The Best Supplement Ever?

TAGS: Ursolic Acid, bodybuilding wonder supplement, supplement, Scott Stevenson

That Supplement Does what?

In today’s health and fitness marketplace, the difference between a “drug” and a “supplement” is blurry at best. We now have prescription fish oil [Lovaza(1, 2)], and “good ole creatine” monohydrate is being explored as a treatment not only for muscle degenerative conditions, but also metabolic abnormalities like diabetes, central nervous system disease (dementia) and even psychiatric disorders like depression)(3).

Merriam-Webster (online) defines a “dietary supplement” as, “a product taken orally that contains one or more ingredients (as vitamins or amino acids) that are intended to supplement one's diet and are not considered food(4).” The U.S. Food and Drug Administration says that a drug may be “articles (other than food) intended to affect the structure or any function of the body of man or other animals.” However, a product fitting this very same description can be considered a “supplement” (not a drug) by the FDA simply if is labeled as such(5).

Sounds pretty simple, eh?  Nonetheless, claims about the action (“structure / function claims”) of a supplement must (legally) be substantiated before a product is put on the market here in the United States. Thus far, supplement manufacturers are dropping the ball on this one. As anyone attuned to the health and fitness industry can attest, what ends up on supplement labels and advertisements can be pretty outrageous. A report by the Office of the Inspector General (U.S. Dept. of Health and Human Services) reviewed 72 supplements and found that only 34% of the 1600+ substantiation documents were studies performed with human subjects. None (zero, zippo, nada) of those studies met the “FDA’s recommendations for competent and reliable evidence.” Not a single study was up to snuff for supporting the claims made by the makers of those 72 products(6).

I’m not Gonna Yank Your Chain

Now that we’ve established the level of credibility (or lack thereof) product label claims in the supplement industry, you’ve got some context for compound that I’m pretty interested in: It has a virtual plethora of bodybuilding-associated actions, albeit mostly only demonstrated in animal research.

Bottle carrosel

Don’t stop reading. (I know what you might be thinking at this point.) I’m not trying to sell you on an untested supplement here, but imagine if you could, the penultimate super-duper bodybuilder’s nutritional supplement, stretching the limits of the imagination (and belief). What could it do?  What would it do? Off the top of my head, I’d hope for something like this:

  • It increases muscle mass.
  • In turns on muscle protein synthesis.
  • It prevents muscle loss.
  • It’s a fat burner, promoting lipolysis and inhibiting lipogenesis.
  • It increases brown fat and uncouples oxidative phosphorylation, which is actually possible in humans(7-10).
  • It enhances insulin’s action in insulin sensitive cells in particular (like muscle cells).
  • It’s an anti-oxidant, increasing the body’s own protective free radical-scavenging abilities.
  • It improves risk factors for cardiovascular disease and is good for your heart in general.
  • It’s a liver protector and neuroprotective.

I Lied

Well, I lied about yanking your chain. Now that you’re brimming with anticipation of this super supplement, I want to pull you back a bit. Don’t give up on having a critical mindset. When my meathead brain gets fired up and I start feeling gung-ho about using a new bodybuilding product, taking a step back has kept out of trouble more than a few times. (Getting “in trouble” can be fun, too, of course, and being excited about “new stuff” is the nature of being an enthusiast, no matter what you’re interested in. Nonetheless, while you may still be vulnerable to placebo effects, thinking critically may at least allow you to isolate a given supplement’s effects and evaluate whether it’s a worthwhile addition for you.)

vitamin or pills drag tablet boxes supplements Man isolated

That being said, the hypothetical “best supplement ever” I’ve been talking about is actually a compound that’s already available over the counter: Ursolic acid (UA). Allow me to present some of the science surrounding UA, so you can see why I thought this compound worthy of an article unto itself.

Ursolic Acid: What is it?...

Found in apples, you get about 50mg of UA in the waxy peel of a medium-size apple(11). It’s also found in a variety of medicinal plants (like ginseng, loquat, eucalyptus, mint, coffee, honeysuckle(12) and thyme(13, 14), as well as prunes, blueberries(12) and cranberries(15). [The bulk UA (25% concentration) I have seen on the market has been derived from loquat and thyme.] Ursolic acid (like its closely related isomer oleanolic acid) is considered a triterpenoid (or triterpenoid saponin)(12) and is technically a steroid(16, 17), but not that kind of steroid.

Ursolic Acid: Muscle Builder?

Using a very cool scientific tool called a “connectivity map(18)” researchers led by Christopher Adams were able to single out UA as the molecule best suited to antagonize human muscle atrophy brought on by fasting and/or spinal cord injury(19). Given this, they put UA to the test in mice. Twenty-four hours of fasting meant a 9% loss of muscle mass, but mice injected with UA actually increased muscle mass by 7%. This happened at least in part because, as they predicted, UA blocked fasting-induced gene expression. Similarly, after simulated spinal cord injury (which causes disuse atrophy) UA also preserved muscle mass and fiber size.

Here’s where it gets good. UA feeding [0.27% diet, which converts to about 3.5 – 5.5g of UA / day for a 100kg bodybuilder(20, 21)] produced mice that had larger muscles with larger, intrinsically stronger fibers, just can result from weight training in humans(22-24). (The mice fed UA also had greater “grip strength,” believe it or not.) This muscle growth was accompanied by elevated intracellular signaling for protein synthesis (e.g., via Akt, which activates mTOR to turn on protein synthesis(25)] and increased muscle IGF-1 levels (without any change in plasma IGF-1).   UA is particularly anabolic in skeletal muscle because enhances the actions of insulin(26) and IGF-1 both(19, 27).  UA “turns off the off switch” for insulin and IGF-1 by inhibiting an enzyme(28) that inactivates both the IGF-I and insulin receptors(29).  [The resulting moderate hypoglycemic action explains why UA is found in many anti-diabetic herbal medicines(27)].

bodybuilder best supplement ever scott stevenson 040114

Thus, by amplifying protein synthesis(30), IGF-1 levels(31) and insulin sensitivity(32), UA is actually mimicking the effects of resistance exercise on skeletal muscle. I won’t go so far as to lend a tagline (e.g., “ursolic acid is like pumping iron in a powder”), but these actions and the animal data above suggests UA supplementation could be a great way to amplify muscular adaptations to resistance training and/or maintain a persistent anabolic state.

Ursolic Acid: Fat Burner?

Wait, it gets better. In the study described above, while the mouse muscle cells were growing (without any training stimulus), the mice’ fat cells were actually shrinking. This repartitioning effect occurred without any change in the amount of food the mice were eating (compared to control mice)(19). In a similar study, these same effects were seen in mice fed a high fat diet, and then some. Adding UA to the (obesity-producing) diet produced mice that could run farther without tiring, had lower blood pressures and resting heart rates, and better glucose tolerance and less fat in their livers. In this study, UA fed mice also ate more and had higher resting metabolic rate, but lower body fat levels: The UA increased brown (thermogenic) fat levels, which explains why they also had better cold tolerance(33).

Other studies have also found UA to have an uncoupling effect(34) – thermogenesis in its purest form, as occurs in brown fat. UA inhibits fat cell (pre-adipocyte) differentiation into full blown fat cells, stimulates fat oxidation, and inhibits fat deposition(35). [Once somewhat abandoned as a possibility in humans, it seems that thermogenic brown is inducible, especially in those that are leaner(7-9). Also, “beige” or “brite” fat cells have been discovered(10, 36), that may be fat cells waiting for the stimulus to make them thermogenically active.]

Ursolic Acid: Health Supplement?

Thus far, in UA we’ve got a supplement that may put the brakes on muscle atrophy and fat gain, but simultaneously stimulate muscle cell growth and fat loss.  In fat-gobbling mice, it reduces obesity, hypertension and insulin resistance, as well as slows the development of fatty liver.

Can it get any better?

Yes. Yes, it can. Ursolic acid not only counters fatty liver, it also protects the liver against the toxic effects of carbon tetrachloride (a very potent liver toxin) and cadmium chloride [a pro-oxidant(37)], as well acetaminophen (good old Tylenol)(12, 38). Not surprisingly, UA also activates(39) the body’s own multi-faceted free-radical, toxin and foreign molecule defense system that protects cells against oxidative injury(40). In rats prone to hypertension and insulin resistance, UA counters these health deficits, and increases the levels of two vital free-radical fighting enzymes, while improving lipid profile(41). UA also inhibits tumor growth and numerous aspects of carcinogenesis(42, 43), is generally cardioprotective(34) and boosting the immune system by raising white blood cell count (in mice)(16).

figure bodybuilding scott stevenson best supplement ever 040114

The Devil is in the Dose

So in ursolic acid, we also have a toxin and cancer-fighting compound that protects the liver and improves cardiovascular risk profile.

So, why aren’t we simply putting this stuff in the water supply?

Well, for one reason, it’s solubility in water is very poor(43), which means that bioavailability suffers as well(44). Being a lipid, it moves across cell membranes(45) relatively easily, but the available data suggests that its oral bioavailability is on the order of 1% or less(46-49).  Nonetheless, because its actions are so promising, a few medical investigators have investigated intravenous formulations for delivering UA(42, 48, 50, 51)}.

Ursolic acid does indeed seem to have low toxicity generally speaking(12, 41, 52), which makes sense, given it’s healthful actions. Anything above an infused dose of about 200mg pure ursolic acid [98mg/m2, which converts into about 215mg for a 5’10” 220lb’er(53)] can cause some nausea and diarrhea. Note that this would roughly equate to an oral dose of 20g of UA (given 1% oral bioavailability), i.e., consuming 80g of a commercially available 25% UA extract (if you could even manage to do so).

Despite all of its potential health benefits, the picture is not entirely rosy (pardon the pun) when it comes to UA.  Although methodological differences probably account for the apparent incongruence(54), not all animal models of cardiovascular disease prevention support UA as heart and vessel-healthy(55, 56). Additionally, it’s possible that some of what we have ascribed to UA may reflect a combination of UA’s actions and those of chemical cousin oleanolic acid, to which UA can convert within the body(57).

Last but not least, when rats were injected daily with a 5mg/kg dose of UA for 15 days, spermatogenesis was severely disrupted(58). The equivalent human dose would be about 80mg / day for a 220lb human(20), roughly the amount that might be delivered orally by 8g of UA (~32g of 25% extract). While this may seem a bit excessive, it’s only about twice the relative (species-translated) doses fed to rats(59) and mice(19, 21, 33) in studies demonstrating the health and muscularity benefits I describe above.

supplements line up best supplement ever scott stevenson 040114

So now you know…

…a few more pieces of the story, and why I (gently) yanked your chain back a bit regarding ursolic acid’s potential. To give perspective, the dietary supplement curcumin, another multi-faceted healthful food component that has poor solubility / bioavailability in its raw form(60), is currently under study in roughly 90 trials supported by the U.S. National Institutes of Health(61). A search “creatine supplementation” yields 352 hits in that same NIH database.  Ursolic acid does not show up at all (zero studies) among ongoing or recently funded NIH clinical trials(62).

I am not privy to the reasons, but the above suggests some reluctance on the part of the scientific community to embrace ursolic acid, despite all the potential it might have. UA is still available OTC in the United States, both in bulk and as a component of supplements, so the option to use it is legally yours, at least in America.

Hopefully you’re not left in a state of cognitive dissonance after I unveiled the seductive bodybuilding-related actions of UA right along side its potential drawbacks. Regardless of your decision to use or forgo UA in your supplement regimen, I do sincerely hope this article reminds you that taking a step back (yanking your own chain, so to speak) might be worthwhile for you the next time you are tempted to go “all in” on the newest bodybuilding wonder supplement.

References

1. Smith, G.I., et al., Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperinsulinaemia-hyperaminoacidaemia in healthy young and middle-aged men and women. Clinical science, 2011. 121(6): p. 267-78. http://www.ncbi.nlm.nih.gov/pubmed/21501117
2. Smith, G.I., et al., Dietary omega-3 fatty acid supplementation increases the rate of muscle protein synthesis in older adults: a randomized controlled trial. The American journal of clinical nutrition, 2011. 93(2): p. 402-12. http://www.ncbi.nlm.nih.gov/pubmed/21159787
3. Gualano, B., et al., Exploring the therapeutic role of creatine supplementation. Amino Acids, 2010. 38(1): p. 31-44.
4. Merriam-Webster Incorporated. Definition of "Dietary Supplement".  2014  [Accessed 3.9.14]; Available from: http://www.merriam-webster.com/dictionary/dietary+supplement?show=0&t=1394386750.
5. U.S. Food and Drug Administration. Federal Food, Drug, and Cosmetic Act (FD&C Act) - SEC. 201. [21 U.S.C. 321] CHAPTER II—DEFINITIONS 1.  2014  [Accessed 3.9.14]; (Definition of a Drug.).
6. United States Department of Health and Human Services Office of the Inspector General, Dietary Supplements: Structure Function Claims Fail to Meet Federal Requirements. D.R. Levinson, Editor. 2012, United States Department of Health and Human Services. https://oig.hhs.gov/oei/reports/oei-01-11-00210.pdf
7. Lee, P., et al., Inducible brown adipogenesis of supraclavicular fat in adult humans. Endocrinology, 2011. 152(10): p. 3597-602. http://www.ncbi.nlm.nih.gov/pubmed/21791556
8. van Marken Lichtenbelt, W.D., et al., Cold-activated brown adipose tissue in healthy men. The New England journal of medicine, 2009. 360(15): p. 1500-8. http://www.ncbi.nlm.nih.gov/pubmed/19357405
9. Vijgen, G.H., et al., Brown adipose tissue in morbidly obese subjects. PloS one, 2011. 6(2): p. e17247. http://www.ncbi.nlm.nih.gov/pubmed/21390318
10. Wu, J., et al., Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell, 2012. 150(2): p. 366-76. http://www.ncbi.nlm.nih.gov/pubmed/22796012
11. Frighetto, R.T.S., et al., Isolation of ursolic acid from apple peels by high speed counter-current chromatography. Food Chemistry, 2008. 106(2): p. 767-771.
12. Liu, J., Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol, 1995. 49(2): p. 57-68.
13. Kontogianni, V.G., et al., Rapid and novel discrimination and quantification of oleanolic and ursolic acids in complex plant extracts using two-dimensional nuclear magnetic resonance spectroscopy-Comparison with HPLC methods. Anal Chim Acta, 2009. 635(2): p. 188-95.
14. Rowe, E.J., et al., Isolation of oleanolic acid and ursolic acid from Thymus vulgaris, L. J Am Pharm Assoc Am Pharm Assoc, 1949. 38(3 Pt. 1): p. 122-4.
15. Neto, C.C., et al., Anticancer activities of cranberry phytochemicals: an update. Mol Nutr Food Res, 2008. 52 Suppl 1: p. S18-27.
16. Raphael, T.J. and G. Kuttan, Effect of naturally occurring triterpenoids glycyrrhizic acid, ursolic acid, oleanolic acid and nomilin on the immune system. Phytomedicine, 2003. 10(6-7): p. 483-9.
17. Price, K.R., et al., The chemistry and biological significance of saponins in foods and feedingstuffs. Crit Rev Food Sci Nutr, 1987. 26(1): p. 27-135.
18. Lamb, J., et al., The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science, 2006. 313(5795): p. 1929-35.
19. Kunkel, S.D., et al., mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Cell metabolism, 2011. 13(6): p. 627-38. http://www.ncbi.nlm.nih.gov/pubmed/21641545
20. Sharma, V. and J.H. McNeill, To scale or not to scale: the principles of dose extrapolation. Br J Pharmacol, 2009. 157(6): p. 907-21.
21. Bachmanov, A.A., et al., Food intake, water intake, and drinking spout side preference of 28 mouse strains. Behav Genet, 2002. 32(6): p. 435-43.
22. Canepari, M., et al., Skeletal muscle fibre diversity and the underlying mechanisms. Acta Physiologica (Oxford, England), 2010. 199(4): p. 465-476. http://search.ebscohost.com/login.aspx?direct=true&db=mdc&AN=20345415&site=ehost-live
23. Parente, V., et al., Long-term resistance training improves force and unloaded shortening velocity of single muscle fibres of elderly women. Eur J Appl Physiol, 2008. 104(5): p. 885-93.
24. Widrick, J.J., et al., Functional properties of human muscle fibers after short-term resistance exercise training. Am J Physiol Regul Integr Comp Physiol, 2002. 283(2): p. R408-16.
25. Bodine, S.C., et al., Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol., 2001. 3(11): p. 1014 - 9.
26. Jung, S.H., et al., Insulin-mimetic and insulin-sensitizing activities of a pentacyclic triterpenoid insulin receptor activator. The Biochemical journal, 2007. 403(2): p. 243-50. http://www.ncbi.nlm.nih.gov/pubmed/17201692
27. Sakuma, K. and A. Yamaguchi, Novel intriguing strategies attenuating to sarcopenia. J Aging Res, 2012. 2012: p. 251217.
28. Zhang, W., et al., Ursolic acid and its derivative inhibit protein tyrosine phosphatase 1B, enhancing insulin receptor phosphorylation and stimulating glucose uptake. Biochim Biophys Acta, 2006. 1760(10): p. 1505-12.
29. Kenner, K.A., et al., Protein-tyrosine phosphatase 1B is a negative regulator of insulin- and insulin-like growth factor-I-stimulated signaling. J Biol Chem, 1996. 271(33): p. 19810-6.
30. Tipton, K.D. and R.R. Wolfe, Exercise-induced changes in protein metabolism. Acta Physiologica Scandinavica, 1998. 162(3): p. 377-387.
31. Adams, G.R. and F. Haddad, The relationships among IGF-1, DNA content, and protein accumulation during skeletal muscle hypertrophy. J Appl Physiol, 1996. 81(6): p. 2509-16. http://jap.physiology.org/content/81/6/2509.long
32. Ivy, J.L., The insulin-like effect of muscle contraction. Exerc Sport Sci Rev, 1987. 15: p. 29-51.
33. Kunkel, S.D., et al., Ursolic acid increases skeletal muscle and brown fat and decreases diet-induced obesity, glucose intolerance and fatty liver disease. PloS one, 2012. 7(6): p. e39332. http://www.ncbi.nlm.nih.gov/pubmed/22745735
34. Liobikas, J., et al., Uncoupling and antioxidant effects of ursolic acid in isolated rat heart mitochondria. Journal of natural products, 2011. 74(7): p. 1640-4. http://www.ncbi.nlm.nih.gov/pubmed/21648406
35. He, Y., et al., Ursolic acid inhibits adipogenesis in 3T3-L1 adipocytes through LKB1/AMPK pathway. PLoS One, 2013. 8(7): p. e70135.
36. Saito, M. and T. Yoneshiro, Capsinoids and related food ingredients activating brown fat thermogenesis and reducing body fat in humans. Current opinion in lipidology, 2013. 24(1): p. 71-7. http://www.ncbi.nlm.nih.gov/pubmed/23298960
37. Stohs, S.J. and D. Bagchi, Oxidative mechanisms in the toxicity of metal ions. Free Radical Biology and Medicine, 1995. 18(2): p. 321-336.
38. Liu, J., et al., The effects of 10 triterpenoid compounds on experimental liver injury in mice. Fundam Appl Toxicol, 1994. 22(1): p. 34-40.
39. Li, L., et al., Ursolic acid promotes the neuroprotection by activating Nrf2 pathway after cerebral ischemia in mice. Brain Res, 2013. 1497: p. 32-9.
40. Wasserman, W.W. and W.E. Fahl, Functional antioxidant responsiveelements. Proceedings of the National Academy of Sciences, 1997. 94(10): p. 5361-5366. http://www.pnas.org/content/94/10/5361.abstract
41. Somova, L.O., et al., Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension. Phytomedicine, 2003. 10(2-3): p. 115-21.
42. Shanmugam, M.K., et al., Ursolic acid in cancer prevention and treatment: molecular targets, pharmacokinetics and clinical studies. Biochem Pharmacol, 2013. 85(11): p. 1579-87.
43. Liu, J., Oleanolic acid and ursolic acid: research perspectives. J Ethnopharmacol, 2005. 100(1-2): p. 92-4.
44. Vasconcelos, T., et al., Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug discovery today, 2007. 12(23): p. 1068-1075.
45. Qiang, Z., et al., Permeability of rosmarinic acid in Prunella vulgaris and ursolic acid in Salvia officinalis extracts across Caco-2 cell monolayers. J Ethnopharmacol, 2011. 137(3): p. 1107-12.
46. Liao, Q., et al., LC-MS determination and pharmacokinetic studies of ursolic acid in rat plasma after administration of the traditional chinese medicinal preparation Lu-Ying extract. Yakugaku Zasshi, 2005. 125(6): p. 509-15.
47. Xia, Y., et al., Quantitation of ursolic acid in human plasma by ultra performance liquid chromatography tandem mass spectrometry and its pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci, 2011. 879(2): p. 219-24.
48. Zhou, X.J., et al., Preparation and body distribution of freeze-dried powder of ursolic acid phospholipid nanoparticles. Drug Dev Ind Pharm, 2009. 35(3): p. 305-10.
49. Frank, K. Ursolic acid.  2104  [Accessed 3.12.14]; Available from: http://examine.com/supplements/Ursolic+Acid/.
50. Wang, X.H., et al., Evaluation of toxicity and single-dose pharmacokinetics of intravenous ursolic acid liposomes in healthy adult volunteers and patients with advanced solid tumors. Expert Opin Drug Metab Toxicol, 2013. 9(2): p. 117-25.
51.  Zhu, Z., et al., A phase I pharmacokinetic study of ursolic acid nanoliposomes in healthy volunteers and patients with advanced solid tumors. Int J Nanomedicine, 2013. 8: p. 129-36.
52. Meyer, B.N., et al., Brine shrimp: a convenient general bioassay for active plant constituents. 1982.
53. Du Bois, D. and E.F. Du Bois, A formula to estimate the approximate surface area if height and weight be known. 1916. Nutrition, 1989. 5(5): p. 303-11; discussion 312-3.
54. Tannock, L.R., Ursolic acid effect on atherosclerosis: apples and apples, or apples and oranges? Atherosclerosis, 2011. 219(2): p. 397-8.
55.  Messner, B., et al., Ursolic acid causes DNA-damage, p53-mediated, mitochondria- and caspase-dependent human endothelial cell apoptosis, and accelerates atherosclerotic plaque formation in vivo. Atherosclerosis, 2011. 219(2): p. 402-8.
56. Ullevig, S.L., et al., Ursolic acid protects diabetic mice against monocyte dysfunction and accelerated atherosclerosis. Atherosclerosis, 2011. 219(2): p. 409-16.
57. Wang, Z.H., et al., Anti-glycative effects of oleanolic acid and ursolic acid in kidney of diabetic mice. Eur J Pharmacol, 2010. 628(1-3): p. 255-60.
58. Akbarsha, M.A., et al., Ursolic acid generates symplasts in rat spermatogenic clones. Phytotherapy Research, 1998. 12(1): p. 32-36. http://dx.doi.org/10.1002/(SICI)1099-1573(19980201)12:1<32::AID-PTR185>3.0.CO;2-4
59. Jang, S.M., et al., Inhibitory effects of ursolic acid on hepatic polyol pathway and glucose production in streptozotocin-induced diabetic mice. Metabolism, 2010. 59(4): p. 512-9.
60. Gupta, S.C., et al., Curcumin, a component of turmeric: From farm to pharmacy. BioFactors, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23339055
61. ClinicalTrials.gov. U.S. National Institutes of Health Clinical Trials involving curcumin.  2014  [Accessed 2.12.14]; (http://clinicaltrials.gov/ct2/results?term=curcumin.) Available from: http://clinicaltrials.gov/ct2/results?term=curcumin.
62. ClinicalTrials.gov. U.S. National Institutes of Health Clinical Trials involving ursolic acid.  2014  [Accessed 2.12.14]; (http://clinicaltrials.gov/ct2/results?term=ursolic.) Available from: http://clinicaltrials.gov/ct2/results?term=curcumin.

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