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Life Extension Magazine

LE Magazine January 2003

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The Anti-Aging Effects of Carnosine

Carnosine protects against excitotoxicity and stroke

Many neurological disorders are caused by excitotoxicity.23 This brain cell damaging effect is often caused by excessive sensitivity to glutamate, the main excitatory neurotransmitter. Excitotoxicity triggers a cascade of events including membrane polarization, ending in cell death.

It is probable that excitotoxic complications determine the long-term effects of stroke. In Alzheimer's disease, laboratory experiments show that amyloid-beta induces cultured neurons to undergo excitotoxic death.

Experimental evidence shows that carnosine protects cells against excitotoxic death. A Russian study showed that rat cerebellar cells incubated in carnosine were resistant to excitotoxic cell death from toxic glutamate analogs.24

Two further Russian studies tested carnosine in animal experiments designed to simulate stroke. In the first experiment, rats were exposed to low pressure hypoxia.11 Rats given carnosine beforehand were able to keep standing and breathing almost twice as long as the others. After the hypoxia, carnosine treated rats were able to stand after 4.3 minutes, as compared to 6.3 minutes for the untreated rats.

The second experiment simulated stroke through arterial occlusion. The scientists found that carnosine acts as a neuroprotector in the ischemic (blood-deprived) brain. Rats treated with carnosine displayed a more normal EEG, less lactate accumulation (a common measure of injury severity), and better cerebral blood flow restoration.25

Carnosine and skin aging

While the epidermis (outer skin layer) changes only subtly with age, profound changes take place in the dermis (inner skin layer). In the dermis, the population of fibroblasts (connective tissue cells) is cut in half by age 80. Collagen becomes disorganized with broken fibers, while the extracellular matrix shows widespread destruction.

HOW CARNOSINE PROTECTS AGAINST BRAIN DEGENERATION

The brain's rich supply of oxygen, glucose, membrane lipids and metals may explain why it is also richly endowed with carnosine. Carnosine suppresses oxidative stress, lipid peroxidation, pathological protein-sugar interactions and copper-zinc toxicity. Moreover, carnosine's ability to forestall cellular senescence may help sustain the long lives of neurons, which do not divide to form new cells.

A major source of oxidative damage and cellular dysfunction in the brain is the oxidation of lipids in the membranes of brain cells.* This generates highly toxic byproducts that damage proteins and inhibit the synthesis of protein and DNA. Lipid peroxidation is particularly significant in Alzheimer's disease, where it is most prominent in the vicinity of senile plaques.** Carnosine dramatically reduces the levels of lipid peroxidation products.

When mice were stressed with electric shocks for two hours, significant increases in lipid peroxidation products in the brain and blood were observed, with decreased antioxidant activity levels.*** However, mice treated with carnosine before the shocks showed opposite effects. After the same series of shocks, their brain and blood lipid peroxidation product levels were more than 85% lower than in the untreated mice. Brain SOD antioxidant activity was six times higher in the carnosine fed mice compared to the untreated mice. When stress was induced, it caused a depression in levels of essential membrane phospholipids by 9% while carnosine treatment actually raised them by 26%. Carnosine also protected against a step in the glycation process, protected cells from damage by lipid peroxidation toxins and increased the "flowability" of cell membranes.

In Alzheimer's disease, lipid peroxidation toxins are thought to interfere with critical membrane proteins involved in cellular signaling and in transporting ions, glucose and glutamate. Carnosine appears to protect against many of the pathologies that have been identified in the Alzheimer's disease process.

* Forster MJ, Dubey A, Dawson KM, et al. Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Proc Natl Acad Sci USA. 1996; 93(10):4765-9.

** Smith MA, Sayre LM, Anderson VE, et al. Cytochemical demonstration of oxidative damage in Alzheimer disease by immunochemical enhancement of the carbonyl reaction with 2,4-dinitrophenylhydrazine. J Histochem Cytochem. 1998; 46(6):731-5.

***Gulyaeva NV, Dupin AM, Levshina IP. Carnosine prevents activation of free-radical lipid oxidation during stress. Bull Exp Biol Med. 1989; 107(2):148-152.

Protein degradation damages all components of the epidermis and dermis, leading to loss of elasticity, wrinkles, macromolecular disorganization, loss of extracellular matrix, and reduced capacity for wound repair, all of which are characteristics of aged skin. Collagen, the protein substance of connective tissue, tends to cross-link with age. It is well known that collagen is cross-linked in the course of glycation and the consequent formation of AGEs (advanced glycation end products). This robs the skin of elasticity and youthful tone.

Once AGEs form, they can directly induce the cross-linking of collagen even in the absence of glucose and oxidation reactions. Researchers have found that neither antioxidants nor metal chelators can inhibit direct cross-linking of collagen by AGEs. Only an anti-glycating agent, in one case the drug aminoguanidine, could inhibit this process. According to several published studies, carnosine offers a superior efficacy and toxicity profile compared to aminoguanidine.2

Carnosine rejuvenates senescent fibroblasts (connective tissue cells).14 This helps to explain a series of research findings that carnosine significantly improves post-surgical wound healing. A Japanese study showed that carnosine enhances granulation, a healing process in which proliferating fibroblasts and blood vessels temporarily fill a tissue defect.26 A Brazilian study showed that granulation tissue matured faster, with a higher level of collagen biosynthesis, in carnosine treated rats.27 This is not surprising in view of carnosine's ability to extend the replicative potential of cultured fibroblasts. These studies further suggest that carnosine can restore the body's regenerative potential.

The skin makes visible the changes that occur throughout the body as damaged proteins. The life cycles of cells and proteins may regulate both our appearance as we age and how long we live. By preserving the integrity and regular turnover of protein, carnosine is a key defense against the downward spirals of degeneration that occur as part of the aging process.28

Summary

Carnosine stands out as a promising multi-modal life extension discovery. It extends life span at the level of the cell and of the organism. The scientific evidence indicates that carnosine could help to preserve the structural, functional and genetic integrity of the body in a natural way.
Some of the age-related conditions that carnosine may help to prevent (and treat) include:

  • Neurological degeneration
  • Cellular senescence (cell aging)
  • Cross-linking of the eye lens
  • Accumulation of damaged proteins
  • Muscle atrophy
  • Brain circulatory deficit
  • Cross-linking of skin collagen
  • LDL cholesterol oxidation
  • DNA chromosome damage
  • Formation of advanced glycation end products (AGEs)

Life Extension members can obtain the recommended 1000 mg daily dose of carnosine by taking either two capsules a day of Super Carnosine Caps or six capsules a day of the Chronoforte formula. Both of these formulas are now fortified with a potent dose of water-soluble quercetin.


References

1. Stadtman ER. Protein oxidation and aging. Science. 1992; 257(5074):1220-4.

2. Preston JE, Hipkiss AR, Himsworth DT, et al. Toxic effects of beta-amyloid(25-35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and beta-alanine. Neurosci Lett. 1998; 242(2):105-8.

3. Stadtman ER, Levine RL. Protein oxidation. Ann NY Acad Sci. 2000; 899:191-208.

4. Bierhaus A, Hofmann MA, Ziegler R, et al. AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovascular Research. 1998; 37(3):586-600.

5. Munch G, Schinzel R, Loske C, et al. Alzheimer's disease-synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts. Journal of Neural Transmission. 1998; 105(4-5):439-61.

6. Hipkiss AR, Michaelis J, Syrris P. Non-enzymatic glycosylation of the dipeptide L-carnosine, a potential anti-protein-cross-linking agent. FEBS Lett. 1995; 371(1):81-5.

7. Munch G, Mayer S, Michaelis J, et al. Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide. Biochim Biophys Acta. 1997; 1360(1):17-29.

8. Hipkiss AR, Chana H. Carnosine protects proteins against methylglyoxal-mediated modifications. Biochem Biophys Res Commun. 1998; 248(1):28-32.

9. Brownson C, Hipkiss AR. Carnosine reacts with a glycated protein. Free Radic Biol Med. 2000; 28(10):1564-70.

10. Hipkiss AR, Preston JE, Himswoth DT, et al. Protective effects of carnosine against malondialdehyde-induced toxicity towards cultured rat brain endothelial cells. Neurosci Lett. 1997; 238(3):135-8.

11. Boldyrev AA, Stvolinsky SL, Tyulina OV, et al. Biochemical and physiological evidence that carnosine is an endogenous neuroprotector against free radicals. Cell Mol Neurobiol. 1997; 17(2):259-71.

12. Hipkiss AR, Preston JE, Himsworth DT, et al. Pluripotent protective effects of carnosine, a naturally occurring dipeptide. Ann NY Acad Sci. 1998; 854:37-53.

13. McFarland GA, Holliday R. Retardation of the senescence of cultured human diploid fibroblasts by carnosine. Exp Cell Res. 1994; 212(2):167-75.

14. McFarland GA, Holliday R. Further evidence for the rejuvenating effects of the dipeptide L-carnosine on cultured human diploid fibroblasts. Exp Gerontol. 1999; 34(1):35-45.

15. Yuneva MO, Bulygina ER, Gallant SC, et al. Effect of carnosine on age-induced changes in senescence-accelerated mice. J Anti-Aging Med. 1999; 2(4):337-42.

16. Horning MS, Blakemore LJ, Trombley PQ. Endogenous mechanisms of neuroprotection: role of zinc, copper, and carnosine. Brain Res. 2000; 852(1):56-61.

17. Huang X, Cuajungco MP, Atwood CS, et al. Cu(II) potentiation of alzheimer Ab neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem. 1999; 274(52):37111-6.

18. Atwood CS, Moir RD, Huang X, et al. Dramatic aggregation of Alzheimer Ab by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem. 1998; 273(21):12817-26.

19. Cherny RA, Legg JT, McLean CA, et al. Aqueous dissolution of Alzheimer's disease Ab amyloid deposits by biometal depletion. J Biol Chem. 1999; 274(33):23223-8.

20. Gulyaeva NV. Superoxide-scavenging activity of carnosine in the presence of copper and zinc ions. Biochemistry (Moscow). 1987; 52(7 Part 2):1051-4.

21. de la Torre JC. Cerebromicrovascular pathology in Alzheimer's disease compared to normal aging. Gerontology. 1997; 43(1-2):26-43.

22. Hipkiss AR, Preston JE, Himswoth DT, et al. Protective effects of carnosine against malondialdehyde-induced toxicity towards cultured rat brain endothelial cells. Neurosci Lett. 1997; 238(3):135-8.

23. Doble A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther. 1999; 81(3):163-221.

24. Boldyrev A, Song R, Lawrence D, et al. Carnosine protects against excitotoxic cell death independently of effects on reactive oxygen species. Neuroscience. 1999; 94(2):571-7.

25. Stvolinsky SL, Kukley ML, Dobrota D, et al. Carnosine: an endogenous neuroprotector in the ischemic brain. Cell Mol Neurobiol. 1999; 19(1):45-56.

26. Nagai K, Suda T, Kawasaki K, et al. Action of carnosine and beta-alanine on wound healing. Surgery. 1986;100(5):815-21.

27. Vizioli MR, Blumen G, Almeida OP, et al. Effects of carnosine on the development of rat sponge-induced granulation tissue. II. Histoautoradiographic observations on collagen biosynthesis. Cell Mol Biol. 1983; 29(1):1-9.

28. Ikeda D, Wada S, Yoneda C, et al. Carnosine stimulates vimentin expression in cultured rat fibroblasts. Cell Struct Funct. 1999; 24(2):79-87.


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