Harness Evolution

SCIENTIFIC BREAKDOWN

Beta Alanine 

Carnosine is a bit of a misunderstood compound. We know that it is crucial for muscle function, and that dietary sources of carnosine are essential, but we don’t know precisely how it works. Moreover, for decades, we had no idea how to increase intramuscular concentrations of carnosine, as exogenous sources degraded in the body so quickly that it seemed to be effectively useless.

Enter beta-alanine. Simply a different iteration of one of the amino acids that comprises carnosine itself (alanine), beta-alanine has proven to be the most effective means of significantly increasing intramuscular concentrations of carnosine – and therefore of promoting all of carnosine’s various beneficial effects on muscle performance. If that weren’t enough, beta-alanine has also demonstrated beneficial physiological effects independent of its parent compound. In order to understand why, though, we need to first understand some of the basics behind carnosine itself.

Carnosine, a cytoplasmic dipeptide synthesized from the precursors L-histidine and l-alanine, is present in high concentrations in skeletal muscle and plays a pivotal role as a “chemical buffer” in myocytes (muscle cells). It has long been known that carnosine concentrations are highest in glycolytic muscle fibers (explosive) rather than oxidative muscle fibers (endurance) and thus long hypothesized that this amino acid is required for sustained performance during supramaximal exercise. Recent research demonstrates that carnosine exerts its physiological effects in long hypoxic (low oxygen) drives by functioning as a high-capacity pH buffer in skeletal muscle, preventing the pH ratio of plasma from dropping too low – and therefore preventing crucial pH-dependent processes such as protein synthesis from being inhibited by acidosis.

Despite its critical role in skeletal muscle anaerobic performance, intramyocellular synthesis of carnosine is rate-limited by the availability of l-alanine. Unfortunately, the majority of literature demonstrates that attempting to increase intramuscular levels of carnosine via either direct carnosine or alanine supplementation is largely ineffective due to carnosine/alanine pharmacokinetics. Enter beta-alanine. Research with beta-alanine demonstrates consistent and dose-dependent increases to intramuscular carnosine concentrations with beta-alanine supplementation, with certain studies showing an increase of 40-60% with chronic administration. These same writings reveal a synergistic effect of exercise on beta-alanine supplementation, whereby the muscles adaptive changes associated with resistance training promote further intramuscular carnosine production in response to beta-alanine supplementation.

In simpler terms, this essentially means that beta-alanine is a dietary supplement that promotes its own effects in combination with exercise. As you exercise, you simultaneously intensify beta-alanine’s physiological actions – both directly, as well as in the production of intramuscular carnosine. Once ingested, beta-alanine’s exercise-specific beneficial activity is well-established. Elevation of intramuscular carnosine content via beta-alanine supplementation has been shown to improve performance in the following ways.

• Both acute and chronic increases in total work capacity, measured by total volume during exercise sessions.
• Highly significant increases to TTE (total time to exhaustion), one of the most accurate and comprehensive measures of endurance. In various trials, beta-alanine supplementation has been shown to increase TTE by upwards of 20%.
• Increases to total muscle power output in both acute and chronic trials, suggesting that beta-alanine’s most significant benefit is to those engaging in power-dependent resistance training.

In total, a significant body of research exists to suggest that beta-alanine may significantly increase muscle power output, strength, training volume and output, overall performance in hypoxic (oxygen-deprived) conditions and peak VO2 max (oxygen holding capacity).

These myriad benefits make beta-alanine both one of the most-studied, and most well-rounded dietary supplements. Beta-alanine not only has direct, actionable physiological effects, but also promotes critical muscle physiologic adaptations that promote its own effects.

L-Citrulline

Citrulline is a non-essential, non-protein amino acid that forms during the urea cycle and forms ornithine when combined with carbon dioxide. Citrulline is also a critical source of endogenous (natural) arginine, as it is rapidly and efficiently converted to arginine in the vascular endothelium and other tissues.

Citrulline’s benefits have been shown to be greater than its parent compound. While arginine undergoes direct hepatic (liver) metabolism through the enzyme arginase, citrulline bypasses hepatic metabolism entirely and it is delivered straight to the bloodstream. The result is that gut absorption and plasma (blood) bioavailability studies comparing citrulline and arginine have shown two things. First, that citrulline is less readily destroyed and has greater absorption than arginine. Second, that citrulline supplementation increases arginine levels more effectively than arginine supplementation itself.

This translates to promising results. For example, animal studies show a significant increase in anaerobic performance at a 250mg/kg/day serving of citrulline, while studies in humans implicate citrulline in both aerobic and anaerobic performance increases. As a critical part of the urea cycle, citrulline’s performance benefits are thought to be a result of its role in ammonia clearance. Citrulline is implicated in reducing the oxygen cost of muscle processes, along with increasing the rate of post-exercise ATP and phosphocreatine replenishment. As ATP and phosphocreatine are the body’s ‘exercise fuel,’ this may result in citrulline delaying time to exhaustion in aerobic and anaerobic exercise.

Betaine Anhydrous

Betaine (trimethyl glycine) is found naturally in most living organisms. It is well known to protect non-mammalian animal life in conditions of osmotic stress (a rapid change in the amount of solute surrounding a cell), in addition to functioning as an osmolyte in mammalian (including human) tissues. Betaine is formed in cells as an oxidation product of choline and can be obtained in the diet from foods such as spinach and beets.

Though data on betaine is limited, and recent, the available literature suggests that this compound may have effects in a few areas. Studies on betaine using servings as little as 1.25g/day and up to 5g/day for up to 14 days have shown promising results. In one study, a 2.5g/day serving was found to enhance endurance and total repetition volume for the squat, bench press, and jump squat in in healthy-exercised trained adults. A similar study using the same serving found that betaine use increased peak power and maximum peak power, along with force and the maintenance of both force and power in healthy, exercise-trained subjects.

Perhaps more interesting, however, is a study which examined betaine’s effect on the endocrine system. This study revealed that betaine may exert an effect on several endocrine processes given the proper conditions, causing the authors to hypothesize that long(er) term betaine supplementation may increase the hypertrophic response to resistance training.

L-Tyrosine

Tyrosine is amongst a class of amino acids known as ‘non-essential’ amino acids, so called because the body can produce them endogenously, and it is therefore not essential to consume dietary tyrosine. That said, tyrosine is also what is known as a conditionally-essential amino acid; conditionally-essential because, along with glucose and ammonia, the synthesis of tyrosine additionally requires adequate levels of phenylalanine. Once synthesized, tyrosine is one of the most critical amino acids, given its prominent role as a substrate in the synthesis of the catecholamines dopamine, norepinephrine, and epinephrine, in addition to both T3 (triiodothyronine) and T4 (thyroxine) thyroid hormones.

In studies on stress modulation, tyrosine has been demonstrated to reverse stress-induced norepinephrine depletion and the depressant-behavioral effects normally associated with it. In simpler terms, tyrosine may, in certain conditions, dampen the extent to which norepinephrine is removed from the bloodstream during a stress event. In simpler terms still, tyrosine may help to mitigate the sense of depletion and fatigue felt at the end of a workout.

Tyrosine may also play important metabolic functions, mostly related to its role in synthesizing compounds which stimulate the nervous system. While not traditionally considered a sympathomimetic amine, studies which have coadministered tyrosine and stimulants demonstrate a synergistic effect. These studies suggest that tyrosine may potentiate the effects of both endogenous and supplemental norepinephrine and its mimetics (in the case of exogenous use) with respect to lipolysis, thermogenesis, and energy expenditure. Meaning that tyrosine may play a role in assisting norepinephrine to break up triglycerides and increase body heat transiently.

Nitrosigine® (Inositol Bonded Arginine Silicate)

Nitrosigine® is a patented blend of arginine, inositol, and potassium silicate that has been clinically studied and shown to be an innovative combination in the realm of nitric oxide production. This unique blend of ingredients that makes up Nitrosigine® has a specific processing component that increases arginine’s bioavailability, an ingredient known for having poor bioavailability. Arginine as a lot of us know is a precursor to nitric oxide, a powerful vasodilator. Arginine is converted into NO within the body with the help of an enzyme called Nitric Oxide Synthase, in which L-Citrulline is a by product of this process. So Nitrosigine® solves a few things, it creates a much more bioavailable form of arginine that the body can use to produce nitric oxide, and it can do so with a much smaller dosage than what might be needed from pure L-Citrulline. In one study, researchers were specifically studying arginase levels in their test subjects through analyzing blood plasma arginine levels after several days of product administration. What these researchers concluded was that the Nitrosigine® administered subjects had lower levels of arginase in the plasma. These results support that Nitrosigine® improves bioavailability by stopping the metabolic breakdown of arginine.

But enough about bioavailability, what does this mean in terms of performance in the gym? In addition to this, the specific blend of ingredients in Nitrosigine® can extend the life of your pump as well. Why is this important? Longer and more efficient pumps is a great piece to the puzzle when looking to optimize maximal physical performance in the gym. The nitric oxide boosting effects of Nitrosigine® kick in quickly (usually within the first 30 min) and last a long time (sometimes as long as 1.5 hours). So this longer lasting pump can equate to much more efficient work in the gym and placing the muscle cells in an environment to promote hypertrophy. So, if you’re looking for a tried and true ingredient that can increase muscle pumps and keep them around, Nitrosigine® is one that can be relied on.

Yerba santa (Eriodictyon californicum) [Aerial parts] Extract (as SantEnergy Nu™)

SantEnergy Nu™ is an extract made from the aromatic dried leaves of santa herba, also called holy herb, which has a strong traditional medicinal usage history in California and Mexico.

The ability to stimulate the body metabolism also has been shown to have a largely effective impact on weight management. The issues with weight management most individuals see is due mostly from unhealthy lifestyles, malnutrition and high amounts of body fat leading to low basal metabolic rates (BMR). These low BMRs can create a slower metabolism and lead to a general lack of energy which can have a cascading effect of increased cravings, chronic fatigue, sleep disorders, and an overall lower quality of life. With this being said, it is important to know that taking control of unhealthy lifestyles is and improving quality of life through proper diet and exercise is of the utmost importance. Supplements can help support better habits being implemented. SantEnergy Nu™ has been shown to have essential antioxidant, anti-bacterial, anti-inflammatory and neuro-protective benefits as well as been shown supports healthy ageing, increased body metabolism and a more balanced metabolic rate. These latter benefits have been seen due largely in part by synergistic interplay of three different mechanisms:

• Reduces formation of undesired glycated products (AGEs) causing metabolic diseases.
• AGE accumulation in adipose and liver tissues can interfere with protein functions, which can contribute to low metabolic rate and increase risk of metabolic disease.
• Protects body from oxidative stress, a risk factor for lowering metabolic rate
• Boosts the energy level with caffeine-like energizing and stimulating effect
• by inhibiting the molecular target of caffeine (adenosine receptor 2A)

One clinical study on weight and body fat loss looked at volunteers with high body fat percentages and their response to SantEnergy Nu™ administration. The group being administered SantEnergy Nu™ significantly lost weight after taking 400mg of the product daily compared to the placebo group after 3 months. This double-blind randomized clinical study also confirmed that a big part of the weight loss is due to the significant reduction in body fat, which can have a positive correlation in a more balanced metabolism, reduced risk of all cause mortality and reduced the risk of metabolic disease.

Caffeine Anhydrous

Caffeine is one of the most widely consumed, and perhaps one of the most reviewed, psychoactive compounds. Its physiological effects in a range of areas have been well-documented, including exercise performance, information processing, alertness and mood enhancement, attention, and awareness, along with its anti-lipogenic and lipolytic abilities.

Most importantly to HARNESS EVOLUTION, caffeine has been shown to have significant effects on exercise performance, even with ingestion in servings as small 3 to 9mg/kg/bw/day (the equivalent of 2 cups of standard coffee, for a 170lb male). In endurance training, possible explanations for caffeine’s performance-enhancing effects lie in its metabolic effects on both lean and fat tissue. It is suggested that caffeine’s potent lipolytic (the breakdown of fat tissue into fatty acids) and oxidative (the actual ‘burning’ of fat) action allow the body to utilize these sources during prolonged submaximal exercise. As a consequence, muscle glycogen is spared and available for use later in the training session. Practically speaking, this means caffeine is forcing your body to preferentially use fat tissue as a fuel source, while sparing the glycogen which gives you the full-bodied look!

In short-term exercise, caffeine’s demonstrated role in the inhibition of cyclic AMP- phosphodiesterase’s (PDE), adenosine receptor antagonism, and adrenoreceptor agonism come into play. These three pathways collectively stimulate lipolytic activity, boost fat metabolism, increase metabolic rate and energy expenditure, and regulate the body’s thermogenic activity. The practical results of activating these pathways are increases to the contractile force of both cardiac and skeletal muscle (harder flexion), an increase in energy expenditure (freeing up more caloric energy to be used in contraction), dilation of vasculature (better blood flow), and improvements to both nitrogen retention and skeletal muscle protein synthesis (key components to muscle building).

In HARNESS EVOLUTION, we have included a per-serving amount of caffeine that is neither excessive, nor arbitrary, but that instead reflects the servings used in clinical research.

VasoDrive-AP®

VasoDriveAP® is a proprietary ingredient derived from fermented casein. The fermentation process produces two lactotripeptides, Valyl-Prolyl-Proline (VPP) and Isoleucyl-Prolyl-Proline(IPP). Based on the available clinical evidence, these tri-peptides work together to reduce angiotensin converting enzyme (ACE).

In a recent meta-analysis researchers found 30 studies – all of which were randomized and some of which were double-blind – wherein Valyl-Prolyl-Proline (VPP) and Isoleucyl-Prolyl-Proline (IPP), either alone or in combination, exerted a statistically significant effect on improving endothelial function. In one of the analyzed studies, 25 men were challenged with casein hydrolysate standardized for tri-peptides in a randomized and placebo-controlled design. At the conclusion of the study, forearm blood flow, a key measure of endothelial function, was found to be increased by 33%. The researchers in this and other studies demonstrate that the tri-peptides that constitute VasoDriveAP® exert an inhibitory effect on ACE. ACE, in turn, is a critical component of the renin-angiotensin (RAS) system, which regulates hemodynamics by controlling plasma fluid volume. While the precise mechanism has not been elucidated, researchers believe that the lactotripeptides in VasoDriveAP® competitively inhibit ACE, thus decreasing the metabolism of bradykinin and systematically dilating the arteries and veins.

Citicoline (Cytidine 5’-diphosphocholine)

Choline is an essential nutrient involved in numerous metabolic pathways, including DNA regulation and repair, protein function, and metabolism. Perhaps most importantly, the critical neurotransmitter acetylcholine is produced directly from free choline via cholinergic neurons. Acetylcholine is then responsible for a number of functions itself, most crucially as the compound which induces muscular contraction, and as the neuromodulator partially responsible for modulating risk/reward, arousal, and enhancing memory.

Choline’s essential role as a substrate for acetylcholine, and therefore brain development, is well documented in animal models. These studies demonstrate that levels of free maternal choline have a direct and fundamental impact on prenatal brain development, with the enhancements or deficits lasting into adulthood. Choline’s enhancing effect is particularly prominent in the hippocampus. In humans, the hippocampus is primarily involved in the consolidation of memory (taking short, episodic memory and translating it into long-term memory) and the learning of new information. Acetylcholine is a critical component in these processes, as mentioned above, and choline may therefore play a potential role in these processes as well by providing the substrate for acetylcholine synthesis.

Citicoline (Cytidine 5’-diphosphocoline), also known as CDP-choline, is a potentially superior form of choline due to its ability to cross the blood brain barrier. In fact, most studies with neurological or nootropic effects used this form. In that regard, studies in otherwise healthy, normal adults demonstrated meaningful and statistically significant impacts on working memory, recall, and attention.

ElevATP® (Ancient Peat Extract and Apple Extract)

Adenosine triphosphate and other ATP metabolites are involved in a number of biological processes including cardiac function, blood flow, muscle contraction and neurotransmission. ATP is the primary molecule that acts as a carrier for energy within cells. It has also often been studied that increased levels of ATP have shown increases in health and performance. Supplementation with exogenous ATP has often shown its ability to increase ATP concentrations in blood. Oral supplementation with ancient peat and apple extracts have exhibited their ability to increase intracellular and intramuscular ATP levels. ElevATP® is a blend these specific polyphenols that works to increase endogenous ATP levels without a simultaneous increase in serum lactate. The significance of this is that usually with an increase in endogenous ATP there is an increase in intracellular free radicals. When these free radicals are not present, oxidative stress is mitigated and there is more potential for the beneficial increases in ATP to take center stage. These increases of ATP are essential as when available energy is increased it can have positive benefits in terms of increased power, strength, and overall exercise performance. One study in particular looked at dosing ElevATP® against placebo and showed that the group who received ElevATP® saw a blood ATP increase of 45% on average along with no increase in oxidative blood glucose. This type of result has been shown repeatedly in studies and has given ElevATP® the reputation to be a beneficial compound for the goals of improving endurance, strength, power, and other training specific adaptations.

zümXR® Extended Release Caffeine

Züm-XR is a patented coating technology that allows the dissolution profile of certain ingredients, primarily caffeine, to have a longer lasting effect in blood serum levels. The release of those ingredients is initiated by an abrasion in the stomach and pH levels between the stomach and the upper gastrointestinal tract. The coating of the microbead technology is a patented timing system with pharmaceutical grade safe polymers. Comparatively speaking, the dissolution profile of züm-XR caffeine to your typical immediate release caffeine showed that züm-XR took a far greater amount of time, well over 120 minutes to complete the process of dissolution.

CognatiQ® (Whole Coffee Fruit Extract) (Coffea arabica)

CognatiQ®, an extract derived from the whole fruit Coffea arabica plant, is a clinically proven ingredient shown to stimulate the production of the neuroprotein, Brain-Derived Neurotrophic Factor (BDNF). BDNF has been shown to be crucial in the development, maintenance and repair of neurons and also protect against neuro-degenertion. One study comparing other coffee, caffeine, and polyphenol compounds, showed that they were not statistically significant in increasing BDNF % compared to CognatiQ®. The unique polyphenol profile found in CognatiQ® showed to be superior in increasing BDNF concentration.

Huperzia serrata Extract (leaf and stem) (1% Huperzine A)

Huperzia serrata is a compound found in the plant families of Huperziaceae, Lycopodiaceae, and Selaginella and is endemic to China. The Lycopodium alkaloid Huperizine-A, was first isolated from a folk medicinal preparation in 1984.

Due to the potent anticholinesterase activities of Huperzine A, the compound was been evaluated in numerous in vitro, in vivo, and human trials. These data suggest that Huperzine’s Ache activities are most potent in the cortex, hippocampus, and striatum (at least in rats) – key regions in the brain responsible for forming, coordinating, and recalling memory. These effects are assisted by Huperzine A’s high oral bioavailability. Studies using microdialysis technique in rats, for example, showed that the response to Huperzine A was dose-dependent and substantially lowered the level of ACh in cortex.

Huperzine A has also shown promise in humans. Used as a reversible inhibitor of acetylcholinesterase, Huperzine A has shown positive benefits on cognition and as a therapy for individuals suffering from Alzheimer’s Disease. This is partly due to its inhibitory factors on acetylcholine but also its neuroprotective properties. In another study on memory and learning performance, 34 pairs of middle school students complaining of memory inadequacy were given a small dose of Huperzine A. The students were then match paired along a number of vectors and provided tests on working memory. The results of this study exhibited that Huperzine A markedly improved the memory function of adolescent students