BCAAs: More than Muscle now Traumatic Brain Injury

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The BCAAs, Leucine, isoleucine and valine, are important amino acids not merely because of their role in protein synthesis and promoting muscle mass, but they have other actions. Often we think of them as signaling molecules in muscle working through mTOR, promoting anabolism and repair.

From this there are applications in body composition changes (promote leanness) as well recovery and repair. However a recent mouse study from researchers in Philadelphia and Portland have suggested that there are benefits in managing cognitive impairment resulting from traumatic brain injury.

Traumatic brain injury establishes an oxidative burst and inflammatory response. But critically, as seen in stroke, there is a biphasic response where there is secondary damage in the latter phase, often associated with the release of excitatory neurotransmitters.

The researchers noted that following a lateral percussion injury (simply put a severe bang to the head) that there was brain injury, particularly to the hippocampal region. This was associated with cognitive impairment. BCAA therapy was able to ameliorate this impairment when measured at 5 or 10 days after the injury, but for full benefits it did require continued administration.

There are some pretty profound implications from this laboratory research. The full restoration of cognition after a traumatic injury is impressive, no matter what the therapeutic agent. But for it to be well known amino acids whose previous applications focused on muscle strength and performance is truly enlightening.

One could make the case for BCAAs to be routine as a pre-administration approach to sports activities as there would be wide benefits on performance and if there was a concussion then potentially damage would be limited.The newsworthy aspects of concussion-induced encephalopathy (cognitive decline associated with sports concussions) is intriguing.

By association it may be possible that other forms of cognitive decline could be suppressed, including aging related dementia. It is speculation as we do not know how the BCAAs work for these applications, but connecting the dots suggest that there are potentially broad benefits for a range of conditions.

Beyond that the research challenges us to think differently about a problem, which is where true advancement occurs. While the herd grazes away at the routine, the lateral thinkers are carving out new terrain. This may be a mere mouse study, but I see a candle shining light on important breakthroughs and I encourage others to see its flickering in the background while the spotlight of BCAAs is mired in muscle enhancement.


Fish Oils: Immunity, Inflammation & Fat cells

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Consumer confidence in fish oils, omega-3 fatty acids, are returning as the single paper that was taken out of context is relegated by the continuing research describing positive benefits of omega-3 fatty acids. So let me add to that stance by describing some recent research.

First let’s define a few things. Why are fish oils they called OMEGA-3 fatty acids? Well fish are not the only source so it is best to not refer to them as fish oils, so we use the term omega-3 fatty acids. And that nomenclature is a simple description of the chemicals structure. It refers to the site of the first double bond counting backwards along the carbon chain from the omega end of the molecule. So an omega-3 fatty acid has its first double bond three carbon atoms back. Similarly, omega-6 fatty acids have their first double bond 6 carbon atoms back from the end. The position of this double bond has a huge impact on the bioactivity of the metabolites of these fatty acids. Not just in a quantitative sense but also qualitative.

The other consideration in these structures in the length of the fatty acid chain. This leads to different names within the same class. For example, DHA and EPA are both omega-3 fatty acids (so yes the first double bond is three carbons back from the omega end, or carboxy terminus), but they differ in overall length.

One more thing, the benefits of omega-3 fatty acids are registered by their ability to compete with oemga-6 fatty acids for various enzymes. Often the enzymes prefer omega-6 as a substrate, so in order to win the battle for enzyme time there has to be a lot of omega-3 to increase the likelihood that it will be chosen. Small amounts are simply not going to do it. They will be ineffectual as they cannot compete adequately.

Now to the latest research. The study focused on the interactions between the immune system, specifically a subset of spleen T cells, and fat cells. In this experiment rats were fed for 2 months either a diet rich in fish oil (from menhaden) or safflower oil (omega-6), and the immune cells were later isolated from the spleen. These extracted T-cells were then mixed with cultured fat cells.

Before we get to the results, it is important to note that fat cells are biologically active. They release hormones (called adipokines), and can be become inflamed when overwhelmed with the tasks of processing & storing certain foods. When overwhelmed they call in reinforcements and they do this by releasing chemokines, which are chemical messengers that attract immune/inflammatory cells. Like scents attracting these cells to come in and assist, albeit with a cost.

In this laboratory setting in order to ratchet up the system the cell cultures were treated with a bacterial wall fragment to create inflammation. What was observed was that T-cells from fish oil fed animals had a remarkable reduction in inflammatory responses (levels of mediators like IL-1 beta, TNF alpha, macrophage inflammatory protein or MIP) and reduced production of chemoattractants (MCP-1, MCP-3) – the chemical scents.

There were also benefits on epigenetics, these are the switches which regulate a cells genetic software – genes are turned on or off. For example, TNF is completely regulated through these epigenetic switches. Turn the switch off and a vast myriad of inflammatory mediators are suppressed. This is in contrast to a drug which may inhibit a single enzyme or block a receptor, by design, this switch-based mechanism offers broad coverage. The fish oils treated group had a significant suppression of two key switches, NF-kB and STAT-3.

So what does this all add up to? Well in obesity the fat tissue is in a state of constant inflammation; a smoldering fire that contributes to the continuation of the obese state (in part by suppressing the activity of insulin) and extending its ramifications to other tissues and organs.

In order to limit this condition and its associated pathologies one must correct the inflammation within fat tissue and negate the invasion of fat tissue by immune cells. This study affirms the concept that omega-3 fatty acids help negate adipose tissue inflammation (here the benefits are similar to what is observed in other tissues), and this is achieved in part through an action on the cellular genetic software – the science of epigenetics.

BOTTOM LINE – For better health have a diet rich omega-3 fatty acids or supplement with high quality omega-3 fatty acids


Peeking into the Future: Nutrient-Microbiome Dynamics

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Early in the 1980’s my colleague, Dr. David Clark, and I identified that the second leading cause of death in premature babies (NEC) was a series of events initiated by a nutrient-microbiome interaction. At the time this concept was largely rebuffed, although now, some 30 years later, it is mainstream. Now common debate is how do we use probiotics for neonatal survival as well as development.

Around the same time I discovered that the endothelium was dysfunctional in cardiovascular disease, with what was later determined to be a lack of nitric oxide production from the isozyme endothelial-NOS or eNOS (Type I NOS).

Fast forward and we are now discussing how a lack of vasodilator gases, nitric oxide being the one that people are most familiar with, plays a significant role in regulating cardiovascular function. Within this concept are threads that the vast majority of the natural products industry and nutritionists are missing.

This concept has layers, but specifically for nitric oxide is that you do not need arginine to form nitric oxide, rather it can be produced on demand from the reduction of its oxidative metabolites, nitrite and nitrate (via nitrite). This can occur under acidic conditions and also under the influence of transition metals as found in mitochondria. Indeed this process can play an important role in the efficiency of energy production by mitochondria, raising the bar on the exhaustion of cellular energy.

So what has this got to do with the microbiome? Well simply put it is a clear understanding of the role of microbes within The Nitrogen Cycle. We used to just consider this a plant concept, where farmers interspersed nitrogen fixing plants with their crops to increase yield. The desire is to raise the soil content of organic nitrates. But interestingly, these fertilizers, organic nitrates, determine our vascular health, and they do it via microbes within our GI tract.

The primary site of importance has been the bacteria in saliva, as they contain an enzyme nitrate reductase that converts nitrate to nitrite, and this is then converted to nitric oxide on a need be basis.

In the PLOS One article by Tiso and Schnechter they identify the importance of dietary nitrates in microbial growth in the intestine, as well as ability of these bacteria – E. coli, and Lactobacillus and Bifidobacterium species to generate nitrite from nitrate. Here we have the setup for a dynamic interaction. Food rich in nitrates stimulate the growth of bacteria that convert it to nitrite for transformation into nitric oxide and cardiovascular health.

In other words, we are peeling back the layers of how diet influences our health, transforming the discussion to include a mandatory evaluation of how the nutrients support the bacteria in our gut, which in turn promote health (or in some cases disease). Understanding these complexities, such as the mammalian-micobiome Nitrogen Cycle will reveal new options to maintain health.

Additionally, the Nitrogen Cycle is not simply to deliver nitric oxide precursors (independent of arginine) but also to account for ammonia production, which also has vasodilatory actions.

Not discussed in this article is the role of another gaseous vasodilatory, Hydrogen sulfide, which is produced from sulfur-containing amino acids as well as dietary sulfur compounds like allicin from garlic. Hydrogen sulfide has many properties that resemble nitric oxide in benefits and tissue protection. This benefit is being explored as new approach for cardiovascular disease by the biotech/pharmaceutical industry. However, the point is that understanding how these gaseous molecules affect and control vascular function can be approached with dietary means now – via either the Nitrogen Cycle or the Sulfur Cycle.

Stay tuned, as the opportunities are remarkable.


Protective Effects of Ashwagandha on Brain Cells

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Ashwagandha is a greatly revered botanical that has been feature of ayuvedic medicine (traditional medicine from India). In translating its benefits into Western medical vernacular we often describe as an anti-stress botanical, or and adaptogen.

In a recent research study Ashwagandha was evaluated for its ability to modify oxidative stress to both neuronal and glial cells. In this situation it was found to be protective against oxidative stress as well as to glutamate, the excitatory neurotransmitter.

A variety of active chemicals seem to be responsible as both water and alcoholic extracts were active. This suggests that the actives are both water soluble and lipid soluble, making the case for the use of the whole medicinal plant.

A number of serious brain health conditions are associated with both oxidative stress and excessive release of glutamate. In these settings, both acute (e.g., stroke) and chronic (cognitive decline) ashwagandha represents an option that should receive serious consideration.


Leucine: Approaching Muscle Soreness and Repair

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The Branch Chained amino acid, L-Leucine, is well appreciated for its pro-anabolic actions. As science advances we appreciate the importance L-Leucine in muscle health. In this recent study leucine was investigated for benefits on muscle soreness and repair following extensive eccentric exercise.

The important concepts that drive these benefits is that while there is continuing underlying inflammation, the processes of repair and recovery cannot get started or at least reach their potential. In short, inflammation suppresses repair.

So given that concept, this research demonstrates Leucine represents a novel approach to both limiting inflammation and therefore activating anabolism and muscle repair. Given the importance of exercise as a health management strategy leucine is an important component of dietary supplementation to execute effective muscle health, and in turn systemic health.


Gene Transfer: Human Evolution via Microbes

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Our microbial friends are important contributors to our health and wellness. Previously we have been occupied in classifying them as simple germs – all dangerous and evil. But we now know that there are many that play a huge role in determining our wellbeing and health.

Indeed just the mass of microbes that live in us and on us, is daunting. It should force us to recommender who are. What is needed is the concept that we are a community, and managing that community is top priority.

Recently scientists have described an even more intimate relationship – that is “Horizontal Gene Transfer” where genes are transferred from microbes to the human genome. Changing at a genetic level who we are. These can be very beneficial, allowing us to fend off fungi and other dangerous microbes, but now the research shows that these benefits can be permanently instead into our genetic hardware.

A nice new twist, but the big picture is embedded in changing the way we think about us, moving to the concept that we are a community; one that needs to be nurtured.



Obesity: Role of LymphoAngiogenic Factors

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High fat diets are known to create a local inflammatory response in adipose (fat) tissue, and this reaction is regarded as being an important contributor to not only obesity but also type II diabetes. Recently attention has been drawn to mechanisms that may contribute to this end result – specifically the role of the growth of new blood vessel and lymphatics.

Karaman et al. (http://www.ncbi.nlm.nih.gov/pubmed/25685697) showed that administration of antibodies to block VEGFR-3 in db/db mice reduced adipose tissue macrophage infiltration and hepatic lipid accumulation, and improves insulin sensitivity. They concluded that the lymphangiogenic factors VEGF-C and -D play a role in the mediation of metabolic syndrome-associated adipose tissue inflammation. Blockage of these lymphangiogenic factors might constitute a new therapeutic strategy for the prevention of obesity-associated insulin resistance.

Whether this effect is a direct action on inflammation, or interruption of the development of new blood vessels or lymphatics or both remains to be seen. Nevertheless this is an interesting new approach to a major society health burden.


Leucine: Is it Helpful for Muscle Wasting?

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Sarcopenia is an issue with a variety of diseases, like cirrhosis, as well as general aging. Which leaves the dilemma of what to do about it. To simply transfer to a protein rich diet may not be as simple as one thinks. Often these patient groups are resistant to that approach. Using specific amino acids to change the way that muscle makes decisions about its form and function is an attractive approach.

Tsien and colleagues set about to test this hypothesis with Leucine, a branch-chain amino acid long appreciated as an important agent in transforming how muscle reacts and responds.One aspect that is linked to the altered muscle decision making is the signally process called mTOR. Activation of mTOR is associated with an anabolic response – muscle growth and improved strength.

In this study Tsien et al., tested whether subjects with sarcopenia as the result of liver cirrhosis would respond to L-leucine. At baseline cirrhotics showed an impaired mTOR as well as lowered GCN2 (an intracellular amino acid sensor), and increased autophagy. The latter is a means for the body to destroy damaged cells increasing cell turnover, as is commonly encountered with cellar stress.

Oral supplementation with leucine raised blood leucine levels in placebo and cirrhotics. Importantly the specify pattern seen with cirrhotics was reversed. Autophagy was decreased and mTOR was activated. Thus a rather simple dietary intervention was able to correct specific deficits leading to poor quality of life.

Oxidative Children of Nitric Oxide and Autoimmune disease

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Nitric oxide is well appreciated as a beneficial chemical, almost universally so in the nutritional industry where there are numerous attempts to promote its production and activity – usually by supplying the amino acid precursors for nitric oxide synthase. What is conveniently not discussed is that there are 3 isoforms of nitric oxide synthase, and the normally dormant inducible isoform, iNOS, is linked to inflammation and tissue damage. I pioneered that later concept back in the early ’90’s when my research group discovered that chronic inflammation could be prevented or interrupted by lowering nitric oxide production, by inhibitors of iNOS or preventing the iNOS enzyme from being expressed (thereby keeping it dormant).

We went on to show in a variety of conditions that this high burden of nitric oxide, in these environments of high free radical and oxidant production, transforms nitric oxide itself into other reactive nitrogen species. These species leave finger prints of there reactive and ephemeral existence. What they leave are nitrosated and nitrated proteins, where a H+ on an amino acid is replaced by either NO+ or NO2+ respectively.

So proteins get nitrosated or nitrated, what does that matter? The publication by Wang et al. describes some of the potential adverse outcomes. In this case exposure to a contaminant trichloroethane (TCE) is the initial trigger for raising iNOS, from its dormancy, and stimulating the production of oxidants. The resultant nitrostative stress and nitrated proteins establishes a positive feedback circuit that leads to autoimmunity. The immune system detects normal protein that is now nitrated (or nitrosated) as being foreign and mounts an attack.

So here an environmental chemical stimulates excessive nitric oxide production and more importantly, creates an chemical milieu that promotes nitrosative and nutritive stress. In other words, the characteristics of nitric oxide has radically changed and now through its chemical children it promotes disease not health.

So when advising people to take more arginine, or citrulline, or whatever approach you think will help raise nitric oxide levels please take into account the “Jekyl and Hyde” nature of this chemistry. Intentions may be to create health, but the end result may be the polar opposite.

Wang G, Wang J, Luo X, Ansari GA, Khan MF.
PLoS One. 2014 Jun 3;9(6):e98660. doi: 10.1371/journal.pone.0098660. eCollection 2014.
PMID: 24892995 [PubMed – indexed for MEDLINE]

Vascular Inflammation, Aging & NF-kB

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Vascular disease is an inflammatory process. It has taken a while to come to grips with this concept, but its been apparent to inflammation researchers for decades. But with that concept comes the potential for new approaches to treat cardiovascular disease like atherosclerosis and hypertension.

A recent review has drawn attention to the master transcription factor, NF-kB, in the process and suggests approaches that could lead to suppression of NF-kB and therefor disease mitigation. NF-kB is a protein that acts as a switch that binds to DNA, essentially turning on a multitude of genes that are active in inflammation. Keeping the switch in the off position (in this case it is embedded with a tag and housed in the cytosol) turns of the genes and thereby limiting inflammation.

Activation of this switch, NF-kB, in the endothelium, is an important driver of cardiovascular disease. The authors suggest that non-coding microRNA’s that block NF-kB activation could be a viable project to limit the role of NF-kB and inflammation in cardiovascular disease. This is an interesting and viable project and time will tell as to its effectiveness and limitations.

Nevertheless, there are numerous redox-active botanicals that are effective NF-kB inhibitors, and I and other researchers have extensively published on them, including a focus on inflammation. One of my favorites, based on its remarkable potency and excellent safety profile is the Amazonian medicinal plant Cat’s claw (Una de gato). Others worthy of consideration include Boswellia serrata and curcumin.

These medicinal plants have a solid foundation of scientific research on their ability to limit the activation of various switches that promote the activity of genes that promote and direct inflammation, including NF-kB. My suggestion, and this is certainly a case of do as I do, is take supplements with these botanicals while the research determines in non-coding microRNAs can be effective in cardiovascular disease. Research can shine the light on potential solutions but perspective based on the entire scientific literature can provide alternative action plans as knowledge expands.