Intermittent Thoughts on Building Muscle: IGF-1, TNF-α, IL-15 & Co and the Emerging Role of an Auto-/Endocrine-Immune Axis in Skeletal Muscle Hypertrophy

Image 1: The word "inflammation" triggers associations which hinder a appropriate understanding of the complexities of the "inflammatory" immune response that is vitally important for (re-)building muscle tissue.

Just to make sure that I do not get off another tangent, again, I will start right off, where I left you in the last installment of the Intermittent Thoughts and that was with the promise to have a closer look at the intricate relationship of (exercise-induced) inflammation and the increases in muscle-specific insulin-like growth factor 1 (IGF-1) and its splice variants, above all the muscle (re-)building mechano-growth factor 1 (MGF-1). Before we are looking how one influences the other, we will yet have to establish a consistent understanding of "inflammation", which, despite being in on everyone's lips these days is commonly (mis-)understood and / or confused with "oxidation", as in the oxidation of "inflammable" substances, you have encountered innumerable times in the form of fire or rust.

What is inflammation? And is it good or bad?

If we simply rely on our everyday understanding of inflammation, we are totally missing the boat on the true significance of a very complex net of biological processes some scientists quite blunderingly labeled "inflammation", which is not the "fire", i.e. the damaging (in many, but by no means all cases oxidative) process, itself, but the appropriate, or, as in the case of auto-immune reactions, inappropriate physiological reaction to it. Whether this misleadingly termed reaction of your immune cells is "appropriate" and thusly healthy or "inappropriate" and thusly detrimental, depends on a whole host of factors, among which the distinction between subclinical chronic inflammation and acute inflammatory responses probably is the most important one.

Illustration 1: The theoretical relationship between the biphasic hormetic curve and exercise salience (Nunn. 2010. Fig. 1)

While scientists believe that a chronic low, yet elevated level of inflammation is the root cause of almost all modern disease, the acute inflammatory response to real threads is the driving force behind those hormetic adaptation processes about which Alistair V. Nunn and his colleagues from Imperial College in London write that their "decline [...] in our daily life may be leading to increased systemic sub-clinical inflammatory tone, decreased metabolic flexibility and suppression of exercise salience" and thusly set the stage for "obesity, the metabolic syndrome, diabetes, vascular disease and even cancer" (Nunn. 2010). It is thusly only consistent of the researchers to demand:

Whether we like it or not, a long and healthy life needs to include regular exposure to occasional doses of environmental stressors, including fasting, natural temperature changes, polyphenols and exercise. Although human intelligence has enabled us to remove most stressors from the environment, common sense may be required to re-introduce some of them.

And while I could unquestionable go into much more detail on the concept of hormesis and its fundamental importance to our health, I am determined not to lose sight of the real intention of this installment of the Intermittent Thoughts, which is to elucidate the intricate relationship between the local inflammatory response to exercise, the intramuscular expression of IGF-1 and its splice variants and the exercise-induced increases in skeletal muscle mass and strength.

The IGF-1 response to acute inflammation

Contrary to what you may have gathered from a cursory read of the literature on the "dangers" of the "growth promoting" and thusly potentially carcinogenic insulin-like growth factor, neither the mature 70 amino acid polypeptide IGF-1 nor any of its splice variants are in and out of themselves carcinogenic. It is the (not even indiscriminate, cf. red box) growth promoting effect they exert on target tissues via interactions with the respective IGF-1 receptors which will promote the growth and proliferation of all sorts of cells, including cancer cells that is responsible for their bad reputation.

Image 2: IGF-1 per se is not fattening,
if anything it is "IGF-resistance"

Did you know that a 2008 study by a group of scientists from the University of Leipzig, in Germany, found that the "growth promoting" effect of IGF-1 on adipocytes is negligable, the effect of the latter on systemic IGF-1 expression via negative feedback, on the other hand pretty profound (Klöting. 2008)? As it turned out, not IGF-1, but its absence, or I should say, its inability to activate the receptor in the IGF-R knock-out mice that were used in the study were the underlying cause of both statistically significant increases in body, fat and organ weight, as well as ~20% elevated serum IGF-1 levels. Similar to the fattening effects of insulin, its structural cousin (cf. insulin vs. insulin-like growth factor discussion in the previous installment), it is thusly not the physiological expression of IGF-1, but its inability to trigger necessary cellular signaling cascades and negative feedback that could be at the heart of the metabolic derrangements that oftentimes go hand in hand with elevated levels of circulating IGF-1.

In this context an important result of a meta-study by Claudio Franceschi and his colleagueson genes involved in the etiology of longevity, comes to mind (Franceschi. 2005):

In a longitudinal survey it has recently been shown that older women having low serum levels of IGF-I and high serum levels of IL-6 have the highest risk of disability and mortality, in comparison with women who have low levels of IL-6 and high levels of IGF-1 (Cappola et al., 2003). Such a beneficial effect of high IGF-1 serum level in the elderly is in apparent contrast with the above reported data showing that reduced IGF-I plasma levels are associated with longevity (Bonafè et al., 2003b). In order to reconcile this apparent discrepancy, it can be hypothesised that the decrease in plasma IGF-1 observed in nonagenarians and centenarians might minimise the risk of cancer in these subjects by decreasing a generalised mitogenic stimulation. The price to pay is frailty and massive reduction of muscle strength, two characteristics of such very old people.

With this connection between overexpression of the inflammatory cytokine interleukine 6 (IL-6) and the low, or as we will see insufficient IGF-1 expression in elderly people, we have come full-circle and back to our initial question: How do "inflammation" and IGF-1 expression go together?

Image 3: Unlike Hermes, the Greek messenger of the Gods, cytokines have no intrinsically mischievous side and their vilification is unjust.

Although it was certainly not a good idea to summarize such a complex phenomenon as the release of signaling molecules and the consequent reponse of the immune system under the term "inflammation", the name "cytokine" is actually quite fitting, because the combination of the Greek words -cyto, for "cell", and -kinos, for "movement", denote the exact consequences the release of respective signaling molecules has: it induces the movement of cells, which, in the case of "inflammatory cytokines", obviously are immune cells. The contemporary vilification of all "inflammatory" cytokines in the lay-press is however unwarranted - or would you hold the guy who takes the calls on the emergency line responsible for either the outbreak of the fire (=immune reaction necessary) or another nuisance alarm (unwanted auto-immune reaction)?

A very important clue that points us into the right direction comes from a 2007 study by Pelosi et al. (Pelosi. 2007), who analyzed the regenerative process skeletal muscle tissue undergoes subsequent to injuries. The scientists analyzed the differential expression of the two major inflammatory cytokines TNF-alpha and IL-1-beta, which in turn triggers the release of the aforementioned (and much better known) IL-6 in skeletal muscle (Luo. 2003), in response to cartiotoxin (CTX) injection in normal (wild-type) mice and mice who were genetically engineered to over-express mIGF-1 specifically in differentiated myofibres (MLC/mIGF-1).

Figure 1: Differential expression (relative to maximum) of TNF-alpha and IL-1b in CTX-injected muscle of wild-type and MLC/IGF-1 mice during the 10 days of recovery (data adapted from Pelosi. 2007)

As the data in figure 1 goes to show, the higher mIGF-1 expression (the "m-" indicates autocrine production, i.e. IGF-1 that is produced right at the target tissue, in this case skeletal muscle) in the genetically engineered mice led to a statistically significant amelioration in the expression of pro-inflammatory cytokines, which are involved in the recruitment of monocytes and macrophages.

An "anomaly" you will probably have noticed is the sudden increase of both inflammatory marker on day 5 post injury. I don't know if you are familiar with the term "deep onset muscle soreness", but the "onset" increase in inflammation certainly reminds me of the feeling I tend to have whenever I have gone overboard on squatting. Do you know what I am talking about? This awkward feeling of cramping pain in the quads that tends to appear right then, when you thought that the soreness was abating? Interestingly enough, this sudden onset of inflammation, which is completely absent in the MLC/mIGF1 mice, goes hand in hand with a the peak of  another, less well-known cytokine that goes by the (telling) name of macrophage migration inhibition factor, or MIF. This stands in contrast to the MIF response in the MLC/mIGF-1 mice, where

the significant down-regulation of MIF at 5 days post-CTX injection in MLC/mIGF-1 injured muscle may facilitate the emigration of infiltrating cell pools, leading to a rapid resolution of the inflammatory response.

These facilitatory, or rather dis-inhibiting effects IGF-1 seems to exert with respect to the MIF-driven "lockout" of the macrophages, allows for a "rapid restoration of injured mIGF-1 transgenic muscle", of which Pelosi et al found that it...

was also associated with connective tissue remodeling and a rapid recovery of functional properties.

Show that autocrine mIGF1 via its modulating effect on the inflammatory response and its (related) ability to reduce the formation of fibrotic muscle tissue "creates a qualitatively different environment for sustaining more efficient muscle regeneration and repair" (Pelosi. 2007).

Image 4: The local administration of platelet (and growth factor) rich plasma is about to become a recognized treatment strategy for muscular injuries and chronic degenerative joint diseases such as tendinopathy.

Did you know that a 2006 study from the University of Melbourne showed that both, IGF-1 gene transfer to the injured muscle (which would be comparable to the autocrine mIGF-1 expression discussed in the previous paragraph), as well as systemic IGF-1 administration via mini-osmotic pump at 1.5 mg/kg/day "hastened functional recovery" in artificially injured tibialis anterior muscles of mice? The injection of platelet rich plasma, which contains various growth factors, into injured muscle tissue is already practiced by many physicians working with competitive athletes (Creany. 2007) and appears to be a promising treatment strategy for other (non-muscular) pathologies such as chronic degenerative tendinopathy, as well (Vos. 2010).

If we set these results into a somewhat broader context, it becoms clear that the inflammatory cytokines that are released as a result of muscular damage, summon macrophages and other immune cells to the injured tissue. The concomitant production of local mIGF-1 facilitates their migration into the muscle where they increase the proliferation of satellite cells (Merly. 1999) and help (re-)building (new) muscle tissue (Chazaud. 2003). The "ameliorative" effect of IGF-1 on inflammation is thusly by no means comparable to the "ameliorative" effect firefighters exert on a fire. IGF-1 does not work against the inflammatory response (remember: in 99% of all cases the latter is a completely healthy and beneficial physiological reaction to an external assault on your body!), it works hand in hand with the driving forces of "inflammation", the monocytes, by "opening the door to the muscle" and rejuvenating the satellite cell pool from which, in turn, relies on the immune cells during the incorporation of these progenitor cells into the existing muscle tissue.

The emerging importance of an endocrine-immune-axis in skeletal muscle hypertrophy

Image 5: Control (A) and IL-15 treated (B) myotubes; nuclei are stained yellow; note the wide myotubes in the IL-15 treated muscle (img. from Quinn. 2002)

This intricate interplay of the endocrine (IGF) and the immune (monocytes) system, which is so characteristic for our emerging understand of the true complexity of the mammalian physiology, reminds me of the question Trevor's Facebook question from last week. Trevor, who has obviously done his homework on the "IGF-1 / cytokine connection" wanted to know my thoughts on interleukin-15, one of the less-researched "inflammatory" cytokines, which appears to play a central role in the accrual of myosin heavy chain (MHC) motor proteins (if you have not done so, already you can read more about the role of the motor proteins in Part II of the Hypertrophy 101). Back in 1995, already, a group of scientists from the American Lake VA Medical Center published a ground-breaking (yet hitherto unfortunately largely overlooked) paper on the role of interleukin-15 in skeletal muscle myogenesis (Quinn. 1995). Quinn et al. were for the first time able to show that

IL-15 used at concentrations of 10 or 100 ng/ml increased MHC accumulation five-fold in C2 myoblast cultures and 2.5-fold in primary bovine myogenic cultures. Moreover, C2 myotubes formed in the presence of IL-15 appeared larger than controls.

Interestingly, the researchers must have apprehended the existence of the previously discussed intreaction of the endocrine and the immune system and tested whether this effect depended on the presence of IGF-1:

Figure 2: Moysin heavy chain expression (arbitrary units) in in bovine muscle cultures after incubation with IL-15 (dose in ng/ml), IGF-1 (dose in ng/ml) or both (data adapted from Quinn. 1995).

From the data in figure 2 it becomes quite obvious that IL-15 has more than a facilitative effect on the IGF-1 induced accrual of motor proteins. A 2002 follow up study on mice myocytes (Quinn. 2002) and a 2003 study using human skeletal muscle myogenic cultures (Quinn. 2003) confirmed the validity of these initial findings.

Figure 3: Myosin heavy chain expression, protein synthesis and protein degradation in rodent muscle in response to IL-15 treatment at different basal levels of IGF-1 (data adapted from Quinn. 2002)

Interestingly, the synergistic effect of IL-15 and IGF-1 appears to be restricted to the accrual of motor proteins (cf. figure 3) and has only marginal effects on protein synthesis and degradation.

mTOR & Co, IGF-1, inflammation ... what's next?

Image 6: Is the role of naturally achievable testosterone levels in the accrual of lean muscle tissue overrated, or not? What exactly does the principal male androgen do on a tissue level and why did your OTC test booster only increase your libido and not the size of your sleeves?  Come back on 01.01.2012 to learn more ;-)

With protein synthesis and degradation, we have come back to one of the initial discussed cornerstones of skeletal muscle hypertrophy (cf. What is Hypertrophy?), of which you should have learned in the previous installment of this series that is a necessary, yet not sufficient prerequisite of sustainable muscle growth. Without the IGF-1 mediated and, as you have learned in this installment, monocyte-driven (re-)construction (increase in myonuclei + accumulation of motor proteins) of the underlying structure of the muscle, however, neither the repair of damaged, nor the accrual new, functional (cf. Hypertophy 101: Part II) muscle tissue would be possible.

The question we still have to answer before we can eventually integrate all those different pathways into a model which would allow us to develop a "hypertrophy-optimized" training, nutrition and supplementation regimen, we do yet still have to shed some light on the role of the legendary "big T": Testosterone! So stick with me and come back next week, or next year, whatever you like better, to learn more about the actual role of the principal male sex in the complex process of skeletal muscle growth.

The A to Z of Effective & Less Effective Immuno-Nutrients to Prevent and Combat Respiratory Tract & Other Infections

Teddy bears are like vitamin C and zinc. They can help you when you are already sick, but what are supplements athletes and gymrats take in advance to survive the flu season without getting sick at all?

Specifically during the winter time, hard working athlete and manic gymrats can be particularly susceptible to all sorts of infections. To help you having to work out with a handkerchief in your hand all winter long, I have compiled a non-comprehensive list of supplements that may help you to maintain and even improve your immune defenses and thus to survive the cold and dark winter times without catching a cold or even the flu.

In their recent review in the Journal of the International Society of Sports Nutrition Vinicius Fernandes Cruzat, Maurício Krause and Philip Newsholme reviewed the extensive literature on nutritional supplements that act as immuno-nutrients, may to reduce immunosuppression and excessive inflammation in hard-training athletes and gymrats like yourself (or yourself in 2015 ;-)

Want to get stronger, bigger, faster and leaner, but not sick? Periodize appropriately!

30% More on the Big Three: Squat, DL, BP!

Block Periodization Done Right

Linear vs. Undulating Periodizationt

12% Body Fat in 12 Weeks W/ Periodizatoin

Detraining + Periodization - How to?

Tapering 101 - Learn How It's Done!

In said paper, the researchers from the CHIRI Biosciences Research Precinct at the Curtin University in Perth and the Laboratory of Cellular Physiology at the Federal University of Rio Grande do Sul in Porto Alegre focus what they call the "key immuno-nutrients" L-glutamine, L-arginine, branched chain amino acids (BCAA) and whey protein. Now this would not be the SuppVersity if I didn't go beyond this list and added a few more or less promising extra supplements to the list. Before we get to any of those extras, let's briefly recap what Cruzat et al. (2014) found:

"Although a balanced diet with high quality and sufficient quantity of nutrients is essential, there is growing evidence that some non-synthetic supplements can assist optimal nutrition. In fact, the use of nutritional supplements especially the provision of amino acids, has grown year-on-year. [...]

The use of proteins and amino acids for supplementation deserves special attention, since these molecules are critical for anti-oxidant and fuel provision, participating in the whole-body energy homeostasis, growth, development, recovery and immune responses.

As Cruzat et al. point out, the key targets for immunonutrition may include provision of key metabolites for immune cells per se. In other words: Immuno-nutrients feed the immune system and don't suppress but optimize the multi-layered immunte response consisting of

• the inflammatory response and cytokine release, 
• the production of chaperone proteins such as the heat shock proteins (HSPs), 
• changes in the redox balance (including glutathione, GSH metabolism), and 
• the protection of skeletal muscle mass (see Figure 1). 

Thus your reasons to consume immuno-nutrients go well beyond warding off the common cold and encompass (a) performance improvements, (b) the general strengthening of the immune system and (c) the shortening of the exercise recovery period (Nieper. 2005).

Figure 1: Biphasic immuno-inflammatory response to severe exercise and the possible immunonutrition role. Immuno-inflammatory response induced by severe exercise or heavy periods of training and the proposed role of specific nutrients with immune benefits, also called immunonutrition (Cruzat. 2014).

In that, the most widely used supplements are vitamins and minerals. Reliable evidence for their immuno-protective effects, however is scarce and the results are ambigious:

• Vitamin C: South African ultramarathon runners did demonstrate that vitamin C (but not E or beta-carotene) supplementation (about 600 mg day7 1 for 3 weeks) was related to fewer reports of upper respiratory tract infections (URTI) symptoms (Peters 1983, 1990, 1993, 1996; Peters-Futre, 1997).
  
  

  

  Classic ROS-scavengers like vitamin C are not just ineffective, when it comes to countering the increased susceptibility to infection they have also been shown to hamper the adaptational response to exercise | read more.

  These beneficial effects have yet not been replicated by other research teams. Himmelstein, Robergs, Koehler, Lewis and Qualls (1998), for example, reported no alteration in URTI incidence among 44 marathon runners and 48 sedentary individuals randomly assigned to a 2 month regimen of 1000 mg /day of vitamin C or placebo. And in view of the fact that most randomized, placebo-controlled studies have been unable to demonstrate that vitamin C supplements modulate immune responses following heavy exertion (Nieman et al., 1997b, 2002b; Nieman, Peters, Henson, Nevines, & Thompson, 2000b), it should be clear that vitamin C must not be counted among the highly effective immune nutrients. 

Zinc + C, not protetive, but effective? While the evidence supplementing with a combination of vitamin C and zinc would protect you from upper respiratory tract infections (URTIs) is scarce, there are studies like Maggini et al. (2012) which indicate that the provision of a combination of 1000 mg vitamin C plus 10 mg zinc in patients with the common cold will lead to a nonsignificant reductionof rhinorrhoea duration (range 9 – 27%) was seen. Moreover, a pooled analyses of the two studies Maggini et al. conducted shows that "vitamin C plus zinc was significantly more efficient than placebo at reducing rhinorrhoea over 5 days of treatment" (Maggini. 2012). Furthermore, symptom relief was quicker and the product was well tolerated. Despite the fact that the subjects in these experiments were ordinary people, upping your zinc and vitamin C intake, when you've already caught a cold may help you to recover faster and thus get back to the grind earlier.

• Vitamin E: As Niemann et al. point out in their review of the efficacy of various immuno-nutrients, vitamin E functions primarily as a non-specific, chain-breaking antioxidant that prevents the propagation of lipid peroxidation. The vitamin is a peroxyl radical scavenger and protects polyunsaturated fatty acids within membrane phospholipids and in plasma lipoproteins.
  
  The effect of vitamin E supplementation on the inflammatory and immune response to intensive and prolonged exercise is largely unstudied and equivocal. Cannon et al. (1991) found that vitamin E supplementation of 800 IU/day for 48 days attenuated endotoxin-induced IL-6 secretion from mononuclear cells for 12 days after running downhill on an inclined treadmill. Singh et al. (1999) showed no effect of vitamin E supplementation (4 days, 800 IU/day) on the increase in plasma IL-6 following a 98 min treadmill run at 65 – 70% V_ O2max to exhaustion. Petersen et al. (2002) reported no influence of vitamin E and C supplementation (500 mg and 400 mg, respectively, for 14 days before and 7 days after) on the plasma cytokine response to a 5% downhill 90 min treadmill run at 75% VO2max.
  
  

  

  Figure 2: Chronic supplementation with 800 IU of vitamin E (as alpha-tocopherol) has significant negative effects on markers of lipid oxidation and inflammation in triathletes (Nieman. 2004).

  A 2004 study in the course of which triathletes competing in the Kona Triathlon World Championship race event received 800 IU/day of a-tocopherol for two months does even indicate that vitamin E can increase the degree of exercise induced lipid peroxidation and the amount of several cytokines in the blood following a triathlon.Against that background and in view of the previously cited ambiguous results, Niemann et al. (2006) rightly conclude that "vitamin E supplementation to counter immune suppression and oxidative stress in endurance athletes cannot be recommended" (Niemann. 2006).
• Vitamin D: For vitamin D a slightly different image emerges. It appears to be indisputable that athletes with low vitamin D levels are at higher risk of upper-respiratory tract infections - specifically during winter times (He. 2013).
  
  The results of clinical trials investigating the benefits of vitamin D supplementation, however, are less unambiguous. In non-athletes, the monthly administration of 100 000 IU of vitamin D did not reduce the incidence or severity of URTIs; and that despite the fact that the supplement brought the 25OHD levels of the healthy subjects up, significantly (Murdoch. 2012). A meta analysis by Bergman et al. (2013), however indicates that "vitamin D has a protective effect against RTI, and dosing once-daily seems most effective".
  
  

  

  Figure 3: Length of time to viral infection related to initial serum concentration of 25-hydroxyvitamin D.
  Shown are the results of the pharmacodynamic model relating 25-hydroxyvitamin D to length of time before a viral respiratory tract infection (Bergman. 2013)

  Bergamn et al. do yet also point out that "[d]ue to heterogeneity of included studies and possible publication bias in the field, these results should be interpreted with caution" (Bergman. 2013). Against that background it may be a good idea to at least make sure that you are in the "normal range" for vitamin D - irrespective of the fact that low levels may rather be a marker than a trigger of an increased susceptibility to infections that results from uncontrolled inflammation (vitamin D as a negative acute phase reactant | cf. Waldron. 2013).

Next to vitamins, many studies have described the use of proteins, such as whey for supplements or isolated amino acids like glutamine (Kreider. 2008; Cury-Boaventura. 2008).

Simply eating enough: It may sound funny, but in the end it's not surprising that a lack of readily usable energy makes you more susceptible to infections. Firstly, a general calorie restriction is often related to an insufficient intake of important micronutrients (Pendergast. 2002). And even if the intake of all micronutrients is adequate. Important immune factors such as glutamine are (ab-)used as a substrate to produce glucose in the liver and are thus no longer available to "feed" your immune cells. Accordingly it should not surprise you that Niemann and Bishop highlight in their review of "nutritional strategies to counter stress on the immune system in athletes" that the existing data indicates that "physiological stress to some aspects of the immune system is reduced when athletes use carbohydrate during intense exertion lasting 90 min or more" and their own experiments suggest that this means "that athletes using carbohydrate beverages during competitive events will lower their risk of sickness afterwards" (Nieman. 2006).

Figure 4: Mechanisms involving whey proteins as a source of different immunonutrients. (Cruzat. 2014).

In their previously cited review, Cruzat et al. included a nice graphical overview (Figure 4) of the mechanisms by which complete proteins and peptides and their individual amino acids effect the immune system of hard training athletes.

As you can see in Figure 4, Cruzat et al. put a particular emphasis on whey protein - for good reasons.

Firstly, whey contains all the "good" amino acids of which previous studies indicate that they may have direct beneficial effects on the immune system:

• Glutamine: As Cruzat et al. point out, "L-glutamine is probably the most widely recognized immuno-nutrient since it can be used as an oxidizable fuel, a substrate for nucleotide synthesis, a modulator of intermediary metabolism of amino acids, HSP expression and a component of GSH-mediated antioxidant defense" (see Figure 5 | Cruzat. 2014).
  
  Put simply glutamine is the food your immune cells thrive on. Accordingly scientists, athletes and coaches have speculated ever since the early 1990s that supplemental glutamine should be able to prevent the exercise induced immune impairments.
  
  

  

  Figure 6: 5g of glutamine per day led to significant reductions in the occurrance of infections in marathon, ultra-marathon, mid distance runners and rowers (Castell. 1996a).

  Why? Well, exercise depletes the amount of circulating glutamine and will thus "steal" the fodder your immune cells need to survive and function (Wernerman. 2008).
  
  And in fact, there are studies that support the logical conclusion that the repletion of the glutamine that has been burned as alternative fuel during a workout with 0.1 g/kg body weight ameliorates the exercise induced reduction of lymphocytes, and could thus eventually reduce the risk of URTI’s (Castell. 1997).
  
  In that, I deliberately used the conditional, because subsequent studies with fixed (20–30 g/day) or variable (0.3 - 0.5 g/kg body wt) doses of glutamine did not report similar outcomes (Castell. 1996b; Krzywkowski. 2001; Hiscock. 2002). Accordingly, Castell et al. write in their contribution to the BMJ A-Z Supplement review (ed. Newsholme. 2011):
  

  "Overall, there is no consensus or unifying concept to explain the efficacy of exogenous provision of glutamine alone on performance in athletes, although in combination with carbohydrate or other amino acids, significant improvements have been reported." (Newsholme. 2011)

  In other words: Benefits can't be guaranteed, but specifically when glutamine is ingested in amounts of at least 20g/day in addition to carbohydrates and protein supplements it appears as if it could be a useful dietary supplement for hard-training athletes.

Where are all the other supplements gone? As I wrote in the introduction, this list is not supposed to be comprehensive. Furthermore, agents like quercetin, beta-glucan, curcumin or astragalus may be backed by animal studies, their efficacy in human beings does yet warrant further testing - specifically in athletes (Nieman. 2006). Other supplements such as the often-used herb Echinacea purpurea have been shown to fail to stimulate the nonspecific immune response and may be useful only when you are already sick or if the preperations are administered intravenously (Schwarz. 2002).

• Arginine: No, this is not a mistake. L-arginine is in fact the #2 on the list of supplemental immune modulators for hard-training athletes. Needless to say that it's not arginine itself, but rather Nitric Oxide (NO) which acts as a mediator of inflammation and immune system activation in the human body (Krause. 2011 & 2012).
  
  As a SuppVersity reader, you know that arginine has little ergogenic effect. It has beneficial effects in diabetics and may offer benefits for people who want to control their blood pressure. As a immuno-modulator, however it is similarly ineffective as it is as an ergogenic. Benefits can only be expected if the blood levels of arginine are depleted and that is - even with heavy exercise - usually not the case.

Whey protein, however, is more than the sum of its amino acid parts. Yes, whey can contain up to 26% of BCAA, plus L-arginine, L-lysine, L-glutamine.

Figure 7: Effect of maltodextrin (filled square) and maltodextrin plus hydrolyzed whey protein enriched with glutamine dipeptide (filled triangle) supplementation on exercise-induced loss of membrane integrity and depolarized mitochondria in lymphocytes and neutrophils, which are essential for the response against viral infections, such as upper respiratory tract infections (URTI), in athletes after intense training (Cury-Boaventura. 2008).

Whey does yet also contain a range of powerful proteins / peptides, namely betalactoglobulin, alpha-lactalbumin, bovine serum albumin, lactoferrin, immunoglobulins (e.g. IgA), lactoperoxidase enzymes, glycomacropeptides, as well as vitamins such as vitamin D, and minerals such as Ca2+, of these...

• lactoferrin and lactoferricin, demonstrate direct anti-microbial activity and may thus protect you from infections,
• lysosome, lactoperoxidase and diverse globulins and peptides in whey provide a synergistic protective “cocktail” activity against viral and bacterial organisms (Ha. 2003), and
• sulphur-containing amino acids, such cysteine and taurine attenuate the reduction of intracellular GSH concentration induced by intensive exercise (Lands. 1999). 

For all three of them, it is yet not fully established to which extend they contribute to the proven immune-modulating effects of whey (note: the levels of these agents will be higher in concentrates compared to isolates, due to the increased number of processing steps). It is in fact likely that Cruzat et al. (2014) are right, when they say that its the cocktail of amino acids, proteins, peptides and other micro- and macronutrients, vitamins and minerals in whey protein that acts via direct and indirect pathways (e.g. via optimizing the redox status / GSH) on the immune function of athletes.

Bottom line: While there is good evidence for vitamin D supplementation (1,000-2,000IU/day in individuals with low levels and / or hard-working athletes during the winter months) and high doses of glutamine in hard working athletes. There is little doubt that the amino acid + protein + peptide coctail in whey proteins is the "goto supplement" you would choose if you wanted to use only one of the supplements discussed in this article.

Whey Beyond Brawn: 10+ Things You Probably Didn't Know Whey & Peptides That Form During its Digestion Can Do | learn more.

In that, a reasonable dosage suggestion would be similar to that for maximal muscle hypetrophy and range from 20-60g per day - with the higher dosage being consumed in 2-3 servings evenly spread accross the day. Furthermore, studies like the one by Cury-Boaventura et al. (2008) indicate that, during periods of intense training, it may be useful to add glutamine. Either in large amounts of 10-20g per day (5-10g on top of each serving of whey) or, as it was the case in said study, as a dipeptide which has a higher chance of making it past the splachnic bed and not ending up as "fuel" for your organs and or glyconeogenic substrate in the liver.

And yes, if you've already caught a cold, 1 gram (in divided doses) of the the good old vitamin C (if you want to along with 5-15mg of zinc) is useful, as well - along with plenty of rest and sleep, of course ;-) Comment on Facebook!

References:

• Cury-Boaventura, Maria Fernanda, et al. "Effects of exercise on leukocyte death: prevention by hydrolyzed whey protein enriched with glutamine dipeptide." European journal of applied physiology 103.3 (2008): 289-294.
• Bergman, Peter, et al. "Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials." PloS one 8.6 (2013): e65835. 
• Castell, L. M., E. A. Newsholme, and J. R. Poortmans. "Does glutamine have a role in reducing infections in athletes?." European journal of applied physiology and occupational physiology 73.5 (1996a): 488-490.
• Castell, L. M., et al. "Some aspects of the acute phase response after a marathon race, and the effects of glutamine supplementation." European journal of applied physiology and occupational physiology 75.1 (1996b): 47-53.
• Castell, Linda M., and Eric A. Newsholme. "The effects of oral glutamine supplementation on athletes after prolonged, exhaustive exercise." Nutrition 13.7 (1997): 738-742. 
• Cruzat, Vinicius F., et al. "Amino acid supplementation and impact on immune function in the context of exercise." Journal of the International Society of Sports Nutrition 201.4 (2014): 11:61.
• Cury-Boaventura, Maria Fernanda, et al. "Effects of exercise on leukocyte death: prevention by hydrolyzed whey protein enriched with glutamine dipeptide." European journal of applied physiology 103.3 (2008): 289-294.
• Ha, Ewan, and Michael B. Zemel. "Functional properties of whey, whey components, and essential amino acids: mechanisms underlying health benefits for active people (review)." The Journal of nutritional biochemistry 14.5 (2003): 251-258.
• He, Cheng-Shiun, et al. "Influence of vitamin D status on respiratory infection incidence and immune function during 4 months of winter training in endurance sport athletes." Exerc Immunol Rev 19 (2013): 86-101. 
• Hiscock, Natalie, and Bente Klarlund Pedersen. "Exercise-induced immunodepression–plasma glutamine is not the link." Journal of Applied Physiology 93.3 (2002): 813-822. 
• Lands, L. C., V. L. Grey, and A. A. Smountas. "Effect of supplementation with a cysteine donor on muscular performance." Journal of Applied Physiology 87.4 (1999): 1381-1385.
• Krause, Mauricio S., et al. "L-arginine is essential for pancreatic β-cell functional integrity, metabolism and defense from inflammatory challenge." Journal of endocrinology 211.1 (2011): 87-97.
• Krause, Mauricio, et al. "Differential nitric oxide levels in the blood and skeletal muscle of type 2 diabetic subjects may be consequence of adiposity: a preliminary study." Metabolism 61.11 (2012): 1528-1537.
• Kreider, Richard B., et al. "Effects of ingesting protein with various forms of carbohydrate following resistance-exercise on substrate availability and markers of anabolism, catabolism, and immunity." Journal of the International Society of Sports Nutrition 4.1 (2007): 1-11.
• Maggini, S., S. Beveridge, and M. Suter. "A combination of high-dose vitamin C plus zinc for the common cold." Journal of International Medical Research 40.1 (2012): 28-42.
• Murdoch, David R., et al. "Effect of Vitamin D3 Supplementation on Upper Respiratory Tract Infections in Healthy AdultsThe VIDARIS Randomized Controlled TrialVitamin D3 and Upper Respiratory Tract Infections." Jama 308.13 (2012): 1333-1339.
• Newsholme, Philip, et al. "BJSM reviews: A to Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance—Part 18." British journal of sports medicine 45.3 (2011): 230-232.
• Nieman, David C., et al. "Vitamin E and immunity after the Kona triathlon world championship." Medicine and science in sports and exercise 36 (2004): 1328-1335.
• Nieman, David C., and Nicolette C. Bishop. "Nutritional strategies to counter stress to the immune system in athletes, with special reference to football." Journal of sports sciences 24.07 (2006): 763-772.
• Nieper, A. "Nutritional supplement practices in UK junior national track and field athletes." British journal of sports medicine 39.9 (2005): 645-649. 
• Pendergast, David R. "Effect of dietary intake on immune function in athletes." Sports medicine 32.5 (2002): 323-337.
• Schwarz, Eveline, et al. "Oral administration of freshly expressed juice of Echinacea purpurea herbs fail to stimulate the nonspecific immune response in healthy young men: results of a double-blind, placebo-controlled crossover study." Journal of Immunotherapy 25.5 (2002): 413-420.
• Waldron, Jenna Louise, et al. "Vitamin D: a negative acute phase reactant." Journal of clinical pathology (2013): jclinpath-2012. 
• Wernerman, Jan. "Clinical use of glutamine supplementation." The Journal of nutrition 138.10 (2008): 2040S-2044S.

On Short Notice: Nucleotide Supplementation Increases Performance & Fortifies Immune Response. Plus: Oleic Acid Increases, SFA Lowers E2, Testosterone & DHT Binding

Are nucleotides a useful supplements for intensity maniacs and can olive oil reduce your free testosterone levels?

If you have been visiting the SuppVersity for a while now, you were probably surprised to see that the "Short News" (aka "On Short Notice") are back. The reason, I changed my mind and reintroduced this assembly of short news items is that I realized that there is an intemediate category of news and infos between the very short Facebook news that (a) disappear in the oblivion of the SuppVersity Facebook Wall, (b) don't allow me to post graphics that would illustrate the study results and (c) still take some time to write and the detailed analysis in the "original" SuppVersity articles.

So, if you disagree and can give me a good reason why I should not post news compilations like the one at hand more regularly, speak now or forever hold your peace ;-)

Nucliotide supplementation counters immune suppressive effects of exercise

(Ostojic. 2013) - I think I mentioned a similar study a couple of weeks ago in the SuppVersity Facebook News, but since this most recent investigation into the ergogenic effects of the small organic nitrogen-based combinations of a five-carbon sugar and a phosphate group that

• form the building blocks of nucleic acids, such as DNA and RNA, and 
• participate in cellular signaling and metabolism

deals with in young, healthy, fit men and their response to the provision of a supplement that looks similar to something you are probably goint to see on the market pretty soon, I thought it may be interesting enough to make it into this "news" article-format.

Figure 1: Illustration of the molecular structure of nuleotides (Sadava. 2000)

The supplement we are talking about is a combination of different nucleotides, i.e. cytidine 5′-monophosphate, uridine 5′-monophosphate, guanosine 5′-mono-phosphate and adenosine 5′-mono-phosphate from partially purified (90%) germinated barley seeds extracted during sporulation and the reason it's worth knowing what was in it, because it was able to ...

• Want a quick performance fix? Use sodium bicarbonate | learn more

  significantly increase time to exhaustion (+7%)
• ramp up serum levels of immunoglobulin A and
• elevate the NKC cytotoxic activity

in the blood of the 14 recreationally active participants (age 22; BMI 24kg/m²; body fat 11%) who participated in a standardized incremental exercise test on the treadmill ("Run till you drop") after taking 50mg/day of this product for 2 weeks.

Oleic Acid Increases E2, Testosterone & DHT Binding

Not from Greece, the land of olive oil and eve's cheese, but from Spain comes a study that links Oleic acid, the mono-unsaturated fat from Olive oil to increases in SHBG. The researchers from the Universitat Autònoma de Barcelona analyzed the lab reports and nutrition data of a total of 315 men and observed that

"SHBG serum levels were significantly higher in subjects using olive oil for cooking in comparison with subjects using sunflower oil. The SHBG levels correlated positively with MUFA (p < 0.001) and negatively with saturated fatty acids (p = 0.003)." (Sáez-López. 2013)

Based on multiple regression analysis of the data, the scientists calculated that the amount of MUFA in the subjects' diets accounted for 20.4% of SHBG variance. Despite the fact that this means that your MUFA intake determines "only" 20% your SHBG levels, the data in Figure 1 (left), clearly indicates that these 20% show pretty significant correlations with important health markers.

Figure 2: Correlation between SHBG levels and BMI, MUFA intake (in % total fat) and fasting blood glucose - left; correlation between phospholipid MUFA and SFA content and SHBG - right (Sáez-López. 2013)

In order to elucidate the underlying mechanisms, the scientists conduced an additional in-vitro study, in the course of which Sáez-López were able to confirm that oleoyl-CoA, a metabolite that's produced, when oleic acid is metabolized, downregulates PPAR-γ in the liver (HepG2 cells).

As a SuppVersity veteran, you'll know that any reduction in PPAR-gamma in the adipose tissue will result in a decreased propensity of fat storage (read up on it). In the liver, PPAR-gamma is  responsible for the production of SHBG, as well. In view of the fact that SHBG binds and deactivates* androgens and estrogens (*this is not essentially correct for all tissues!), your MUFA intake could thus be one of the set-screws that determine the level of unbound sex-steroids in your blood.

With 60-80% olive oil is one of the best sources of oleic acid and this is not a reason to stop consuming it - irrespective of T-binding (read more)

Bottom Line: Based on the currently available evidence it appears as if nucleotide supplements could have a future as immune and performance booster for intense training athletes.

Despite the fact that it is unlikely that there will be any side effects, (a) the increased immune activity, which could be a problem for people with auto-immune disease and (b) the non-existence of scientific evidence to support their long-time efficacy (and safety), I would wait and see how things develop before investing significant amounts of money in supplemental RNA / DNA precursor.

Something very similar is true for results of the Sáez-López study that investigated the "SHBG raising" effects of oleic acid. In view of the negative association between SHBG levels BMI and fasting blood glucose, which have, by the way, been observed in previous studies: Phillips & Gerald, for example, observed a significant negative correlation between SHBG and the waist / hip ratio in 55 obese men aged 21 to 70 (Philips. 1993). And while SHBG binds testosterone the small change will not render all your testosterone useless, so that you don't have to be afraid of sudden olive oil induced anti-virility effects ;-)

References:

• Ostojic, Sergej M., Kemal Idrizovic, and Marko D. Stojanovic. "Sublingual Nucleotides Prolong Run Time to Exhaustion in Young Physically Active Men." Nutrients 5.11 (2013): 4776-4785.
• Phillips, Gerald B. "Relationship between serum sex hormones and the glucose-insulin-lipid defect in men with obesity." Metabolism 42.1 (1993): 116-120.
• Sadava, D. et al. Life: The Science of Biology, 9th ed. 2009
• Sáez‐López, Cristina, et al. "Oleic acid increases hepatic sex hormone binding globulin production in men." Molecular nutrition & food research (2013).

Baking Soda For Stressed White Blood Cells: 0.3g/kg NaCO3 90min Before an Anaerobic Workout Protect Your Immune Cells From "Stress" and Oxidative Damage

Image 1: Pure baking soda is not (yet?) a staple of the supplemental arsenal of many athletes. The scientific evidence with regard to its immediate ergogenic effects is ambigious and the mere presence of the word "sodium" in "sodium bicarbonate" scares the hack out of those athletes (bodybuilders and figure competitors) who may benefit most from a few grams of this potent alkalizer.

"Sodium"! This word alone is usually enough to scare bodybuilders and fitness athletes to death. "Sodium!? Isn't that the stuff that makes me look bloated?" The answer is easy: No! While sodium will help you retain enough water in your body to perform in the gym, the amount of sodium you ingest usually has little impact on the amount of water you will be holding, only when you start modulating your sodium intake, your body will react with changes in the renin-andiotensin-aldosterone system and you will be fluctuating "nicely" back and forth from super-bloated to weak and dehydrated... this is yet commonly ignored within the fitness community and thus it is no wonder that most supplement producers are anxious not to include any ingredients in their products that would show up on the label as "sodium" - after all, there are still costumers out there who have not enrolled at the SuppVersity and will thusly run away screaming as soon as they take a closer look on the label of a product they were just about to buy.

It is thusly no wonder that (at least to my knowledge) KreAlkalyn, where NACO3 is the working ingredient of the highly advertised buffering system, is the only product using sodium bicarbonate, or soda ash, as it is also called, as one of its main constituents (more on this topic in the SuppVersity Creatine Special). In medical settings NACO3 was and, in parts, still is still the "drug" of choice to combat acute acidosis. It is thus no wonder that Daniel J. Peart and his colleagues from the University of Hull in the United Kingdom, as well as the Bond University in Queensland, Australia are not the first scientists who speculated that athletes, especially those competing in (primarily) anaerobic sports, could benefit from the alkalizing effects of their grandmothers' secret weapon in the war against fungi and bacteria on her kitchen furnishings (Peart. 2011).

Image 2: "Cholesterol is the devil and sodium is his little brother!" Everyone who still believes everything the medical orthodoxy says, please raise your hands!

A note on the dangers of "salt": Firstly, baking soda is "only" ~28% sodium, which means that for every 4 grams you ingest you get roughly 1 g of sodium. Secondly, it is arguable how much of the sodium is effectively taken up and will be floating around in your blood. As T. Lakhanisky points out in his dossier for the Belgian government: "The uptake of sodium, via exposure to sodium carbonate, is much less than the uptake of sodium via food. Therefore, sodium carbonate is not expected to be systemically available in the body." (Lakhanisky. 2002) And thirdly, there is more and more evidence that suggests that the chloride rather than the sodium content of common table salt (NaCl = NatriumChloride) is the root cause of "sodium induced hypertension" in "sodium sensitive" individuals / animal models. Only recently, a study by Schmidlin et al. showed that chloride loading induced hypertension in the stroke-prone spontaneously hypertensive rat despite profound sodium depletion (Schmidlin. 2010). So, if you asked me, rather than pointing at salt as the #2 on the list of greatest evils (obviously cholesterol is still #1, here) the medical orthodoxy would be better advised to address the imbalances between sodium and potassium, which are so characteristic of the western diet, instead of painting yet another black and white picture where sodium is the bad guy and potassium the dangerous mineral that cannot be sold OTC in dosages >80mg.... but hey, this would be the topic for a whole new blogpost and as gross as it may sound, the chance that you get diarrhea from the baking soda is probably 1000x higher than the remote possibility of increases in blood pressure. A 1990 study by Luft et al. even found that the blood pressure of 10 mildly hypertensive and normal subjects decreased by 5mmHg after 7 days in the course of which they drank 3 liters of sodium bicarbonate containing water per day (Luft. 1990)

In their study, Peart et al. had a group of seven recreationally active men (age 22.3 ± 2.9 years,
height 181.6 ± 4.5 cm, body mass 78.1 ± 8.1 kg, and physical activity 4.2 ± 0.6 h/week) "with no history of supplementing their diet with ergogenic agents" perform a 4-min bout of all-out exercise on an air-brake cycle ergometer on three different occasions (spaced exactly 1 week apart). While the first was an acclimatization session the second and third bout were performed after the ingestion of either 0.3g/kg sodium bicarbonate (trial 2) or plain table salt (trial 3) in "low-energy flavored water" 90 minutes prior to exercise.

Figure 1: Blood ph levels after ingestion of placebo or 0.3g/kg sodium bicarbonate (data adapted from Peart. 2011)

As you can see in figure 1, the ingestion of ~23.4g of baking soda produced a rather slight but significant shift towards a more alkaline blood ph level (compared to placebo), which became much more pronounced after the exercise bout (p<0.003). Interestingly, there was yet no significant difference (p>0.26) in exercise performance as measured by average and peak power (means ± SD; average power 292 ± 43 W vs. 291 ± 50 W; peak power 770 ± 218 W vs. 775 ± 211 W; work completed 71 ± 10 kJ vs. 68 ± 10 kJ) between the groups.

Baking soda: A non-ergogenic ergogenic?

The latter observation, i.e. no or statistically non-significant increases in acute exercise performance upon sodium bicarbonate ingestion, stands in line with ~75% of the previous findings, a recent meta-analysis by Carr et al. summarizes as follows:

The remaining 38 studies and 137 estimates for sodium bicarbonate produced a possibly moderate performance enhancement of 1.7% (90% CL ± 2.0%) with a typical dose of 3.5 mmoL/kg/BM (∼0.3 g/kg/BM) in a single 1-minute sprint, following blinded consumption by male athletes. In the 16 studies and 45 estimates for sodium citrate, a typical dose of 1.5 mmoL/kg/BM (∼0.5 g/kg/BM) had an unclear effect on performance of 0.0% (±1.3%), [...] Study and subject characteristics had the following modifying small effects on the enhancement of performance with sodium bicarbonate: an increase of 0.5% (±0.6%) with a 1 mmoL/kg/BM increase in dose; an increase of 0.6% (±0.4%) with five extra sprint bouts; a reduction of 0.6% (±0.9%) for each 10-fold increase in test duration (e.g. 1-10 minutes); reductions of 1.1% (±1.1%) with nonathletes and 0.7% (±1.4%) with females. Unexplained variation in effects between research settings was typically ±1.2%.

Despite these rather mediocre immediate effects of bicarbonate pre-loading, the main finding of the study at hand hints at hitherto overlooked long(er)-term immune benefits the consumption of sodium bicarbonate might have.

Figure 2: HSP-72 expression in mono- and lymphocytes in response to anaerobic exercise after ingestion of placebo or 0.3g/kg sodium bicarbonate (data adapted from Peart. 2011)

As you can see in figure 2 the stress-induced HSP-72 expression in white blood cells (lymphocytes and monocytes) in response to the HIT exercise was almost completely abolished. Along with the nullification of the already low amount of oxidative stress (cf. T-BARs in figure 3), these results suggest that bicarbonate supplementation has a stress-protective effect on immune cells during anaerobic exercise.

Figure 3: Oxidative stress due to anaerobic exercise as measured by TBAR expression after ingestion of placebo or 0.3g/kg sodium bicarbonate (data adapted from Peart. 2011)

It is yet important to note that the scientists point out that it "is unclear at this stage whether the attenuation was due to a reduced state of acidosis, reduced oxidative stress or a combination of both." Moreover, it is difficult to say which consequences this would have on future bouts of exercise and whether and to which degree athletes would actually benefit - or, if we think of the hormesis hypothesis and the ongoing debate concerning the effects of antioxidants on exercise induced adaptations - maybe even compromise their performance, would yet need further investigations.

We may yet assume that, just as it is the case with antioxidants, the dosage will have to be matched to the individual workload to see optimal results. With people exercising just enough to see any adaptations seeing no and people who do crossfit 2x a day seeing the most beneficial results from (partially) blocking the exercise induced oxidative stress.

480mg/day Polypodium Leucotomos Reduce Infection Rates in High Performance Athletes by 75%! Plus: Extract Protects Against UV Radiation, Cancer, Trauma & Could Be Ergogenic

Don't worry if you have not heard of Polypodium leucotomos before. After all, that's why you're here! To get your daily dose of SuppVersity news and learn, right?

It's starting to get cold and wet outside and aside from my always healthy self, everyone around is getting sick... sounds familiar? Or are you one of those ailing people who always wonder how the others beard the common cold and did not have a single flu in their whole life? I can assure you, it's not just zinc + vitamin C ;-)

That said, I honestly don't believe that the supplement today's news is about will get the job done, if you don't have your diet and workout regimen in check, but if it reduces the incidence of infections in high performance athletes by 75% it can hardly be useless when it comes to protecting yourself from the sniffers and nose blowers all around, can it?

Dear SuppVersity reader, meet Polypodium leucotomos your immune systems best friend!?

Assuming that I've now gotten your attention, let's get right to the facts. The said supplement is an extract from Polypodium leucotomos a fern that is native to the tropical and subtropical regions of the Americas and has a long history as a folk remedy in Honduras, where it is used for a wide variety of ailments. Interestingly, respective extracts have been sold under the label "anapsos" ever since the 1970s. Nevertheless, I am not sure if anybody who does not know the LEF product catalog by heart has ever heard of Polypodim (if you did, probably in relation to skin health) -- specifically not in the context of infectious diseases in high performance athletes, which was what Bartolomé Marí Solivellas and Teo Cabanes Martín were interested in, when they conducted their 3 months study on the effects 480 mg/day Polypodium leucotomos extract (Armaya fuerte; Centrum laboratories, Alicante, Spain / researchers report no conflict of interest) on the onset of infectious processes and relapses during an 8-month follow up from June 2010 to January 2011 (Solivellas. 2011).

The study participants were all athletes who took part in competitive activity, trained or competed for 20 hours per week and had and still were periodically monitored in a sports medicine clinics. Overall, a total of 116 athletes (58 men and 58 women, aged 18-30 years) were included. 63 of them in the Polypodium leucotomos extract-treated group (PL) and 53 in the control group (C), with 58 males and
58 females aged 18–30 years (subjects with autoimmune or chronic disease were excluded; 14 additional athletes were excluded during the trial, either because they left or were non compliant, i.e. didn't take their supps). Most of them were competitive volleyballers, football players, track & field athletes and cyclists.

The protocol: A 2x 240mg/day preload from June to August

The participants in the active arm of the trial had to consume their daily dose of 480mg in two 240 mg servings, one in the morning and one at night, while the the control group did not take Polypodium
leucotomos extract (no question: The fact that the study was not placebo controlled is a bummer!). This means that the acute supplementation did not coincide with the aforementioned period of sniffing and nose blowing, and any effect that would be seen over the whole 8-months follow-up must be due to permanent benefits in response to the supplementation in those first three months (it also reduces the influence of the placebo effect, after all we are quite forgetful and don't really think about the pills we popped in the summer, when we are getting sick in autumn).

The results: 75%! less infections in the treatment group

Table 1: Prevalence of infectious processes in the control group and study group (Solivellas. 2012)

Even at a very cursory glance at the data in table 1 you should notice the two most important figures: "28" and "7", as in 28 infections in the control (=unsupplemented group) and only 7 infections in the treatment (=480mg/day Polypodium leucotomos extract) group - that's a pretty impressive number. Since, both study arms had been of the same size (n = 50), after a couple of athletes had been excluded from the active arm due to non-compliance, this is a 75% reduced risk of catching any type of infection (see table 1 for detailed breakdown). According to the authors, of those, ...

"[...] the cases of pharyngoamygdalitis were the most noteworthy – 12 patients (24%) in the control group compared to three patients (6%) in the Polypodium leucotomos extract"-treated group." (Solivellas. 2011)

The incidence of infections was yet not the only thing that was reduced. What's probably about as important as the number / rate of infections are the facts that

• the "symptomatic improvement was more favorable" (Solivellas. 2011) in patients from the study and 
• the number of relapses, i.e. a 1/7 vs. 12/28 in the active and passive arm of the study, were significantly lower (-66%)

Since the SuppVersity user stats tell me that most of you are living in the Northern Hemisphere and that it stands out of question that all of you work out (right? ;-), these results alone would be reason enough to take a closer look at Polypodium leucotomos, Calaguala, Anapsos, Heliocare, Kalawalla, Polypodiaceae or whatever other funky name the herb may go, where you are currently living.

Anapsos can do more than render athletes 'infectious disease proof', much more!

This would not be the SuppVersity, though, if I would not tell you "the whole story" about what turns out to be quite an outstanding fern species with beneficial health effects that go well beyond giving your immune system a major boost. And though I have to admit that I did not go back into the 1970s, when the first commercially available extract that goes, as I've mentioned before, by the name Anapsos hit the market. Even the research that has been done in the 21st century only did suffice to compile a pretty impressive list of scientifically backed beneficial health effects, of which I have selected only those, I thought you may be interested in:

• Protection against skin cancer  and related pathologies - PL protects the melanocytic nevi in your skin from forming sporadic melanoma in response to UV radioation, dark eyed patients with higher UVR sensibility (lower basal minimal erythematous dose) would benefit most (dosage 1080mg of PL; Aguilera. 2012). Similar results in rodents, where 300mg/kg of PL 5 days before UVR exposure "reduced the number of proliferating cells by 13%, increased the number of p53(+) cells by 63%, enhanced the antioxidant plasma capacity (ORAC) by 30% and reinforced the network of dermal elastic fibres" (Rodríguez-Yanes. 2012). Also helps against photo aging, polymorphic light eruption, idiopathic photodermatosis, UV-B induced immuno-suppression in the skin,
• Prevention of hyperpigmentation (and psoriasis) - Hydroquinone has been a cornerstone for the treatment of hyperpigmentation; however, concerns regarding adverse effects have prompted a search for alternative agents, one that was suggeted only recently is Polypodium leucotomos (Konda. 2012). Ameliorative effects have also been observed in psoriasis patients, although it appears that more research would be necessary to make any recommendations (Middelkamp-Hup. 2004)
• Remission of subacute cutaneous lupus erythematosus (SCLE) - SCLE is an uncommon autoimmune disease that results in substantial photosensitivity of affected patients. Eruptions often are triggered or exacerbated by UV light (UVL) exposure and a recent case in Cutis shows that while the disease was at best "moderately controlled" with hydroxychloroquine sulfate, "near total remission of disease" was achieved after the addition of oral Polypodium leucotomos supplement (Breithaupt. 2012).
• Amelioration of atopic dermatitis, reduction of antihistamine requirements - Scientists have only shown recently in a phase IV randomized, double-blind, placebo-controlled, multicenter trial involving 105 patients aged between 2 and 17 years who were receiving topical corticosteroids to treat moderate atopic dermatitis that PL administered for 6 months led to a statistical significant reduction in oral histamine use of  4.5% (for those interested, patients received Anapsos 120 mg manufactured by Especialidades Farmacéuticas; Ramirez-Bosca. 2012).
• Prevention of the shift in Th1/Th2 (immune characteristics) in response to trauma - In 2007 already researchers from the University of Zaragzoa found that PL blocked the postoperative (day 1) increases in IL-6 and IL-10 in rats undergoing fracture..On postoperative day 7, "rats undergoing fracture showed an increase of IL-6 levels", the latter was not observed in the PL supplemented rats who had increased levels of the "good" inflammatory cytokine IL-12 on postoperative day 7, instead (Navarro-Zorraquino. 2007)

"Hold on, but didn't you say on SHR and in a couple of blogposts that ROS are necessary?" True, ROS (radical oxygen species) are necessary, as they are a signalling molecule and 'toxic junk', both at a time. Whenever your body is however, figuratively speaking, unable to 'read the signals for the signals' -- which happens to be the case for unfortunate majority of the sedentary Western society -- you better cut back on the forest of signs than have them accumulate in the form of toxic metabolic waste and damage (oxidize) your tissue. Always keep in mind: Whenever we are talking about physiological processes it's all about balance and simply about good or bad and black and white.

The list above did already skip a couple of skin related benefits and still: As I mentioned before, there is probably lots more you could find once you start digging deeper and going further back in the archives. What the hitherto elucidated and probably also all future benefits do have in common is that they are in one way or another related to the potent antioxidant effects of certain not exactly specified molecules the (sub-)tropical fern apparently contains.

Whatever antioxidant (I rather suppose it's a synergistic cocktail) Polypodium leucotomos may contain, it must -- contrary to many other antioxidants which fall victim to their own kamikaze tactics (aka "free radical scavenging") often way before they make it to the target tissue-- actually get to where it is needed and can thus exert its potent antioxidant effects right in the skin, the wound, the broken bone,... and maybe the strained muscle!?

If the latter was the case, and the antioxidants in this peculiar American farn had similar effects in muscle tissue as they were observed by Navarro-Zorraqino et. al. in their rodent model -- namely the induction of an increase in IL-12 and a faster decrease in IL-10 expression -- the concerns about 'too much of a good thing' I addressed in the red box to the right, would not just have been unwarranted; in view of the established pro-anabolic effect of IL-10 (cf. Argilé. 2001) they would actually be absurd (just as the common understanding that all cytokines were "bad", by the way).

Bottom line: I guess, you will agree: This stuff is interesting. However, there have been plenty of "interesting" supplements in the past, which did not deliver. So, if you are merely interested in the last mentioned ergogenic effects, which could obviously be present, you better wait for a respective trial and the corresponding SuppVersity news, before you fill your supplement rack with tons of Polypodium leucotomos. If you are supplement fanatic, got some money to spare and are interested in the immune boosting or UV protective effects, you may want to give it a try.

References:

• Aguilera P, Carrera C, Puig-Butille JA, Badenas C, Lecha M, González S, Malvehy J, Puig S. Benefits of oral Polypodium Leucotomos extract in MM high-risk patients. J Eur Acad Dermatol Venereol. 2012 Jul 31.
• Argilés JM, Meijsing SH, Pallarés-Trujillo J, Guirao X, López-Soriano FJ. Cancer cachexia: a therapeutic approach. Med Res Rev. 2001 Jan;21(1):83-101.
• Breithaupt AD, Jacob SE. Subacute cutaneous lupus erythematosus: a case report of Polypodium leucotomos as an adjuvant therapy. Cutis. 2012 Apr;89(4):183-4.
• Konda S, Geria AN, Halder RM. New horizons in treating disorders of hyperpigmentation in skin of color. Semin Cutan Med Surg. 2012 Jun;31(2):133-9.
• Middelkamp-Hup MA, Pathak MA, Parrado C, Garcia-Caballero T, Rius-Díaz F, Fitzpatrick TB, González S. Orally administered Polypodium leucotomos extract decreases psoralen-UVA-induced phototoxicity, pigmentation, and damage of human skin. J Am Acad Dermatol. 2004 Jan;50(1):41-9.
• Navarro-Zorraquino M, García-Alvarez F, Martínez-Fernández AR, Pastor C, Larrad L, Salinas JC, Lozano R. Pharmacological immunomodulation of surgical trauma. J Invest Surg. 2007 Sep-Oct;20(5):283-9. 
• Ramírez-Bosca A, Zapater P, Betlloch I, Albero F, Martínez A, Díaz-Alperi J, Horga JF; Grupo de Anapsos en Dermatitis Atópica y centros de realización del estudio. Polypodium leucotomos extract in atopic dermatitis: a randomized, double-blind, placebo-controlled, multicenter trial. Actas Dermosifiliogr. 2012 Sep;103(7):599-607. Epub 2012 May 3.
• Rodríguez-Yanes E, Juarranz Á, Cuevas J, Gonzalez S, Mallol J. Polypodium leucotomos decreases UV-induced epidermal cell proliferation and enhances p53 expression and plasma antioxidant capacity in hairless mice. Exp Dermatol. 2012 Aug;21(8):638-40.
• Solivellas B, Martin TC. Polypodium leucotomos Extract use to prevent and reduce the risk of infectious diseases in high performance athlete. Infection and Drug Resistance. 2012 Oct 15.