl Lanore's slogan is still largerly under-researched if you asked me, the nutritional angle, which does not appear in the slogan, but is still a major theme of the show is really taking off, these days. Nutrigenomics, i.e. the science of (a) how what we eat determines how our genes functions - keyword: epigenetics and (b) how our very individual genes determine how we're supposed to eat, is really talking off these days. Reason enough for me to invite you to take a peak at what we already know in terms of the modern version of the ancient

 "Let food be thy medicine and medicine be thy food."

One of the primary objectives researchers in the field have subscribed to is the battle against cancer. No other disease appears to be more suited to the modulating effect of the chemical compounds in foods, which is - and that's something you've heard on the Science Round Up several times, as well, capable of both preventing and inducing the instability of the DNA synthesis and gene expression that's finally causing our cells to play havoc.

Table 1: Epigenetic roles of nutrition in physiologic and pathologic processes (from Nepomuceno, originally based on Choi. 2010)
As Júlio César Nepomuceno writes in a recent paper which actually re-instigated my interest in the whole matter,
"[...t]he nutrients are able to affect the genome and its expression through the synthesis of nucleotides, prevention and repair of DNA damage, or through epigenetic mechanisms including methylation of histones, proteins responsible for chromatin structure that play an important role in regulating gene expression." (Nepomuceno. 2013)
Now, while all the cells in our bodies share an identical genome, there are many "epige‐ nomes", which are the unique  sets  of  epigenetic  instructions  for  establishing  and maintaining  lineagespecific expression profiles.

And it is at this cross-roads between the general and the specific where DNA methylation and histone acetylation which can be brought about by the foods we eat an the supplements we take will have more powerful effects than the latest blockbuster drug from the laboratories of Phizer, Merck, Bayer, and co. (Fuji. 2010).

The methylation / acetylation cycle: The genomic switchboard of your cells

Against that background, you as an avid listener and reader of SHR and the daily news and articles on the SuppVersity won't be surprised that nutrients that are part of the so-called "methylation cycle" are considered among the most important agents in nutrigenomics. It's their presence, adequate enzymatic conversion and use that ensures the integrity of the genome of each and every cell in your body and once the tightly controlled and constantly operating machinery is broken, cancer and - as more and more scientists believe "premature" aging and other diseases of epigenetic origin can ensue.

One (not Two!) Kiwi(s) A Day Keeps the Doctor Away. (learn more)
Despite the fact that the word methylation is tightly linked to all these pathologies, it's actually a completely unbiased process.

And while this should be self-evident, most of us need tabular overviews like the one to in table 1 to remind ourselves of the critical and for most of us highly beneficial effect folate, for example, had on our embryonic development, or - just another example - the epigenetic roots of the beneficial effects compounds such as curcumin, resveratrol or choline will have on obesity, inflammation or neurocognition.

In fact, the integrity of our DNA is under constant assault. Simple "mechanistic" errors during the replication process, electromagnetic radiation (from X-Rays to very low frequency EM), alkylating agents, spontanous mutations and the often-heard of reactive oxygen species threaten the integrity of each and every cell in our body leading (in the best case) to cell cycle arrest and apoptosis, in the worst case to mutations, cancer and genetic diseases. Moreover,
"[...c]urrent cancer models comprise those that are inherited through the germline and represent only  ∼5% of total cases of human cancers. These tumors originate because of mutational events. The remaining ∼95% originate as sporadic events and evolve as a result of exposure to the environment,  which  includes  exposure  to  both  environmental  contaminants  and  dietary agents. The multistage model of carcinogenesis identifies various phases, initiation, promotion, and progression, appears to be influenced by tissue microenvironment and organization." (Nepomuceno. 2013)
Yet, as frightening as it may see, these threats and the effects specific nutrients will have on their ability to harm us may  be our best chance to avoid cancer, premature aging. In fact, scientists argue that the age-increased susceptibility to cancer may actually be the results of an accumualtion of epigenetic changes, many of which could be ameliorated, if not prevented by dietary nutrients that will affect the profile of transcripts, which may - and this is where things get complicated - yet be modulated by inter-individual differences in our genetic make-up (Miller. ) - so-called polymorphisms, such as the "cancer gene" Carl and I have been talking about in the last installment of the Science Round Up in the context of Angelina Jolie's double-mastectomy (see table 2 for a selection of these polymorphism).
Table 2:Polymorphic genes, dietary components and cancer: possible candidates (Nepomuceno. 2013)
Now while scientists have already been successful (or they believe they were) in identifying dietary patterns that are associated with an increased and decreased risk of certain cancers. You have to keep in mind that these associations, as they were proposed by the experts from the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) are largely based on epedimiological data and will thus neither include the modulating effects of the said polymorphisms nor have the status of undebatable facts.

"Red meat will cause cancer!"

One of my favorite examples is the association between red meat intake and the development of cancer, of which th AICR researchers believe that there was a 15% to 20% increased risk of cancers of the colon and/or rectum per 100 grams of red meat or 50 g of processed meat consumed per day (is that true?).

Suggested Read: "Meat-Ology: A Brief Glance at the Latest Data on The Link Between Red Meat, Cooking Techniques & Prostate Cancer" - How bad is it?
If you take a close enough look at the respective papers and don't rely on the mainstream media coverage, exclusively, the American Cancer Society openly admits that
  • the mutagens and carcinogens (heterocyclic amines and polycyclic aromatic hydrocarbons) in meat are produced by cooking meat at high temperatures and/or by charcoal grilling and that 
  • the nitrates/nitrites and salt used to process meat contribute to the formation of nitrosamines, which are known mutagens and carcinogens in animals
and not "meat per se" are the true - or we should say "most likely" - mechanistic factors involved, here.

In the end, a similar "most likely" should also accompany the well-accepted conclusion from accumulating evidence on the beneficial effects of a diet that's high in fruits and vegetables after all, diets on the other end of the extreme are notorious for providing sub-optimal amounts of vitamin B12 and could thus also increase the risk for malfunctions in the methylation cycle and the subsequent development of cancer.

Tea, coffee and the other mainstream polyphenol sources

Contrary to the associations with vitamins, the influences polyphenols have on our overall and genetic health are actually a comparatively "novel" topic of scientific research. In fact, scientists argue that these common constituents of foods of plant origin and not the previously hailed vitamins are the major antioxidants in our diets. Vegetables and fruits like apple, grape, pear, cherry, and various berries contain up to 200–300 mg polyphenols per 100 g fresh weight and coffee, teas, cereals, chocolate, and dry legumes also contribute to the polyphenol intake.

Did you know that flavenols are only a subclass of polyphenols? They comprise a large and diverse family of compounds synthesized by plants. Flavonoid subclasses include anthocyanidins in berries and grapes, flavanols in tea, flavanones in citrus fruits, flavonols in onions, flavones in herbs and peppers, and isoflavones in soy.
In that, the term polyphenol is actually an umbrella term that comprises various powerful antioxidants such as flavonoids and stilbenes, many of which have been implicated in cancer prevention and the promotion human health without recognizable side effects, which are - even in such prominent cases like red wine, which contains a wide range of different polphenols - far from being completely understood. The recently mentioned negative effects of cholorogenic acid supplements on the glucose metabolism of rodents, are another example, where certain molucules - in this case chlorogenic acid - of which we believed that they were responsible for the beneficial health effect of coffee turn out to exert different or even downright hazardous effects, when they are administered in isolation.

Similar observations have been made for the classic anti-oxidant vitamins A, C and E and as of late vitamin D. Not everything that looks good on paper or works in the petri dish will also work in a complex organism and even fewer things did eventually make the translation from the bench to the bedside.
Table 3: Selected trials involving "classic" antioxidant vitamins esp. beta carotene (based on Tanaka. 2012)
For science the disappointment surrounding beta carotene (see table 3) was actually highly productive, Without the conflicting data on the real world effects of foods such as yellow-orange vegetables, green leafy vegetables, orange and yellow foods and all the other carotenoid-containing food items and the negative outcomes in the above cited studies, we would probably still lack an appropriate grasp of what carotenoids actually are.

A group of chemicals known as isoprenoid polyenes that are found in lipid-soluble form in the  yellow-orange-red pigments in all higher plants and some animals. Scientists further distinguish
    Table 4: Sources, function, and effects of different carotenoids (Tanaka. 2012)
  1. vitamin A precursors that do not pigment such as β-carotene;
     
  2. pigments with partial vitamin A activity such as cryptoxanthin, β-apo-8'-carotenoic acid ethyl ester;
     
  3. non-vitamin A precursors that do not pigment or pigment poorly such as violaxanthin and neoxanthin; and
     
  4. non-vitamin A precursors that pigment such as lutein, zeaxanthin and anthaxanthin. 
As Tanaka points out, the specific form of the molecules, in particular their stereoisomerism (take a look at your left hand and compare it to the right one and you know what this is ;-) exerts a marked influence on the physical properties.

Vitamin C is vitamin C, is vitamin C, is ... useless?

While research on the different types of carotenes has made huge progress and scientists are finally grasping the notion that there is a difference between folic acid and its biologically active cousins, the one on the most prominent dietary anti-oxidant and it's proctetive effects on cancer stalls - with mainly negative outcomes:
If you add some reactive oxygen species to this mitochondrium, this will trigger beneficial, (mito-)hormetic adaptations, that could be blunted by too many antioxidants. Could be blunted, but what exactly is the latest evidence for the average individual or the corresponding rodent model (learn more)?
"Regarding the use of vitamin C in cancer patient the results were not promising. In a double- blind study 100 patients with advanced colorectal cancer were randomly assigned to treatment with either high-dose vitamin C (10 g daily) or placebo. Overall, these patients were in very good general condition, with minimal symptoms. None had received any previous treatment with cytotoxic drugs. Vitamin C therapy showed no advantage over placebo therapy with regard to either the interval between the beginning of treatment and disease progression or patient survival. Among patients with measurable disease, none had objective improvement.

On the basis of this and our previous randomized study, it can be concluded that high-dose vitamin C therapy is not effective against advanced malignant disease regardless of whether the patient has had any prior chemotherapy."
On the other hand, studies investigating the dietary intake of vitamin C as a part of the natural nutrient matrix ascorbic acid comes with in the vegetables and fruits in our diets (phenols, flavones, and terpenes, beta carotene, selenium), provides at least preliminary evidence that vitamin C intake may be more important for prevention of lung cancer than beta-carotene (e.g. Kromhout. 1987). The necessary amount of vitamin C to get the job done is yet not higher than 70mg (!) of ascorbic acid and almost certainly dependent (if not solely brought about) by the presence of phenols, flavones, and terpenes in the corresponding foods.



Bottom line: The examples of vitamin C and beta carotene show that our understanding of the complex interaction of chemicals with the ability to influence our health through epigenetic changes or the prevention of the latter is still limited. For the latter, which have been around for decades, we already know not one, but rather a mixture - and in that, a mixture at the right ratios - is necessary to see actual benefits.

"Does the Usefulness of Vitamin E Supplementation Depend on Your Activity level?" - Hitherto largely overlooked are the complex interactions of exercise and nutrient induced epigenetic changes, which may well determine the usefulness of antioxidant supplements (learn more)
That being said, the combination of gene essays, in-vitro, in vivo and epidemiological science under the beneath the rood of "nutrigenomics" must be considered one of the most promising research directions of the future. At the moment it's results are yet about as preliminary as the various definitions you will find, when you look around in the scientific community.

Most importantly, however, most of the reasonably reliable results this comparatively new branch of research has and is producing is simply confirming the stuff you've been learning on SHR and the SuppVersity about diet and nutrition over the past years and you can take my word for it: this is not going to go change much in the future.

References:
  • Choi, Sang-Woon, Friso S. Epigenetics: A New Bridge between Nutritionand Health. Adv Nutr 2010;1: 8–16.
  • Fujii T.M.M., Medeiros R., Yamada R. Nutrigenomics and nutrigenetics: important concepts for the nutrition science. J Brazilian Soc Food Nutr 2010;35(1): 149-166.
  • Kromhout D. Essential micronutrients in relation to carcinogenesis. Am J Clin Nutr May 1987;45(5):1361-1367
  • Milner JA, Romagnolo DF. Nutrition and Health: Bioactive Compounds and Cancer. Humana Press. 2010.
  • Nepomuceno, J.C. Nutrigenomics and Cancer Prevention. In: Cancer Treatment - Conventional and Innovative Approaches. Rangel, L. (ed.). InTech. 2013.
  • Tanaka T, Shnimizu M, Moriwaki H. Cancer Chemoprevention by Carotenoids, Molecules 2012;17: 3202-3242.