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Which of the dirty dozen of supplements and foodstuffs in todays SuppVersity review can really help you to make sure, youre not the one out of those nine men who develops prostate cancer?

Supplements that are supposed to protect you from developing prostate cancer and/or agents that may help patients with existing prostate issues are - obviously - in high demand. And as W. Merkle points out in a recent article in the German science journal Urologe using them - even if they may not be as effective as some patients may believe - makes sense: from a psychological perspective, alone (Merkle. 2014).

Taking a pill with selenium, for example, has been shown to alleviate some of the side effects of chemotherapy. General protective effects against prostate cancer, on the other hand, have not been established. In fact, the most recent studies rather suggest that "supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status" (Kristal. 2014).
Luckily, there are other supplements with more promising data. Supplements that will actually complement, a healthy diet and active lifestyle, the two pillars of all (not just prostate) cancer protection. Supplements like...

• Curcumin - As a SuppVersity reader youve probably already expected to see the curcumin on the list. Its potent anti-inflammatory effects and more specifically its ability to target multiple inflammatory pathways, which include NF-KappaB, COX2, STAT3 and high levels of CRP, Prostaglandins and TNF-alpha make it a particularly valuable anti-tumor agent of which Guo et al. observed in a recent study that it will induce cell cycle arrest and apoptosis of prostate cancer cells by regulation the expression of IkappaBalpha, c-Jun and androgen receptor (Guo. 2013)
• Genistein - Just like curcumin, genistein acts on NF-KappaB (Adjakly. 2013). In addition it will upregulate a protein called miR-574- 3p that will have cancer cells "kill themselves" (go into apopotosis; Chiyomaru. 2013). In addition scientists have found genistein to support the efficiacy of Cabazitaxel which is used for the treatment of hormone-refractory prostate cancer.
• Pomegranate - Pomegranate extracts or rather its ingredients, i.e. ellagic acid, caffeic acid, luteolin and punicic acic, have been shown to inhibit the proliferation and induce apoptosis in prostate cancer cells (NCI. 2013).

  Figure 1: If you look at the actual increase in apoptotic cancer cells in response to the pomegranate treatment, it is obvious that some patients (e.g. #53) benefited more than others (Pantuck et al. 2006)

  A clinical trial by Pantuck et al. (2006) was also able to show that the time it takes for the PSA levels, an albeit debatable marker of prostate cancer risk, to double decreased significantly, when the subjects, men with rising PSA after surgery or radiotherapy, were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Unfortunately, a more recent study by Stenner-Liewen et al. (2013) could not confirm these effects. 
• Brassica vegetables (cruciferous vegetables) - While general vegetable intake is already associated with a -39% reduced risk of developing extraprostatic prostate cancer (cancer, eating tons of cruciferous vegetable, it was the intake of broccoli and cauliflower that made the biggest impact in a 2007 study by Kirsh et al.
  
  

  Even if they dont protect you from prostate cancer broccoli & co will inhibit myostatin and could help you to grow more muscle... well, at least theoretically, you know about the difference between the petri dish and the real world, so dont expect monster gains | more.

  As it is usually the case the evidence is yet ambiguous. In a 2002 review of the evidence, Kristal, et al. found that of the six studies they could clearly interpret, only three reported statistically significant reduced risks (P < 0.05), while one reported a borderline significant reduced risk (P = 0.06). Against that background Verhoeven et al. are right, when they say: " Further epidemiological research should separate the anticarcinogenic effect of brassica vegetables from the effect of vegetables in general" (Verhoeven. 1996).
  
  More recently, Joseph et al. found that the existing differences in the epidemiological data may be due to genetic polymorphisms due to which only men with a certain genetic polymorphisms in glutathione S-transferases M1 and T1 will benefit from eating tons of cruciferous veggies (Joseph. 2004).
• Green tea - Green tea is good for everything, right? Well unless its not loaded with toxic molecules (see previous SuppVersity article) this may in fact be right. Convincing evidence from human trials is albeit scarce. What we do have are rodent studies like the ones that were conducted with TRAMP mice, which model closely mirrors the pathogenesis of human prostate cancer.
  
  In these mice EGCG, one of the main catechins in green tea, decreased the proliferation of prostate cancer cells and reduced the PSA levels. Scientists believe that these effects are mainly mediated by the effects EGCG has on the growth promoting proteins ERK1/2. Unfortunately, the same rodent studies also suggest that it is probably too late for many of you to start drinking green tea, now, because said beneficial effects are only observed in young, not in old TRAMP mice (Donald. 2012).

• Coffee is for the ladies, too! Studies show significantly reduced risks of breast cancer with 5+ cups of coffee. Tee and cacao help, as well | more

  Coffee - Obviously I am biased, when it comes to coffee. I still hope you believe me when I say that drinking 5+ cups of coffee per day has been associated with significantly reduced risk of prostate cancer in what is probably the most large-scale meta-analysis of the topic today.
  
  In their meta-analsis of 12 peer-reviewed case-control studies, Lu et al. calculated a 4% risk reduction for Europeans who consumed five or more cups of coffee and Americans who consumed 4 or more regular cups of coffee (equ. to approximately 400-500mg of caffeine). Moreover, the scientist found "a significant inverse association in all categories of prostate cancer except Gleason <7 grade" in both the "fixed-effects model" and the "random-effects model" (Lu. 2014).
  
  Wilson et al. also report an inverse association between coffee consumption and the incidence of highly malignant prostate cancer (Wilson. 2013). This means that drinking coffee is not only going to reduce your overall risk of developing prostate and other cancers (Geybels. 2013), it will also increase your chance that in the unfortunate case you still develop cancer, its going to be a benign and treatable form of prostate cancer.
• Lignans (e.g. from flaxseed) - While many of you will probably know them as "bad anti-androgens", there is little doubt that lignans from flax and other foodstuff inhibit cancer growth. What is particularly interesting about these agents is that they dont work via the "regular" NF-kappaB pathway but inhibit the expression of the vascular endothelial growth favtor (VEGF; cf. Azrad. 2013).
• Lycopene - Its the bright red carotene and carotenoid pigment and phytochemical that gives tomatoes and other red fruits and vegetables, such as red carrots, watermelons, gac, and papayas, although not in strawberries, red bell peppers, or cherries their color.
  
  Based on the currently available evidence it appears to help not just with prostate, but also with pancreatic, intestinal and lung cancer (Giovannucci. 1999). In that, it makes a particularly effective adjunct to classic cancer therapy (Tang. 2011).

  Figure 2: Prostate cancer risk w/ high vs. low intakes of the given antioxidants according to XRCC1 genotype (Goodman. 2006)

  Unfortunately, the data is ambigious... as usual. Unlike for other agents, it does yet appear as if scientists have already identified a certain gene, i.e. XRCC1, which appears to determine whether you do or do not benefit from the consumption of increased amounts of tomato lycopene (Goodman. 2006).
  
  In view of the fact that certain genotypes actually increase their prostate cancer risk specifically if they are consuming both, a high amount of lycopene and vitamin E (alpha-tocopherol), the latest Cochrane Review on the protective effects of lycopene against prostate cancer considers the evidence for "preliminary" and "insufficient" (Ilic. 2011).
• Fish oil / omega-3 - In spite of the fact that the media jumped at the finding of the SELECT trial (learn more) that claimed that selenium would be bad, while a high fish consumption or rather a high amount of omega-3s in the blood would protect you against prostate cancer, a close re-analysis of the data you can read up on at the website of the Life Extension Foundation indicates that this was all media hype.
  
  With a de facto difference of only 0.18% the difference was... well, youd say a joke, scientists would say "within the margin of statistical error" and thus by no means significant. If you take an even closer look at the data, it would even seem as if omega-3 fatty acids would increase the risk of prostate cancer.
• Resveratrol - If you look at the existing evidence you will be surprised to find studies that indicate that resveratrol increases (Klink. 2013) and studies that show that it inhibits prostate cancer growth (Iguchi. 2012; Kai. 2011).
  
  Again, it took a closer look at the data and another experiment to find out what really was going on: a dose-dependent effect with increased risk with low and decreased risk with high doses of resveratrol (Benitez. 2007). Bad news: With the current low biovailable oral resveratrol preparations youre likely to end up in the "increased risk" resveratrol exposure zone.
• Selenium - While I have mentioned it in the introduction already, its certainly worth taking a closer look at what selenium is actually supposed to do.
  
  In their 2011 review of the literature, Rizky Abdulah et al. didnt just highlight the many different molecular pathways, by which selenium could protect you from developing cancer, they also point out that the type of selenium supplement used could be of critical importance with respect to the success of your efforts to avoid the development of cancer. In that,...

  In rodents selenium acts as corrosion inhibitor in the brain | learn more

  "[...] methylselenol is believed to be the critical metabolite in selenium chemoprevention. Since methylselenol is highly reactive, methylselenol precursors such as Semet and Se-mSC are important both in in vitro and in vivo experiments. Semet and Se-mSC conversion to methylselenol, however, requires enzymatic conversion by the enzyme ?-lyase, which is 800 times less prevalent in human tissues than in mouse tissues.

  This may explain why the results of Semet and Se-mSC anticancer studies in humans were not as impressive as in vivo experiments. Although researchers have now turned to other Se compounds such as mSeA, which do not need enzymatic conversion to methylselenol, or selenite, which does not need to be converted to methylselenol for its anticancer properties, more substantial research on selenium compound metabolism in human tissues is necessary." (Abdulah. 2011)

  In other words, as of now, we dont know which form of selenium we actually have to use in human trials to generate similar impressive results as they have been observed in rodents.
  
  And as if that wasnt already "bad" enough, a meta-analysis of intervention studies by Hurst et al. (2012) indicates that there is a very narrow "band" of serum concentrations, where selenium is actually good for you! When your selenium level passes 170 ng/ml the tumor-protective effect disappears and - worst case scenario - your risk increases. So remember: More does certainly not help more!
• Silibin (from milk thistle) - You probably think of milk thistle as a "liver supplement". In fact, its main active constituent will yet also reduce the efficacy of osteoclast cytokines and reduce the concentration of RANKL-ligands. Thus it will regulate the NF-?B und AP1 levels in cells and inhibit the proliferation, invasion and migration of metastatic prostate cancer (Ting. 2011; Chen. 2012) 
• Vitamin D - Believe it or not: There are things vitamin D3 cannot do! One of this things is to protect you prostate cancer. Thats the prerogative of active vitamin D aka calciferol. In rodent studies and studies on human cell lines calciferol and multiple analogs of active vitamin D have shown to be promising drugs for prostate cancer protection, though (Tokar. 2005).
  
  

  Underestimated Vitamin D Sources: Eggs, Chicken, Pork, Fish & Dairy Contain Ready-Made 25OHD | more

  Since simply popping tons of vitamin D3 is (luckily) without effect on the levels of calciferol (otherwise you would run the risk of being calcified from the currently prevalent abuse of vitamin D3 supplements), using vitamin D3 is less effective, but not useless.
  
  In 2010, for example, Woo et al. observed that the time it took for the PSA levels of prostate cancer patients to double was significantly reduced, when the subjects received 2,000 IU of vitamin D3 per day (Woo. 2005) - an effect of which previous in vitro studies suggest that it could be due to the local conversion of D3 to active vitamin D in prostate cancer cells (Tokar. 2005).
• Vitamin E - Needless to say that vitamin E has gotten a bad rep ever since scientists observed an increased risk when they gave the subjects of the SELECT trial vitamin E (learn more). Still, as long as you stay away from "classic" vitamin E and buy one of the still expensive tocotrienol supplements (or eat red palm oil), you can expect an anti-proliferative effect of the vitamins E (Conte. 2004; Srivastava. 2006)

References:

• Abdulah, Rizky, et al. "Molecular targets of selenium in prostate cancer prevention (Review)." International journal of oncology 39.2 (2011): 301-309. 
• Andersson, Swen-Olof, et al. "Lifestyle factors and prostate cancer risk: a case-control study in Sweden." Cancer Epidemiology Biomarkers & Prevention 5.7 (1996): 509-513.
• Azrad, Maria, et al. "Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer." Journal of medicinal food 16.4 (2013): 357-360.
• Benitez, Dixan A., et al. "Mechanisms Involved in Resveratrol?Induced Apoptosis and Cell Cycle Arrest in Prostate Cancer—Derived Cell Lines." Journal of andrology 28.2 (2007): 282-293. 
• Chen, Rongxin, et al. "The significance of MMP-9 over MMP-2 in HCC invasiveness and recurrence of hepatocellular carcinoma after curative resection." Annals of surgical oncology 19.3 (2012): 375-384.
• Chiyomaru, Takeshi, et al. "Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer." PloS one 8.3 (2013): e58929. 
• Conte, Carmela, et al. "??Tocotrienol Metabolism and Antiproliferative Effect in Prostate Cancer Cells." Annals of the New York Academy of Sciences 1031.1 (2004): 391-394.
• Donald, J. L. "Plasma metabolic profiling reveals age-dependency of systemic effects of green tea polyphenols in mice with and without prostate cancer." Molecular BioSystems 6.10 (2010): 1911-1916.
• Geybels, Milan S., et al. "Coffee and tea consumption in relation to prostate cancer prognosis." Cancer Causes & Control 24.11 (2013): 1947-1954. 
• Giovannucci, Edward. "Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature." Journal of the National Cancer Institute 91.4 (1999): 317-331.
• Guo H, Xu YM, Ye ZQ, Yu JH, Hu XY. "Curcumin induces cell cycle arrest and apoptosis of prostate cancer cells by regulating the expression of IkappaBalpha, c-Jun and androgen receptor." Pharmazie 68.6 (2013):431-4.
• Hurst, Rachel, et al. "Selenium and prostate cancer: systematic review and meta-analysis." The American journal of clinical nutrition 96.1 (2012): 111-122.
• Iguchi, Kazuhiro, et al. "Antiandrogenic activity of resveratrol analogs in prostate cancer LNCaP cells." Journal of andrology 33.6 (2012): 1208-1215. 
• Joseph, Michael A., et al. "Cruciferous vegetables, genetic polymorphisms in glutathione S-transferases M1 and T1, and prostate cancer risk." Nutrition and cancer 50.2 (2004): 206-213.
• Kai, Li, and Anait S. Levenson. "Combination of resveratrol and antiandrogen flutamide has synergistic effect on androgen receptor inhibition in prostate cancer cells." Anticancer research 31.10 (2011): 3323-3330.
• Kirsh, Victoria A., et al. "Prospective study of fruit and vegetable intake and risk of prostate cancer." Journal of the National Cancer Institute 99.15 (2007): 1200-1209.
• Klink, Joseph C., et al. "Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell?line specific manner, through paradoxical effects on oncogenic pathways." The Prostate 73.7 (2013): 754-762.
• Kristal, Alan R., et al. "Baseline selenium status and effects of selenium and vitamin E supplementation on prostate cancer risk." Journal of the National Cancer Institute 106.3 (2014): djt456.
• Lu, Yu, et al. "Coffee consumption and prostate cancer risk: an updated meta-analysis." Cancer Causes & Control 25.5 (2014): 591-604. 
• Merkle, W. "Prostatakarzinomprophylaxe durch Nahrungsergänzungsmittel." Der Urologe (2014): 1-7.
• NCI (2013) Pomegranate: prostate cancer, nutrition and dietary supplements (PDQ). NCI, Bethesda. http://www.cancer.gov
• Ornish, Dean, et al. "Intensive lifestyle changes may affect the progression of prostate cancer." The Journal of urology 174.3 (2005): 1065-1070.
• Pantuck, Allan J., et al. "Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer." Clinical Cancer Research 12.13 (2006): 4018-4026.
• Putnam, Shannon D., et al. "Lifestyle and anthropometric risk factors for prostate cancer in a cohort of Iowa men." Annals of epidemiology 10.6 (2000): 361-369.
• Stenner-Liewen, Frank, et al. "Daily Pomegranate Intake Has No Impact on PSA Levels in Patients with Advanced Prostate Cancer-Results of a Phase IIb Randomized Controlled Trial." Journal of Cancer 4.7 (2013): 597. 
• Srivastava, Janmejai K., and Sanjay Gupta. "Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells." Biochemical and biophysical research communications 346.2 (2006): 447-453.
• Tang, Yaxiong, et al. "Lycopene enhances docetaxels effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels." Neoplasia 13.2 (2011): 108-119. 
• Ting, Harold, Gagan Deep, and Rajesh Agarwal. "Molecular mechanisms of silibinin-mediated cancer chemoprevention with major emphasis on prostate cancer." The AAPS journal 15.3 (2013): 707-716. 
• Tokar, Erik J., and Mukta M. Webber. "Chemoprevention of prostate cancer by cholecalciferol (vitamin D3): 25-hydroxylase (CYP27A1) in human prostate epithelial cells." Clinical & experimental metastasis 22.3 (2005): 265-273.
• Verhoeven, Dorette T., et al. "Epidemiological studies on brassica vegetables and cancer risk." Cancer Epidemiology Biomarkers & Prevention 5.9 (1996): 733-748.
• Wilson, Kathryn M., et al. "Coffee and risk of prostate cancer incidence and mortality in the Cancer of the Prostate in Sweden Study." Cancer Causes & Control 24.8 (2013): 1575-1581.
• Woo, Tony Choon Seng, et al. "Pilot study: potential role of vitamin D (cholecalciferol) in patients with PSA relapse after definitive therapy." Nutrition and cancer 51.1 (2005): 32-36.

Pyruvate = Recomp agent, not performance enhancer?

I am not sure if you even remember that pyruvate, which is made from glucose through glycolysis, and can be converted back to carbohydrates (such as glucose) via gluconeogenesis, or to fatty acids through acetyl-CoA, has once been touted as (yet another) "next big thing" by parts of the supplement industry.

The idea was that pyruvic acid could supply energy to working muscles through the citric acid cycle (also known as the Krebs cycle) when oxygen is present (aerobic respiration), and alternatively ferment to produce lactate when oxygen is lacking (fermentation) - this would make it the perfect workout fuel for high intensity exercise, but theory and practice are two very different animals.
Past studies investigating its efficacy have however yielded mixed results. In the year 2000, Michael A. Morrison , Lawrence L. Spriet , David J. Dyck reported that "oral pyruvate supplementation does not increase blood pyruvate content and does not enhance performance during intense exercise in well-trained cyclists." (Dyck. 2000)

Similarly disappointing results have been reported by Ebersole et al., likewise in the year 2000 for improvements in critical power (there were none) and stand in contrast to observations by JL Ivy who found that pyruvate, when "provided as an oral supplement for several days", whill "enhance aerobic endurance capacity" in rodents (Ivy. 1998) or Stanko et al. who found back in 1990 that feeding  dihydroxyacetone and pyruvate for 7 days  increased  arm  muscle  glucose  extraction  before  and  during exercise,  thereby  enhancing  submaximal  arm  endurance  capacity of (albeit) untrained men.
Olek, et al. the authors of the most recent pyruvate paper in the open access journal nutrients, were well aware of the fact that pyruvate (PYR), in spite of its importance in energy metabolism, has not been shown to have ergogenic effects after prolonged supplementation. In view of the fact that Morrison et al. indicated that acute oral intake of calcium PYR (Calcium Pyruvate), even at a dose of 25 g, did not modify the PYR concentration in the whole blood or in the plasma, while Olek et al. have previously shown that a single dose of sodium PYR (NaP) does, the researchers from the Gdansk University ofPhysical Education and Sport in Poland decided to re-examine the effect of a single NaP ingestion on blood acid-base status and the exercise metabolism markers.

"Since 0.1 g of sodium bicarbonate per kg of body mass induces metabolic alkalosis 60 min following ingestion [14,15], we hypothesized that a similar NaP treatment before commencing the high intensity physical exertion may change the exercise metabolism." (Olek. 2014)

Nine active, but non-specifically trained, malesubjects (mean ± SEM: 23 ± 1 year old, 1.75 ± 0.02 m height, 72 ± 2 kg body mass) participated in the double-blind, placebo-controlled, crossover study.

"On separate days, the subjects reported to the laboratory in the morning, then rested for 30 min and then ingested placebo or NaP in a random order. In the previous studies the subjects consumed PYR in the amount of ~0.07–0.08 g/kg body mass;  therefore, the subjects in our study ingested NaP in a single dose of 0.1 g/kg body mass (which is ~0.08 g of PYR per kg body mass). " (Olek. 2014)

An hour following the ingestion, the subjects performed the physical exertion. The exercise protocol consisted of 2 min at a power output of 50 W and then for 6 min at a constant power output, corresponding to ~90% O2max. To determine  O2max, participants performed a graded cycle ergometry test on an electromagnetically-braked, cycle ergometer. After an initial warm-up period, the work rate was increased by 25 W/min until volitional exhaustion was achieved.

Figure 1: Lactic acid and blood pH during the placebo (•) and (o) pyruvate trial (Olek. 2014)

As you can see in Figure 1 the lactic acid concentration after the workout was significantly higher in the dotted pyruvate trial. Interestingly, though, the pH and thus the acidity of the blood was only marginally elevated - a clears sign that the buffering function of sodium pyruave Olek et al. had speculated about is real.

Table 1: Gas exchange, ventilation and heart rate responses during and after severe-intensity exercise following placebo and sodium pyruvat eingestion. Values are the means ± SEM (Olek. 2014) | As you can see, there are no asterisks (*) which means: None of the differences reached statistical significance.

A brief glimpse at the measured differences in O2 uptake, CO2 output, minute ventilation, respiratory exchange ratio, and heart rate (see Table 1) does yet reveal that the study at hand generally confirms what previous studies by Ebersole et al (2000) and Morrison et al. (2000)  suggested: In spite of the fact that it would be 100% logical, if we saw performance improvements with pyruvate supplementation, the parameters Olek et al. recorded do not suggest that there were any.

And even when it was administered as creatine pyruvate, Van Schuylenbergh et al. did not find any benefits on cycling performance in a 2003 study.
References:

• Ebersole, Kyle T., et al. "The Effect Of Pyruvate Supplementation On Critical Power." The Journal Of Strength & Conditioning Research 14.2 (2000): 132-134.
• Ivy, John L. "Effect of pyruvate and dihydroxyacetone on metabolism and aerobic endurance capacity." Medicine and science in sports and exercise 30.6 (1998): 837-843.
• Kalman, Douglas, et al. "Effect of pyruvate supplementation on body composition and mood." Current Therapeutic Research 59.11 (1998): 793-802.
• Koh-Banerjee, Pauline K., et al. "Effects of calcium pyruvate supplementation during training on body composition, exercise capacity, and metabolic responses to exercise." Nutrition 21.3 (2005): 312-319.
• Morrison, Michael A., Lawrence L. Spriet, and David J. Dyck. "Pyruvate ingestion for 7 days does not improve aerobic performance in well-trained individuals." Journal of Applied Physiology 89.2 (2000): 549-556.
• Stanko, Ronald T., Denise L. Tietze, and Judith E. Arch. "Body composition, energy utilization, and nitrogen metabolism with a 4.25-MJ/d low-energy diet supplemented with pyruvate." The American journal of clinical nutrition 56.4 (1992): 630-635.
• Van Schuylenbergh, Reinout, Marc Van Leemputte, and Peter Hespel. "Effects of oral creatine-pyruvate supplementation in cycling performance." International journal of sports medicine 24.02 (2003): 144-150. 
• Wilson, Leanne, et al. "Pyruvate induces mitochondrial biogenesis by a PGC-1 ?-independent mechanism." American Journal of Physiology-Cell Physiology 292.5 (2007): C1599-C1605.

The "Paleo" cult has repopularized eating and preparing your own (Chicken) bone broth, but will this also help with bone and cartilage health?

Although youre probably thinking of collagen as the stuff thats important for joint health, its implications in human health are more far-reaching than most of us believe.

In fact, collagens are the most abundant group of organic macro-molecules in human and animal body. Because of their tensile strength, they perform numerous structural functions within the body - specifically in connective tissues which include among other tissue also organs as your heart, your intestines, your lungs and the parenchymal organs like the liver and the kidneys and even the fibrous matrix of skin and blood vessels.

As I already said, collagens are yet by far best known as structural components of the protein matrix of the skeleton and its related structures, like bones, teeth, tendons, cartilage and ligament, which bring us back to the original question that bothered me after assuring Chris who emailed me asking about the necessity of taking glycine and proline supplements in the absence of any other protein (my answer was "thats bullocks"): Do glycine and problem supplements even help with collagen synthesis and joint health? Or is the supplement vendor next door the only person who benefits?
We do have evidence (from rodent studies) that the ingestion of low molecular weight (=small peptides) collagen hydrolysates with intact glycyl-prolyl-hydroxyproline tripeptides that actually make it through the gut into the bloodstream and will increasee the organic substance content and decreased the water content of the left femur (Watanabe-Kamiyama. 2009). Previous studies had already shown hat the content of an orally administered gelatin hydrolysate will be incorporated into the cartilage tissue of rats (Oesser. 1999). Similar observations have been made by Iwai et al. for human volunteers and porcine gelatine hydrolysate, as well.

"After the oral ingestion, the peptide form of Hyp significantly increased and reached a maximum level (20-60 nmol/mL of plasma) after 1-2 h and then decreased to half of the maximum level at 4 h after the ingestion. Major constituents of food-derived collagen peptides in human serum and plasma were identified as Pro-Hyp. In addition, small but significant amounts of Ala-Hyp, Ala-Hyp-Gly, ProHyp-Gly, Leu-Hyp, Ile-Hyp, and Phe-Hyp were contained." (Iawai. 2005)

If we assume a similar physiological effect as it was observed by Watanabe-Kamiyama in rodents, the ingestion of (large) quantities of gelatine could thus very well, after its hydrolysation in the gut, have similar effects on human cartilage tissue as the collagen hydrolysate that was used in the Watanabe-Kamiyama study.

Table 1: Summary of Structure and Recovery of Food-Derived Collagen Peptide in Human Serum or Plasma after Oral Ingestion of Gelatin Hydrolysates (Iawai. 2005).

With respect to the occurence of glycyl-polyl-hydroxproline tripeptides, of which the Watanabe-Kamiyama study suggests that they may be responsible for the beneficial effects on cartilage synthesis it should yet be said that it occurred in human plasma only after the ingestion of chicken, but not in porcine collagen in the Iawai study (see Table 1). If thats no coincidence, HARIBO, which is usually made with porcine gelatine is no "collagen builder", a real chicken soup, cooked with bone, on the other hand, could be.

Given that your stomach is working properly a nice paleo bone broth (preferably from chicken bone) could thus produce similar results as a collagen hydrolysate of which a recent review in Current Medical Research and Opinion says that its ingestion stimulates a statistically significant increase in synthesis of extracellular matrix macromolecules by chondrocytes.

Figure 1: Physician rated (top) and subject-rated (bottom) improvement in joint pain walking (left) and standing (right) in the Clark study (Clark. 2008).

The authors, researchers from the University of Illinois College of Medicine at Chicago and the University of Kiel in Germany add:

"These findings suggest mechanisms that might help patients affected by joint disorders such as OA. Four open-label and three double-blind studies were identified and reviewed; although many of these studies did not provide key information – such as the statistical significance of the findings – they showed collagen hydrolysate to be safe and to provide improvement in some measures of pain and function in some men and women with OA or other arthritic conditions." (Bello. 2006)

Subsequent studies such as Benito-Ruiz et al. (2009) or Clark et al. who evaluated data from 97 athletes from a varsity team or a club sport in Pennsylvania support Bellos conclusion (see Figure 1).

Similar beneficial effects were also observed by  et al. in a more recent study with "normal" subjects with articular pain in response to 1,200mg/day of collagen hydrolysate (Bruyère. 2012). When were looking into the effects of single amino acids, however, things look different. If theyre ingested separately, glycine and proline are not going to form a tripeptide in the course of the digestive process. And while they may still serve as a raw material for the endogenous synthesis of such peptides the chance that they actively promote the synthesis of new collagen is slim.
References:

• Bello, Alfonso E., and Steffen Oesser. "Collagen hydrolysate for the treatment of osteoarthritis and other joint disorders: a review of the literature." Current Medical Research and Opinion® 22.11 (2006): 2221-2232.
• Benito-Ruiz, P., et al. "A randomized controlled trial on the efficacy and safety of a food ingredient, collagen hydrolysate, for improving joint comfort." International journal of food sciences and nutrition 60.S2 (2009): 99-113. 
• Bruyère, Olivier, et al. "Effect of collagen hydrolysate in articular pain: a 6-month randomized, double-blind, placebo controlled study." Complementary therapies in medicine 20.3 (2012): 124-130.
• Iwai, Koji, et al. "Identification of food-derived collagen peptides in human blood after oral ingestion of gelatin hydrolysates." Journal of agricultural and food chemistry 53.16 (2005): 6531-6536.
• Oesser, Steffen, et al. "Oral administration of 14C labeled gelatin hydrolysate leads to an accumulation of radioactivity in cartilage of mice (C57/BL)." The Journal of nutrition 129.10 (1999): 1891-1895. 
• Ross, B. D., R. Hems, and H. A. Krebs. "The rate of gluconeogenesis from various precursors in the perfused rat liver." Biochem. J 102 (1967): 942-951.
• Saito, Masataka, et al. "Effect of collagen hydrolysates from salmon and trout skins on the lipid profile in rats." Journal of agricultural and food chemistry 57.21 (2009): 10477-10482.
• Watanabe-Kamiyama, Mari, et al. "Absorption and effectiveness of orally administered low molecular weight collagen hydrolysate in rats." Journal of agricultural and food chemistry 58.2 (2009): 835-841.

If you want other to see your pump, you got to be ripped. If not, why care about reductions in BMR?

If you remember my posts about the first generation, arginine-based pre-workout products you will be aware that the only pump they produced was the word "pump" in their name or product description. The reason was and still is simple. The mere provision of l-arginine, which is a precursor to nitric oxide does not lead to an increase in nitric oxide production. Why? Well, think of a building a house: Just buying some concrete wont make you a proud home owner, either ;-)

The bad thing: Arginine didnt work. The good thing: This means it didnt decrease your BMR, either

Against that background its quite astonishing that arginine and citrulline based pre-workout products have dominated the top-seller lists of the big supplement vendors for decades. A fact thats probably partly due to other potential benefits of these amino acids, of which one - you as a SuppVersity reader know that - could be fat loss | learn more about the potential fat loss effects.
With more and more people openly declaring that they would no longer waste money on "good tasting, but expensive and disfunctional products", they industry was yet pressed to develop alternatives. Luckily, our body has two options it can chose from, when producing nitric oxide.

Fortunately, the industry has developed better alternatives...?

You know option #1, the arginine ? nitric oxide pathway, and - with all the hype and hyperbole that surrounded the introduction of the first nitrate supplements - I am pretty sure, you know the other one as well, the nitrate-nitrite ? nitric oxide pathway

Figure 1: The Arginine- and the Nitrate-Nitrite - NO pathway are the yin and yan of nitric oxide production (Lundberg. 2008).

As the illustration (Figure 1) I have "borrowed" from a comment by Jon. O. Lundberg et al. (2008) illustrates quite nicely, the arginine and nitrite nitric oxide pathway are the yin and yan of NO production.

With the "yan", i.e. the nitrate-nitrite ? nitric oxide pathway being a relatively "new kid on the NO block", that recycles (=reduces) inorganic anions nitrate and nitrite to form bioactive NO in blood and tissues during physiological hypoxia.

It goes without saying that there is a bottle neck to this process as well, but the rate limiting availablility of oxygen which hampers the argine-based NO generation by NOS becomes limited as oxygen levels fall is actually a signal for the nitrate–nitrite ? nitric oxide to really kick in.

There is more yin and yan, here

If you take a closer look at the results of a study in the America Journal of Clinical Nutrition (Figure 2), you will yet have to realize that there is "more yin and yan", here than youd probably hope for. According to the data scientists from the venerable Karolinska Institutet in Stockholm, Sweden, present in their paper, "[d]ietary inorganic nitrate reduces the RMR." (Larsen. 2014)

Figure 2: VO2 consumption (marker of fatty acid oxidation) and basal metabolic rate (BMR) relative to means (left), thyroid hormone (T3, T4) levels after 3-d dietary intervention with sodium nitrate (Larsen. 2014)

Whut? Yes, you read Larsen et al. right: In their randomized, double-blind, crossover study, in the course of which the Swedish scientists measured the resting metabolic rate (RMR) of 13 perfectly healthy 18–49 y olds (17 women) via indirect calorimetry after a 3-d dietary intervention with sodium nitrate (NaNO3 @ 0.1mmol/kg body weight) or a placebo (NaCl), Larsen, Schiffer, Ekblom et al. observed a statistically and (probably) physiologically significant reduction BMR reduction of 4.2% which correlated strongly to the degree of nitrate accumulation in saliva (r²= 0.71) and fits in nicely with the reduced O2 consumption of which Bailey et al. were the first to observe it in response to nitrate supplementation during exercise (Bailey. 2009).

Interestingly, these effects were not - as you may have been speculated - brought about by changes in thyroid hormone status. And the subjects insulin sensitivity, glucose uptake, plasma concentration of isoprostanes, as well as their total antioxidant capacity were unaffected, as well.
Reference:

• Bailey, Stephen J., et al. "Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans." Journal of Applied Physiology 107.4 (2009): 1144-1155.
• Hotta, Yuji, et al. "Oral l?citrulline supplementation improves erectile function and penile structure in castrated rats." International Journal of Urology (2014).
• Larsen, Filip J., et al. "Dietary inorganic nitrate improves mitochondrial efficiency in humans." Cell metabolism 13.2 (2011): 149-159.
• Lundberg, Jon O., Eddie Weitzberg, and Mark T. Gladwin. "The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics." Nature Reviews Drug Discovery 7.2 (2008): 156-167.
• Neuzillet, Y., et al. "A randomized, double?blind, crossover, placebo?controlled comparative clinical trial of arginine aspartate plus adenosine monophosphate for the intermittent treatment of male erectile dysfunction." Andrology 1.2 (2013): 223-228.

Blueberries and other foods w/ tons of polyphenols are GSH boosters (Moskaug. 2005) and make supplements obsolete.

If you have been interested in dietary supplements for some time, I am pretty sure that you will have heard about oral glutathione ob(GSH) supplements in one of the "snake oil warnings" on various websites. The "master antioxidant" as it is called is after all believed by many to be not bioavailable - at least not orally. Studies in animal models, however, have already shown that oral GSH, administered either in the diet or by gavage, has the ability to increase plasma and tissue GSH levels ( Loven. 1986; Aw. 1991; Favilli. 1997; Kariya. 2007). It would thus be more appropriate to say that the efficacy of oral glutathione in humans has not yet been tested in peer-reviewed studies.
Now, the absence of human studies should definitely ring an alarm bell in the head of every healthily skeptic supplement user, what it should not do, though is mislead you to believe that GSH supplements dont work in human beings.

Now this is where John P. Richie Jr. and his colleagues from the Penn State Cancer Institute, the Department of Microbiology and Immunology at the Penn State University College of Medicine and the Orentreich Foundation for the Advancement of Science, come into play. As the scientist state, their "objective was to determine the long-term effectiveness of oral GSH supplementation on body stores of GSH in healthy adults." (Richie. 2014)
To this end, they conducted a 6-month randomized, double-blinded,placebo-controlled trial in the course of which the subjects, 41 women and 13 men (6 dropouts not included) with a normal BMI and no known health issues, consumed either ...

• an oral GSH supplement dosed at 250mg/day,
• an oral GSH supplement dosed at 1,000mg/day, or
• an identically looking placebo.

The main study outcomes were obviously analyses of the GSH levels in (a) blood, (b) erythrocytes, (c) plasma, (d) lymphocytes and (e) exfoliated buccal mucosal cells (the effects on a battery of immune markers was tested only in a handful of subjects).

Figure 1: Effects of 6 months GSH supplementation on ratio of oxidized to reduced GSH and natural killer cell cytotoxicity in healthy men and women aged 28-72y (Richie. 2014)

As the data in Figure 1 already suggests, there was a dose-dependent increase in GSH levels. With the high dose (1,000mg/day) producing GSH increases of 30–35 % in erythrocytes, plasma and lymphocytes and 260 % in buccal cells (P<0.05) and increases of 17 and 29 % in blood and erythrocytes, respectively, in the low-dose group (P<0.05 - data not shown in Figure 1).

These improvements had beneficial downstream effects on the overall status of the subjects antioxidant defense system. A fact you can conclude based on the decreased ratio of oxidized (used) to reduced (fresh) glutathione in whole blood the scientists observed in their subjects after 6 months. These benefits came hand in hand with an increase in natural killer cytotoxicity (+100%), another potentially highly desirable health benefit.

References:

• Aw, Tak Yee, Grazyna Wierzbicka, and Dean P. Jones. "Oral glutathione increases tissue glutathione in vivo." Chemico-biological interactions 80.1 (1991): 89-97.
• Favilli, Fabio, et al. "Effect of orally administered glutathione on glutathione levels in some organs of rats: role of specific transporters." British journal of nutrition 78.02 (1997): 293-300.
• Kariya, Chirag, et al. "A role for CFTR in the elevation of glutathione levels in the lung by oral glutathione administration." American Journal of Physiology-Lung Cellular and Molecular Physiology 37.6 (2007): L1590.
• Loven, Dean, et al. "Effect of insulin and oral glutathione on glutathione levels and superoxide dismutase activities in organs of rats with streptozocin-induced diabetes." Diabetes 35.5 (1986): 503-507.
• Moskaug, Jan Ø., et al. "Polyphenols and glutathione synthesis regulation." The American journal of clinical nutrition 81.1 (2005): 277S-283S.
• Richie Jr, John P., et al. "Randomized controlled trial of oral glutathione supplementation on body stores of glutathione." European journal of nutrition (2014): 1-13.