Are There Benefits to Carnosine? The Research Reviewed

Carnosine is a small dipeptide molecule that occurs naturally in the bodies of a wide variety of animals, plays important roles in energy metabolism, anti-oxidation, gene expression, protein integrity and phosphorylation, among others, but scientific research, up to this day, hasn’t come up with an explanation about what, exactly is its biological function.

(8)

Let’s elaborate on this, because it is important: when we talk about a xenobiotic – a molecule that is produced by an organism different than the one consuming it or is even synthesized in a lab – and we discuss its biological activity, we are assuming this molecule, that doesn’t belong in the organism, may be either beneficial, neutral or detrimental to the function of the organism.

However, when it is a naturally occurring molecule, meaning that the body makes its own supply of that (in part or all of it), it makes sense to talk about a “function” for that molecule.

Examples: adenosine tri-phosphate (ATP) is most organisms’ chief “energy currency”, storing energy, which can be obtained by the breakdown of the phosphate bond. There are several well described pathways for the production of ATP.

Citric acid is an intermediary in the Krebs oxidative phosphorylation cycle that occurs in all oxidative organisms and generates ATP, precursors for other molecules, such as amino acids, and NADH. Creatine is an intermediary for the recycling of ATP, especially in muscle and brain tissue, and certain forms of muscle activity rely on phosphocreatine to take place.

There is a reason for the molecule to be there, and that reason is a role in certain known reactions or functions in the body. The body simply cannot function without that molecule.

Carnosine doesn’t fall into that class of molecules, neither it is a xenobiotic. It has many identified biological activities, among which:

  • Delay on onset of senescence (the natural loss of biological function) in cultured cells (28)
  • Rejuvenation of already senescent cultured cells (28)
  • Inhibition of the growth of cultured cancer cells (11)
  • Intracellular signaling regulation (11)
  • Regulation of gene expression (23, 11)
  • Metal ion chelation (35)
  • Promoting decrease in glycolytic energy systems in cells (20, 32).

We know for sure that carnosine does all these amazing things. But is this the reason it is there? In other words: did it evolve for that purpose (“pluripotent molecule”) and, if taken away, does it cause the body to die or become ill? Is there a carnosine metabolic pathway that affects other bodily functions? There are no answers for these questions. That is why it is frequently referred to as the “enigmatic” or “intriguing” molecule.

It occurs naturally in the bodies of fish, birds and mammals

We also have evidence that the ingestion of carnosine as a supplement can have beneficial effects (detailed below), such as:

  • Antioxidant activity in vivo (12)
  • Anti-aging (14, McFarland & Holliday 1994)
  • Neuroprotection (35)
  • Muscle mass gain, muscle strength gain, muscle endurance gain, exercise recovery (see item below)

Among many others, and the list grows fast.

Because the absorption of carnosine involves the breakdown of the molecule and, therefore, the loss of its potential benefit (only about 40% of ingested carnosine is absorbed), as soon as beta alanine was discovered as a carnosine precursor that could increase the latter’s levels much more effectively than the final compound itself when ingested, most of the attention in the supplement industry shifted to beta alanine.

How Much Research Is There?

The state of the art in carnosine research is paradoxical: there is a small, but constantly growing interest in carnosine.  The number of published peer reviewed articles on carnosine doesn’t comprise even 15% of the number of articles on beta alanine, but both keep growing. Apparently, given recent interest on topics other than sports performance, carnosine has attracted increasing interest, while beta alanine seems to have reached a plateau and slight decrease in publication.

Research on carnosine is not recent at all: it was discovered 117 years ago (11, 13), but, to this, day, despite the increasing biological activities it has been shown to have, its precise physiological function remains unknown.

Pubmed searches on carnosine render 2226 results, with only 1079 with the search term in the title. Most of the publication about biological activity in humans, particularly its interest in sports performance, is actually a result of beta alanine supplementation research.

The inverse is also true: much of the research on beta alanine (which renders 16874 results on Pubmed, with 1124 as title search term) is related to its effect in increasing the levels of carnosine. Most recent research on beta alanine concerns its effect on muscle fatigue and recovery as a result of increased carnosine levels.

Most of the recent research on both (carnosine and beta alanine) ends up in reasonable journals. By reasonable I mean peer reviewed journals with a h-index of at least 120.

Examples:

Very prestigious journals

Nature – 1011

Journal of Cell Biology – 336

Reasonably prestigious journals (where research on carnosine appears)

Journal of the Science of Food and Agriculture – 109

Biochimica et Biophysica Acta – Molecular Cell Research – 143

Diabetes – 286

Journals with lower reputation

Journal of Holistic Nursing – 35

Indian Journal of Medical Research – 68

The trend for the future is probably more research into carnosine’s biological activity other than muscle health and recovery, but there is no indication that a consensus or even a more solid hypothesis concerning its function is to come any time soon.

Does Carnosine Help Muscle Gain?

As mentioned before, since carnosine itself is degraded in the digestive process, making only 40% of it bio-available, and since beta alanine supplementation has been shown to effectively increase carnosine levels, most of the research about muscle gain involves beta alanine.

There is one study with carnosine itself, though (7), basically suggesting that its most important activity in muscle gain was decreasing fatigue through an ion buffering effect.

Today there is evidence of more possible mechanisms by which carnosine improves muscle contractile function and recovery, but most authors point out that more research is needed to elucidate the well documented fact that supplementation leads to better recovery, muscle gain, strength gain and endurance gain (25, 31). An “improved exercise homeostasis and excitation-contraction coupling” is cited (Bancquaert et al 2015, 18).

For unknown reasons, carnosine (and beta alanine) seems to be a more effective ergogenic (performance enhancing agent) for trained individuals, versus untrained. In other words, it helps athletes more than it helps non-athletes in terms of performance (9).

The same is true for muscle gain. For example, in the study by Kern and collaborators (25) with 15 college football players and 22 college wrestlers, with beta alanine supplementation for 8 weeks, the supplemented wrestlers gained 1.1lbs average lean body mass (while the placebo group lost lean mass by 0.98lbs) and the supplemented football players gained 2.1lbs lean mass (compared to a 1.1.lbs gain for the placebo group).

Bottom line: if you are interested in muscle gain, is carnosine a good choice of supplement? No, but if, and only if, you are a trained individual or athlete involved in regular strength training, beta alanine, its precursor, will help you gain muscle most probably as a “side effect” of strength gain. The results for this effect were published in one of the most reputable journals about strength training, the Journal of Strength and Conditioning Research.

Does Carnosine Help Diabetes and cardiovascular disease?

And here is when the story starts to get interesting: there is a growing body of research associating carnosine levels to a whole range of degenerative and chronic disorders. Considering that diabetes and cardiovascular diseases comprise some of the most important morbidities in urban areas and the world, we have a case.

The key to understanding all that follows may be one piece of the aging puzzle. As organisms mature, there is a shift, in energy metabolism, from more glycolytic (based on glycolysis) to more oxidative forms of generating ATP, which takes place in mitochondria. However, aging also involves damaged mitochondria.

In fact, mitochondrial dysfunction is common to many of the “aging diseases” (20). Carnosine levels increase as organisms mature and when added to cell cultures, it has been shown to decrease glycolysis and enhance oxidative processes.

Carnosine doesn’t prevent or interfere with diabetes itself. However, one of the reasons diabetes kills people is because the high glycemic levels and a shift towards a glycolytic metabolism increases the levels of toxic compounds, methylglyoxal (a product of glycolysis) being one of the most relevant. It is also related to increases in formaldehyde levels (19). Methylglyoxal is considered one of the main sources of age-related proteotoxicity.

(22)

One of the actions of carnosine in the body is scavenging methylglyoxal. Apparently, many of the beneficial effects of carnosine are related to its general scavenging activity (not unlike glutathione) and also chelating action (the ability to bind to certain metal ions and make them unavailable).

Studies have shown that carnosine administration stabilizes both glucose and fasting insulin levels on overweight humans (27). Another study has shown it to restore glomerular ultrastructure on diabetic nephropathy. It has also shown to improve glucose metabolism and albuminuria (protein in the urine) (1).

These are no longer only cell culture or animal model studies, but actual documented beneficial results in humans. It is safe to say that carnosine administration is a promising treatment research.

Does Carnosine Have “Anti Aging” Effects?

With all that was discussed in the previous item, it could (21, 22). But does it? There are several lines of evidence, from cultured cell senescence to animal models, including convulsion and other neurodegenerative disorders, that suggest a positive response.

It could even be a potential treatment – at least adjuvant – to Alzheimer’s disease and dementia. Some of the bold arguments made, especially concerning the regulation of gene expression and telomerase, make one think it could actually turn back the biological clock.

There is still not enough evidence to positively affirm it does, though.

Does Carnosine Help ADHD, Depression and other mental or cognitive disorders?

The answer here is that it could, given all the evidence concerning “protection from neurodegenerative diseases and in management of cognitive deficits, depression and intellectual disabilities” (5). Up to now, though, there hasn’t been one published study specifically showing carnosine administration’s results on ADHD, depression or other cognitive or mood disorders.

Does Carnosine fight cancer?

The number of studies suggesting it does is large and increasing. It is obvious that the scientific community is excited with the potential of carnosine in the war against cancer. There is evidence relating the presence of carnosine to decreased growth on most major cancer cells.

However, all these studies are in vitro, meaning on cell cultures. There is also evidence correlating low carnosine levels or high carnosidase activity in vivo and poor cancer prognosis. All these results point in the same direction: carnosine is a strong candidate in the toolbox of cancer treatments. But it is still just that: a strong candidate (17, 30, 24, 29, 3).

Does Carnosine Help Weight Loss?

It is important to understand how this question is approached. Increased exercise capacity, specifically increased strength output and endurance, combined with increased exercise frequency, will inevitably affect body composition, resulting in a higher lean-to-fat mass ratio. The studies that show precisely this outcome with beta-alanine supplementation, with concomitant measurement of carnosine level increases, might be showing the indirect result of beta alanine/carnosine’s ergogenic effect.

That means we don’t know if any of these molecules alone will have any effect on body composition in general or weight loss in particular. We do know that, as an ergogenic aid, it will improve performance (the more trained the individual, the more it will help); with improved performance, calorie intake control and frequent exercise, there will be weight loss.

One study, however, with inactive elderly subjects, measured an increased muscle carnosine content and increased physical capacity after 12 weeks of beta-alanine supplementation.

The experimental group presented a slight increase in lean mass (LBM (kg) of 50.1 ± 9.7 versus 47.1 ± 10.1 in the control group) and body fat (body fat(%) of 33.4 ± 5.2 versus 34.8 ± 8.2 in the control group). However, supplementation alone improved their ventilatory anaerobic threshold (VAT) and VO2 peak (16). Other studies showed no effect (26).

At this point of our understanding of carnosine and its effects, nothing points in the direction of it being helpful in weight loss, unless combined with regular exercise and diet.

Does carnosine help autism?

There is one single study about the effects of carnosine on autistic children (15). It deserves mention because it was performed with sound methodology, with human subjects and published in a respected peer reviewed journal. The double blind study included 31 children in the autistic spectrum.

The experimental group received 800 mg L-carnosine daily for 8 weeks. These children showed statistically significant improvements on the Gilliam Autism Rating Scale (total score and the Behavior, Socialization, and Communication subscales) and the Receptive One-Word Picture Vocabulary test (all P < .05). Other improvements were also noted as compared to the control group, where no significant changes were observed.

Again: the mechanism of action is unknown, but these were the results. Given how positive they were, why there were no other studies involving autism and carnosine in the past 15 years is anybody’s guess.

Does Carnosine Help Cataracts?

I left this item last because of the knowledge-Pandora effect: after all the evils and suffering of the “I don’t know”, “it is unclear”, “it is unknown”, finally we do know and we know it works! In a study published in 2009 including over 50,500 older patients, N-acetylcarnosine topical eyedrops showed to be efficient in preventing and treating visual impairment due to senile cataracts, primary open-angle glaucoma, age-related macular degeneration, diabetic retinopathy, and aging (6, 4).

Observe that the two cited articles are from the same group, a patent holding company for the developed carnosine eye-drops.

There are, however, many other studies using animal models that corroborate the proposed mechanisms from the previous articles and show, overall, positive results (34, 33).

Is Carnosine Safe?

You may see mention to carnosinase-related diseases, a set of conditions related to the dysfunctional expression of the enzyme carnosinase. Its mechanisms are unclear. They may be related to forms of mental retardation, paraplegia, seizures and nephrotic disorders (8, 2).

The epidemiological importance of these diseases is unknown. Also, it seems that the problem is the enzyme’s “overexpression” (the breakdown of carnosine), which decreases the levels of carnosine in the body to pathological ones. Is sounds like the concern would be not to have enough carnosine, and not the other way round.

I would say that, considering the present scientific evidence, that ingesting either carnosine or beta alanine is quite safe.

Summary

The takeaway here is that carnosine is generally safe and harmless. There is no evidence of toxicity.

However, a few thoughts: first, if the bio-availability level falls so sharply upon digestion, you might want to consider all the beta alanine options first. Second, if your goal is enhanced athletic performance and you are an athlete, it makes total sense to supplement with beta alanine in order to increase your carnosine levels.

By all means, go ahead. But if you are not an athlete, research has shown that this supplement is less effective for you. Unless your doctor prescribes it because you are recovering from some serious illness, you may consider first getting your training and your diet straight before you think about performance enhancement. Performance enhancement is for people who already have some performance to enhance.

For all the other potential benefits carnosine has shown potential in, some alternatives to circumvent the loss of bioavailability due to the action of carnosidases during digestion are being devised. One of them is using modified forms of carnosine that are resistant to carnosidases. Another is intra-nasal delivery to combat neurodegeneration and brain tumors and using N-acetyl-carnosine containing eye drops for cataracts (22)

So, why not? Honestly, if you or your loved one has Alzheimer’s disease, advanced diabetes, cancer, neurodegenerative disorders or cataract, and if a treatment is harmless, try it. It’s not like you have a lot of time to wait for research to provide you with a solid recommendation. Your disease is incurable, progressive and sometimes it progresses fast. You’ve got nothing to lose.

References

  1. Albrecht, Thomas, et al. “Carnosine Attenuates the Development of both Type 2 Diabetes and Diabetic Nephropathy in BTBR ob/ob Mice.” Scientific Reports 7 (2017).
  2. Alkhalaf, A., et al. “A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus.” Diabetologia 53.12 (2010): 2562-2568.
  3. Arner, Peter, et al. “Circulating carnosine dipeptidase 1 associates with weight loss and poor prognosis in gastrointestinal cancer.” PloS one 10.4 (2015): e0123566.
  4. Babizhayev, Mark A. “Bioactivation antioxidant and transglycating properties of N‐acetylcarnosine autoinduction prodrug of a dipeptide L‐carnosine in mucoadhesive drug delivery eye‐drop formulation: powerful eye health application technique and therapeutic platform.” Drug testing and analysis 4.6 (2012): 468-485.
  5. Babizhayev, Mark A. “Biochemical, biomedical and metabolic aspects of imidazole-containing dipeptides with the inherent complexity to neurodegenerative diseases and various states of mental well-being: a challenging correction and neurotherapeutic pharmaceutical biotechnology for treating cognitive deficits, depression and intellectual disabilities.” Current pharmaceutical biotechnology 15.8 (2014): 738-778.
  6. Babizhayev, Mark A., et al. “N-acetylcarnosine lubricant eyedrops possess all-in-one universal antioxidant protective effects of L-carnosine in aqueous and lipid membrane environments, aldehyde scavenging, and transglycation activities inherent to cataracts: a clinical study of the new vision-saving drug N-acetylcarnosine eyedrop therapy in a database population of over 50,500 patients.” American journal of therapeutics 16.6 (2009): 517-533.
  7. Begum, Gulshanara, Adam Cunliffe, and Michael Leveritt. “Physiological role of carnosine in contracting muscle.” International journal of sport nutrition and exercise metabolism 15.5 (2005): 493-514.
  8. Bellia, Francesco, Graziella Vecchio, and Enrico Rizzarelli. “Carnosinases, their substrates and diseases.” Molecules 19.2 (2014): 2299-2329.
  9. Bex, Tine, et al. “Muscle carnosine loading by beta-alanine supplementation is more pronounced in trained vs. untrained muscles.” Journal of applied physiology (2013).
  10. Blancquaert, Laura, Inge Everaert, and Wim Derave. “Beta-alanine supplementation, muscle carnosine and exercise performance.” Current Opinion in Clinical Nutrition & Metabolic Care 18.1 (2015): 63-70.
  11. Boldyrev, A. A. “Carnosine: new concept for the function of an old molecule.” Biochemistry (Moscow) 77.4 (2012): 313-326.
  12. Boldyrev, A. A., et al. “A comparative study of synthetic carnosine analogs as antioxidants.” Comparative Biochemistry and Physiology Part B: Comparative Biochemistry 94.2 (1989): 237-240.
  13. Boldyrev, Alexander A., Giancarlo Aldini, and Wim Derave. “Physiology and pathophysiology of carnosine.” Physiological reviews 93.4 (2013): 1803-1845.
  14. Boldyrev, Alexander A., Steven Ch Gallant, and Gennady T. Sukhich. “Carnosine, the protective, anti-aging peptide.” Bioscience reports 19.6 (1999): 581-587.
  15. Chez, Michael G., et al. “Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders.” Journal of Child Neurology 17.11 (2002): 833-837.
  16. Del Favero, Serena, et al. “Beta-alanine (Carnosyn™) supplementation in elderly subjects (60–80 years): effects on muscle carnosine content and physical capacity.” Amino acids 43.1 (2012): 49-56.
  17. Ding, Minghui, et al. “Investigations on in vitro anti-carcinogenic potential of l-carnosine in liver cancer cells.” Cytotechnology: 1-5, 2017.
  18. Glenn, Jordan M., et al. “Effects of 28-day beta-alanine supplementation on isokinetic exercise performance and body composition in female masters athletes.” The Journal of Strength & Conditioning Research 30.1 (2016): 200-207.
  19. Hipkiss, Alan R. “Depression, Diabetes and Dementia: Formaldehyde May Be a Common Causal Agent; Could Carnosine, a Pluripotent Peptide, Be Protective?.” Aging and disease 8.2 (2017): 128.
  20. Hipkiss, Alan R. “Energy metabolism, proteotoxic stress and age-related dysfunction–Protection by carnosine.” Molecular aspects of medicine 32.4 (2011): 267-278.
  21. Hipkiss, Alan R. “Would carnosine or a carnivorous diet help suppress aging and associated pathologies?.” Annals of the New York Academy of Sciences1067.1 (2006): 369-374.
  22. Hipkiss, Alan R., et al. “Carnosine: can understanding its actions on energy metabolism and protein homeostasis inform its therapeutic potential?.” Chemistry Central Journal 7.1 (2013): 38.
  23. Ikeda, Daisuke, et al. “Carnosine stimulates vimentin expression in cultured rat fibroblasts.” Cell structure and function 24.2 (2001): 79-87.
  24. Iovine, Barbara, et al. “l-carnosine dipeptide overcomes acquired resistance to 5-fluorouracil in HT29 human colon cancer cells via downregulation of HIF1-alpha and induction of apoptosis.” Biochimie 127 (2016): 196-204.
  25. Kern, Ben D., and Tracey L. Robinson. “Effects of β-alanine supplementation on performance and body composition in collegiate wrestlers and football players.” The Journal of Strength & Conditioning Research 25.7 (2011): 1804-1815.
  26. Kresta, Julie Y., et al. “Effects of 28 days of beta-alanine and creatine supplementation on muscle carnosine, body composition and exercise performance in recreationally active females.” Journal of the International Society of Sports Nutrition 11.1 (2014): 55.
  27. Lombardi, Carlo, and Marco Metra. “Carnosine: Potential aid for diabetes and cardiovascular disease.” Obesity 24.5 (2016): 989-989.
  28. McFarland, Gail A., and Robin Holliday. “Retardation of the senescence of cultured human diploid fibroblasts by carnosine.” Experimental cell research212.2 (1994): 167-175.
  29. Mikuła-Pietrasik, J. U. S. T. Y. N. A., and Krzysztof Książek. “l-Carnosine prevents the pro-cancerogenic activity of senescent peritoneal mesothelium towards ovarian cancer cells.” Anticancer research 36.2 (2016): 665-671.
  30. Ooi, Theng Choon, Kok Meng Chan, and Razinah Sharif. “Antioxidant, Anti-inflammatory, and Genomic Stability Enhancement Effects of Zinc l-carnosine: A Potential Cancer Chemopreventive Agent?.” Nutrition and cancer 69.2 (2017): 201-210.
  31. Outlaw, Jordan J., et al. “Effects of β-Alanine on Body Composition and Performance Measures in Collegiate Women.” The Journal of Strength & Conditioning Research 30.9 (2016): 2627-2637.
  32. Renner, Christof, et al. “Carnosine inhibits ATP production in cells from malignant glioma.” Neurological research 32.1 (2010): 101-105.
  33. Shi, Qiong, and Hong Yan. “Changes of the thiol levels in the corneas of the diabetic rats: effect of carnosine, aspirin and a combination eye drops.” International journal of ophthalmology 3.3 (2010): 211.
  34. Tianyang, Zhou, et al. “Ocular pharmacokinetics of carnosine 5% eye drops following topical application in rabbit.” Journal of Ocular Pharmacology and Therapeutics 27.1 (2011): 93-97.
  35. Trombley, P. Q., M. S. Horning, and L. J. Blakemore. “Interactions between carnosine and zinc and copper: implications for neuromodulation and neuroprotection.” BIOCHEMISTRY C/C OF BIOKHIMIIA 65.7 (2000): 807-816.
Summary
Are There Benefits to Carnosine? The Research Reviewed
Article Name
Are There Benefits to Carnosine? The Research Reviewed
Author
Healthy But Smart

Leave a Reply

Your email address will not be published. Required fields are marked *