Human Study: OTC Supplement Doubles T-Levels & Boosts Erections More Than Tadalafil - Too Good to Be True?

Just to make sure you don't suffer from withdrawl symptoms until Adelfo posts the next update on his current contest prep, I thought I'd share a photo that shows where he is currently at - not bad for someone of whom a handful of you have been shocked to hear that he eats at least 200g carbs per day and ice-cream almost every evening, right?

It's Thursday and before I'll get to a question on a very recent study I received via the SuppVersity Facebook page, I will brief you on the line-up of today's installment of the SuppVersity Science Round-Up on the Super Human Radio Network. By now, most of you should actually be familiar with the modus operandi: In case you cannot listen live at 1PM EST, you can always download the show ~2h later either from the "Physical Culture for Your Ears" menu in the sidebar of the SuppVersity, or right over at www.superhumanradio.com - obviously, you can also wait for tomorrow's SuppVersity Science Round-Up Seconds, in which I am providing some additional information on things we have discussed and post selected topics that did not make it into the show.

Apropos topics, the first topic we are going to address does actually pertain to the second part of this post and revolves around a recently published paper by Fabrizio Iacono et al. whose results do - just as SuppVersity reader Mark, who pointed me towards this article, says - look "too good to be true".

Now, upon closer scrutiny it turns out that they may well be "true", but are not just as "good" as they may initially look like. From this testosterone-laden topic we are then going to proceed with topics revolving around male and female longevity, optimal workout types and intensities for different trainees,the health effects of garlic, colostrum and chocolate and related topics.

I could mention more, but am afraid that this will just increase the risk of rushing through the items too quickly. Optimally, you just tune in live and pick up the rest in "print" in tomorrow's SuppVersity Science Round-Up Seconds!

200% increase in total and 130% increase in free testosterone

Just a reminder: Taurine has also (rodent) data showing up to 180% increases in testosterone and that's not exclusively in the sick and old.

This subheading sounds as if I was to pimp the "revolutionary new testbooster" by "whatever company" that will get you muscular and ripped in no time, right? Well, in the end it could well be the text of an advertisement, yet not one from any of the usual suspects but rather one for TRADAMIX®, a blend of "three natural substances with an 'anti-aging' effect on the tissues of the male genitourinary apparatus" (Tradapharma Sagl. 2012) - I know, without the usual "-bols", "-diols", or at least some indirect references to illegal anaobolic substances in the product name, this does not sound like it would work, but the +200% increas in total and +130% increase in free testosterone are for real and documented in a peer-reviewed study involving seventy patients (67.3± 3.7 years) with stable marital relations and reduced libido, with or
without erectile dysfunction who received either the infamous PDE-5 inhibitor Tadalafil (5mg/day) or two servings of the aforementioned 'testicular anti-aging supplement' (Iacono. 2012).

But before we even get to the testosterone levels, let's tackle the main problem of these guys and the actual research interest of the scientists from the University “Federico II” of Naples in Italy first. After all, the main outcome of the study at hand were the improvements in sexual desire and erectile function and those were almost identical in both groups - from 16 to 33 and 16 to 31, in the supplement vs. drug groups, respectively. If you go by the results of the international index of erectile function (IIEF) questionnaire (see figure 1, left), on the other hand, the dietary supplement yielded actually outperformed the blockbuster prescription drug by almost 10%:

Figure 1: Results of international index of erectile function (IIEF) questionnaire and RigiScan (device to measure penile tumescence and rigidity continuously that's used to differentiate vascular from psychogenic erectile dysfunction) before and after 2 months of treatment with Tradamixina and Tadalafil (Iacono. 2012).

What's probably even more impressive, though, are the differential effects of Tradamixina vs. Tadalafil on the RigiScale values (see figure 1, right). The RigiScale is an etablished means to differentiate psychogenic from organ-related (vascular) erectile dysfunction (Basar. 2001) and the fact that there was a significant reduction of RigiScale positive subjects in the Tradamixina group does already suggest a possible reason for the initially mentioned 200% increase in total and 130% increase in free testosterone (see figure 2).

Figure 2: Total and free testosterone levels before and after the administration of Tradamaxine (2 servings per day) or Tadalafil (2mg/day) to Seventy patients (67.3± 3.7 years) with stable marital relations and affected by reduced libido for 2 months (data based on Iacono. 2012)

What this underlying reason is? Well, probably reduced systemic inflammation, which leads to reductions in cortisol, blood glucose, insulin resistance, oxidative damage to the testes etc. and thus simply facilitates the restoration of normal testosterone levels.

If you know how google works, it'll take you maybe 5 minutes and a credit card and you'll have a couple of pounds of the ingredients right on the way to your doorstep.
Yep, you heard me right: A boost of +200% just brought those guys who started with 10ng/dl below the already way too broad normal range from 260-1080ng/dl (values may vary from lab to lab) in a quasi hypogonadal state, back to midrange levels of 680ng/dl.

Real world implications for healthy young men: The chance that a healthy, fit individual with normal testosterone levels would see a boost of 200% in his total or 130% in his free testosterone levels is not low, it is simply ZERO!

Notwithstanding, Tradamixina (or rather its ingredients) is actually more than just a cilialis alternative. While the latter is a short term solution to get rid of the symptoms of an underlying disease, the combination of Ecklonia Cava, tribulus, and d-glucosamine + n-acetyl-d-glucosamine could actually tackle the most frequent cause of erectile dysfunction, which is the triad of inflammation, insulin resistance and arteriosclerosis (for more details see info-box to the right).

So how does this stuff work? Although investigations into the mechanism by which the provision of Tradamaxine did work its magic was actually not part of the study, it's actually not difficult to hypothesize what may be the underlying cause of these unquestionably astonishing results. Firstly, the brown algae Ecklonia Bicyclis (better known as Ecklonia Cava!)of which each serving has 150mg has a very high content of sterols, polyphenols and tannins and is probably the main active ingredient of a formula which includes 396mg of tribulus and 144mg of d-glucosamine and n-acetyl-d-glucosamine as a 'support'. The phlototannins 7-phloro eckol and 6,6′-bieckoll that have been isolated from Ecklonia, a marine brown algae which has been used for centuries in traditional medicine in Asia, are more or less unique with respect to the potency of their antioxidant activity (Li. 2009). In conjunction with tribulus, d-glucosamine and n-acetyl-d-glucosamine, which also exhibit a certain degree of anti-inflammatory activity, a decrease in systemic inflammation is the most likely cause of the profound pro-sexual and pro-hormonal effects of this blend, which is yet by no means as unique as the producers would have it.

Bottom line: It is no coincidence that erectile dysfunction has been identified as a "harbinger of cardiovascular clinical events" (Thompson. 2005) and "a sentinel event for CAD [coronary artery disease]" (Irekpita. 2009). So if you are in the unlucky situation to suffer from vascular (and not physogenic) erectile dysfunction, and had the choice between a drug that will ameliorate the symptoms, i.e. Tadalafil, or a supplement that will treat the underyling cause, the decision for the supplement and against the lifestyle drug should be obvious, right?

Still, there is one, ... no, actually there are two things I would like to ask you, before you run all spiked up to the next best supplement shop: Firstly, how accurate would you say is the authors' claim that there was "no conflict of interest", if no one else, but the lead author of the study, has been granted a patent on the formula on April 4th, 2012 (US2012/089722 A1)? And secondly, do you really believe that it is a mere coincedence that the researchers deliberate use the hardly known appellation Ecklonia Bicyclis for a brown algae all of you probably know as Ecklonia Cava (see "Ecklonia Cava Polyphenols Help Shed Weight Even in The Presence of a Slight Caloric Surplus") throughout the whole paper without mentioning once that it is better known as "Ecklonia Cava"? I am well aware that studies are expensive and need to be financed and I am by no means suggesting that the results are - as Mark suspected - "too good to be true" (remember. the men were hypogonadal to begin with), but this paper does still have a somewhat peculiar aftertaste.

References:

• Basar MM, Atan A, Tekdogan UY. New concept parameters of RigiScan in differentiation of vascular erectile dysfunction: is it a useful test? Int J Urol. 2001 Dec;8(12):686-91.
• Iacono F, Prezioso D, Illiano E, Romeo G, Ruffo A, Amato B. Sexual asthenia: Tradamixina versus Tadalafil 5 mg daily. BMC Surg. 2012 Nov 15;12 Suppl 1:S23.
• Irekpita E, Salami TA. Erectile dysfunction and its relationship with cardiovascular risk factors and disease. Saudi Med J. 2009 Feb;30(2):184-90. 
• Li Y, Qian ZJ, Ryu B, Lee SH, Kim MM, Kim SK. Chemical components and its antioxidant properties in vitro: an edible marine brown alga, Ecklonia cava. Bioorg Med Chem. 2009 Mar 1;17(5):1963-73.
• Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, Moinpour CM, Coltman CA. Erectile dysfunction and subsequent cardiovascular disease. JAMA. 2005 Dec 21;294(23):2996-3002. 
• Tradapahrm Sagl. Tradamix. 2012 < http://www.tradamix.com/en/ > retrieved on 11/29/2012.

Build a Bigger Mitochondrial Engine and Double Your Endurance With Chitooligosaccharides! Glucosamine Mix from Chitosan Acts on Sirt1 & AMPK, Similar to Resveratrol

Figure 1: Glucosamine composition of the chitooligosaccharide used in the study (data adapted from Jeong. 2012).

Usually I try to avoid this term, as it seems to imply that there is, or at least soon will be a pill that would allow you to stay the lazy bastard you are now and still make it into your old age, healthy lean, attractive and vigorous, but in this case the word "exercise mimetic" is unquestionably what describes the effects of 6 weeks of oral supplementation with chitooligosaccharide described in a recently published paper by scientists from the Amorepacific Corporation Research & Development Center and the Kyung Hee University in South Korea best. I have to give props to my friend Carl Lanore the voice (and brain) of Super Human Radio who shot me an email on this issue, yesterday.

A brief glance at the full-text was enough to realize that Carl who likes to pretend he was the idiomatic "blind man" with no scientific degree (I could hardly care less, by the way ;-) who hits upon things like this only perchance was up to something - those who now the show, will be aware that he is smarter than many of the experts he interviews, anyways... but I am getting derailed, here. Where was I? Ah yeah, the study...

COS - What we already know

• Ameliorates weight gain (-15%) and high blood lipids on HFD in mice in the absence of reduced energy intake (Choi. 2012)
• Promotes cytokine release in intestinal epithelial cells (Bahar. 2012)
• Inhibits pancreatic lipase and thus breakdown and subsequent uptake of dietary fat (Kang. 2012)
• Suppresses TNF-alpha induced collagen breakdown in-vitro (Ryu. 2012)
• Has neuroprotective effects (Joodi. 2011)

Promising in vivo rodent + in vitro cell line data: Very promising, but not yet field-tested

Hyun Woo Jeong and his colleagues fed 39 female Sprague-Dawley rats either normal or 0.05% chitooligosaccharide (COS produced by Bioland Korea Co. Briefly from chitosan by enzyme digestion, followed by deacetylation of chitin; cf. Hirano. 1989) enriched rodent chow for 6 weeks.

At the end of the study period, 50% of the rodents had performed an exercise test on the treadmill, in the course of which they had to run at a pace of 20m/min until exhaustion, while the rest of the animals were sacrificed before this final workout to assess their pre-exercise plasma profiles including ALT, AST, triglyceride, total cholesterol, lactate, and free fatty acid levels (none of which showed significant changes over the course of the 6-week study period).

Despite the fact that the scientists did not measure the total lean and fat mass of the rodents, the collective data in figure 2 clearly suggests that the -72% reduction in weight gain was not at the expense metabollically active muscle tissue.

Figure 2: Body weight and energy intake (left) and muscle weight vs. body weight (right) data at the end of the 6-week trial (data adapted from Jeong. 2012).

Despite a statistically non-signficant reduction in food intake (-6%) the chitooligosaccharide treated rodents had heavier soleus (slow twitch, type II fiber dominant muscle) muscles and a more favoreable plantaris (fast twitch, type II-X fiber dominant muscle) to total body weight ratio (indicative of a lower body fat percentage), than their non-supplemented peers. Moreover, a cursory glance at figure 3 does also reveal why this is the case.

Figure 3: Electron microscopic image of muscle tissue (top; small arrows and green areas indicate the presence of mytochondria), mitochondrial density in in-vitro control experiment after exposre to different doses of  resveratrol vs. chitooligosaccharide (bottom, left) and time to exhaustion during treadmill test (adapted from Jeong. 2012)

Even as a non-expert it is easy to see that the chitooligosaccharides had profound "anabolic" effects on the mitochondria of the lab animals.

COS activated AMPK and increased the cellular NAD+ / NADH ratio to induce Sirt1 activation. The activation of AMPK and Sirt1 increased the expression and activity of PGC1 and augmented the expression of mitochondrial genes. As a result of activation of AMPK, Sirt1, and PGC1, COS facilitated mitochondrial biogenesis. In rodents, the administration of COS significantly increased intramuscular mitochondrial content, resulting in enhanced exercise endurance and reduced plasma lipid profiles. (Jeong. 2012)

In the Petri-dish, it may be less potent than resveratrol on a per mg base (figure 3, bottom-left), but the real world effects in terms of both, increased mitochondrial biogenesis (see green mitochondria in the electron microscopic image of skeletal muscle; figure 3, top) and subsequent increases in average running time to exhaustion (+96%; figure 3, bottom right) speak for themselves.

Implications: Other than resveratrol, which has an oral biovailability that is hardly high enough to be quantified (Walle. 2004), chitooligosaccharide could actually be suitable for oral supplementation - at least if we assume similar pharmacokinetics in humans as in rats (which is likely, but not necessarily the case).

• especially sedentary individuals or people who rarely train could benefit from the exercise-mimicking effects 
• in a previous study by Cho et al. chitooligosaccharide lactate has been found to be superior to chitooligosaccharide HCL (Cho. 2010)
• the optimal dosage and, more importantly, whether trained and well-conditioned individuals would benefit to a similar extend / at all, would yet require further studies. 
• the human equivalent dosages for the study at hand would be 600-900mg/day depending on the individuals body weight

Image 1: COS is rather something for the "old" Mr C. than for Adelfo

Aside from the fact that there are (at least to my knowledge) no over-the-counter chitooligosaccharide supplements on the market, so that you would probably have to order a metric ton right from China at Alibaba.com, I would not expect too much from it, anyways. Firstly, the chances that it turns out to be another supplemental non-starter like resveratrol are high. And second- and more importantly, the beneficial effects will be less pronounced for well-conditioned individuals and could even be close to zero (and certainly not practically relevant) for people who go to the gym to train and not to pose, to chat or to flirt. People like you and me and Adelfo Cerame, whose new client Mr. C. is soon going to join the ever-growing community of physical culturists, who don't need a "mimetic" for something they love: Exercise!

References:

• Bahar B, O'Doherty JV, Maher S, McMorrow J, Sweeney T. Chitooligosaccharide elicits acute inflammatory cytokine response through AP-1 pathway in human intestinal epithelial-like (Caco-2) cells. Mol Immunol. 2012 Jul;51(3-4):283-91. Epub 2012 Apr 16.
• Cho SY, Lee JH, Song MJ, Park PJ, Shin ES, Sohn JH, Seo DB, Lim KM, Kim WG, Lee SJ. Effects of chitooligosaccharide lactate salt on sleep deprivation-induced fatigue in mice. Biol Pharm Bull. 2010;33(7):1128-32.
• Choi EH, Yang HP, Chun HS. Chitooligosaccharide ameliorates diet-induced obesity in mice and affects adipose gene expression involved in adipogenesis and inflammation. Nutr Res. 2012 Mar;32(3):218-28.
• Hirano S, Tsuchida H, Nagao N. N-acetylation in chitosan and the rate of its enzymic hydrolysis. Biomaterials. 1989;10: 574–576.
• Jeong HW, Cho SY, Kim S, Shin ES, Kim JM, Song MJ, Park PJ, Sohn JH, Park H, Seo DB, Kim WG, Lee SJ. Chitooligosaccharide Induces Mitochondrial Biogenesis and Increases Exercise Endurance through the Activation of Sirt1 and AMPK in Rats. PLoS One. 2012;7(7):e40073.
• Joodi G, Ansari N, Khodagholi F. Chitooligosaccharide-mediated neuroprotection is associated with modulation of Hsps expression and reduction of MAPK phosphorylation. Int J Biol Macromol. 2011 Jun 1;48(5):726-35.
• Kang NH, Lee WK, Yi BR, Park MA, Lee HR, Park SK, Hwang KA, Park HK, Choi KC. Modulation of lipid metabolism by mixtures of protamine and chitooligosaccharide through pancreatic lipase inhibitory activity in a rat model. Lab Anim Res. 2012 Mar;28(1):31-8. Epub 2012 Mar 21.
• Ryu B, Himaya SW, Napitupulu RJ, Eom TK, Kim SK. Sulfated chitooligosaccharide II (SCOS II) suppress collagen degradation in TNF-induced chondrosarcoma cells via NF-κB pathway. Carbohydr Res. 2012 Mar 1;350:55-61.
• Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos. 2004 Dec;32(12):1377-82. Epub 2004 Aug 27.

Fighting to Stay Lean? These 20+ Anti-Obesity Agents Have the Potential to Inhibit Fat Gain Right at the Cellular Level

No, none of the 20 agents in the list below is going to do the work for you, but they could help you "conserve" the results, keep you lean on a bulk and/or avoid the hazardous Yoyo effect when you go off a die.

It's actually normal that the introduction is the last part of an article I write. What's special about today's SuppVersity article is thus not that I write the introduction at the end, but that I did not really know what I would be writing here, when I set out to compile the unsorted (but not chaotic) list of potential anti-obesity agents below. All of them act by pathway(s) you as a SuppVersity reader will have read about before, most prominently AMPK, and the peroxisome proliferator receptors (PPARs), of which the blockade of the obesogenic PPAR-gamma pathway, which is the main working principle of CLA turned out to be the go-to explanation for the ability of these agents to block both the differentiation of adipocytes and the storage of triglycerides in existing fat cells.

20 more or less proven anti-obesity agents for the weekend

As you are about to see, the list, which was never intended to be complete, got pretty and I guess I could add a couple of additional items, if I spent more time digging. In order not to steal your and waste more of my precious time on this sunny (finally!) Sunday, I did yet decide to call it a day, when I hit the 20-items mark. Now it's up to you to invest some of your sunny Sunday time, to read up on the details. 

• On a side note: The "holy" vitamin D does the exact opposite, if you incubate preadipocytes with 25(OH)D(3) this will lead to a significant increase in the active 1,25(OH)(2)D(3) and enhanced adipogenesis in primary mouse. Reason enough for a group of Thai researchers to conclcude that "vitamin D status may [actually] regulate human adipose tissue growth and remodeling." (Nimitphong . 2012)
  Vitamin A - Retinoic acid upregulates the expression of the adipogenesis inhibitors Pref-1, Sox9, and Kruppel-like factor 2 (KLF2) to "suppress adipogenesis in vivo and that the activity significantly contributes to the ability of the hormone to counteract diet-induced obesity." (Berry. 2012) Previous studies have also shown that all-trans-retionic acid directly increases the activity of PPARbeta/delta and so that Berry & Noy conclude "RA may be a uniquely efficacious agent in the therapy and prevention of the metabolic syndrome." (Berry. 2009) Similar results have been reported and conclusions have been drawn by Brun et al. and Sagara et al. (Brun. 2012; Sagara. 2013). Finally, Hisada et al report that - just like testosterone (learn more) - retinoic acid ensures that mesenchymal stem cells (MSCs) become osteoblasts (bone precursor cells), not fat cells (Hisada. 2013).

• Bromocriptine - If you do know it at all, then probably for it's ability to decrease the "milk hormone" prolaction. If you take a look at the broad spectrum of physiological effects of prolactin, the effect it has on the mammalian mammary gland is really negligible. A recent study from the Department of Biotechnology at the Daegu University in The Republic of Korea does now suggest that the inhibition of adipogenesis (formation of new fat cells) and lipogenesis (storage of lipids in existing fat cells) via decreased expressions of the adipogenic activators Pparα, Pparγ, and Cebpα, as well as major lipogenic target genes, including Me1, Acc1, 6Pgd, Fasn, and Prkaa1 is one of these "auxiliary functions" (Mukherjee. 2013)

• 

  EC also boosts erectile performance and testosterone (learn more)

  Ecklonia cava (EC) - or rather the dioxinodehydroeckol (DHE) molecules that are contained in this type of brown seaweed "exert[s] its anti-adipogenic effect on adipocyte differentiation through the activation and modulation of the AMPK signaling pathway" (Kim. 2010a). As a SuppVersity reader, you will be aware that this effect has been confirmed in in-vivo studies, later on (learn more).
  
  What's probably Interestingly DHE is not the only anti-adipogenic agent in brown sea algae, Fucoidan, a sulfated polysaccharide from brown seaweeds has likewise been reported to affect the development of adipocytes. In 2010, Kim et al. were able to show that it targets the MAPK kinase pathway by inhibiting the the expression of both early CCAAT-enhancer-binding proteins alpha (C/EBPalpha) and peroxisome proliferator-activated receptors gamma (PPARgamma), as well as the late activating protein 2 (aP2) adipogenic transcription factors (Kim. 2010b).

• Curcumin - While you my get the impression there was nothing curcumin cannot do (learn more), I am not whether the anti-PPAR gamma effects of curcumin are a result of it's anti-inflammatory effects or not... be that as it may, Lee et al. have demonstrated in 2009 already that the stimulatory effect curcumin exerts on the AMPK expression of adipocytes results in a down-regulation of PPAR-gamma in 3T3-L1 adipocytes (Lee. 2009).

• Resveratrol - Similar popularity, similar "cures it all" status and similar effects on AMPK and downstream PPAR-gamma expression in 3T3-L1 adipocytes... actually I would not need another bulletin point for resveratrol which acts by the exact same pathway(s) s curcumin to inhibit fat cell differentiation (Chen. 2011)

• 

  Creatine RT by Athletic Edge Nutrition; contains a cousin of ASL and is supposed to be another "super creatine" -  True or False? The 2011 SuppVersity article has the answer (read it!).

  Artemisia sacrorum Ledeb. (ASL) - Extracts from the small shrub have been used in Oriental Medicine for centuries, in 2011 Yuan et al. were able to show that ASL "down-regulate[s] the adipogenesis-related gene expression of the sterol regulatory element-binding protein 1c (SREBP1c) and its target genes, such as fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1) and glycerol-3-phosphate acyltransferase (GPAT) in a concentration-dependent manner" (Yuan. 2011) The effects are meediated by a reduced expression of the peroxisome proliferator-activated receptor γ (PPARγ) and of the CCAAT/enhancer binding protein-α (C/EBPα), both of which are key transcription factors in adipogenesis.
  
  With the concomitant reduction in adipocyte fatty acid binding protein (aP2) gene expression, ASL is another potential anti-obesity agent of which Yuan et al. propose that it works its  anti-adipogenic magic via AMPK activation. In view of the fact that the same is true for the fat accumulation in human liver cells, it could serve a viable tool "in the prevention of serious diseases such as fatty liver and type-2 diabetic mellitus" (Yuan. 2010). Related increases in fatty acid oxidation have been observed in a rodent study by Hong later in 2009 with another variety of Aertemisia, namely Artemesia Capillaris (Hong. 2010). The human equivalent dosage in this trial wast 8mg/kg of the ethyl acetate fraction of the shrub.

• Phosphorylated glucosamine - While you will probably remember that large doses of regular glucosamine have been associated with insulin resistance (see previous installment of "True Or False"), it's phosphorylated variety glucosamine-6-phosphat (PGlc), Kong et al. synthesized using methanesulfonic acid, phosphorus pentoxide (P(2)O(5)), NH(2)NH(2) and DMF "significantly reduced lipid accumulation during adipocyte differentiation and induced down-regulation of peroxisome proliferator-activated receptor-gamma, sterol regulatory element binding protein 1 and CCAAT/enhancer binding protein-alpha in a dose-dependent manner." (Kong. 2010)
  

  

  Phosphorylated glucosamine works (like most of the anti-obesity agents, including the well-known conjugated linoleic acid by reducing the expression of PPAR-gamma (left). It's dose-dependent effects are yet not restricted to the peroxisome proliferator receptor, but affect the pro-adipogenic genes C/EBP-alpha and SREBP1, as well (right; Kong. 2010)

  What's also worth mentioning is that the in-vitro study from the Marine Bioprocess Research Center at the Pukyong National University in South Korea also revealed that PGcl also hampered the maturation of pre-adipocytes by down-regulating adipocyte-specific gene promoters such as adipocyte fatty acid binding protein, fatty acid synthase, lipoprotein lipase and leptin. In conjunction "[t]hese results suggest that the inhibitory effect of PGlc on adipocyte differentiation might be mediated through the down-regulation of adipogenic transcription factors, such as peroxisome proliferator-activated receptor-gamma, sterol regulatory element binding protein 1 and CCAAT/enhancer binding protein-alpha, which are related to the downstream adipocyte-specific gene promoters" (Kong. 2010) 

• 

  Add. reads: "Temporary +100kcal/Day Cold Thermogenesis Response W/ Exotic Ginger Extract" (more) "250-1000mg of Freeze-Dried Ginger Reduce Visceral Fat Even When Rodents Are Fed an Obesogenic High Fat Diet" (more).

  6-gingerol (6G) - The active ingredient in ginger has just been shown to block the obesity effects of the anti-diabetes med rosiglitazone (Tzeng. 2013). It does so by blocking the PPAR-gamma mediated effects of the "store the superfluous energy as body fat"-drug and was thus able to suppress the oil droplet accumulation and reduce the sizes of the droplets in the course rosiglitazone(RSG)-induced adipocyte differentiation in 3T3-L1 cells. Since it also blunted the increased levels of mRNA and protein in adipocyte-specific fatty acid binding protein 4 and fatty acid synthase induced by RGZ, it can be expected that 6G will not only inhibit the accrual of new, but also the (re-)filling of existing fat cells. 

• Piperine and capsaicin - In view of the fact that piperine is a "quasi-cousins" of 6-gingerol, it is actually not really surprising that it shares similar effects on the expression of PPAR-gamma (Park. 2012). It is therefore not surprising that the third member of this spicy triumvirate, i.e. capsaicin, shares the exact same PPAR-gamma reducing effects (Joo. 2010).

• Berberin - Contrary to many other items on the list, berberin's anti-PPAR-gamma effects are actually pretty well-known. There is ample evidence from in-vitro (Huang. 2006; Liu. 2009) and in-vivo (Lee. 2006) evidence that it blunts fat gain by increasing the catabolism of high energy intermediates, upregulating AMPK, modulating the expression of the GATA-2 and 3 gene and reducing the expression of (you guessed it) PPAR-gamma (Hu. 2009).

  

  Table 1: Berberine content of various commercially available supplements (Brown 2008)

  Berberine has also been shown to improve endothelial function in man (Wang. 2009) and promote the "longevity and mitochondrial health gene" SIRT1 in obesity ridden, insulin resistant skeletal muscle (Gomes. 2012).

• Ginsenosides (spec. ginsenoside Rg3) - Just like ginereol (see above) ginsenoside Rg3 has been shown to block the adipogenic effects of the anditiabetic drug rosiglitazone via an AMPK/PPAR-gamma dependent pathway (Hwang. 2009). It may be worth mentioning that at least the effect triglyceride storage was not dose-dependent. Once  a threshold amount of 40µM was reached, the adipocytes that were incubated with Rg3 did not "lose" any additional triglycerides, when the dosage was increased to 80µM.

• On a side note: Although promoted in the same health and longevity circles as CAPE, the hailed "telomerase lengthener" Astraglaus is a PPAR-gamma promoter and will thus "enhance the accumulation of lipid drops, and increase the terminal differentiation of preadipocytes" (Liu. 2007)
  Caffeic acid phenethyl ester (CAPE) - You've heard about the anti-inflammatory, muscle protective ability of this compound from bee propolis only recently (go back). In addition to being a potent anti-inflammatory, the natural phenolic compound that's also found in a variety of plants, has also been found to block the conversion of mouse fibroblasts into fat cells (Juman. 2010). As for most of the other agents the effects of CAPE appear to be mediated by a reduction inperoxisome proliferator-activated receptor (PPAR) gamma and CCAAT/enhancer-binding protein (C/EBPalpha) and concomittant reduction isn fatty acid synthetase and the expression of adipocyte-specific fatty acid binding protein (aP2). 

• Lysimachia foenum-graecum (LFE) - LFE is a Chinese herb and well-known anti-inflammatory from Oriental Medicine. The anti-obesity effect of L. foenum-graecum extract was first discovered by Seo et al., when they simply screened a whole host of potential natural agents for their anti-adipogenic effects. In 2011 the researchers found that "LFE blocked the differentiation of 3T3-L1 preadipocyte in a dose-dependent manner with an IC50 of 2.5 μg/ml". The underlying mechanism which has also been observed in an in-vivo rodent study with 100 mg/kg/day, are - how else could it be - mediated by the inhibition of PPARγ and C/EBPα expression.

  

  Effects of the administration of an lysimachia foenum-graecum ethanol extract on lipid and glucose metabolism and adipokine signalling in mice on an obesogenic diet (Seo. 2011)

  Moreover, LFE stimulated fatty acid oxidation in an AMPK-dependent manner, greatly improved serum levels of obesity-related biomarkers such as glucose, triglycerides, and adipocytokines leptin, adiponectin, and resistin and lead to an effective decrease in total body weight gain in mice who received 30, 100, and 300 mg/kg/day of an Lysimachia foenum-graecum ethanol extract (50:6; LFE) in addition to their obesogenic high fat diet (see figure above). The mice in the HFD + LFE group did simply have lower body weights, they also had a reduced amount of adipose tissues especially within the metabolically active and highly unhealthy abdominal subcutaneous, epididymal, and perirenal adipose tissue.

• 

  Photos of the lean (A and D), HFD-fed (B and E) and HFD-fed + SRLE supplemented (C and F) mice in the Thounaojam study (2011).

  Sida rhomboidea. Roxb leaf extract (SRLE) - SRLE does only sound like the stuff many supplement companies used after the ban of mua huang (natural source of ephedrine). It is however a different variety of Sida (Batyάlaka, Sida cordifolia)... well, at least it is from the same family which lacks the CNS stimulating activity of mua huang. With its ability to prevent high fat diet (HFD) induced visceral adiposity by down-regulation of PPARγ2 and leptin gene expression it could in fact work synergistically with ephedrine, though. After all the HED of the 24% w/w water extract Thounaojam et al. used to prevent the obesogenic effects of a hypercaloric high fat diet in their rodent study amounts to no more than ~40mg/kg and since SRLE has been shown to be non-toxic up to 3g/kg (in mice; HED ~240mg/kg) it would be interesting to see studies that probe whether it works in humans (Thounaojam. 2011).

• SH21B is an anti-obesity composition composed of seven herbs: Scutellaria baicalensis Georgi, Prunus armeniaca Maxim, Ephedra sinica Stapf, Acorus gramineus Soland, Typha orientalis Presl, Polygala tenuifolia Willd and Nelumbo nucifera Gaertner (active ingredients; see figure below) that has been used for the treatment of obesity in traditional medical clinics in Korea and has recently been shown to decrease the expression of major transcription factors of the adipogenesis pathway and result in the down-regulation of lipid metabolizing enzymes involved in the transport, uptake and synthesis of lipids - unfortunatedly, only in vitro (Lee. 2009)

  

  Effects of SH21B on fat droplet formation in 3T3-L1 cells (top) and size of adipocytes in adipose tissue. (bottom), as well as active ingredients in SH21B (based on Lee. 2009)

  As you can see in the stains from the adipose tissue of the above, the effects are clearly mediated by both an inhibition of the maturation of preadipocytes (top) and the inhibition of fat storage... now you tell me the world needs "new" anti-obesity agents!? I mean, it's quite obvious that the Koreans knew all along what keeps you lean ;-)

• Lactobacillus plantarum KY1032 cell extract - Before you begin to jubilee about the triumph march of probiotics, let me tell you this: I am not sure how on earth the remnants of a gut bacterium are supposed to reach your adipocyte tissue in a healthy individual without a leaky gut. Against that background I am not sure, whether it is even necessary to mention that Park et al. observed in 2011 that a cell exctract of the KY1032 strain of lactobacilli is another compound that can down-regulate the expression of peroxisome proliferator-activated receptor-γ2, CCAAT/enhancer binding protein-α, fatty acid synthase, and adipocyte-fatty acid binding protein and thus blunt fat gains in vitro... ah, now I wrote it down, so I'll just leave it here ;-) 

• Irvingia gabonensis seed extract - Likewise not a newcomer to the supplement the African / Southeast Asian tree, respectively an extract from its seeds has been shown to dose-dependently decrease the expression of PPAR-gamma in murine adipose cells in the petri dish in a 2008 study by scientists from  Faculty of Science, University of Yaoundé in Cameroon and the Wake Forest University School of Medicine in Winston-Salem, USA (Oben. 2008).

The in-vitro study shows, CAF may inhibit fat storage, but it does not "squeeze" the fat out of the cells (data based on Kim. 2012)

• Citrus aurantium falvenoids (CAF)- Despite the fact that most of you will probably have realized in N=1 experiments that citrus aurantium is a supplemental non-starter as a fatburner. It has (in-vitro) the ability to reduce the epxression of C/EBPβ and subsequently inhibit the activation of PPARγ and C/EBPα. So unless you have taken tons of pure CAF supplements during your last bulk, it is no wonder that you did not realize any effect from the fat burner you bought last summer. After all you are not storing any fat when you are dieting anyway... and I guess you have been dieting, when you took that product, right?
  
  Apropos dieting, the data in the figure on the right also shows that citrus aurantium, alone, won't help with that. After all it lacks the ability to increase LPL and thus the release of free fatty acids from the triglyceride stores in your fat stores.

• Silibinin (from milk thistle) - You will probably have heard that milk thistle can help replenish the antioxidative defenses of your liver and thus prevent all sorts of systemic toxicities (learn more). At least in-vitro silibinin (aka silybin), the major active ingredient in silymarin, can also prevent the accumulation of triglycerides in existing, as well as the formation / maturation of future adipocytes. From a mechanistic point of view, the effect is mediated by the usual suspects respectively their downregulation (CAAT/enhancer binding protein-alpha, fatty acid synthase, sterol response element binding protein 1c, adipocyte-specific lipid binding protein, peroxisome proliferator-activated receptor gamma and lipoprotein lipase; cf. Ka. 2009).

• Stem bromelain (SBM) - Just as so many of the previously mentioned agents, SBM, a specific member of the bromelain family you may know as "pineapple enzyme", is by no means a "new kid on the anti-fatloss block". Rather than that it has been used for centuries in traditional medicine as - guess what? - an anti-obesity agent. Now, I would never suggest that all TCM medicines work, but for stem bromelain it does at least seem as if the in-vitro studies, Dave et al. conducted about a year ago would support the notion that the ingestion of respective supplements can in fact exert beneficial effects on the accumulation of body fat (Dave. 2012).

  

  Illustration of the mechanism and selected downstream effects of stem bromelain (SBM) on fat cells in the petri dish (compiled based on data from Dave. 2012)

  At the molecular level, SBM targets the same adipogenesic genes as (almost all) of the previous agents. What's interesting though, is the fact that the scsientists also found that "SBM's ability to repress PPARγ expression seems to stem from its ability to inhibit Akt and augment the TNFα pathway." (Dave. 2012) In other words, it's the increase in "bad" TNF-alpha and the decrease in the purportedly muscle, but in fact simply "mass building" Akt-TSC2-mTORC1 pathway that entails the apoptosis (controlled cell death) of mature adipocytes and lipolysis.

With the stem bromelain this comprehensive, but by no means all-encompassing list of "proven" (mostly only in vitro) anti-adipogenic agents, has come full circle. After all, Dave et al. point out that their data would indicate that stem bromelain, together with all-trans retinoic-acid (atRA), which is a metabolite of vitamin A, the first item on our list "may be a potent modulator of obesity by repressing the PPARγ-regulated adipogenesis pathway at all stages and by augmenting TNFα-induced lipolysis and apoptosis in mature adipocytes." (Dave. 2010).

It's not just beyond the scope of this article, but - in the majority of the cases simply not known - whether or not the TNFα increase is an integral part of the anti-obesity effects of all of the aforementioned compounds. As far as the inhibition of PPAR-gamma is concerned things are different, though. With PPAR-gamma being the central "fat storage" switch, its deactivation and the entailing blockade of adipocyte differentiation, pre-adipocyte maturation and triglyceride storage is currently probably the most effective anti-obesity  mechanism we know. A mechanism that is way more fundamental than the diet-induced and stimulant / alpha/beta-agaonist (caffeine, ephedra, clenbuterol, yohimine) supported emptying of existing adipocyte triglyceride stores.

---

I know it's not popular, but in the case of vitamin D we already have evidence of it's obesity promoting effects (read more). It's straight forward experimental evidence, much contrary to the epidemiological guesswork on the basis of which people are popping vitamin D pills, these days.

Keep in mind: Most of the data is derived from in-vitro studies. Few compounds do have actual evidence from rodent studies and the number of substances that showed beneficial effects in human studies is even smaller.

Nevertheless, the above list harbors a number of compounds which could be of great interest for the lean physical culturist, for whom (at least physique-wise) stuff like vitamin D (note: the effects could be dose-dependent with benefits at low, and detrimental effects at high levels), astragalus and the rest of the healthy, but pro-adipogenic agents that can help obese individuals to stash away the tons of sugar and fat floating through their arteries are of little use.

Against that background I want to close this post with a warning, or I should say a reminder of the the fact that the effects of PPAR-gamma are physiologically important (e.g. prevention of lipotoxicity, Medina-Gomez. 2007) and go beyond "just making you fat" in how it would be worth striving to suppress it altogether is thus questionable (suggested read: CLA Destroys Body Fat). Since for all of the previously discussed agents that have in-vivo data to support their efficacy have postivite, not negative "side effects" (think of curcumin, gingerol, ginseng, etc.), it is yet unlikely that the use of reasonable amounts of one or a stack of many of them is going to harm you.

Just keep in mind: The goal should be to keep the PPAR-gamma activity in check, not to annihilate it. Consequently you should not and cannot expect to be able to "eat whatever you want and still stay lean" by supplementing with any of the agents above. On the other hand, they can hardly be even less useful than the vast majority of currently available arsenal of OTC "fat burners" ;-)

References:

• Berry DC, Noy N. All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta and retinoic acid receptor. Mol Cell Biol. 2009 Jun;29(12):3286-96.
• Berry DC, DeSantis D, Soltanian H, Croniger CM, Noy N. Retinoic acid upregulates preadipocyte genes to block adipogenesis and suppress diet-induced obesity. Diabetes. 2012 May;61(5):1112-21. 
• Brown PN, Roman MC. Determination of hydrastine and berberine in goldenseal raw materials, extracts, and dietary supplements by high-performance liquid chromatography with UV: collaborative study. J AOAC Int. 2008 Jul-Aug;91(4):694-701.
• Brun PJ, Yang KJ, Lee SA, Yuen JJ, Blaner WS. Retinoids: Potent regulators of metabolism. Biofactors. 2012 Dec 22. doi: 10.1002/biof.1056. 
• Chen S, Li Z, Li W, Shan Z, Zhu W. Resveratrol inhibits cell differentiation in 3T3-L1 adipocytes via activation of AMPK. Can J Physiol Pharmacol. 2011 Nov;89(11):793-9.
• Gomes AP, Duarte FV, Nunes P, Hubbard BP, Teodoro JS, Varela AT, Jones JG, Sinclair DA, Palmeira CM, Rolo AP. Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis. Biochim Biophys Acta. 2012 Feb;1822(2):185-95.
• Hisada K, Hata K, Ichida F, Matsubara T, Orimo H, Nakano T, Yatani H, Nishimura R, Yoneda T. Retinoic acid regulates commitment of undifferentiated mesenchymal stem cells into osteoblasts and adipocytes. J Bone Miner Metab. 2013 Jan;31(1):53-63.
• Hong JH, Hwang EY, Kim HJ, Jeong YJ, Lee IS. Artemisia capillaris inhibits lipid accumulation in 3T3-L1 adipocytes and obesity in C57BL/6J mice fed a high fat diet. J Med Food. 2009 Aug;12(4):736-45.
• Hu Y, Davies GE. Berberine increases expression of GATA-2 and GATA-3 during inhibition of adipocyte differentiation. Phytomedicine. 2009 Sep;16(9):864-73. doi: 10.1016/j.phymed.2009.03.002. Epub 2009 Apr 28.
• Huang C, Zhang Y, Gong Z, Sheng X, Li Z, Zhang W, Qin Y. Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARgamma pathway. Biochem Biophys Res Commun. 2006;348:571–578.
• Hwang JT, Lee MS, Kim HJ, Sung MJ, Kim HY, Kim MS, Kwon DY. Antiobesity effect of ginsenoside Rg3 involves the AMPK and PPAR-gamma signal pathways. Phytother Res. 2009 Feb;23(2):262-6.
• Joo JI, Kim DH, Choi JW, Yun JW. Proteomic analysis for antiobesity potential of capsaicin on white adipose tissue in rats fed with a high fat diet. J Proteome Res. 2010 Jun 4;9(6):2977-87.
• Juman S, Yasui N, Okuda H, Ueda A, Negishi H, Miki T, Ikeda K. Caffeic acid phenethyl ester inhibits differentiation to adipocytes in 3T3-L1 mouse fibroblasts. Biol Pharm Bull. 2010;33(9):1484-8.
• Ka SO, Kim KA, Kwon KB, Park JW, Park BH. Silibinin attenuates adipogenesis in 3T3-L1 preadipocytes through a potential upregulation of the insig pathway. Int J Mol Med. 2009 May;23(5):633-7.
• Kim SK, Kong CS. Anti-adipogenic effect of dioxinodehydroeckol via AMPK activation in 3T3-L1 adipocytes. Chem Biol Interact. 2010a Jun 7;186(1):24-9.
• Kim KJ, Lee OH, Lee BY. Fucoidan, a sulfated polysaccharide, inhibits adipogenesis through the mitogen-activated protein kinase pathway in 3T3-L1 preadipocytes. Life Sci. 2010b May 22;86(21-22):791-7.
• Kim GS, Park HJ, Woo JH, Kim MK, Koh PO, Min W, Ko YG, Kim CH, Won CK, Cho JH. Citrus aurantium flavonoids inhibit adipogenesis through the Akt signaling pathway in 3T3-L1 cells. BMC Complement Altern Med. 2012 Apr 3;12:31.
• Kong CS, Kim JA, Eom TK, Kim SK. Phosphorylated glucosamine inhibits adipogenesis in 3T3-L1 adipocytes. J Nutr Biochem. 2010 May;21(5):438-43. 
• Lee YS, Kim WS, Kim KH, Yoon MJ, Cho HJ, Shen Y, Ye JM, Lee CH, Oh WK, Kim CT, et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes. 2006;55:2256–2264. 
• Lee YK, Lee WS, Hwang JT, Kwon DY, Surh YJ, Park OJ. Curcumin exerts antidifferentiation effect through AMPKalpha-PPAR-gamma in 3T3-L1 adipocytes and antiproliferatory effect through AMPKalpha-COX-2 in cancer cells. J Agric Food Chem. 2009 Jan 14;57(1):305-10.
• Lee H, Kang R, Yoon Y. SH21B, an anti-obesity herbal composition, inhibits fat accumulation in 3T3-L1 adipocytes and high fat diet-induced obese mice through the modulation of the adipogenesis pathway. J Ethnopharmacol. 2010 Feb 17;127(3):709-17.
• Liu Y, Wang WJ, Chen WH, Yin J. [Effects of Astragalus polysaccharides on proliferation and differentiation of 3T3-L1 preadipocytes]. Zhong Xi Yi Jie He Xue Bao. 2007 Jul;5(4):421-6.
• Liu Y, Lou SY, He YM. [Effects of berberine on cell proliferation, peroxisome proliferation activated receptor gamma, CAAT/enhancer binding protein mRNA and protein expression in 3T3-L1 pre-adipocytes]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2008 Nov;28(11):1005-9.
• Medina-Gomez G, Gray SL, Yetukuri L, Shimomura K, Virtue S, Campbell M, Curtis RK, Jimenez-Linan M, Blount M, Yeo GS, Lopez M, Seppänen-Laakso T, Ashcroft FM, Oresic M, Vidal-Puig A. PPAR gamma 2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism. PLoS Genet. 2007 Apr 27;3(4):e64.
• Mukherjee R, Yun JW. Bromocriptine inhibits adipogenesis and lipogenesis by agonistic action on α2-adrenergic receptor in 3T3-L1 adipocyte cells. Mol Biol Rep. 2013 May;40(5):3783-92.
• Nimitphong H, Holick MF, Fried SK, Lee MJ. 25-hydroxyvitamin D₃ and 1,25-dihydroxyvitamin D₃ promote the differentiation of human subcutaneous preadipocytes. PLoS One. 2012;7(12):e52171.
• Oben JE, Ngondi JL, Blum K. Inhibition of Irvingia gabonensis seed extract (OB131) on adipogenesis as mediated via down regulation of the PPARgamma and leptin genes and up-regulation of the adiponectin gene. Lipids Health Dis. 2008 Nov 13;7:44.
• Park DY, Ahn YT, Huh CS, Jeon SM, Choi MS. The inhibitory effect of Lactobacillus plantarum KY1032 cell extract on the adipogenesis of 3T3-L1 Cells. J Med Food. 2011 Jun;14(6):670-5.
• Park UH, Jeong HS, Jo EY, Park T, Yoon SK, Kim EJ, Jeong JC, Um SJ. Piperine, a component of black pepper, inhibits adipogenesis by antagonizing PPARγ activity in 3T3-L1 cells. J Agric Food Chem. 2012 Apr 18;60(15):3853-60.
• Sagara C, Takahashi K, Kagechika H, Takahashi N. Molecular mechanism of 9-cis-retinoic acid inhibition of adipogenesis in 3T3-L1 cells. Biochem Biophys Res Commun. 2013 Mar 29;433(1):102-7. 
• Seo JB, Choe SS, Jeong HW, Park SW, Shin HJ, Choi SM, Park JY, Choi EW, Kim JB, Seen DS, Jeong JY, Lee TG. Anti-obesity effects of Lysimachia foenum-graecum characterized by decreased adipogenesis and regulated lipid metabolism. Exp Mol Med. 2011 Apr 30;43(4):205-15.
• Thounaojam MC, Jadeja RN, Ramani UV, Devkar RV, Ramachandran AV. Sida rhomboidea. Roxb Leaf Extract Down-Regulates Expression of PPARγ2 and Leptin Genes in High Fat Diet Fed C57BL/6J Mice and Retards in Vitro 3T3L1 Pre-Adipocyte Differentiation. Int J Mol Sci. 2011;12(7):4661-77.
• Tzeng TF, Chang CJ, Liu IM. 6-Gingerol Inhibits Rosiglitazone-Induced Adipogenesis in 3T3-L1 Adipocytes. Phytother Res. 2013 Mar 21.
• Wang JM, Yang Z, Xu MG, Chen L, Wang Y, Su C, Tao J. Berberine-induced decline in circulating CD31+/CD42- microparticles is associated with improvement of endothelial function in humans. Eur J Pharmacol. 2009;614:77–83.
• Yuan HD, Yuan HY, Chung SH, Jin GZ, Piao GC. An active part of Artemisia sacrorum Ledeb. attenuates hepatic lipid accumulation through activating AMP-activated protein kinase in human HepG2 cells. Biosci Biotechnol Biochem. 2010;74(2):322-8.
• Yuan HD, Piao GC. An active part of Artemisia sacrorum Ledeb. inhibits adipogenesis via the AMPK signaling pathway in 3T3-L1 adipocytes. Int J Mol Med. 2011 Apr;27(4):531-6.

Will Glucosamine Make Us Live Forever? Probably Not, But in Mice the Low-Carb Mimetic Effects Make 10% Possible - In Humans, This Would be ~9 Years! Too Good to Be TRUE?

One of the lead scientists is so convinced that the 10% life-extension the resear- chers observed in rodents will occur in humans, as well, that he is already taking glucosamine supps everyday!

Next to not eating at all, not eating any carbs has recently become all the rage in the "how do extend the lifespan of stupid worms"-research all over the world. Now, I am all for eating less carbohydrates than the people who came up with "Your Plate", my American friends consider optimal.

Yes! I am even in for skipping carbs altogether, but not for a lifetime (!) which is what would be necessary to reproduce the life-extending effects Schulz et al. observed in their 2007 study on the effects of carbohydrate restriction on the lifespan of the notorious (not B.I.G but) B.I.R. as in "big bad roundworm" (Schulz. 2007).

You can learn more about hormesis & life extension at the SuppVersity

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Now, about seven years later, my favorite anti-ROS-theory-of-aging researcher Michael Ristow and his colleagues some of whom had been involved in the previously cited experiment as well was able to show that bathing the worms in glucosamine will elicit similar life-extending effects (Weimer. 2014).

With only 5% the overall increase in life-expectancy was yet significantly lower than in the "carb restriction" study from 2007, but - and that's actually way more important - unlike cutting carbs, which had failed to produce any effects in a rodent model, the mice who received the glucosamine as an adjunct to their diet, when they were already 100 weeks of age (in human years that's approximately 65 years) lived almost 10% longer than their peers in a non-glycosamine-enhanced control group.

Just to make that clear: We are talking about around 8 additional years of human lifespan! If the results translate from a small mouse who does not stuff itself with junk food all day to the average fast-food addicted Westerner, who follows Winston Churchill's motto "No sports!"

Even if the life-extension did not work, though, couch potato and aging athlete will would probably both benefit from the pronounced improvements / amelioration of the age-induced defects in glucose control, which were significantly reduced in the rodents on the high glucosamine groups.

Figure 1: The decreased ATP stores that come with the "low carb mimicry" effect are not exactly what someone who wants to hit the weights in his old age, would want (Weimer. 2014)

Unfortunately, theses improvements in glucose metabolism come at cost. Ristow et al. found out, glucosamine feeding promotes the breakdown of amino acids in both worms and mice - a breakdown of which the scientists say that it is characteristic of the "metabolic state of a low-carb diet".

In view of the fact the both groups of mice consumed identical amounts of carbohydrates, it's thus only logical to assume that the provision of adequate amounts of glucosamine inhibits the use of glucose from the diet and will thus yield similar metbolic (side) effects as a real low-carb diet - yet without having to skip on pasta, pizza and (of course ;-) tons of sweet potatoes.

Figure 2: At normal glucose levels (<35%) glucosamine reduces skeletal muscle  GLUT-4 expression and glucose disposal (Baron. 1995),

Should we now all start to take glucosamine supplements? According to the accompanying press release Michael Ristow thinks so and actually he even acts on his believe stating: "This [i.e. that everyone should take glucosamine supplements] may be considered a valid option, and yes, I have started taking glucosamine myself."

Whether that's actually a good idea or not, is in my humble opinion still questionable. Previous studies have after all linked high glucosamine to the development of insulin resistance (Baron. 1995; Rossetti. 1995; Shankar. 1998); and a compromised glucose metabolism would certainly not the best premise for a 10% longer life - right?

On the other hand, recent reviews have refuted the notion that glucosamine supplementation increases the risk of insulin resistance, because the necessary tissue levels to generate negative effects as they are displayed in Figure 2 would never be reached with oral supplement (Anderson. 2005). Moreover, Ristow himself mentions that two recent epidemiological studies on more than 77,000 individuals suggest that intake of glucosamine supplements is associated with reduced mortality in humans (Pocobelli. 2010; Bell. 2012) and says: "Unlike with our longer living mice, such an association is no definite proof of the effectiveness of glucosamine in humans, but the chances are good, and since unlike with most other potentially lifespan-extending drugs there are no known relevant side effects of glucosamine supplementation, I would tend to recommend this supplement" (from press release from the ETH Zurich).

References:

• Anderson, J. W., R. J. Nicolosi, and J. F. Borzelleca. "Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy." Food and Chemical Toxicology 43.2 (2005): 187-201.
• Baron, A. D., et al. "Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity." Journal of Clinical Investigation 96.6 (1995): 2792.
• Bell, Griffith A., et al. "Use of glucosamine and chondroitin in relation to mortality." European journal of epidemiology 27.8 (2012): 593-603.
• Pocobelli, Gaia, et al. "Total mortality risk in relation to use of less-common dietary supplements." The American journal of clinical nutrition 91.6 (2010): 1791-1800.
• Rossetti, Luciano, et al. "In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats." Journal of Clinical Investigation 96.1 (1995): 132.
• Shankar, R. R., J-S. Zhu, and A. D. Baron. "Glucosamine infusion in rats mimics the β-cell dysfunction of non—insulin-dependent diabetes mellitus." Metabolism 47.5 (1998): 573-577.
• Weimer, Sandra et al. "D-Glucosamine supplementation extends lifespan of nematodes and of ageing mice." Nature Communications (2014), doi: 10.1038/ncomms4563 

True or False!? Glucosamine Doesn't Help Cartilage Repair. Carcacrol Based Weight Loss Products Shed Body fat. N-Acetyl-L-Glutamine Is Not Worth the Extra Bucks.

Compared being obese and chronically inflamed heavy squats entail a comparably low risk of "wearing off your" joints.  (Spector. 1996)

If I just go by the mere visitor counts the new "True or False" category appears to turn out to be one of the best innovations of the past weeks. That being said, I am happy that many of you have been submitting questions, but had to realize that even those of which I initially thought they would be easy to answer, require more research than I had expected.

Therefore this installment contains one long and two short TOF items, which I came across more or less accidentally in the course of the past week. I hope you enjoy those as well and don't freak out that your inquiry has not been answered this week (tip: you can increase your chance of having your question answered if you pick something simple, like the two latter items in this installment).

 Glucosamine supplements cannot help with cartilage repair

It depends -- Like many of the true or false item the purported benefits of glucosamine supplements on cartilage health belong to those "gems" of common wisdom which have been reiterated so often that everybody is inclined to believe they must be true. Fortunately, science does not operate by the principle of majority rule, which is why you will have to spend reading the following lines if you want to know whether the use of respective supplements is going to help heal your joints.

More often than not your pain is not (yet) the result of worn of ligaments, but simply a consequence of muscular imbalances. Your shoulder hurts, whenever you bench? Try the impingement no more protocol and reduce or even resolves shoulder pain in 6 weeks (learn more)

• age related decline in joint health  - there is currently no convincing evidence that "glucosamine modulates ageing phenotype" (Henrotin. 2013), on the other hand the mere absense of long-term studies does not exclude that it may sill have practical value. Benefits are yet only likely to occur if the ability of human chrondocytes to produce glucosamine from glucose declines with age.

• general prophylaxis - Aside from the by no means unambiguous evidence from animal studies a prophylactic effect of GlcN supplementation in human trials has - as of now - not been presented (Hernrotin. 2014). In this context, a specific weakness of many human studies is the use of inappropriate, often subjective measures instead of reliable MRI or other imaging methods. 

• treatment of arthritis (OA) - While the general evidence is scarce, it appears as if GlcN could have an ameliorative effect on the progression of OA. Promising evidence that it could help, yet via a pathway much different from the original concept of "providing raw material for joint health" - comes from animal models in which the administration of high doses of glucosamine had ameliorative effects on systemic inflammation (C-reactive protein, TNF-alpha, Largo. 2009). Unfortunately, this is yet another of the many "promises" that has up to now not been reproduced in controlled human studies, in which the administration of allegedly lower amounts of GlcN (1,500 mg) did not affect any of the common markers of inflammation (Nakamura. 2007).

I guess the previously mentioned points are all "nice to hear", but not exactly what you wanted to read about, right? So what about this one, then, ...

• CCE the paleo glucosamine? You know that despite my frequent allusions to the (a-)buse of "paleolithic" line argumentations, I am alway open for scientific evidence that would prove any of the bazillion "paleo solutions" people are throwing around on the web (no offense to Robb Wolf, here). Therefore I don't want to miss the chance to let you know that at chicken comb extract (CCE)-containing supplement taken in dosages of 4.8g/day yielded significant improvements in pain scores for the dominant and most affected foot of 23 soccer players (Yoshimura. 2012). Aside from the "eat the whole animal" mantra, this is also interesting as far as the production of future supplements is concerned. After all CCE contains hyaluronic acid (glycosaminoglycan) and are thus themselves made up of glucosamine (or rather D-glucuronic acid and D-N-acetylglucosamine). Whether this makes them more or less effective will yet still have to be elucidated.
  prevention / strengthening of cartilage in athletes: The maintenance of joint health in conditions, where the joints are exposed to excessive loads is probably the area of application GlcN is most heavily marketed for. On the other hand, it is also the area that is the least researched. The current scientific consensus is to acknowledge the evidence from two heavily cited randomized, double-blind,
  placebo-controlled trial, of which ...
  • ... one dealt with 121 male patients who had a recent history of acute knee sport injury (Ostojic. 2007) -- the participants received either 1.5 g GlcN (n=62) per day orplacebo (cellulose; n = 59) for 28 days; despite the fact that the GlcN group demonstrated significant improvements in knee flexion and extension, neither the pain nor swelling subsided
     
  • ... the other analyzed the effect of three months 1.5g or 3.0g of GlcN on the 21 male college aged soccer players (19–22 years of age, mean 20.3) and compared the outcomes to 10 male age-matched college students (Yoshimura. 2009) -- the administration of the supplement decreased the urine levels of CTX-II, but the observed reduction of this marker of collagen turn-over was transient and disappeared after withdrawal of the administration.
  In view of the fact that the significance of the reduced CTX-II levels in the Yoshimura study is not clear these are promising, but by no means conclusive results which would suggest that strength trainees could benefit from the chronic and timely initiated supplementation of 1.5-3.0g of GlcN per day.

Another thing to keep in mind is that therapeutic doses start at 1,500mg per day (information on optimal dosing regimen for different purposes, age groups, etc. are lacking - also because the bioavailability of glucosamine is highly species dependent and the available literature on horses has little to no value for human beings; cf. Hernrotin. 2013).

There is still the unresolved issue of adequate vs. excessive dosages

While the recommended dosage may be enough to achieve serum concentrations of 10µm which are 1-2x more than those the average human being will have floating around in the non-supplemented state, these are still 50x-500x lower than the concentrations scientists use in the petri-dishes of the in-vitro studies producers of respective supplements like to cite to provide evidence for the efficacy of their products (Largo. 2003; Block. 2010).

Does glucosamine precipitate or even cause insulin resistance? While it probably ain't much of a problem with short term administration of low doses of glucosamine (1g in 2x500mg dosages is safe; cf. Muniyappa. 2005), taking glucosamine in amounts as it would be necessary to achieve serum levels similar to those that have been shown to actually work in in-vitro studies, will almost certainly induce muscular insulin resistance (Largo. 2003; Bailey. 2004; Block. 2010). Moreover, pre-existing insulin resistance (Pham. 2007), as well as diabetogenic diets (Chien. 2009) and/or systemic inflammation (Biggee. 2007) appear to increase the risk of experiencing this nasty side-effect as a consequence of the chronic ingestion (6+ weeks) of dosages of 1.5g+ per day (Dostrovsky. 2011). And let's be honest the sentence "Owing to limitations in study design, conclusions based on studies that report adverse affects of GlcN on insulin sensitivity and glucose tolerance in pre-diabetic subjects are suspect" by the means of which a 2011 review written by employees and counselors of Cargill, a major producer of respective supplements, tries to refute the aforementioned negative scientific evidence is at least as "suspect" as the studies the review is criticizing (Simon. 2011) - no?

With all that being said, the usefulness of glucosamine supplements as a means to prevent, let alone treat cartilage degeneration is unquestionably overblown. This goes irrespective of the existing in-vitro evidence of the stimulatory effect very high concentrations of GlcN exert on their own usage and incorporation and my - at least in part - be due to another, hitherto overlooked, bottleneck that limits our bodies capacity to use the the "raw material" in the way we intend it.

Now that you have the evidence right in front of you I'll leave it up to you to decide whether you want to take the (by no means non-existent) chance that the chronic ingestion of high dosages (at least 3g/day) of GlcN could ward of some of the wear and tear of your workouts or whether you simply stop squatting your 1-RM max for reps using a horrible technique and thus ruining not just your knees, but also your back.

You should be aware, though, that the latter does imply that you trust the Cargill guys' judgment that the hitherto published animal and human studies have "limitations" and any "conclusions based on studies that report adverse affects of GlcN on insulin sensitivity and glucose tolerance in pre-diabetic subjects are suspect" (Simon. 2011; for more info see red box to the right).

Carvacrol supplements will promote weight loss

False -- Despite the fact that a recent study in mice shows that the administration of isopropyl-ortho-cresol aka cravacrol, the predominant monoterpene phenol from the essential oils of plants from the Labiatae family (Origanum, Satureja, Thymbra, Thymus, and Coridothymus), is a potent inducer of hepatic AMPK and sirtuin-1 activity (Kim. 2013), the currently available supplements are so hilariously underdosed that even the researchers could not deny themselves the following side kick:

Cravacrol could work, if there was a supplement with adequate amounts of it on the market (data based on Kim. 2013).

"The daily carvacrol intake of the mice in our study (100 mg/kg body weight) was equivalent to an intake of approximately 8.1 mg/kg human body weight (486 mg/60 kg person), when calculated on the basis of normalization to body surface area as recommended by Reagan-Shaw et al. and the US Food and Drug Administration.

The daily doses of commercial dietary supplements range from 9 to 288 mg carvacrol (0.15–4.8 mg/kg body weight) for a 60 kg human." (Kim. 2013)

This spares me to tell you that you are wasting your money, if you throw one of the carcacrol based fat burners into your virtual or real shopping basket.

On a more general note: Irrespective of any dosage issues, it is by no means sure that any of the many "proven" anti-inflammatory weight loss agents, i.e. herbs & co that help reduce weight gain in rodents on HFD and/or help obese and metabolically deranged individuals to lose weight will do anything at all in healthy, insulin sensitive, non-inflamed, normal-weight individuals (e.g. "Epigallocatechin Gallate (EGCG), Capsaicins, Piperine & Carnitine: Rather a Health Than a Fat Loss Stack?", read more). In other words: "Not everything that's good for your obese neighbor will be beneficial for you, as well."

Due to its stability in water N-Acetyl glutamine is way superior to regular l-glutamine

False -- Irrespective of the never-ending debate on the usefulness of glutamine supplementation for hard-working athletes (learn more), respective supplements are still part of the most commonly used bulk-powders among bodybuilders, physique athletes and average gymrats. Contrary to the potential benefits of respective supplements, which can, despite being far from scientifically established, not be denied altogether, there is one thing that's about as sure as the eggs I had for breakfast: The allegedly more stable N-acetyl variety of glutamine (NAG) does not just taste like **** it is also a complete waste of money and probably less effective than the cheap free-form glutamine you can buy for a couple of pennies at every of the major bulk suppliers on the Internet.

Figure 1: Glutamine content in the blood of 15 pigs (15–20 kg weight) maintained on either a 1kg/day standard diet (C) or C + 8 g L-glutamine and C + 10.5 g N-acetyl-L-glutamine provided at 1000 g/day after "breakfast" (333g of the chow) and detailed analysis of intact glutamine and glutamic acid in the jejunum mucosa, after 180min of intestinal infusion (Arnaud. 2004)

After you have taken a look at the data in figure 1, any further elaborations that go beyond the confirmatin f the high accuracy and usefulness of porcine models for human digestion and metabolism (cf. Litten-Brown. 2010) should be dispensable... as dispensable as NAG supplements, by the way ;-)

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That's it for today: As mentioned in the introduction, I am well aware that some of you will be missing their suggestions, but I have to say that answering those inquiries in more than just a "probably no", "probably yes" fashion takes its time. No reason for the rest to keep submitting suggestions, I will keep track of them and have already done some research into the more complex stuff, which may give rise to a post of their own in the future.

References:

• Bailey CJ, Turner SL. Glucosamine-induced insulin resistance in L6 muscle cells. Diabetes Obes Metab. 2004 Jul;6(4):293-8. 
• Biggee BA, Blinn CM, Nuite M, Silbert JE, McAlindon TE: Effects of oral glucosamine sulphate on serum glucose and insulin during an oral glucose tolerance test of subjects with osteoarthritis. Ann Rheum Dis 2007, 66:260-262. 
• Block JA, Oegema TR, Sandy JD, Plaas A:  The effects of oral glucosamine on joint health: is a change in research approach needed? Osteoarthr Cartil. 2010; 18:5–11. 
• Chen HC, Shah S, Stabler TV, Li YJ, Kraus VB: Biomarkers associated with clinical phenotypes of hand osteoarthritis in a large multigenerational family: the CARRIAGE family study. Osteoarthr Cartil. 2008; 16:1054–1059. 
• Chien CS, Cheng SC, Wu HT, Tsao CW, Cheng JT: Insulin resistance induced by glucosamine in fructose-fed rats. Horm Metab Res 2009, 41:542-547.
• Dostrovsky NR, Towheed TE, Hudson RW, Anastassiades TP: The effect of glucosamine on glucose metabolism in humans: a systematic review of the literature. Osteoarthritis Cartilage 2011, 19:375-380.
• Henrotin Y, Chevalier X, Herrero-Beaumont G, McAlindon T, Mobasheri A, Pavelka K, Schön C, Weinans H, Biesalski H. Physiological effects of oral glucosamine on joint health: current status and consensus on future research priorities. BMC Res Notes. 2013 Mar 26;6(1):115.
• Kim E, Choi Y, Jang J, Park T. Carvacrol Protects against Hepatic Steatosis in Mice Fed a High-Fat Diet by Enhancing SIRT1-AMPK Signaling. Evid Based Complement Alternat Med. 2013;2013:290104.
• Largo R, Alvarez-Soria MA, Diez-Ortego I, Calvo E, Sanchez-Pernaute O, Egido J, Herrero-Beaumont G:  Glucosamine inhibits IL-1beta-induced NFkappaB activation in human osteoarthritic chondrocytes. Osteoarthr Cartil. 2003, 11:290–298.  
• Litten-Brown JC, Corson AM, Clarke L. Porcine models for the metabolic syndrome, digestive and bone disorders: a general overview. Animal. 2010 Jun;4(6):899-920.
• Muniyappa R, Karne RJ, Hall G, Crandon SK, Bronstein JA, Ver MR, Hortin GL, Quon MJ. Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects. Diabetes. 2006 Nov;55(11):3142-50.
• Nakamura H, Masuko K, Yudoh K, Kato T, Kamada T, Kawahara T. Effects of glucosamine administration on patients with rheumatoid arthritis. Rheumatol Int. 2007 Jan;27(3):213-8.
• Ostojic SM, Arsic M, Prodanovic S, Vukovic J, Zlatanovic M: Glucosamine administration in athletes: effects on recovery of acute knee injury. Res Sports Med. 2007; 15:113–124. 
• Pham T, Cornea A, Blick KE, Jenkins A, Scofield RH: Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci 2007, 333:333-339.
• Simon RR, Marks V, Leeds AR, Anderson JW. A comprehensive review of oral glucosamine use and effects on glucose metabolism in normal and diabetic individuals. Diabetes Metab Res Rev. 2011 Jan;27(1):14-27.
• Spector TD, Harris PA, Hart DJ, Cicuttini FM, Nandra D, Etherington J, Wolman RL, Doyle DV. Risk of osteoarthritis associated with long-term weight-bearing sports: a radiologic survey of the hips and knees in female ex-athletes and population controls. Arthritis Rheum. 1996 Jun;39(6):988-95.
• Yoshimura M, Sakamoto K, Tsuruta A, Yamamoto T, Ishida K, Yamaguchi H, Nagaoka I: Evaluation of the effect of glucosamine administration on biomarkers for cartilage and bone metabolism in soccer players. Int J Mol Med. 2009; 24:487–494.
• Yoshimura M, Aoba Y, Naito K, Watari T, Murakami S, Yoshimura K, Nakagawa T, Yamamoto T, Yamaguchi H, Nagaoka I. Effect of a chicken comb extract-containing supplement on subclinical joint pain in collegiate soccer players. Exp Ther Med. 2012 Mar;3(3):457-462.