Hair Loss: Finasteride, Laser Light or Minoxidil - What Will Really Help Men & Women Regrow Lost Scalp Hair?

Men may be at a higher risk, but androge-netic hair loss is not a male exclusive.

Minoxidil, Finasteride, and low-level laser light therapy are Food and Drug Administration-approved/-cleared treatments for androgenetic alopecia, but do they actually work? That was one of the questions Areej Adil and Marshall Godwin tried to answer in a recent review; a systematic review and meta-analysis the scientists from the Memorial University of Newfoundland published in the Journal of the American Acadamy of Dermatology very recently and a paper of which its authors claim that I will clear up the confusion about the seemingly conflicting results of individual studies.

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For their paper, Adil and Godwin searched the usual suspect databases, i.e. PubMed, Embase, and Cochrane including all relevant articles that were published before or in December 2016, with no lower limit on the year. Included were only randomized controlled trials (RCT) of "good or fair quality based on the US Preventive Services Task Force quality assessment process" (Adil 2017). The initial search produced a list of 45 articles of which 22 were excluded.

The "Norwood-Hamilton" classification is used to qualify the degree and type of hair loss. IIIa-V is the type subjects in most studies in this meta-analysis had. If you have hair loss and want some hints that may help you identify the type and cause of losing hair, check out this free article in the American Family Physician.

Eventually, the scientists' insights into the efficacy of nonsurgical treatments of androgenetic alopecia in comparison to placebo for improving hair density, thickness, growth were thus based on 23 papers - and 24 interventions.

• 4 studies on minoxidil 5% in men
• 5 studies on minoxidil 2% in men
• 5 studies on minoxidil 2% in women
• 3 studies on low-level laser light (LLLLT)
• 4 studies on finasteride 

Based on this dataset Adil et al. conducted a separate meta-analysis for 5 groups of studies that tested the following hair loss treatments: low-level laser light therapy in men, 5% minoxidil in men, 2% minoxidil in men, 1 mg finasteride in men, and 2% minoxidil in women.

Women w/ increased hair shedding tend to have low ferritin and high folate levels (Rushton 2002).

Other forms of hair loss and treatments: I can only repeat that the results of Adil's & Marshall's study apply only to subjects with androgenetic alopecia, which is one of the most common forms of hair loss in men and can be observed increasingly often in women. Hair is usually lost in a well-defined pattern, beginning above the temples (you can see this early stage in Figure 1 cf. degrees I+II).

Accordingly, finasteride is only useful with androgenetic alopecia (in men or PCOS women). Minoxidil and low-level laser light therapy, which both seem to work by increasing scalp blood flow, on the other hand, may work for other forms of hair loss, too (e.g. due to metabolic disease).

Other common reasons for hair loss are caloric deprivation or deficiency of several components, such as proteins, minerals, essential fatty acids, and vitamins. If a nutrient deficiency is, in fact, the reason you're losing hair, supplements containing l-lysine and/or l-cysteine, biotin, B12, zinc, niacin, essential fatty acids or iron have some scientific back-up to help in deficiency or low-intake scenarios (Rushton 2002; Finner 2013). Overdoses of selenium or vitamin A, on the other hand, can easily trigger hair loss.

In addition to these well-known essentials of healthy hair growth, studies also suggest that taurine supplements can promote follicle cell survival - at least in vitro. Furthermore, evidence exists that carnitine can stimulate hair follicle cells and components derived from soybeans may also have an effect on hair growth through anti-inflammatory and estrogen-dependent mechanisms. None of these treatments, however, will achieve similar benefits as LLLLT or minoxidil outside of full-blown nutrient deficiencies (esp. in women, iron can work wonders though if they are sign. deficient). Insufficient evidence exists for the effects of topical caffeine or caffeine shampoos. While studies do confirm that caffeine will accumulate in the skin, "it must be borne in mind that penetration and accumulation cannot be equated with stimulation of the hair root" (Dressler 2017).

All treatments were superior to placebo (P < 00001) in the 5 meta-analyses. Other treatments were not included because the appropriate data were lacking.

Figure 2: The meta-analysis confirms the efficacy of each and every of the treatments (Adil 2017).

The meta-analysis main message is: these treatments actually work. Or, to say in the scientists' own words:  "all treatments were superior to placebo (P < 00001)" (Adil 2017). In that, it should be obvious that the majority of studies investigating treatments for androgenetic alopecia were done in men. However, with the ever-increasing number of women (both obese and normal-weight) suffering from PCOS, it is particularly interesting to see that the over-the-counter minoxidil solutions (for women those are usually dosed at "only" 2%) are similarly effective as the high(er)-dose treatments for men.

How much hair can you expect to regrow?

For women Adil et al. (2017) report an average increase in hair growth amounted to 112.41 hairs/cm² in response to 2% minoxidil (vs. placebo). For men, the treatments that showed a mean difference in hair count listed from highest to lowest for men are

• finasteride 1 mg daily - 18.37 hairs/cm²,
• low-level laser light therapy (LLLLT) - 17.66 hairs/cm², 
• 5% minoxidil twice daily - 14.94 hairs/cm², 
• 2% minoxidil twice daily - 8.11 hairs/cm², and
• platelet rich plasma injections (3 months post) - 27.6 hairs/cm² (see bottom line)

In view of its - in some cases - extreme systemic (side) effects and considering the fact that it was the only treatment in which the scientists observed a significant heterogeneity (I² = 91%; P < 0.001 | note: I² statistic describes the percentage of variation across studies that is not due to chance), I would clearly recommend you stay away from finasteride until you've tried all the other venues.

Addendum: Using platelet-rich plasma as a "one-time" treatment alternative

Figure 3: Scalp of 29-year old at baseline (left) and 3 months (right) after treatment w/ PRP (Gkini 2014).

Studies investigating the effects of platelet-rich plasma injections, such as Gkini et al. (2014), found significant increases in hair growth after only three treatment sessions that were performed with an interval of 21 days. The unfortunate truth, however, is that, after a peak at 3 months (see photo on the right for a visual of the results in a 29-year old man | +27.6 hairs/cm²), the hair density started declining again and a single "booster session" after 6 months alone only slowed that decline, it didn't reverse it. Accordingly, it would seem as if you'd have to undergo the procedure thrice a year to get optimal results.

Speaking of which: Other studies confirm the observations Gkini et al. made, reporting an average increase of 28.37 hairs/cm² (45.9 hairs/cm², 12.3 hairs/cm² and 27.7 hairs/cm² in Gentile 2015; Kang 2009 and Cervelli 2014, respectively).

Quite impressive, but, with an average cost of $300-$500 per session, i.e. $900-$1500 for a single treatment, not exactly cheap (make sure the PRP for the is produced from your blood according to a standardized procedure - Gentile et al. for example combined PRP they extracted using the Cascade-Selphyl-Esforax system and PRP extracted according to the P.R.L. Platelet Rich Lipotransfert system).

Don't make a mistake: Unless it's an ultra-sophisticated device with a broad range of frequencies and emitters you cannot use the same low-level-laser-light therapy device for performance enhancement and hair growth.

What to do if you're losing/have already lost hair? At least if your hair loss is a result of being genetically predisposed to androgen-induced hair loss, there's hope: all four treatment options Adil and Gowin analyzed in their latest systematic review are scientifically backed.

With that being said, the low-level laser light therapy has the best risk-benefit, while the 5% (in men) and 2% (in women) have the best cost-benefit-side effect ratio... at least in the short run. In the long run, it may be more economical to invest $250+ in a home LLLLT-device (Leavitt et al. (2009), for example, used a cheap HAIRMAX Laser Comb and found sign. effects compared to a sham device after 26 wks).

Speaking of the costs: If you choose minoxidil, you can save up to 50% if you avoid the highly advertised "R*****" and buy a cheap generic form of minoxidil 5%. Also: keep in mind that all treatments will have to be used/applied regularly: With finasteride and minoxidil being taken/used every day and low-level laser light therapy 2-3 times per week | Comment on Facebook!

References:

• Adil, Areej, and Marshall Godwin. "The effectiveness of treatments for androgenetic alopecia: A systematic review and meta-analysis." Journal of the American Academy of Dermatology (2017).
• Cervelli, V., et al. "The effect of autologous activated platelet rich plasma (AA-PRP) injection on pattern hair loss: clinical and histomorphometric evaluation." BioMed research international 2014 (2014).
• Dressler, Corinna, et al. "Efficacy of topical caffeine in male androgenetic alopecia." JDDG: Journal der Deutschen Dermatologischen Gesellschaft 15.7 (2017): 734-741.
• Finner, Andreas M. "Nutrition and hair: deficiencies and supplements." Dermatologic clinics 31.1 (2013): 167-172.
• Gentile, Pietro, et al. "The effect of platelet‐rich plasma in hair regrowth: a randomized placebo‐controlled trial." Stem cells translational medicine 4.11 (2015): 1317-1323.
• Gkini, Maria-Angeliki, et al. "Study of platelet-rich plasma injections in the treatment of androgenetic alopecia through an one-year period." Journal of cutaneous and aesthetic surgery 7.4 (2014): 213.
• Kang, J‐S., et al. "The effect of CD34+ cell‐containing autologous platelet‐rich plasma injection on pattern hair loss: a preliminary study." Journal of the European Academy of Dermatology and Venereology 28.1 (2014): 72-79.
• Leavitt, Matt, et al. "HairMax LaserComb® laser phototherapy device in the treatment of male androgenetic alopecia: A randomized, double-blind, sham device-controlled, multicentre trial." Clinical drug investigation 29.5 (2009): 283.
• Rushton, D. H. "Nutritional factors and hair loss." Clinical and experimental dermatology 27.5 (2002): 396-404.

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 ;-)

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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 reduction of 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.

Hair Mineral Analysis: Significant Correlations Between Calcium, Magnesium, Potassium & Sodium and Met. Syn., Insulin Resistance, Waist, BP etc. - Implications?

Does her hair hold the secret to her fitness body? Actually that's unlikely, but it appears possible that a hair analysis could reveals what's keeping you back from a similarly amazing physique.

Hair mineral analyses have been discredited by certain snake oil vendors who use them to sell their "oils" in form of an endless list of "essential" supplements you'd have to take if you don't want to end up as dead as the hair they used to produce the analysis. Still, they share one big strength with the more expensive RBC or other cell tests: They give you an idea of your actual calcium, magnesium, sodium and potassium balance.

Much in contrast to serum levels, by the way. If those are off, it's either due to an acute event (like diarrhea, for example ;-) or you have a real reason to be concerned. There is after all a really good reason these minerals are also called "electrolytes": They are heavily involved in the ion and thus charge-exchange that keeps your heart beating!

Serum analyses tell you if your heart will keep beating, but what do hair analysis tell you? That's a very valid question and the answer is NOTHING! You can use them to estimate your mineral balance, but a high calcium level in the hair, does not necessarily imply a high level in other body parts. Moreover, correlations as I am about to report them in today's SuppVersity article allow for hypotheses about causative effects, what they don't do, though is to prove cause and effect! Please keep that in mind while reading this article and before your next visit at your favorite quack.

Before we get to the actual hair mineral analysis data, let's briefly have a look at another set of striking and not so striking differences between the "normal" subjects and those with established metabolic syndrome:

Figure 1: Serum mineral concentrations, visceral (VAT) and subcutaneous body fat and smoking status in subjects w/ and w/out metabolic syndrome (Choi. 2014)

If you take a closer look at the data in Figure 1 you will see that - aside from marginal, but statistically non-significant differences in serum phosphor - the often-checked total Ca, Mg, K, Na & Ph concentrations did not differ between the two groups.

Potassium, insulin resistance & obesity: Later in this article you will learn that there was a negative association between the amount of potassium in the hair of the subjects and their HDL and insulin sensitivity. It's important not to confuse this with the message "potassium is bad for your insulin sensitivity" - in fact, in 1980, Rowe et al. observed significant decreases in plasma insulin response  to sustained hyperglycemia and a ~30% reduction in glucose metabolism (Rowe. 1980).

Moverover, visceral fat was a much more reliable parameter to distinguish the healthy and unhealthy subjects than subcutaneous fat and... a bit to my surprise: Smoking appears to be associated with a lower metabolic risk than non-smoking.

Let's take a look at the hair analysis, now

Much in contrast to the serum levels, the hair mineral analysis did reveal significant inter-group differences and corresponding correlations:

Of all potentially toxic molecules the researchers measured only the levels of arsenic and lead differed significantly between the two groups. The concentrations of cadmium, mercury, and aluminum were not different between the two groups, on the other hand, did not.

And what does that mean? If we take a parting look at the data in Table 1, you will see that, the one parameter that makes all the difference is none of the minerals. It's rather an old acquaintance: The total amount of visceral fat. With a p-value of p = 0.000 it's the best parameter we have to identify someone with metabolic syndrome. The hair minerals, on the other hand, may present with associations with individual features of the metabolic syndrome, namely...

Table 1: Multiple logistic regression analysis for hair mineral concentrations with metabolic syndrome (Choi. 2014)

• low calcium, low magnesium ➮ high blood pressure, high blood sugar, triglycerides, weight and waist,
• high sodium, high potassium ➮ low HDL,
• high copper ➮ low blood pressure, low weight, low waist, high insulin sensitivity,
• high chromium ➮ high weight, high waist, and
• high cobalt ➮ low blood pressure

Now, since, we don't know how exactly the hair mineral content ant the nutritional intake are connected, it is very difficult to make any recommendations based on these observations.

What appears to be relatively certain, though, is that these new findings don't change anything about my previous recommendation to make sure that you get enough calcium and magnesium - the thing about potassium, on the other hand, strikes me as odd. As an antagonist to calcium, the negative effects of K may yet simply be a result of a Ca deficiency in the average mid-40s subjects in the study at hand.

References:

• Choi, Whan-Seok, Se-Hong Kim, and Ju-Hye Chung. "Relationships of Hair Mineral Concentrations with Insulin Resistance in Metabolic Syndrome." Biological Trace Element Research (2014): 1-7.
• Rowe, John W., et al. "Effect of experimental potassium deficiency on glucose and insulin metabolism." Metabolism 29.6 (1980): 498-502.

Quackery or Solid Science: The Zinc Tally Test - Does it Work? How Does It Work? And How Reliable is It?

"Any idea if zinc tally test is reliable? Google spits somewhat mixed conclusions." That's what SuppVersity reader David Salda asked two days ago on the SuppVersity Facebook Page and this article is a somewhat lengthy answer to a short, but very valid question.

I know that only few of you are running a website, let alone one with daily updates, but if you do you the following incident may sound vaguely familiar: You are just trying to keep up with the comments on questions on the Facebook page of your website, when an innocent question like "Any idea if zinc tally test is reliable? Google spits somewhat mixed conclusions." someone (in this case David Salda) posted on your Facebook wall, reminds you of the written, yet never finalized and published articles that lie dormant in the depth of your website's draft folder... don't get me wrong, this is unquestionably a good thing - I mean I guess there will be more people than David, who would like to have the following two questions answered, correct?

How does the Zinc Tally Test work?

Actually the procedure is pretty straight forward. You hold a 10ml solution of zinc sulphate hydrate in a distilled water base (can be bought at the pharmacy) in your mouth for 10 seconds (don't swallow it!) and see how it tastes: (1) If you don't taste anything you are zinc deficient, (2) if there is no immediate taste, but a furry/dry mineral taste develops, your are low on zinc, (3) if a definite taste is detectable right away, you are supposedly in the lower normal range, and (4) if a strong unpleasant taste is immediately present, you got plenty of zinc already.

Is the Zinc tally test an adequate means to test whether you should Supplement W/ Zinc?

No. While it cannot be totally excluded that you can identify individuals with low zinc status on the basis of the Zinc Tally Test the scientific evidence for the accuracy of this method is clearly insufficient, highly conflicting and in large parts bugged with the usual methodological flaws you see in studies on topics most allopath would deem nuturapathic *bs*.

Take a short cut to the answer to your question: If we take into consideration the currently available literature (an ebook someone sells on his own website is no "literature"), there is little to add to the conclusion the researchers from the Southern Cross University in Lismore,  Australia fomulate in the abstract of their study: Despite being widely used, the Zinc Tally Test does is not sensitive and specific enough to assess marginal zinc status in humans. It's thus not really surprising that a 1999 study by Jenna Jameson shows that its results don't even correlate with with dietary zinc intake (Jamison. 1999)

In 2012 Gruner & Arthur conducted a systematic review of the available literature in which they included only studies which provide full reports of clinical trials comparing the tally test (ZTT) to at least one other zinc test within the same sample population. The mere number of studies which matched these more or less self-evident minimum requirements, is telling, already: "3", in words "three" studies matched the criteria of inclusion.

If your breakfast looks even close to this extraordinary beans, eggs and bacon breakfast, it's him time that you learn and apply(!) the "Three Simple Rules of Sensible Supplementation" | more

"Study I compared the ZTT with sweat zinc in patients with food intolerance, reporting moderate correlation. Study II recruited pregnant women using the ZTT and serum zinc to assess zinc status, with above 70% congruence between the two tests at the start of the trial and 100% congruence at the end. Study III also recruited pregnant women at three stages during gestation, assessing ZTT and leukocyte zinc initially, later adding dietary zinc intake and at delivery cord blood zinc. No significant correlation was found between the results of these different methods; however, statistically significant differences in the ZTT responders (tasters and nontasters) were found for pregnancy outcomes." (Gruner. 2012)

And guess what: Even these studies suffered from all sorts of methodological problems. The laboratory assays that were used in the studies lacked sensitivity to zinc status. They were poorly standardized and did often deviate from the original design of the zinc tally test as it is described on the Internet.

Zinc deficiency alters general taste acuity - but not in a linear / reliable fashion

Something else that's worth mentioning in this context is the influence of low zinc levels on taste acuity in general. While the number of respective studies is not exactly high, there is good evidence that subjects with a generally impaired ability to taste tend to have lower zinc concentration in the blood and exhibit a lower ratio of apo/holo-activities of angiotensin converting enzyme (ACE), a zinc dependent enzyme in the serum (ACE ratio), than controls (Ueda. 2006). A 2010 follow up study did yet reveal that a definitive correlation between serum zinc levels and the scores on a visual analogue scale for the severity of the symptoms of did not correlate in after supplementation - whether zinc is the the cause or as so often just a corollary factor is therefor still in the open (Takaoka. 2010)

Suggested: " Zinc: 15mg Are Plenty - After 120 Days Rodents on Diets Containing 2xRDA of Zinc Develop Metabolic Syndrome" | more

Bottom line: While it stands out of question that the zinc tally test should not be your method of choice, when it comes to testing your zinc status, the observation Ueda et al. and Takaoka et al. made with respect to the ratio of apo/holo-activities of angiotensin converting enzyme (ACE) could actually be used as a measure of your zinc status. It would provide an alternative and accurate tests to determine the adequacy of your dietary zinc intake.

That's at least what the results of a 2012 experiment by Sarakura et al. in the course of which mice were zinc depleted for 9 days would suggest (Sarakura. 2012). The ACE ratio would thus be #4 on the list of tests that are considered to reflect the zinc status human beings more or less adequately. The other three tests are plasma, urinary, and hair zinc analysis (Lowe. 2009).

References:

• Jamison, JR. Mineral Deficiency: A Dietary Dilemma? Journal of Nutrition and Environmental Medicine.1999; 9(2):149-158.
• Lowe NM, Fekete K, Decsi T. Methods of assessment of zinc status in humans: a systematic review. Am J Clin Nutr. 2009 Jun;89(6):2040S-2051S.
• Sarukura N, Takai S, Ikemoto S, Korin T, Ueda Y, Kitamura Y, Kalubi B, Yamamoto S, Takeda N. Effects of dietary zinc deprivation on zinc concentration and ratio of apo/holo-activities of angiotensin converting enzyme in serum of mice. Auris Nasus Larynx. 2012 Jun;39(3):294-7.
• Takaoka T, Sarukura N, Ueda C, Kitamura Y, Kalubi B, Toda N, Abe K, Yamamoto S, Takeda N. Effects of zinc supplementation on serum zinc concentration and ratio of apo/holo-activities of angiotensin converting enzyme in patients with taste impairment. Auris Nasus Larynx. 2010 Apr;37(2):190-4.
• Ueda C, Takaoka T, Sarukura N, Matsuda K, Kitamura Y, Toda N, Tanaka T, Yamamoto S, Takeda N. Zinc nutrition in healthy subjects and patients with taste impairment from the view point of zinc ingestion, serum zinc concentration and angiotensin converting enzyme activity. Auris Nasus Larynx. 2006 Sep;33(3):283-8.

Dietary Zinc & Copper Improve Glucose & Lipid Metabolism. High Cortisol Amplitudes Counter Belly Fat. Hypoxic Hearts Love Creatine + Ribose. Apples Counter Cancer & Obesity

I guess this is about as close as we have hitherto gotten to understand why we got fat. Wrt to the hilarious pace at which we got fat and are still getting fatter, we are much better informed though.

After you've learned about the general importance of exercise for your health and a couple of tweaks that may or, as in the case of sugary "energy drink", may not help you maximize the benefits and performance gains on Saturday. The focus of today's SuppVersity article is on the results of non-exercise related studies that highlight non-exercise related confounders of your health.

Before we get to the actual news, I would yet like to invite all of you to take a look back at the increasingly obese history of the US... I suppose those of you who have not yet seen the link on my Facebook wall, will enjoy the animated obesity map in the Atlantic article from April 11. I mean, even if we still don't have anything but over-simplistic cookie-cutter "explanations" of why we get fat, the map shows that we do at least know how fast we got fat!

You don't feel knowing about how fast we got fat is good news? Ok, maybe you'll like one the following results from recent studies better:

• Dietary zinc & copper influence glucose & lipid metabolism in women (Shab-Bidar. 2013) According to a recent study from the Obesity Research Center at Shahid Beheshti University of Medical Sciences in Tehran, Iran, there is a gender specific effect of copper and zinc in the diet on glucose and lipid metabolism of men and women in Iran - statistical significant effects were observed only in women with...

  

  Odds ratios for the MetS and low HDL across quartiles of copper intake (Shab-Bidar. 2013)

  • higher zinc intakes being associated with higher HDL-C, lower triglycerides (TG) and lower 2-hour blood glucose, and 
  • higher copper intake correlating with higher HDL-C, lower fasting blood glucose (FBG), significantly lower TG and a huge 81% reduction in the risk for suffering from metabolic syndrome (highest vs. lowest copper intakes)
  These observations stand in contrast with the current notion of the "bad" copper and the "good" zinc and reamphasize the importance of both nutrients for metabolic health.

  ---

  Remember: Two questions that will still have to be resolved pertain to (a) the gender-specificity of the effects and (b) confounding effects of food quality / choice and thus whether the same beneficial effects would be observed with the standard American diet.
  For both, but espicially for copper a little more than the RDA does not appear to hurt: What's particularly interesting, is that contrary to the zinc intakes in quartile 4 (>14mg/day; RDA 9mg/day) the copper intake in quartile 4 was more than 3x higher than the current RDA for women (0.9 mg). In fact, even the copper intake in the lowest quartile ~1.5mg/day was way above the RDA. If that's something we have to be surprised about is yet questionable, after all, there is not exactly much research on "optimal copper nutrition" (much contrary to zinc, by the way) and the RDA is based on age-old depletion-repletion studies and will thus probably reflect the absolute minimum to maintain "normal" serum levels.

• Evidence from human study: Flat cortisol profile not averages or spikes are associated with increased adiposity and visceral obesity (Sharp. 2013) In their most recent paper that's soon going to be published in the American Journal of Human Biology Dan S. Sharp and his colleagues from the Center for Disease Control and the State University of New York provide conclusive evidence for the irrelevance of mean cortisol levels with respect to the purported negative effects of cortisol on visceral obesity.

  

  Associations between sextiles of within-subjects cortisol standard deviation (SD) in 217 Buffalo policemen and adjusted lean-mass trunk index (Sharp. 2013)

  As the data in the figure above clearly shows, the police officers with the greatest cortisol fluctuations (spikes and troughs) had the highest ratio of lean body mass to trunk mass. It is thus, as the scientists phrase it,
  

  "not the average level of salivary cortisol among 18 specimens on each officer that drives the association; it is the variation among specimens."

  The oral cortisol measures were taken on 3 subsequent days in standardized procedures that involved a venipuncture and a standardized high protein meal as "challenges", on day 1, six measures that were taken by the police officers over the course of the day, on day 2, and series of tests that was taken after a dexamethasone challenge after waking on day 3 (the subjects had ingested 0.5mg of dexamethasone the night before).

  ---

  Bottom line: While the scientists are careful in pointing out that it will still have to be established that the results translate to other populations. The results corroborate the uselessness (if not potential detrimental effects) of "cortisol blockers", I've discussed in my previous in the Science Round Up Seconds on March 29, 2013 (read more).

• Combination of creatine and d-ribose heals damaged, but unscarred rodent-hearts (Caretti. 2013) While the many of the "daggered" claims* on the boxes of various "advanced" creatine products (learn more about their uselessness) are probably a little overblown (*the dagger refers to the "not verified by the FDA"), that's nothing compared to the absolutely disappointing results trainees had with d-ribose. Meanwhile, it seems as if even the last jerk knew that the unbearably sweet simple sugar is nothing worth spending his/her money on.
  
  

  

  Ribose regulates the novo synthesis and restoration nucleotides, can relieve the energy toll of ischemia  and its usefulness in the context of CVD is backed by rodent and human studies (Shecterle. 2011)

  In view of it's physiological role in the recovery of ATP levels (Helsten. 2004), it was assumed that supplementatal D-ribose would ameliorate the ATP depleting effects on exercise and improve endurance in glycolytic and/or long endurance activities, yet...
  

  "[...s]tudies examining the effect of ribose on performance during intense intermittent exercise and rowing have not been able to demonstrate improved performance in humans." (King. 2012)

  Other than the non-existence of side-effects, pertaining studies, which used up to ∼40 g/day, as well as acute and chronic supplementation regimen did  yet not yield any positive results
  
  Now, the aforementioned studies on the ergogenic effects of d-ribose were conducted in healthy individuals, in whom the ATP re-synthesis obviously does not depend (and not even benefit) from the provision of the monosaccharid that was discovered by Emil Fischer in 1891, when he analyzed the carbon structure of gum arabic (Prince. 2012). "Healthy" would yet not be the correct term to describe the rodents in the recently conducted study by Caretti et al. who observed that five week-old mice who were exposed to an atmosphere containing 10% O2 for 10 days in order to induce right ventricle hypertrophy and left ventricle apoptosis did not show any signs of cardiac damage, when they were gavaged creatine + D-ribose, every day.
  
  And while both phenotypes, i.e. the hypertrophy of the right and apoptosis of the left ventricle, were blunted to a certain degree by creatine or d-ribose, only their reversed the pathogenic changes to the heart muscle "almost" completely, by normalizing the expression of AMPK and Akt signaling in the hearts of the rodents.

  ---

  

  Light micrograph of representative nuclear pro-files (background, red = atypical, green = normal nuclei; my emphasis) and volume (%) of atypical cardiac cells in anterior left ventricle of rodents on caffeine + nicotine + ephedrine combo (learn more)

  Bottom line: While they may not be beneficial for the average trainee, people "on" the literally heart-breaking combination of nicotine + caffeine and ephedrine, could be able to reduce their detrimental effects on the heart (learn more), by adding this combination of proven (creatine) and disproven (d-ribose) ergogenics to their supplement regimen. People with sleep-apnea and other conditions which will leave the heart poorly oxygenized for longer time-periods should obviously benefit, as well.
  
  Based on the likewise promising results of previous studies in (human!) subjects with congestive heart failure (e.g. Omran. 2003), a daily dose of 5g d-ribose, along with the tried an proven chronic ingestion of 5g of creatine appears to be a good starting point, until respective human trials have been conducted.

• Further evidence for the "An apple a day..." theory (Rago. 2013) In an allegedly methodically complicated, but very comprehensive analysis of the effects of raw, whole apples on the plasma metabolome of rodents, researchers from the University of Copenhagen found
  

  

  Total antioxidant activity (µmol vitamin C equivalents/g) of various fruits (Boyer. 2004)

  "that the intake of fresh apple in rats has a considerable and specific impact on the plasma metabolite profile, reflecting altered gut microbial metabolism, retarded lipid- and protein catabolism, and lowered metabolic, oxidative and steroid-related stress". (Rago. 2013)

  These results stand in line with the recent observations a group of Spanish researchers made, when they added a polyphenol extract from apples to the chow of rodents on an obesogenic high-fat + high sugar (HFS) diet:
  

  "Our results from histological studies demonstrated that supplementation of HFS with AP markedly reversed the enlargement of adipocyte volume induced by HFS diet intake in the epididymal fat pad, reducing it by almost 28% [...it also] reversed the increase in the population of large epididymal adipocytes, especially with diameters higher than 130m." (Boqu. 2013)

  The visceral specific effects of the apple polyphenols in the Boqué study could thus be interpreted as supportive evidence for the real-world significance of the metabolomic changes Rago et al. observed in the afore-cited study.

  ---

  Bottom line: No reason to be scared of the "high fructose fruit" apple. It comes with all HFCS sweetened beverages don't have. Polyphenols, vitamins, minerals and most importantly a flesh from which the fructose is extracted only slowly. Still, I have to warn you: Apple consumption can have profound beneficial effects on your health, such as (random examples)
  
  •  - 17% colorectal cancer risk (Michels. 2006)
  •  - 37% wheeze risk in your offspring (Willers. 2007)
  •  - 21% reduced risk for cancers of the oral cavity and pharynx (Gallus. 2005)
  •  - 25% reduced risk for oesophagus (Gallus. 2005) 
  •  - 18% / -15% / -9% risk red. for breast / ovary / prostate cancer (Gallus. 2005)
  and obviously the - 15% reduced breast cancer risk, the if you want to avoid these, you should thus better keep obsessing about the high fructose content of apples and stick to sausages and lard ;-)

References:

• Boqué N, de la Iglesia R, de la Garza AL, Milagro FI, Olivares M, Bañuelos O, Soria AC, Rodríguez-Sánchez S, Martínez JA, Campión J. Prevention of diet-induced obesity by apple polyphenols in Wistar rats through regulation of adipocyte gene expression and DNA methylation patterns. Mol Nutr Food Res. 2013 Mar 25.
• Boyer J, Liu RH. Apple phytochemicals and their health benefits. Nutr J. 2004 May 12;3:5.
• Caretti A, Bianciardi P, Marini M, Abruzzo PM, Bolotta A, Terruzzi C, Lucchina F, Samaja M. Supplementation of creatine and ribose prevents apoptosis and right ventricle hypertrophy in hypoxic hearts. Curr Pharm Des. 2013 Apr 10. [Epub ahead of print]  
• Gallus S, Talamini R, Giacosa A, Montella M, Ramazzotti V, Franceschi S, Negri E, La Vecchia C. Does an apple a day keep the oncologist away? Ann Oncol. 2005 Nov;16(11):1841-4. 
• Hellsten Y, Skadhauge L, Bangsbo J. Effect of ribose supplementation on resynthesis of adenine nucleotides after intense intermittent training in humans. Am J Physiol Regul Integr Comp Physiol 2004;286:R182–8.
• Michels KB, Giovannucci E, Chan AT, Singhania R, Fuchs CS, Willett WC. Fruit and vegetable consumption and colorectal adenomas in the Nurses' Health Study. Cancer Res. 2006 Apr 1;66(7):3942-53. PubMed PMID: 16585224.  
• Omran H, Illien S, MacCarter D, St Cyr J, Lüderitz B. D-Ribose improves diastolic function and quality of life in congestive heart failure patients: a prospective feasibility study. Eur J Heart Fail. 2003 Oct;5(5):615-9.  
• Price, NPJ. The Name of the–ose: An Editorial on Carbohydrate Nomenclature. J Glycobiol. 2012; 1(e105).
• Rago D, Kristensen M, Gözde G, Federico M, Morten P, LarsOve D. LC–MS metabolomics approach to investigate the effect of raw apple intake in the rat plasma metabolome. Metabolomics. 2013; 1573-3882.
• Shab-Bidar S, Hosseini-Esfahani F, Mirmiran P, Mehran M, Azizi F. Dietary intakes of zinc and copper and cardiovascular risk factors in Tehranian adults: Tehran Lipid and Glucose Study. Nutrition & Dietetics. 2013
• Sharp DS, Andrew ME, Fekedulegn DB, Burchfiel CM, Violanti JM, Wactawski-Wende J, Miller DB. The cortisol response in policemen: Intraindividual variation, not concentration level, predicts truncal obesity. Am J Hum Biol. 2013 Apr 20.
• Shecterle LM, Wagner S, St Cyr JA. A sugar for congestive heart failure patients. Ther Adv Cardiovasc Dis. 2011 Apr;5(2):95-7.
• Willers SM, Devereux G, Craig LC, McNeill G, Wijga AH, Abou El-Magd W, Turner SW, Helms PJ, Seaton A. Maternal food consumption during pregnancy and asthma, respiratory and atopic symptoms in 5-year-old children. Thorax. 2007 Sep;62(9):773-9. Epub 2007 Mar 27.
   

Histidine As a Fat Loss Adjuvant? 6% Fat Loss Without Dietary or Exercise Intervention & More Than Half a Dozen Other Reasons Not To Ignore This Essential Amino Acid

Histidine as a fat loss adjuvant? Laughable? Not for the obese! For lean folks like her? We'll see...

If I had to guesstimate the number of fitness enthusiasts who have ever heard of histidine at all, I would say that 50% probably don't even know what it is, while the majority of the lightened ones will re-iterate what the supplement business has been preaching them "You get more than enough histidine, anyway. So don't worry our superior beta-alanine supplement will work even if you don't take additional histidine."

Short term studies confirm this notion. It looks as if we usually have more than enough histidine to have it recombine with beta alanine and form carnosine, but long-term studies are missing and let's be honest: How likely is it that an essential amino acid is nothing but a servant to a non-essential amino acid from the 2nd row?

Early results: Histidine modulates feed efficiency

Actually we could have known that histidine could have some merit as a standalone supplement for more than 50 years now, so I am not sure if the recent publications of two studies by Feng et al. in Diabetolgy and Kumi Kimura et al. in Diabetes, the journal of the American Diabetes Association are going to change that over night. What is certain, though, is that they clearly support findings that date way back into early mid 20th century, when Ellison & King found that the provision of a low histidine diet to rodents increased the feed efficiency (=weight gain per energy unit) by 75%, while the addition of 0.75% histidine (per kg chow) to an already histidine sufficient diet  (Ellison. 1968) led to a 30% decrease in food efficiency.

About 45 years later, the previously mentioned studies on the effects of histidine on hepatic gluconeogenesis (Kimura. 2013) and insulin resistance (Feng. 2013) in rodents and human volunteers, respectively, could bring the hitherto often depreciated histamine precursor back to the center of scientific attention.

4g/day histidine improve insulin restiance, reduce fat mass and suppress inflammation

In that, the study by Feng et al., which investigated the effect of 4g/day supplemental histidine on the degree of insulin resistance, inflammation, oxidative stress and metabolic disorders in 100 obese women with the metabolic syndrome (aged 33–51 years; BMI≥28 kg/m²), is probably of greater significance for the average physical culturist that the nevertheless enlightening rodent trial by Kimura et al. we are going to address later.

Figure 1: Changes in amino acid levels, glucose & lipid metabolism, body composition and markers of inflammation after 12 weeks on placebo or 4g/histidine per day (Feng. 2013)

The effects the 4g/day of histidine had especially on the markers of inflammation are quire impressive for an amino acid of which you probably thought as either the "abundant" essential amino acid that's only an adjutant to 100% non-essential and on it's own just about as useless carnosine precursor beta alanine or - even worse - as the nasty precursor to the "allergy inducing", "inflammatory" organic nitrogen compound histamine.

"Hold on, but histidine is an allergy causing nasty bitch, isn't it?"

While the former perspective on histidine is laughable anyway, the fact that there were no increases in histamine levels and none of the participants experienced side effects such as headaches, which have been observed in previous trials with whopping amounts of 64g(!) of histidine per day (Geliebter. 1994) as they have been used, when scientists still believed that the main mechanism of histidine on body weight modulation was mediated by appetite reduction, are probably relevant. After all, histamine does play a role in the inflammatory response system of your body that the latter is not negatively, but positively affected by the consumption of pretty high amounts of histidine, is thus an important and in a way counterintuitive observation. On the other hand,

First the glucose repartitioning effects of isoleucine (learn more), now the benefits of histidine - what other secrets are still out there in the world of amino acids?

[h]istidine is a free radical scavenger and can chelate divalent metal ions (Babizhayev. 1994; Lee. 1999). Its effects against oxidative stress have been well investigated in animals and cells. Histidine has beneficial effects on liver and lung injury in rats and has been reported to protect against diabetic complications in a mouse model of diabetes through its actions against oxidative stress (Lee. 2005; Cuzzocrea. 2007; Yan. 2009). It can restrict accumulation of free radicals and delay activation of extracellular signal-regulated kinase and c-jun N terminal kinase in neuronal cells (Kulebyakin. 2012).

Against that background it is actually not surprising that the levels of TNF-α, IL-6 and c-reactive protein (CRP) dropped by 33%, 35% and 33% in the course of the 12 week study period.

Health and weight loss, two independent pairs of shoes?

If histidine is a metal chelator, do I have to be afraid of losing zinc? That's easy to answer and the answer is no and not just because I believe that the importance of zinc is way overrated (cf. "15mg of Zinc are plenty"). Schechter & Prakesh have shown in 1979, already that the ingestion of 4g of histidine on a daily basis influences the excretion of zinc only in the very short run. After 2 weeks the body achieves a new steady state and the zinc excretion returns to normal. What? No you did not pee out all the zinc before. In fact histidine increases the absorption of dietary zinc as well (cf. Freeman. 1977).

Moreover the changes in serum histidine were correlated with the changes in HOMA-IR, NEFA, TNF-α, SOD, GSH-Px, WC, FM and BMI even after further adjustment for age and serum histidine, protein intake, physical activity, alcohol use, current smoking and menopause at baseline.

"Thus, improved insulin sensitivity and alleviation of inflammation and oxidative stress could be due to the increased serum histidine." (Feng. 2013)

What's questionable, though, is how interrelated the modest, but statistically significant weight, or rather fat loss (-6% total fat mass) and the improvements in inflammation are. If we take a peek at the aformentioned rodent study by Kimura et al. who observed that the effects of histidine are mediated mainly centrally via histamine action on the H1 receptors in the brain, which will - independently of insulin (!) - downregulate the hepatic glucose production, it becomes more and more evident that non-obese / insulin-resistant individuals for whom an abundant hepatic glucose production hardly ever is a problem are less likely to benefit than the patients with type 2 diabetes, Kimura et al. implicate as the group that would be most likely to benefit from high histidine diets.

What else do we know about l-histidine?

In the end, we are thus back to square one. But maybe we can find other arguments in favor or against keeping an eye on adequate histidine intake that would be significant for the non-diabetic majority(!?) of the SuppVersity readers, as well. Let's see, what about

• Ok, put up or shut up - where is the relation between histidine, histamine and obesity? As so often I have to say in advance that the intricacies of the role the histamine receptors in the brain play in the regulation of food intake and metabolism are not yet fully understood. What we do know is that histidine is the dietary precursor for histamine and that the latter can interact with the same receptors (H1-H3) which participate in the regulation of dopamine, serotonin, and norepinephrine release and exert direct modulatory effects on food intake, meal frequency, adiposity and thermogenesis (Masaki. 2003; Masaki. 2004; Yoshimoto. 2006; Yoshimatsu. 2008).
  improved absorption of vitamin B12 and increased liver folate levels (Williams. 1976) 
• low histidine intake increases carnosine breakdown, so that the ant-inflammatory intra-cellular buffer carnosine you are trying to increase by taking BA would decrease to be used as a histidine source if you actually got too little histidine in your diet (Tamaki. 1984)
• increased absorption and excretion of zinc, with a primer on the former, when intakes are low, so that the overall result is an improved management of zinc (Sandström. 1985; Van Wouwe. 1989) 
• potential anti-Alzheimer's effects; if we simply assume that an increased amount of dietary histidine could ameliorate the histidine and histamine reductions in the brains of Alzheimer patients (Mazurkiewicz-Kwilecki. 1989), it would be logical to assume that the presence of this metal-chelator could prevent the accumulation of toxic levels of copper in the brain
• significant increases in UCP-1 activity (+57%) in brown adipose tissue and thus higher energy expenditure, reduced appetite, significantly lower feed efficiency (-30%), reduced insulin levels (-48%) and significantly lowered visceral fat pad weights; allegedly in rodents w/ additional 5% histidine in the diet (Kasaoka. 2004) 

Now you could certainly argue that the studies which support the weight loss effects Feng et al. observed in their obese subjects were almost exclusively conducted on rodents... what am I supposed to say? You're right and you know that I am very skeptical that UCP-1 and brown adipose tissue activity play a significant role in human weight / body fat control. Still, the high correlations between the histidine / total protein ratio Okubo et al. observed in a cohort of non-obese 18y-old female Japanese students does clearly suggest that at least part of the effects are not species specific (Okubo. 2005).

Additional health effects 
 

Milk thistle is unquestionably the more prominent liver protectant (learn more)

Furthermore, histidine also prevented colitis by reducing gastric inflammation (Andou. 2009) and exerted  ameliorative effects on

• LDL oxidation and glycation (Lee. 2005), 
• alcohol induced liver failure (Liu. 2008), 
• acetaminophen induced liver injury (Yan. 2009), 
• diet induced hepatic steatosis (Mong. 2011)

when it was co-administered with carnosine. Unfortunately, none of the studies tested, whether the same results would have been observed if only one of the compounds had been used in the respective rodent trials.

So, no strings attached? Well, not exactly...

As usually the dose-response curve is yet non-linear and an exuberantly high intake of histidine (8% of the diet in rodents → far more than 70g per day for humans) can lead to copper depletion and corresponding lipid disturbances in cholesterol metabolism (Harvey. 1981). Needless to say that for people with a messed up histamine metabolism far lower doses could potentially exert negative effects. It should be mentioned though that the equation"more histidine = more histamine" does not necessary hold - just take a look at the data from the Feng study: More histamine? Yes! Beneficial effects? Yes! Increased circulating histamine? No!

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Bottom line: Wile it appears likely that the provision of supplemental histidine in amounts of up to 4g/day could provide a highly beneficial adjunct to exercise and diet intervention in obese and/or diabetic individuals, it remains to be seen, whether or not lean, healthy and insulin sensitive fitness enthusiasts benefit to a similar degree.

Histidine content of various foods; w/ a focus on high histidine food items

While I would exclude that the profound anti-inflammatory effects Feng et al. observed could hamper your performance / gains, I would not exclude that the non-vegetarian majority of the SuppVersity readers is not exactly at risk of running out of histidine anytime soon (see table on the right for good dietary sources). Against that background, you may have to revise your perspective on this rarely talked about amino acid. What you probably don't have to do, though, is to go and buy a pouch of l-histidine to up your histidine intake to exorbitantly high levels... well, at least not until research on human beings confirms the beneficial effects on UCP-1, insulin and the body fat levels Ksaoka et al. observed in non-obese rodents.

References:

• Andou A, Hisamatsu T, Okamoto S, Chinen H, Kamada N, Kobayashi T, Hashimoto M, Okutsu T, Shimbo K, Takeda T, Matsumoto H, Sato A, Ohtsu H, Suzuki M, Hibi T. Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages. Gastroenterology. 2009 Feb;136(2):564-74.e2.
• Babizhayev MA, Seguin MC, Gueyne J, Evstigneeva RP, Ageyeva EA, Zheltukhina GA. L-carnosine (beta-alanyl-L-histidine) and carcinine (beta-alanylhistamine) act as natural antioxidants with hydroxyl-radical-scavenging and lipid-peroxidase activities. Biochem J. 1994; 304(Pt 2):509–516.
• Cuzzocrea S, Genovese T, Failla M et al. Protective effect of orally administered carnosine on bleomycin-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 2007; 292:L1095–L1104
• Ellison JS, King KW. Mechanism of appetite control in rats consuming imbalanced amino acid mixtures. J Nutr. 1968 Apr;94(4):543-54.
• Feng RN, Niu YC, Sun XW, Li Q, Zhao C, Wang C, Guo FC, Sun CH, Li Y. Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial. Diabetologia. 2013 Jan 30. 
• Freeman RM, Taylor PR. Influence of histidine administration on zinc metabolism in the rat. Am J Clin Nutr. 1977 Apr;30(4):523-7.
• Geliebter AA, Hashim SA, Van Itallie TB Oral L-histidine fails to reduce taste and smell acuity but induces anorexia and urinary zinc excretion. Am J Clin Nutr. 1981; 34:119–120.
• Harvey PW, Hunsaker HA, Allen KG. Dietary L-histidine-induced hypercholesterolemia and hypocupremia in the rat. J Nutr. 1981 Apr;111(4):639-47.
• Kimura K, Nakamura Y, Inaba Y, Matsumoto M, Kido Y, Asahara SI, Matsuda T, Watanabe H, Maeda A, Inagaki F, Mukai C, Takeda K, Akira S, Ota T, Nakabayashi H, Kaneko S, Kasuga M, Inoue H. Histidine augments the suppression of hepatic glucose production by central insulin action. Diabetes. 2013 Mar 8.
• Kulebyakin K, Karpova L, Lakonsteva E, Krasavin M, Boldyrev A. Carnosine protects  neurons against oxidative stress and modulates the time profile of MAPK cascade signaling. Amino
  acids. 2012; 43:91–96
• Lee JW, Miyawaki H, Bobst EV, Hester JD, Ashraf M, Bobst AM. Improved functional recovery of ischemic rat hearts due to singlet oxygen scavengers histidine and carnosine. J Mol Cell Cardiol. 1999; 31:113–121.
• Lee YT, Hsu CC, Lin MH, Liu KS, Yin MC. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J
  Pharmacol. 2005. 513:145–150.
• Liu WH, Liu TC, Yin MC. Beneficial effects of histidine and carnosine on ethanol-induced chronic liver injury. Food Chem Toxicol. 2008 May;46(5):1503-9. doi: 10.1016/j.fct.2007.12.013.
• Mong MC, Chao CY, Yin MC. Histidine and carnosine alleviated hepatic steatosis in mice consumed high saturated fat diet. Eur J Pharmacol. 2011 Feb 25;653(1-3):82-8. doi: 10.1016/j.ejphar.2010.12.001.
• Okubo H, Sasaki S. Histidine intake may negatively correlate with energy intake in human: a cross-sectional study in Japanese female students aged 18 years. J Nutr Sci Vitaminol (Tokyo). 2005 Oct;51(5):329-34.
• Sandström B, Davidsson L, Cederblad A, Lönnerdal B. Oral iron, dietary ligands and zinc absorption. J Nutr. 1985 Mar;115(3):411-4.
• Schechter PJ, Prakash NJ. Failure of oral L-histidine to influence appetite or affect zinc metabolism in man: a double-blind study. Am J Clin Nutr. 1979 May;32(5):1011-4.
• Tamaki N, Funatsuka A, Fujimoto S, Hama T. The utilization of carnosine in rats fed on a histidine-free diet and its effect on the levels of tissue histidine and carnosine. J Nutr Sci Vitaminol (Tokyo). 1984 Dec;30(6):541-51.
• Van Wouwe JP, Hoogenkamp S, Van den Hamer CJ. Histidine supplement and Zn status in Swiss random mice. Biol Trace Elem Res. 1989 Oct;22(1):35-43.
• Williams DL, Spray GH. The effects of dietary histidine, methionine and homocystine on vitamin B12 and folate levels in rat liver. Br J Nutr. 1976 May;35(3):299-307
• Yan SL, Wu ST, Yin MC, Chen HT, Chen HC. Protective effects from carnosine and histidine on acetaminophen-induced liver injury. J Food Sci. 2009: 74:H259–H265.