N-acetyl L-Carnosine

Introduction and relationship to L-carnosine

Below we present a summary of the major research results taken from published studies in the peer-reviewed literature, for N-acetyl L-carnosine (also just N-acetyl carnosine) which we abbreviate as NALC to distinguish it from N-acetyl L-cysteine (also just N-acetyl cysteine) which first received the NAC abbreviation. The acetylation of carnosine should make it both quicker and easier to digest (as with most amino acids) and resistant to cleavage of its dipeptide into its consituent amino acids, beta-alanine and L-histidine, by the plasma and cellular carnosinase enzymesR. This allows NALC to be distributed through the body and interact as carnosine before it is is cleaved and deactivated (although there is also evidence that its component amino acids are also beneficial). Since NALC is thus effectively a timed-release form of carnosineR, this review will also include many of the benefits of carnosine, but not its constituent amino acids, which are more effeciently obtained by taking them or carnosine rather than NALC.

Safety, Interactions and Bioavailability

NALC is found as a product of carnosine systhesis in mammalian cardiac and skeletal musclesR and brainR. NALC has been administered to horses by naso-gastric tube at 70 mg/kg body weight with no negative side effectsR. This same study found that intravenous administration of NALC (at 20 mg/kg body weight) raised serum levels; naso-gastric administration did not. The reason for this is unknown, but since horses have a far different digestive system than humans (they also have no serum carnosinase enzyme) and acetylated amino acids are generally as well or better absorbed than their non-acetylated forms, this result does not imply that NALC will not be absorbed from the GI tract by humans. Still, bioavailability results for NALC in humans is currently unproven and needed.

Proven Benefits

  1. "This is the first report showing that carnosine can protect the chaperone activity of alpha-crystallin. This chaperone may protect against cataractous changes. In addition to demonstrating the effects of carnosine on prevention crosslinking, our studies also bring out important evidence that carnosine reacts with F6P [fructose 6-phosphate] and ribose, which suggests carnosine's potential as a possible nontoxic modulator of diabetic complications."R
  2. "A dose-related effect of blueberry, green tea, catechin, carnosine, and vitamin D(3) was observed on proliferation with human bone marrow as compared with human granulocyte-macrophage colony-stimulating factor (hGM-CSF). We further show that combinations of nutrients produce a synergistic effect to promote proliferation of human hematopoietic progenitors. This demonstrates that nutrients can act to promote healing via an interaction with stem cell populations."R
  3. "[NALC] can act as a time release (carrier) stable version of L-carnosine during application in ophthalmic pharmaceutical and cosmetics formulations which include lubricants. ..."An important chemical difference between carnosine and Nacetylcarnosine is that carnosine is relatively insoluble in lipids (fats and fatty compounds), whereas N-acetylcarnosine is relatively soluble in lipids (as well as in water). This means that N-acetylcarnosine may pass through the lipid membranes of the corneal and skin cells more easily than carnosine, and may thereby gain access more readily to the cells’ interior, which is primarily aqueous. N-acetylcarnosine can be gradually broken down to carnosine which then exerts its beneficial effects."R
  4. "These results provide further evidence for carnosine's role as an anti-glycation compound. It is also proposed that carnosine may be an anti-steroid agent."R
  5. "These data suggest that histidine and carnosine are potential multiple-protective agents for diabetic complications prevention or therapy."R
  6. "The results of this study provide a substantial basis for further evaluation of [NALC] in the treatment and prevention of vision impairment in the older population of drivers for legal driving. The developed ophthalmic drug [NALC] formula showed potential for the non-surgical treatment of age-related cataracts."R
  7. "Cells continuously grown in 20 mM carnosine exhibited a slower telomere shortening rate and extended lifespan in population doublings. When kept in a long-term nonproliferating state, they accumulated much less damages in the telomeric DNA when cultured in the presence of carnosine. We suggest that the reduction in telomere shortening rate and damages in telomeric DNA made an important contribution to the life-extension effect of carnosine."R
  8. Both meat and carnosine-supplemented diets increased total anti-oxidant activity in human sera.R
  9. "The conclusion was made that carnosine protects the brain against oxidative injury and thereby increases the survival of the animals."R
    "The data indicate that carnosine can be used as an anti-ischemic drug. ... Acetylated carnosine was more efficient in suppressing ischemic contracture, and its influence on cardiac contractility was more pronounced. Moreover, acetylcarnosine restored myocardial contractility during ischemia"R
  10. "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..... 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.... Transfer of cells approaching senescence in normal medium to medium supplemented with carnosine rejuvenates the cells... Neither D-carnosine, (beta-alanyl-D-histidine), homocarnosine, anserine, nor beta-alanine had the same effects as carnosine on human fibroblasts."R
    "We have confirmed and extended previous results on the beneficial effects of L-carnosine on growth, morphology, and longevity of cultured human fibroblasts.... We have shown that late-passage ... 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. ... We have also demonstrated that very late-passage ... cells ... 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."R
    For an additional review of the work see: "A role for carnosine in cellular maintenance."R
  11. "Carnosine attenuates the development of senile features when used as a supplement to a standard diet of senescence accelerated mice (SAM). Its effect is apparent on physical and behavioral parameters and on average life span. Carnosine has a similar effect on mice of the control strain, but this is less pronounced due to the non-accelerated character of their senescence processes."R
  12. "Our results indicate that carnosine and related compounds are effective scavengers of reactive oxygen species generated by activation of ionotropic glutamate receptors, but that this action does not prevent excitotoxic cell death. Some other process which is sensitive to carnosine but not the related compounds is a critical factor in cell death."R
  13. "The results show that carnosine can (1) protect cultured rat brain endothelial cells against MDA-induced toxicity and (2) inhibit MDA-induced protein modification (formation of cross-links and carbonyl groups)."R
  14. "The observed phenomena of heart muscle protection by acetylated derivatives of carnosine and anserine under ischemia correlates with the preferential localization of these compounds in high quantities in the myocardium."R

Potential Benefits

  1. "The results suggest that carnosine might be an endogenous anticonvulsant factor in the brain and can be used as a new antiepileptic drug in future."R
  2. "Carnosine (beta-alanyl-L-histidine) and related peptides such as homocarnosine (gamma-amino-butyryl-histidine), balenine beta-alanyl-L-3-methylhistidine) and anserine beta-alanyl-L-1-methylhistidine) are histidine-containing dipeptides (HD) particularly abundant in excitable tissues such as nervous system and skeletal muscle. Although their biochemical role is still unknown, several evidences indicate that these endogenous compounds act as quenchers of reactive and cytotoxic carbonyl species."R
  3. "The effect of carnosine on overcoming muscle fatigue appears to be related to its ability to buffer the increased H(+) concentration following high-intensity work. Carnosine, however, has other roles such as an antioxidant, a metal chelator, a Ca(2+) and enzyme regulator, an inhibitor of protein glycosylation and protein-protein cross-linking."R
  4. "The ophthalmic [NALC] drug shows promise in the treatment of a range of ophthalmic disorders that have a component of oxidative stress in their pathogenesis (including cataract, glaucoma, dry eye, vitreous floaters, inflammatory disorders, and corneal, retinal and systemic diseases"R
  5. "Formation of nitric oxide by astrocytes has been suggested to contribute, via impairment of mitochondrial function, to the neurodegenerative process..... Our results sustain the possibility that carnosine might have anti-ageing effects to brain cells under pathophysiological conditions leading to degenerative damage, such as aging and neurodegenerative disorders."R
  6. "The study suggests that carnosine may be an endogenous anticonvulsant factor in the brain and could be used as a new antiepileptic drug in the future."R
  7. "Carnosine protects against the adverse effects of high glucose levels on renal cells."R
  8. "It is suggested that nasal administration of carnosine should be explored as a possible way of suppressing zinc/copper-mediated proteasome inhibition and consequent neurodegeneration."R
    "Should the peptide prove beneficial, olfactory carnosine administration could provide a direct route to compromised tissue, avoiding serum carnosinases."R
  9. "These observations support the hypothesis that beta-alanine [one moiety of carnosine] has chaperone-like activity and may play a cellular role in the preservation of enzyme function."R
  10. "These results suggest that carnosine had a protective effect against oxidative stress in intestinal epithelial cells."R
  11. "Among 29 dipeptides of the carnosine family tested as potential substrates for a highly purified human serum carnosinase preparation, [NALC] and few other compounds were not hydrolysed [14] thus promising a prolongation of physiological responses to the therapeutical treatments.... [NALC] is proposed to treat ocular disorders which have the component of oxidative stress in their genesis (cataracts, glaucoma, retinal degeneration, corneal disorders, ocular inflammation, complications of diabetes mellitus, systemic diseases)."R

Reviews and Additional Reading

  1. "the natural hydrophilic antioxidant and anti-glycating agent carnosine efficiently prevents oxidative modification of proteins and increases the life span of experimental animals under unfavorable conditions. It can be considered a potent natural geroprotector."R
  2. "carnosine (beta-alanyl-L-hystidine) is a dipeptide commonly present in mammalian tissue, and in particular in skeletal muscle cells; it is responsible for a variety of activities related to the detoxification of the body from free radical species and the by-products of membrane lipids peroxidation, but recent studies have shown that this small molecule also has membrane-protecting activity, proton buffering capacity, formation of complexes with transition metals, and regulation of macrophage function. It has been proposed that carnosine could act as a natural scavenger of dangerous reactive aldehydes from the degradative oxidative pathway of endogenous molecules such as sugars, polyunsaturated fatty acids (PUFAs) and proteins. In particular, it has been recently demonstrated that carnosine is a potent and selective scavenger of alpha,beta-unsaturated aldehydes, typical by-products of membrane lipids peroxidation and considered second messengers of the oxidative stress, and inhibits aldehyde-induced protein-protein and DNA-protein cross-linking in neurodegenerative disorders such as Alzheimer's disease, in cardiovascular ischemic damage, in inflammatory diseases. The research for new and more potent scavengers for HNE and other alpha,beta-unsaturated aldehydes has produced a consistent variety of carnosine analogs, and the present review will [organize and summarize], through the scientific literature and the international patents, the most recent developments in this field."R
  3. "It is suggested that carnivorous diets contain a potential anti-glycating agent, carnosine (beta-alanyl-histidine), whilst vegetarians may lack intake of the dipeptide. The possible beneficial effects of carnosine and related structures on protein carbonyl stress, AGE formation, secondary diabetic complications and age-related neuropathology are discussed."R
  4. "By controlling oxidative stress, suppressing glycation, and chelating metal ions, carnosine is able to reduce harmful sequelae such as DNA damage. AGEs are known contributors to the pathology of Alzheimer's disease, and carnosine therefore merits serious attention as a possible therapeutic agent."R
  5. "N-acetylcarnosine ..., has been found to be suitable for the nonsurgical prevention and treatment of age-related cataracts. This molecule protects the crystalline lens from oxidative stress-induced damage, and in a recent clinical trial it was shown to produce an effective, safe and long-term improvement in sight. When administered topically to the eye ..., N-acetylcarnosine functions as a time-release prodrug form of L-carnosine resistant to hydrolysis with carnosinase. N-acetylcarnosine has potential as an in vivo universal antioxidant because of its ability to protect against oxidative stress in the lipid phase of biological cellular membranes and in the aqueous environment by a gradual intraocular turnover into L-carnosine. In our study the clinical effects of a topical solution of N-acetylcarnosine ... on lens opacities were examined in patients with cataracts and in canines with age-related cataracts. These data showed that N-acetylcarnosine is effective in the management of age-related cataract reversal and prevention both in human and in canine eyes."R
  6. "It has now been demonstrated that carnosine has the ability to protect cells against oxidative stress as well as to increase their resistance toward functional exhaustion and accumulation of senile features. Mechanisms of such protection are explained in terms of proton buffering, heavy metal chelating, as well as free radical and active sugar molecule scavenging, preventing modification of biomacromolecules and keeping their native functional activity under oxidative stress. Several carnosine derivatives are characterized by different rates of splitting by tissue carnosinase and by different biological efficiencies, thus the biological significance of enzymatic modification of carnosine during its tissue metabolism may be increased resistance of cells operating under unfavorable conditions."R
  7. "We propose that carnosine (which is remarkably nontoxic) or related structures should be explored for possible intervention in pathologies that involve deleterious aldehydes, for example, secondary diabetic complications, inflammatory phenomena, alcoholic liver disease, and possibly Alzheimer's disease."R

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