Carnosine is a dipeptide (a combination of two amino acids) found in human tissues that has a wide range of health benefits. It is primarily known as an anti-aging nutrient and is found naturally in small amounts in animal meats. Pre-clinical studies have found impressive results in carnosine’s ability to reverse cellular aging. It is a powerful antioxidant and inhibits protein glycation; therefore addressing two of the most important drivers behind the aging process. Carnosine protects cells and helps maintain healthy cellular function by getting rid of damaged proteins that make cells old and dysfunctional. Studies in human subjects have also found carnosine to enhance exercise performance and tissue repair due to its effects on cellular rejuvenation and protein maintenance. A unique mechanism of carnosine is that it regulates acidity and alkalinity inside the cell, optimizing the cellular environment.
Brain health is another promising application for carnosine. A study on autistic children found that autistic behaviour improved with carnosine supplementation. There is exciting new research being conducted using carnosine in areas such as brain health, stroke recovery, anti-aging, cataract treatment, immune stimulation, athletic performance and many others. Anti-aging enthusiasts, vegetarians, and athletes are those who will benefit most from carnosine. AOR’s Carnosine-500 is one of the only stand-alone formulations available on the market that contain an evidence-based dose of this powerful antioxidant.
Carnosine is found in high concentrations in brain and muscle tissues, and it is a potent inhibitor of damage to proteins from sugar (glycation) and scavenger of free radicals. Carnosine has been shown to reverse cellular senescence in culture.
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Carnosine is a simple dipeptide (that is, two amino acids joined together – in this case, beta-alanine and histidine). But don’t let that simplicity fool you: simply put, Carnosine is the most exciting anti-aging nutrient ever discovered. Carnosine is made by many cells in your body – and especially in muscle, heart, and brain cells. Longer-lived animals tend to have more Carnosine in their cells than do shorter-lived species, and preliminary research suggests that levels of Carnosine decline with aging (by 63% between the ages of 10 and 70 in humans).
Carnosine plays a central part in muscle contraction and in preventing fatigue, fending off lactic acidosis and allowing isolated muscle cells that have been pushed beyond their workload limits to contract again. In nerves, its concentration is so targeted, and its release so regular, that it was once thought to be a neurotransmitter; while it now looks as if that’s unlikely, Carnosine does play an important role in modulating brain cell function, simultaneously making neurons more sensitive to certain signals and protecting neurons from toxicity from overstimulation. In heart cells, Carnosine appears to be a central player in regulating the heartbeat through its role in regulating calcium ions. But none of that explains its ability to make old cells young.
A Remarkable Rejuvenation
The recent interest in Carnosine began with the work of doctors Gail McFarland and Robin Holliday at Australia’s Commonwealth Scientific and Industrial Research Organization (CSRIO). The experiment was simple. First, raise lung and skin cells in one of two standard cell culture mediums. Then keep half of the cells in the original medium, but transfer the other half into the same medium supplemented with Carnosine.
The Carnosine-supplemented cells were able to keep reproducing longer, achieving anywhere from one to seven more population-doublings. And they lived longer: in fact, the longest-lived cells receiving the Carnosine bath survived up to two-thirds longer than the cells in the standard mediums. But most excitingly, adding Carnosine to the cell medium made the cells younger. McFarland and Holliday described the results as “Striking effects on the cell morphology [shape and structure],” saying that, “Carnosine preserved a nonsenescent [youthful] morphology.” The cells raised in the usual medium got old, blotchy, and irregular, and were broken apart into scattered islands of twisted debris. Yet clearly, the cells raised in Carnosine still had the same appearance as when they were young: the colonies were flat and maintained their youthful whirling patterns; they were still smooth, regular, and even. And, remarkably, cells bathed in Carnosine stayed youthful almost until the very end of their lives.
McFarland and Holliday later showed that they could take cells from the Carnosine medium, move them into the standard culture, and see them grow old – but then move them back into the Carnosine bath, and have them spring back into youth again. “Switching cells between media with and without carnosine also switches their phenotype [visibly observable properties] from senescent [aged] to juvenile, and the reverse.” They “propose that Carnosine is an important component of cellular maintenance mechanisms,” and “favor the view that it may have a very important role in controlling cellular homeostasis” – that is, in keeping cells in the tightly-regulated condition that optimizes their function.
More Resistant to Features of Aging
In a recent series of experiments, one group of SAM mice had Carnosine added to their drinking water (the human equivalent of about one gram each day, adjusting for metabolic considerations), while another received no supplement. Animals receiving Carnosine lived 20% longer, on average, than their non-Carnosine littermates – and more excitingly, the maximum survivorship was 6% longer, too.
Animals who got the Carnosine supplement looked and acted younger throughout their lives when held up against animals not fed Carnosine. Examined at midlife, the Carnosine-fed animals showed over 40% less loss of hair fullness and color, and suffered 61% fewer skin ulcers, than the control animals. The animals that got the supplemental Carnosine also showed significantly less of the sores around the eyes that developed in animals not given Carnosine, and 13% less senile spinal curvature.
Perhaps most excitingly, Carnosine-fed animals kept their mental faculties sharper, longer than their unsupplemented littermates. Animals fed Carnosine performed 29% better on tests of passive avoidance and nearly six and a half times better on tests of “reactivity” (a measure of youthful exploratory curiosity). In short, the scientists concluded Carnosine supplements made them “more resistant to features of aging.”
When the researchers looked at the brains of the SAM animals, they discovered some of the biochemical changes that underlay these results. First, the scientists examined the binding of the brain messenger glutamate to the NMDA (N-methyl-D-aspartate) receptor, a process that is crucially involved in long-term memory formation. The scientists found that Carnosine therapy increased the binding of glutamate to this receptor.
A Promising Agent in the Therapy of Brain Stroke
In animal studies, Carnosine has been shown to reduce mortality, and to prevent much of the brain damage and loss of mental function, after a simulated stroke. Animals receiving Carnosine before blocking the blood vessels that feed their brains are less than half as likely to die, and the memory function and the activity of key brain enzymes is better preserved in Carnosine-supplemented survivors than in survivors who did not receive the supplement. In fact, rodent “stroke” survivors who get Carnosine perform as well on many memory tests as they did before the “stroke!”
Pluripotent Protective Effects
But if we try to pin down just how it is that Carnosine can exert its other wide-ranging anti-aging effects, we’ll have a hard time choosing among all the options. The protective properties of Carnosine have been described as “pluripotent” – that is, “many-powered.” Carnosine is a highly versatile antioxidant, and also has indirect antioxidant powers through the chelation of pro-oxidant metals and the prevention of the destruction of the antioxidant enzyme superoxide dismutase (SOD) normally seen in cells exposed to hydrogen peroxide.
The power of these combined antioxidant actions was shown in experiments in which cells were exposed to toxic levels of oxygen. Carnosine treatment preserved healthy cell structure and reduced damage to the cells’ DNA even though no other tested antioxidant could do so: not vitamin C, not vitamin E, not N-acetylcysteine (NAC), nor the potent synthetic antioxidant ethoxyquin.
Carnosine protects against the formation of Advanced Glycation Endproducts (AGEs), warped cellular proteins that have been damaged by sugar. Preliminary studies in animals fed a high-fructose diet suggest that Carnosine’s AGE-fighting ability helps preserve the flexibility of blood vessels, preventing some of the increase in blood pressure that is otherwise suffered under such circumstances. As well, Carnosine also maintains more youthful levels of proteolysis (the ability to tear down old, defective cellular proteins) in cells, – a process which slows down in old cells, interfering with cellular function. And Carnosine has been shown to react with certain abnormal proteins in a way which some research suggests may make them more readily broken up and disposed of by the cell’s “garbage disposal” systems.
Carnosine changes gene expression in cells exposed to it, including increasing the expression of vimentin, a protein involved in maintaining the integrity and complex internal structure of the cell. Carnosine enhances various aspects of immunity, and protects cells against damage from a variety of toxins produced in the body as a part of normal metabolism. One clinical study found that Carnosine supplementation benefited children with Autistic Spectrum Disorder. The list of protective functions goes on and on.
Carnosinase and Effective Dosing
The body has a family of enzymes called carnosinases, which break Carnosine down into its component amino acids. Researchers believe that this may be a way of storing histidine in a form that does not trigger inflammation, allowing it to be released as needed. Because of these enzymes, Carnosine doses below a certain threshold are rapidly metabolized away by the body. Experiments clearly show that feeding laboratory animals Carnosine in dosages equivalent to a human taking over four hundred milligrams of Carnosine a day have no effect on Carnosine levels in muscles, heart, or liver, while higher dosages increase muscle Carnosine levels and (as we have seen) have clear therapeutic benefits to the brain and body. While the exact cutoff point is uncertain, and indeed may vary from one individual to another, benefits clearly and consistently emerge at dosages equivalent to 945 milligrams per day and up for a person of average weight (70 kilograms).
Jump In – The Water’s Fine
We still haven’t explored many possible roles of Carnosine in human health, including preliminary studies suggesting that forms of Carnosine may prove to be a useful treatment for wound healing, and is a remarkable heart-protective nutrient which increases the heart’s ability to contract and helps blood vessels to relax. As more and more research is done, the promise of this remarkable nutrient begins to shine more and more brightly.
Exercise, Fatigue and Muscle Function
It has been demonstrated in a clinical study that Beta-alanine supplementation affects muscle carnosine levels and alleviates fatigue during repeated isokinetic contraction bouts in trained sprinters (W. Derave et all, 2007). Carnosine (beta-alanyl-L-histidine) is present in high concentrations in human skeletal muscle. The intake of beta-alanine known as the rate-limiting precursor of carnosine can elevate the muscle carnosine content. Using proton magnetic resonance spectroscopy (proton MRS) it was investigated whether oral supplementation with beta-alanine during 4 weeks would raise the level of carnosine content in the calf muscle and therefore affect exercise performance in 400m sprint-trained competitive athletes. Fifteen male athletes took part in a placebo-controlled, double-blind study and were supplemented orally for 4 weeks with either 4.8g/day beta-alanine or placebo. Muscle carnosine was increased as a result of the oral β-alanine supplementation in sprint-trained athletes. Carnosine increase attenuated fatigue in repeated rounds of exhaustive dynamic contractions, however the carnosine in the muscle did not improve the isometric endurance or race time of the subjects.
In another study the influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and the cycling capacity of thirteen male subjects that were supplemented with beta-alanine (CarnoSyntrade mark) for 4 wks, 8 of these for 10 wks was investigated. Muscle carnosine synthesis is limited by beta-alanine availability. Biopsies of the vastus lateralis were obtained from 6 of the 8 at 0, 4 and 10 wks. Participants then undertook a cycle capacity test to determine total work done (TWD) at 110% (CCT(110%)) of their maximum power (W(max)). Twelve subjects received a placebo. Eleven of the subjects finished the CCT(110%) at 0 and 4 wks, and 8, 10 wks. Then muscle biopsies were obtained from 5 of the 8 and one additional subject. It was found that muscle carnosine was significantly increased by 58.8% and 80.1% after 4 and 10 wks of beta-alanine supplementation. Carnosine, initially 1.71 times higher in type IIa fibres, increased equally in both type I and IIa fibres but not in the control subjects. After 4 wks beta-alanine supplementation, it resulted in a significant increase in TWD ( 13.0%); with a further 3.2% increase at 10 wks. TWD was unchanged at 4 and 10 wks in the control subjects. The increase in TWD with supplementation followed the increase in muscle carnosine.
In a double-blind, placebo-controlled study of L-Carnosine supplementation in children with autistic spectrum disorders, it was discovered that L-Carnosine can enhance frontal lobe function or be neuroprotective. It can also correlate with y-aminobutyric acid (GABA)-homocarnosine interaction, with possible anticonvulsive effects. 31 children with autistic spectrum disorders took part in an 8-week, double-blinded study to determine if 800 mg L-carnosine daily would result in observable Gilliam Autism Rating Scale, the Expressive and Receptive One-Word Picture Vocabulary tests, and Clinical Global Impressions of Change. Children on placebo did not show statistically significant changes. After 8 weeks on L-carnosine, children showed statistically significant improvements on the Gilliam Autism Rating Scale and the Receptive One-Word Picture Vocabulary test (all P < .05). Improved trends were noted on other outcome measures. Although the mechanism of action of L-carnosine is not well understood, it may enhance neurologic function, perhaps in the entorhinal or temporal cortex.
Carnosine supplements are most commonly taken for the purposes of protecting the body from the effects of free radical damage, reducing age related cellular dysfunction and keeping muscle tissue healthy.
Carnosine has demonstrated its effects as a potent cellular protector and is available in an effective dosage in AOR’s Carnosine-500.
Chez MG, Buchanan CP, Aimonovitch MC, Becker M, Schaefer K, Black C and Komen J. Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorder. J Child Neurol 2002;17;833-837.
Derave W, Ozdemir MS, Harris R, Pottier A, Reyngoudt H, Koppo K, Wise JA, Achten E. Beta-alanine supplementation augments muscle carnosine content and attenuates fatigue during repeated isokinetic contraction bouts in trained sprinters. J Appl Physiol. 2007 Aug 9
Hill CA, Harris RC, Kim HJ, Harris BD, Sale C, Boobis LH, Kim CK, Wise JA. Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity. Amino Acids. 2007 Feb;32(2):225-33.
Hipkiss AR, Brownson C, Carrier MJ. “Carnosine, the anti-ageing, anti-oxidant dipeptide, may react with protein carbonyl groups.” Mech Ageing Dev. 2001 Sep 15; 122(13): 1431-45.
Holliday R, McFarland GA. “Inhibition of the growth of transformed and neoplastic cells by the dipeptide carnosine.” Br J Cancer. 1996 Apr; 73(8): 966-71.
McFarland GA, Holliday R. “Retardation of the senescence of cultured human diploid fibroblasts by carnosine.” Exp Cell Res. 1994 Jun; 212(2): 167-75.
McFarland GA, Holliday R. “Further evidence for the rejuvenating effects of the dipeptide L-carnosine on cultured human diploid fibroblasts.” Exp Gerontol. 1999 Jan; 34(1): 35-45.
Nagai K, Suda T. “Antineoplastic effects of carnosine and beta-alanine–physiological considerations of its antineoplastic effects.” Nippon Seirigaku Zasshi. 1986; 48(11): 741-7.
Stvolinsky S, Kukley M, Dobrota D, Mezesova V, Boldyrev A. “Carnosine protects rats under global ischemia.” Brain Res Bull. 2000 Nov 1; 53(4): 445-8.
Yuneva MO, Bulygina ER, Gallant SC, Kramarenko GG, Stvolinsky SL, Semyonova ML, Boldyrev AA. “Effect of carnosine on age-induced changes in senescence-accelerated mice.” J Anti-Aging Med. 1999 Winter; 2(4): 337-42.
Beta-alanine supplementation augments muscle carnosine content and attenuates fatigue during repeated isokinetic contraction bouts in trained sprinters.
J Appl Physiol. 2007 Aug 9;
Derave W, Ozdemir MS, Harris R, Pottier A, Reyngoudt H, Koppo K, Wise JA, Achten E.
Carnosine (beta-alanyl-L-histidine) is present in high concentrations in human skeletal muscle. The ingestion of beta-alanine, the rate-limiting precursor of carnosine, has been shown to elevate the muscle carnosine content. We aimed to investigate, using proton magnetic resonance spectroscopy (proton MRS), whether oral supplementation with beta-alanine during 4 weeks would elevate the calf muscle carnosine content and affect exercise performance in 400m sprint-trained competitive athletes. Fifteen male athletes participated in a placebo-controlled, double-blind study and were supplemented orally for 4 weeks with either 4.8g/day beta-alanine or placebo. Muscle carnosine concentration was quantified in soleus and gastrocnemius by proton MRS. Performance was evaluated by isokinetic testing during 5 bouts of 30 maximal voluntary knee extensions, by endurance during isometric contraction at 45% MVC and by the indoor 400m running time. beta-Alanine supplementation significantly increased the carnosine content in both the soleus ( 47%) and gastrocnemius ( 37%). In placebo, carnosine remained stable in soleus while a small and significant increase of 16% occurred in gastrocnemius. Dynamic knee extension torque during the fourth and fifth bout was significantly improved with beta-alanine but not with placebo. Isometric endurance and 400m race time were not affected by treatment. In conclusion, 1) proton MRS can be used to non-invasively quantify human muscle carnosine content; 2) muscle carnosine is increased by oral β-alanine supplementation in sprint-trained athletes; 3) carnosine loading slightly but significantly attenuated fatigue in repeated bouts of exhaustive dynamic contractions; 4) the increase in muscle carnosine did not improve isometric endurance or 400m race time. Key words: Buffer capacity, ergogenic supplements, nuclear magnetic resonance (NMR), exercise performance, track-and-field.
Neuroprotective effect of carnosine on necrotic cell death in PC12 cells.
Neurosci Lett. 2007 Mar 6;414(2):145-9. Epub 2006 Dec 29.
Shen Y, Fan Y, Dai H, Fu Q, Hu W, Chen Z.
The nervous tissue of many vertebrates, including humans, can synthesize beta-alanyl-L-histidine (carnosine). The biological functions of carnosine are still open to question, although several theories supported by strong experimental data have been proposed. The objective of this study was to examine the effects of carnosine on neurotoxicity in differentiated rat pheochromocytoma (PC12) cells. Neurotoxicity was induced by N-methyl-D-aspartate (NMDA), which caused time- and concentration-dependent cell death as measured by MTT and LDH assays. Pretreatment with carnosine significantly prevented the neurotoxicity in a concentration-dependent manner. The protective effect of carnosine was antagonized by the H1 receptor antagonist pyrilamine, but not by the H2 receptor antagonist cimetidine. In addition, alpha-fluoromethylhistidine, a histidine decarboxylase inhibitor, slightly reversed the protective action of carnosine. These results indicate that carnosine can effectively protect against NMDA-induced necrosis in PC12 cells, and its protection may in part be due to the activation of the postsynaptic histamine H1 receptor. The study suggests that carnosine may be an endogenous protective factor and calls for its further study as a new anti-excitotoxic agent.
Protective effect of orally administered carnosine on bleomycin-induced lung injury.
Am J Physiol Lung Cell Mol Physiol. 2007 Jan 12;
Cuzzocrea S, Genovese T, Failla M, Vecchio G, Fruciano M, Mazzon E, Di Paola R, Muia C, La Rosa C, Crimi N, Rizzarelli E, Vancheri C.
Carnosine is an endogenously synthesized dipeptide composed by beta-alanine and L-histidine. It acts as a free radical scavenger and possesses antioxidant properties. Carnosine reduces pro-inflammatory and pro-fibrotic cytokines such as TGF-beta, IL-1 and TNF-alpha in different experimental settings. In the present study, we investigated the efficacy of carnosine on the animal model of bleomycin-induced lung injury. Mice were subjected to intra-tracheal administration of bleomycin and were assigned to receive carnosine daily by an oral bolus of 150 mg/Kg. One week after fibrosis induction, BAL cell counts and TGF-beta levels, lung histology and immunohistochemical analysis for myeloperoxidase, TGF-beta, inducible nitric oxide synthase (iNOS), nitrotyrosine, and poly-ADP-ribose polymerase (PARP) were performed. Finally, apoptosis was quantified by TUNEL assay. Following bleomycin administration, carnosine treated mice exhibited a reduced degree of lung damage and inflammation when compared to WT mice as shown by the reduction of:(i)loss of body weight, (ii)mortality rate, (iii)lung infiltration by neutrophils (myeloperoxidase activity, BAL total and differential cell counts), (iv)lung edema, (v)histological evidence of lung injury and collagen deposition, (vi)lung myeloperoxidase, TGF-beta, iNOS, nitrotyrosine and PARP immunostaining, (vii)BAL TGF-beta levels and (viii)apoptosis. Our results indicate that orally administered carnosine is able to prevent bleomycin induced lung injury likely through its direct antioxidant properties. Carnosine is already available for human use. It might prove useful as an add-on therapy for the treatment of fibrotic disorders of the lung where oxidative stress plays a role such as idiopathic pulmonary fibrosis, a disease that still represents a major challenge to medical treatment.
Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity.
Amino Acids. 2007 Feb;32(2):225-33.
Hill CA, Harris RC, Kim HJ, Harris BD, Sale C, Boobis LH, Kim CK, Wise JA.
Muscle carnosine synthesis is limited by the availability of beta-alanine. Thirteen male subjects were supplemented with beta-alanine (CarnoSyntrade mark) for 4 wks, 8 of these for 10 wks. A biopsy of the vastus lateralis was obtained from 6 of the 8 at 0, 4 and 10 wks. Subjects undertook a cycle capacity test to determine total work done (TWD) at 110% (CCT(110%)) of their maximum power (W(max)). Twelve matched subjects received a placebo. Eleven of these completed the CCT(110%) at 0 and 4 wks, and 8, 10 wks. Muscle biopsies were obtained from 5 of the 8 and one additional subject. Muscle carnosine was significantly increased by 58.8% and 80.1% after 4 and 10 wks beta-alanine supplementation. Carnosine, initially 1.71 times higher in type IIa fibres, increased equally in both type I and IIa fibres. No increase was seen in control subjects. Taurine was unchanged by 10 wks of supplementation. 4 wks beta-alanine supplementation resulted in a significant increase in TWD ( 13.0%); with a further 3.2% increase at 10 wks. TWD was unchanged at 4 and 10 wks in the control subjects. The increase in TWD with supplementation followed the increase in muscle carnosine.
High level of skeletal muscle carnosine contributes to the latter half of exercise performance during 30-s maximal cycle ergometer sprinting.
Jpn J Physiol. 2002 Apr;52(2):199-205.
Suzuki Y, Ito O, Mukai N, Takahashi H, Takamatsu K.
The histidine-containing dipeptide carnosine (beta-alanyl-L-histidine) has been shown to significantly contribute to the physicochemical buffering in skeletal muscles, which maintains acid-base balance when a large quantity of H( ) is produced in association with lactic acid accumulation during high-intensity exercise. The purpose of the present study was to examine the relations among the skeletal muscle carnosine concentration, fiber-type distribution, and high-intensity exercise performance. The subjects were 11 healthy men. Muscle biopsy samples were taken from the vastus lateralis at rest. The carnosine concentration was determined by the use of an amino acid autoanalyzer. The fiber-type distribution was determined by the staining intensity of myosin adenosinetriphosphatase. The high-intensity exercise performance was assessed by the use of 30-s maximal cycle ergometer sprinting. A significant correlation was demonstrated between the carnosine concentration and the type IIX fiber composition (r=0.646, p < 0.05). The carnosine concentration was significantly correlated with the mean power per body mass (r=0.785, p < 0.01) during the 30-s sprinting. When dividing the sprinting into 6 phases (0-5, 6-10, 11-15, 16-20, 21-25, 26-30 s), significant correlations were observed between the carnosine concentration and the mean power per body mass of the final 2 phases (21-25 s: r=0.694, p < 0.05; 26-30 s: r=0.660, p < 0.05). These results indicated that the carnosine concentration could be an important factor in determining the high-intensity exercise performance.
Double-Blind, Placebo-Controlled Study of L-Carnosine Supplementation in Children With Autistic Spectrum Disorders.
J Child Neurol 2002; 17; 833.
Chez MG, Buchanan CP, Aimonovitch MC, Becker M, Schaefer K, Black C and Komen J.
L-Carnosine, a dipeptide, can enhance frontal lobe function or be neuroprotective. It can also correlate with y-aminobutyric acid (GABA)-homocarnosine interaction, with possible anticonvulsive effects. We investigated 31 children with autistic spectrum disorders in an 8-week, double-blinded study to determine if 800 mg L-carnosine daily would result in observable Gilliam Autism Rating Scale, the Expressive and Receptive One-Word Picture Vocabulary tests, and Clinical Global Impressions of Change. Children on placebo did not show statistically significant changes. After 8 weeks on L-carnosine, 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). Improved trends were noted on other outcome measures. Although the mechanism of action of L-carnosine is not well understood, it may enhance neurologic function, perhaps in the enterorhinal or temporal cortex.
Retardation of the senescence of cultured human diploid fibroblasts by carnosine.
Exp Cell Res 1994 Jun; 212(2): 167-75.
McFarland GA, Holliday R.
We have examined the effects of the naturally occurring dipeptide carnosine (beta-alanyl-L-histidine) on the growth, morphology, and lifespan of cultured human diploid fibroblasts. With human foreskin cells, HFF-1, and fetal lung cells, MRC-5, we have shown that carnosine at high concentrations (20-50 mM) in standard medium retards senescence and rejuvenates senescent cultures. These late-passage cultures preserve a nonsenescent morphology in the presence of carnosine, in comparison to the senescent morphology first described by Hayflick and Moorhead. Transfer of these late-passage cells in medium containing carnosine to unsupplemented normal medium results in the appearance of the senescent phenotype. The serial subculture of cells in the presence of carnosine does not prevent the Hayflick limit to growth, although the lifespan in population doublings as well as chronological age is often increased. This effect is obscured by the normal variability of human fibroblast lifespans, which we have confirmed. Transfer of cells approaching senescence in normal medium to medium supplemented with carnosine rejuvenates the cells but the extension in lifespan is variable. Neither D-carnosine, (beta-alanyl-D-histidine), homocarnosine, anserine, nor beta-alanine had the same effects as carnosine on human fibroblasts. Carnosine is an antioxidant, but it is more likely that it preserves cellular integrity by its effects on protein metabolism.
Further evidence for the rejuvenating effects of the dipeptide L-carnosine on cultured human diploid fibroblasts.
Exp Gerontol 1999 Jan; 34(1): 35-45.
McFarland GA, Holliday R.
We have confirmed and extended previous results on the beneficial effects of L-carnosine on growth, morphology, and longevity of cultured human fibroblasts, strains MRC-5 and HFF-1. We have shown that late-passage HFF-1 cells retain a juvenile appearance in medium containing 50 mM carnosine, and revert to a senescent phenotype when carnosine is removed. Switching cells between medium with and without carnosine also switches their phenotype from senescent to juvenile, and the reverse. The exact calculation of fibroblast lifespans in population doublings (PDs) depends on the proportion of inoculated cells that attach to their substrate and the final yield of cells in each subculture. We have shown that carnosine does not affect cell attachment, but does increase longevity in PDs. However, the plating efficiency of MRC-5 cells seeded at low density is strongly increased in young and senescent cells by carnosine, as shown by the growth of individual colonies. We have also demonstrated that very late-passage MRC-5 cells (with weekly change of medium without subculture) remain attached to their substrate much longer in medium containing carnosine in comparison to control cultures, and also retain a much more normal phenotype. Carnosine is a naturally occurring dipeptide present at high concentration in a range of human tissues. We suggest it has an important role in cellular homeostasis and maintenance.
Carnosine, the anti-ageing, anti-oxidant dipeptide, may react with protein carbonyl groups.
Mech Ageing Dev 2001 Sep 15; 122(13): 1431-45.
Hipkiss AR, Brownson C, Carrier MJ.
Carnosine (beta-alanyl-L-histidine) is a physiological dipeptide which can delay ageing and rejuvenate senescent cultured human fibroblasts. Carnosine\’s anti-oxidant, free radical- and metal ion-scavenging activities cannot adequately explain these effects. Previous studies showed that carnosine reacts with small carbonyl compounds (aldehydes and ketones) and protects macromolecules against their cross-linking actions. Ageing is associated with accumulation of carbonyl groups on proteins. We consider here whether carnosine reacts with protein carbonyl groups. Our evidence indicates that carnosine can react non-enzymically with protein carbonyl groups, a process termed \’carnosinylation\’. We propose that similar reactions could occur in cultured fibroblasts and in vivo. A preliminary experiment suggesting that carnosine is effective in vivo is presented; it suppressed diabetes-associated increase in blood pressure in fructose-fed rats, an observation consistent with carnosine\’s anti-glycating actions. We speculate that: (i) carnosine\’s apparent anti-ageing actions result, partly, from its ability to react with carbonyl groups on glycated/oxidised proteins and other molecules; (ii) this reaction, termed \’carnosinylation,\’ inhibits cross-linking of glycoxidised proteins to normal macromolecules; and (iii) carnosinylation could affect the fate of glycoxidised polypeptides.
Inhibition of the growth of transformed and neoplastic cells by the dipeptide carnosine.
Br J Cancer 1996 Apr; 73(8): 966-71.
Holliday R, McFarland GA.
Human diploid fibroblasts growth normally in medium containing physiological concentrations of the naturally occurring dipeptide carnosine (beta-alanyl-L-histidine). These concentrations are cytotoxic to transformed and neoplastic cells lines in modified Eagle medium (MEM), whereas these cells grow vigorously in Dulbecco’s modified Eagle medium (DMEM) containing carnosine. This difference is due to the presence of 1 mM sodium pyruvate in DMEM. Seven human cell lines and two rodent cell lines were tested and all are strongly inhibited by carnosine in the absence of pyruvate. Experiments with HeLa cells show that anserine is similar to carnosine, but D-carnosine and homocarnosine are without effect. Also, the non-essential amino acids alanine and glutamic acid contribute to the effect of pyruvate in preventing carnosine toxicity, and oxaloacetate and alpha-ketoglutarate can substitute for pyruvate. We have used mixtures of normal MRC-5 fibroblasts and HeLa cells to demonstrate that 20 mM carnosine can selectively eliminate….. This has obvious implications which might be exploited in in vivo and in vitro studies. Carnosine is known to react strongly with aldehyde and keto groups of sugars by Amadori reaction, and we propose that it depletes certain glycolysis intermediates. It is well known that tumour cells are more dependent on glycolysis than normal cells. A reduction of glycolysis intermediates by carnosine may deplete their energy supply, but this effect is totally reversed by pyruvate.
Carnosine protects rats under global ischemia.
Brain Res Bull 2000 Nov 1; 53(4): 445-8.
Stvolinsky S, Kukley M, Dobrota D, Mezesova V, Boldyrev A.
Rat brain subjected to 45-min global ischemia is characterized by decreased activity of K-p-nitrophenyl phosphatase and monoamine oxidase B and a disordering of the membrane bilayer by reactive oxygen species attack, the latter being monitored by the fluorescence of the membrane fluorescent probe, 1-anilino, 8-naphtalene sulphonate (ANS). Ischemic injury resulted in 67% mortality of the animals. In the group of animals pre-treated with the neuropeptide carnosine the mortality was only 30%. At the same time, carnosine protected both the activity of the above-mentioned enzymes and the brain membrane disordering, which was also tested by ANS fluorescence. The conclusion was made that carnosine protects the brain against oxidative injury and thereby increases the survival of the animals.
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