CARNOsiNeCARNOsiNeSummary overview

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expands the constricted vessels

removes pain in extremities

increases uptake of oxygen

decreases blood pressurerecovery of

aging cells

cardio-vascular system

motoric apparatus

younger and elastic skin

treatment of neurologic degenerative diseases

removes vessel disorders of

brain

antiglycating effects

transfer of impulses in brain and nerves

reduces activity of free radicals

removes toxic heavymetals from body

kidney disorders

catar

improves memory

endurance of the heart muscle

arteriosclerosis(prevention of

LDP-cholesterol oxidation)

Autism Spectrum Disorders

increased buffering capacity

of skeletal muscles

buildingand regeneration of muscle mass

antioxidant

cells

nervous system

digestive system

diabetes

increases blood flow in heart, brain, organs,

and extremities

CARNOsiNeCARNOsiNe

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Content

Assessment of Carnosine EXTRA productdoc. MUDr. Igo Kajaba, PhD.

Briefly about carnosine

Who is MUDr. Michael Kučera?

Research preview – CarnosineMUDr. Michael Kučera

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Main components of the preparation are consist of carnosine - a dipeptide of two amino acids: semi-essential L-histidine (essential in a period of intensive growth, pregnancy, conditions of physical and mental stress, and others), and basic β-alanine at protheosynthetic processes in tissue.

It is also synthesised in human body from the mentioned amino acids by means of enzyme carnosine- synthetasis, mainly in brain and muscles, including myocardium, intake with food as well. It is absorbed only in upper parts of intestine (jejunum), and then distributed by blood to almost all organs.

From the broad diapason of health beneficial response of carnosine, in exact preview listed in the book of MUDr. Michael Kučera, I would like to mention some from the key ones. Carnosine is the most intensive antioxidant, it inhibits processes of glykosylation and carbonylation of proteins, and also phospholipids. Remarkably depresses creation of protein related, advanced end products of glykosylation – AGE, as well as the unfavourable impact of the final product of lipid peroxidation – malondialdehyde on proteins, and not only in several serious clinical conditions, but also significantly in prevention of processes of premature aging of organism.

The feature of carnosine to form chelae compounds enables to remove harmful products of metabolism, as well as toxic effects of heavy metals and other alien substances. In sum it is to say that based on EBM (Evidence Based Medicine) carnosine has significant protective effects cardiovascular, cerebronervous, immunomodular, cell protective and regenerative, antioxidative, antisclerotic, antidiabetic, antimulagnous, and by that also anticancerous. In no case it is to leave out a reference of carnosine in association with its valuable sexually stimulating function.

Next components of the product are vitamin E, most efficient antioxidant from the vitamin group, mainly in interplay with vitamin C, which has to reduce the oxidated form of vitamin E and thus restore its function.

Coenzyme Q10 represents one of the fundamental substances of the new modern direction – mitochondrial medicine. It is an important component of respiratory chain of mitochondria, has a key importance at ATP creation in mitochondria, where it participates and decides on course of energetic metabolism in cells.

CARNOsiNe EXTRACARNOsiNe EXTRA

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Coenzyme Q10 has strong antioxidative features, it neutralizes free oxygen and other radicals, and similarly as vitamin C it is able to regenerate vitamin E. It shows antiperoxidative effect with lipids, by which it avoids lipoprotein disorders, and onset and development of atherosclerotic changes.

It is known that human body is equiped with the ability of its biosynthesis, however fully functional only up to age of 40. Its biosynthesis is then continually reduced, it is very low in senior age, and its insufficient content in food there is a risk of initiation of some or several mitochondrial diseases. Next risk is with persons taking statins. These inhibit the enzyme HMG-CoA reductase and thus prevent from endogenic cholesterol creation, however at the same time avoids metabolism of mevalonate, which is precursor of Co Q10, and therefore by lack of mevalonate is this important metabolite CoQ10 absent, and onset of various clinical demonstrations of this shortage is threatening. From this results that a 50 year old individual who moreover takes statins must necessarily reach for nutritional additive with content of CoQ10.

L-carnitin is biologically important, it is contained also in breast milk, and therefore products of artificial milk nutrition of newborns are enriched with carnitine together with taurine.

L-carnitin is generously represented in metabolically active organs, mainly in muscles, where it significantly participates in metabolic processes, mitochondrial β-oxidation of fatty acids with long chain by means of enzyme activity of carnitinpalmitoyl- transpherase 1, as well as at creation of ATP in myocardial mitochondria, which emphasizes the cardioprotective effect.

In frame of the product complexity it is also completed with an extract from blueberries and wine grapes, which are known by rich content of beneficial flavonoids, and mainly wine grape with polyphenolic agent – resveratrol.

From the given assessment of nutritional additive it is recommended to approve the preparations, as well as agree with import, distribution, and sales in chain of pharmacies and nutritional retails in SR.

Doc. MUDr. Igo Kajaba, PhD.Lead of the Nutrition screening SZU

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Briefly about carnosine

Carnosine (ß-alanyl-L-histidine) is a dipeptide, naturally found in the body (the body produces it on its own). It is a natural antioxidant, appears in human body since birth, but later in time its creation is reduced. It is located in skeletal muscles, brain, and myocardium. Antioxidative mechanism of carnosine is explained as chelating of metal. Experiments show that carnosine inhibits oxidation of lipids, which is catalysed by iron, and oxidation of haemoglobin, which is activated by hydrogen peroxide. Carnosine effectively reduces activity of singlet oxygen, lipoxygenase, and hydroxylated radicals.

In intestine the carnosine is absorbed by specific active transport system in membranes of brush edge cells, it enters the blood, and is further transported to kidneys, liver, and muscles. Absorbed carnosine is used in peripheral tissue, or it is hydrolysed by carnosinase.

Carnosine decreases oxidation of LDL-cholesterol, and chelating of copper ions show that carnosine could inhibit development of atherosclerosis. As of now it is still unknown whether the antioxidative effect of carnosine is applicable with regards to malignancies. Growth of malignant cells was reduced after dispending carnosine at breast carcinoma in experiment. Lately it was identified that carnosine modulates concentration of intracellular Ca2+, and therewith the contractibility of myocardium or skeletal muscle. Carnosine is an important component of skeletal muscles, it concentrated also in fast fibres of type II. It binds H+, and delays the drop in pH .

Possibilities of usage in clinical medicine at atherosclerosis, cancer, diabetes, and gastrointestinal disorders result from metabolic features of carnosine. Presence of carnosine in body assures maximum efficiency in cell multiplication, it protects against DNA oxidation, and eliminates free radicals, accelerates healing of wounds and joint tissue, increases sport output, protects brain against plaque creation, which is one of the reasons of Alzheimer’s disease, improves ability to think logically, memory, as well as space thinking, moreover the reaction time was improved, as well as the global speed and accuracy of data processing in brain.

Carnosine was yet in past used in treatment of muscles, joints, digestive system, in treatment of diabetes complications, various wounds, in treatment of cataract, kidney diseases, it was applied to oncologic diseases, Alzheimer’s disease, but also in body fitness as such. It is known to protect brain against ravaging impact of aging, as well as to remove some “reversible” damages caused by aging.

Activity of carnosine is strengthened by parallel reception of oxidants (e.g. vitamins E, C).

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Recently, more than than 900 studies have been published about carnosine. Research is performed by experts in several countries worldwide. MUDr. Michael Kučera undoubtedly belongs among these experts. A Czech internal physician since 1994 cooperating with prof. Dr. R. M. Baevski (Institute for Bio-medical Problems Academy of Sciences Russian Federation) in range of application of cosmic medicine into practice, mostly in the field of prevention and strengthening adaptation mechanisms on stress. Research activities of internationally accepted expert on mitochondrial medicine Dr. Kučera were awarded in 2000 with IMMA-Prize 2000 for clinically relevant achievements in this area.

cytoplasm

centriols in centrosome nucleolus

nucleus

mitochondriaendoplasmaticreticulum

cytoskeleton

Golgi apparatusribosomes

(small spots)

Who is MUDr. Michael Kučera?

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CARNOsiNeCARNOsiNeResearch preview

2006, MUDr. Michael Kučera, Karla Čapka 4, 36 001 Karlovy Vary, Czech republic

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1. Preface.

2. Pharmacology and biochemistry.

3. Brief history.

4. Strong antioxidant.

5. Chelatogenous effect.

6. Prevention of glycation.

7. Prevention of carbonylation.

8. Beneficial effect against aging.

9. Carnosine rejuvenates skin.

10. Muscle aging, muscle diseases.

11. Carnosine in sport.

12. Disorders of potency.

13. Cataract.

14. Diabetes and its complications.

15. Cardiovascular diseases.

16. Neurologic and mental disorders – carnosine as nerve protection.

– Alzheimer’s disease and mild disorders of perception and cognition (mild cognitive

impairment)

– Parkinson’s disease

– Epilepsy and schizophrenia

– Autistic disorders

– Brain vessel disorders, brain vessel events (stroke).

17. Next health beneficial effects.

18. Carnosine for longevity.

19. Carnosine as drug and nutrition additive.

20. Posology.

21. Conclusion.

22. References.

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1. Preface.Increasing attention and interest in the recent years is dedicated to phenomenal features of carnosine, which is considered a substance of the century, and it is assumed to become a fundamental daily medicine for people of all ages, particularly those who reached 40 years of age and above. Research projects concerning carnosine are conducted in the US, Australia, the UK, Japan, Scandinavia, Russia and China, and it is recommended by specialists dealing with aging as a significant and valuable nutrition additive. Carnosine is examined by top scientists (e.g. Dr. Bruce Ames and his team from UCLA Berkley. Nobody suspects his high expertise in molecular biology).

Laboratory research in field of cellular senescence (aging) – i.e. end of life cycle of two dividing cells reports that the gained facts cannot be random. Carnosine has remarkable abilities of cell rejuvenation in senescence process, recovers their normal features, and extends their lifetime. How can carnosine rejuvenate the cells? Not all questions are answered so far, but features of carnosine point to key mechanisms of cell and tissue aging – protects against shortening of telomeres and against damaging DNA at cell dividing.

Later on a list of wholesome impacts on organism was proven. Mechanisms of these impacts are characterized by following processes:

Physiologic (normal) concentration (20-30 μM/l) in standard media in- vitro extend lifetime of human fibroblasts, and strongly reduce their aging performance.

Carnosine significantly improved the image of laboratory animals, and prolonged their life. Carnosine could be very useful at the following disorders associated with age:

● neurologic degenerative disorders (Alzheimer’s and Parkinson’s disease, epilepsy, depressive disorders, schizophrenia, mild cognitive impairment, dementia, various aetiology, conditions after brain vessel events)

● range of autistic diseases (Asperger syndrome, ADHD, dyslexia a dyspraxia, Tourett syndrome, etc.)

● general disorders of cell aging● cross-linking of eye lens, cataract● cross-linking of skin collagen (skin aging)● formation of AGES (Advanced Glycation End Products), i.e. advanced terminal products

of protein glycation● conditions of accumulation of damaged proteins● muscle dystrophy● cardiovascular diseases● brain vessel disorder● diabetes and its complications

Carnosine is as a multifunctional nutrition additive relatively new. It is physiologic and 100 % natural super antioxidant with a spectrum of biologic functions (apart from features listed above):

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● has universal and multilateral antioxidative activity● supports muscle vitality● increases muscle power and endurance● accelerates recovery after sprinting● reduces cell damages caused by alcohol● acts as impulse transferring agent in brain and nerves

2. Pharmacology and biochemistry. Biologic effect.Carnosine is 100 % natural substance, a so-called dipeptide created by two amino acids (ß-Alanyl-L-histidine). It is often called a neuropeptide because of its protective action in brain. It is commonly found in the body. Based on new trials its highest concentration is in skeletal muscles, heart, cerebellum and brain. Homocarnosine exists only in brain and cerebellum. Was not detected in blood plasma, liver, kidneys and lungs. Muscles contain around 20 μmol/g dry

(The more carnosine is contained in meet, the more is the shelf life extended because carnosine as a highly efficient antioxidant prevents

its spoiling)

Fig. 1. Chemical formula L – Carnosine(NH2CH2CH2CONHCH (C4H5N2) CO2H)

COOH O

CNHCHCH2

HN1 N3

CH2

CH2

NH2

Carnosine acts more effectively with other biologic antioxidants, e.g. vitamins C and E, zinc and selenium, and reduces its consumption in tissues. It is created in the body from amino acids alanine and histidine via enzyme carnosine-synthetasis. This reaction runs mainly in brain and muscles. Other group of enzymes called dipeptidases or carnosinases vice-versa dissociate carnosine in blood and other tissues. Many scientists presume and their trials prove that some positive features of carnosine are just caused by these reactions, breakdown of carnosine at the rise of alanine and histidine, so the degradation has in this case a positive nature.

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Meat is the main external supplier of carnosine. Absorption of carnosine from food is 30-70 % (depending on the content of other amino acids in food), but in cases of intake of pure carnosine, its absorption is more than 70 %. Almost all carnosine is absorbed in upper parts of intestine (in jejunum, not ileum). It is then carried by blood directly to muscles, heart, brain, and some other organs. Human plasma does not contain measurable amount of carnosine, therefore blood tests cannot serve as a test of its eventual deficiency (lack) – on a contrary with horses, where plasma contains more than 100 μmol/l. Content of carnosine in plasma is however increased at muscle injuries: then the content of carnosine in plasma may serve as a detector of muscle injuries.

Biologic functions of carnosine are mainly:● buffering effect for lactic acid ― maintenance of pH (= acidity) in muscles at burden● chelating effect for heavy metals (in particular copper and zinc)● removing (“scavenging”) effect for free radicals, strong antioxidant● removing effect for active molecules of sugar = prevention of glycation● prevention of protein carbonylation = so-called carnosinylation (glycation and

carbonylation ― processes typical for protein aging)● separation of aldehydes (aldehyde-sequestring)● preventive effect on modification of bio macromolecules, i.e. maintenance of their natural

functionality yet at condition of oxidative stress (i.e. at condition of prevalence of free radical formation and lack of antioxidative capacity)

● function of nerve impulse transmitting agent (neurotransmitter)● protective effect on proteasomes● depression of anti-inflammatory and cancerogenous effect of cytokine IL-8

Finally, carnosine is remover of aldehydes and is able to eliminate terminal harmful waste products of metabolism, such as degradative parts of proteins (damaged chains of proteins, sugar and phospholipids), while at the same time acts as key substance for creation of new more resistant structures. As a nutrition additive carnosine is a possible modulator of diabetic complications, atherosclerosis, Alzheimer’s and Parkinson’s diseases, epilepsy, autism, dyslexia, schizophrenia and similar syndromes. Copper and zinc are released during normal synaptic activity.

In presence of slightly acidic environment characteristic for Alzheimer’s disease these metals are reduced into their ionized forms and so become toxic for the nervous system. Research has proven that carnosine neutralizes (with its buffering effect) toxicity of copper and zinc in brain.

Further on it was proven “in vitro” that carnosine depresses nonenzymatic glykosylation and formation of cross linked proteins, caused by reactive aldehydes, aldose and ketose, some trioselike intermediary products and malondialdehyde (MDA=product of lipid peroxidation, i.e.. product, arising under influence of oxygen radicals on fatty substances). Carnosine depresses formation of advanced (protein related) products of glykosylation (Advanced Glycosylation End products – AGEs) induced by MDA.

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Also depresses formation of crosslinked DNA proteins, which use to be developed by acetaldehyde and formaldehyde. Product of lipid peroxidation, MDA, create adducts with proteins, which are detected at routine tests as prove of protein carbonylation.

3. Brief history.Carnosine was discovered (and its structure was identified) beginning of 20th century by a Russian scientist W. S. Gulevič. It was the first and most simple example of biologically active peptide (dipeptide in our case), which opened a long list of broad spread natural protein regulators of metabolism. First decades were dedicated to structure studying, distribution, and features. It was identified that carnosine has direct relations with functions of triggering tissues such as muscles and brain. In 1953, next Russian scientist S. E. Severin, proved that carnosine effectively balances pH (acting as a buffer), buffering the lactic acid produced in working muscles, and that supplying carnosine increases the contractility of the muscles and their resistance against tiredness. Working muscle accumulates lactic acid as its own product, pH is dropping (i.e. acidity grows), which is the main cause of muscle tiredness. When carnosine is administered, the muscle recovers almost immediately, and keeps working as if was never exhausted. This process of rapid recovery of muscles caused by carnosine is known as so called “Severín phenomenon”.

Everybody with certain experience with sports knows by sure the meaning of physical exhaustion, and a certainly understands how tremendous importance can a carnosine supplementation bring to sport activities. Scientific interest in this extraordinary, absolutely nontoxic substance has grown in the last years – in particular after dramatic Australian and British discoveries on carnosine effect in aging process. Then the scientific work of Dr. Michael Chez team in 2002 in US was well surprising, as their report on dramatic improvement in autistic kids after carnosine was published. There is more than 900 carnosine trials published in MEDLINE database recently.

4. Strong antioxidant.Carnosine is an antioxidant, stabilising and protecting cell membranes. Specifically as a water soluble antioxidant it prevents lipid peroxidation inside cell (double layer) membrane. Many antioxidants (as vitamin C and E) protect the tissues before entering them, but they possess minor effect, when this first line protection is overridden. Free radicals then cause so-called oxidative stress of organism. Carnosine reacts generally with all reactive forms of oxygen (Reactive Oxygen Species ROS = free oxygen radicals), and prevents from development of oxidative stress. Carnosine does not act just preventively – it is also active, when dangerous compounds were already created by free radicals, such as lipid peroxides and their secondary products. So is the tissue protected against harmful effect of the substances of the “second wave”. For example, a very reactive final product of lipid peroxidation is malondialdehyde (MDA), dangerous product of free radical reaction, is blocked by carnosine. MDA, in case not eliminated, may cause damage of lipids, enzymes and DNA, has an important role in

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developing atherosclerosis, inflammatory and degenerative processes of joints, cataract, and aging processes in general. Carnosine with its reaction and inactivation of MDA is itself sacrificed in favour of amino acid protection in protein molecules. Ability to reduce concentration of reactive forms of thiobarbituric acid (Thiobarbituric Acid Reactive Substances TBARS) is a pretty strange antioxidative feature of carnosine. Carnosine is a substance protecting and extending functional life cycle of key building units of the organism – proteins, DNA and lipids – and can be quite seriously called as substance of longevity.

Carnosine moreover protects biologic tissue against oxidation, reaction with aldehydic products of lipid oxidation, which form so-called adducts with DNA, proteins, enzymes and lipoproteins followed by harmful changes in their biologic acting.

Oxidative stress and stressing injury is enabled by low concentration of carnosine, which explains the increased fatality of elderly people after stressful events. Therefore sufficient antioxidative protection is crucial for maintenance of good health, especially at seniors.

Properties of carnosine against aging not only question of its antioxidative features. Next mechanism how carnosine protects cells against oxidative stress is its chelategenous effect, explained by the team of prof. Bruce N. Ames from UCLA, Berkeley. Formation of chelates with heavy (transitory) metals – e.g. such as cadmium, copper, iron, mercury – prevents participation of these metals in the harmful Fenton reaction with peroxides.

5. Chelategenous effect.Carnosine has ability to chelate metals.What does it mean? The term chelate originates from Greek: “chele” = “claw”, which expresses ability of joining, adding some substance (carnosine in this case) with surplus of metals in tissues and blood. Chelates are substances which could be excreted from organism through liver and kidneys. Chelate therapy is a traditional classical detox treatment deployed mainly in occupational medicine. Various chelatogenous medicines such as penicillamin or EDTA (and others) are used in intravenous form. This treatment effectively removes heavy metals (e.g. lead) from the body. Chelate treatment is also used as complementary at many other diseases (not only disorders caused by poisoning with heavy metals), because it can bring following beneficial effects:● expands the constricted vessels● suppresses increased blood pressure● reduces activity of free radicals ● increases oxygen uptake in cells● removes toxic heavy metals from organism● improves memory● removes pain in extremities● increases vessel elasticity● increased blood flow to heart, brain, organs, and extremities● increases enzymatic activity

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In relation with vaccination usage of carnosine could be crucial, as carnosine removes organic compounds of mercury (thiomersal or thimerosal) from the child body. These organic compounds of mercury are part of several vaccines as antimicrobial preservants despite the fact they have been indicated as toxic substances for central nervous system since 1930. Thus it is suitable for every vaccinated person, no matter if child or adult, to take carnosine as a prophylactic measure aiming to remove thiomersal as soon as possible.

Chelate therapy by means of EDTA used to be quite a popular method of treating atherosclerosis– EDTA was deployed to remove calcium

from the walls of sclerotic vessels with aim to restore their elasticity. This therapy was however very expensive and time consuming, because

EDTA was administered intravenously with one session lasting around 3 hours, and the course demanded 10 to 20 sessions to achieve the

desired effect..

Carnosine as a nutrition additive proves the same chelatogenous effect as EDTA, and offers inexpensive, oral chelatetherapy. It is able to chelate prooxidative metals like copper, zinc, iron and other toxic metals – arsenic, lead, mercury, cadmium, and nickel.

6. Prevention of glycation (glycosylation).All the diabetics certainly know what HbA1c is. It is glycosylated haemoglobin, which offers quite good information on glycaemia in the course of last months. Latest research shows that the most important effects of carnosine are probably the antiglycating ones.

What is glycation? Every second in the whole body a process called glycation (glycosylation) takes place. This reaction could be described as formation of a bound of protein molecule with molecule of sugar (glucose) followed by the creation of damaged, non-functional structures.

Process of glycation alters the structure of protein, and suppresses the biologic activity of this protein. Glycated proteins accumulated in the touched tissues are reliable indicators of disorders. Many diseases associated with higher age, such as atherosclerosis, cataract, and some neurologic disorders are at least partly attributed to glycation.

Carnosine, which prevents glycation, plays an important role also in removal of glycated proteins. So called carnosynilation (process, where carnosine is bound to denatured molecules) enables removal of glycated proteins from cells.

Glycation, in biochemistry known as Maillard reaction, runs between proteins and glucose, is considered as important aging factor and probably also a factor in malignant tumours, including complications caused by diabetes. Glucose is a “fuel” for glycation, malicious binding of protein/glucose, followed by creation of free radicals, ends up in AGEs (Advanced Glycation Endproducts).

When the AGEs are formed, they react with neighbour proteins and build pathologic cross-links, which cause hardening, stiffness of the tissue. It is an object of ongoing discussion, that in fact no other molecule has such important potential toxic impact on

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proteins as AGEs. Diabetics build enormous amount of AGEs considerably earlier in life course than healthy individuals – this process totally disrupts normal organ functions, which are dependent on flexibility. It was proven that just glycation processes are those resulting in “hardening” arteries of diabetics.

AGEs launch a full cascade of destructive processes when bound to cell binding structures. One of the results is 50x higher formation of free radicals. So diabetes in fact a disease of accelerated aging becomes a source for AGEs, and arteries, eye lens and retina, peripheral nerves and kidneys are specifically attacked. Inhibiting glycation then means that damage of kidneys followed by inflammatory and degenerative changes are softened. Rats with diabetes not treated with glycation inhibitors, showed double damage of kidney glomerules caused by AGEs in comparison with control group treated with these inhibitors.

Cataract – next complication of diabetes – is also result of glycation process. Inhibitors of glycation, as carnosine and calciumpyruvat, protect against this damage.

Supplying inhibitors of glycation may allow preventing many deviations accompanying the aging process. Since carnosine structurally contains sites that are attacked by glycation, it must be sacrificed to protect the aim. Carnosine also supports the protheolytic paths, i.e. removal of damaged and unnecessary, often harmful proteins.

Therefore carnosine with anti-glycating effect could be useful in prevention and treatment of diabetic complications like cataract, neuropathy, atherosclerosis, and kidney failure.

It may also be useful for everyone of us, despite not being attacked by AGEs so rapidly as the diabetics are.

7. Prevention of carbonylation.Why are old people, and animals, visually different to the young?It is given mainly by the changes in body proteins. Proteins are substances most important for daily functioning living organisms. Therefore their modification has dramatic impact on function of organism and its image. A number of research tasks of the last decade have been focused on investigating protein modifications as most important reason of aging and degenerative diseases. These modifications (deterioration, change of structure, etc.) of proteins are consequences of oxidation (thus impact of free radicals), and similar following processes such as glycation.

Our body consists mainly of proteins. However the antioxidative system, and other protective processes cannot completely protect the proteins, these tempt to undergo destructive changes in the course of life, in particular by means of free radicals, glycation, and also by process named carbonylation. In another words, carbonyl groups (> C = O) are bound to protein molecule (alternatively to phospholipids) – resulting in disrupting protein structure in process named proteolysis. Since protein carbonylation stands before loss of cell membrane integrity, it is associated with toxic processes leading to cell aging, and cell death.

Majority of protein modification processes, their “de facto” denaturation, and proteolysis (break down) are caused by oxidation (free radicals), carbonylation,

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building cross links, glycation, and formation of advanced final glycation products (AGEs) as described above. These processes do not show up only in general changes associated with aging, but are typical for changes that manifest themselves with skin aging, development of cataract, and degenerative processes of nerve cells (e.g. loss of memory, dementia, etc.).

A number of scientific trials point to carnosine as effective substance acting against all mentioned possesses of protein denaturation. Carnosine reacts with

carbonyl group and forms so called protein-carbonyl-carnosine adduct, and thereby protects this protein, and on the top of it turns this process into recovery of disrupted protein structure.

How is carnosine capable of causing it? It simply restores normal management of cell cycles. For better understanding of how carnosine works it is possible to imagine the following: every “engine” needs regular oil change, because during its operation various microscopic and larger particles caused by abrasion appear. Oil contains detergents, which keep the particles resolved. Once the detergents are spent, the waste particles grow bigger, and damage the smooth internal surface, the engine looses power up to total failure. A body also needs an effective method of removing metabolic waste, mainly remains of destroyed protein structures. This protein “mud” piles up – if not removed – in the cell and causes that functional life cycles of this cell are slowed down until they come to a full stop. This could also disturb effective cell division and possibly even more significantly allows next reproduction of this disrupted abnormal cell. This leads to increased chromosomal instability, resulting in degenerative changes, or malignant tumours. Another possible outcome is the development of cell senescence (aging), when the “worn” cell stops its division. Carbonylation of proteins becomes the main condition of cell life termination. Carnosine represents the main factor of sustainability and safeguarding intact healthy proteins, their functionality, and early replacement. Carnosine represents a substance that significantly exceeds traditional antioxidants such as vitamin E or selenium, which are not so effective as we had hoped in the past. Traditional antioxidants play certainly an important role in various processes of removing free radicals, but have no effect on carbonylation, and glycation. There is no doubt that the influence of antioxidants represent a key process of biochemical reactions protecting against damaging biologic structures by free radicals. To expect that traditional antioxidants shall protect against savage processes of glycation and carbonylation is the same as building a house with a screwdriver – a basic tool but totally unable to substitute other important tools.

Carnosine is pure natural, versatile, multipurpose, and universal means of protein protection which was developed by evolution to manage numerous factors cooperating at protein degradation processes. Chemical side reactions which disturb biologic structures and functions in the course of aging are outcome of toxic impacts of many own and fundamental elements of chemical composition of organism – oxygen, sugar, fats, and essential metals. Organisms cannot exist without these biochemical elements, and recent science about nutrition provides us with information to better understand their side effects, and have better control. Proteins are not the only ones denaturised by carbonylation –

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phospholipids are carbonylated, too. Carbonylation of phospholipids causes damage mainly of central, and peripheral nervous system, which leads memory and perception disorders. Carnosine in this case is able to protect phospholipids against carbonylation, possibly regenerate them (as proteins do), so it is not incidental that this miraculous dipeptide is unbelievably important neuroprotectant (safeguards neural cells) – see later in text.

In sports and bodybuilding, carnosine participates in detoxicating processes of removing harmful reactive aldehydes, which are created by peroxidation of lipids in skeletal muscles at endurance performances (sportsmen). Carnosine protects muscles against damaging, increases muscle power, endurance, and significantly accelerates processes of recovery after extreme excercises, see next chapters.

8. Beneficial effect against aging.Carnosine has many literally “rejuvenating” wholesome effects – it is to admire how such a small molecule of dipeptide may have such a tremendous effect in sense of rejuvenating organism. Carnosine has extraordinary ability to rejuvenate old and aging cells and turn the fully functional and healthy. It was assumed that old cells are not able to be rejuvenated before the trial results on carnosine effect were known. Recent knowledge shows that carnosine prolongs the period between two cell divisions and at the same time increases the number of divisions. It means that the cell life is significantly extended, whereas the relation is direct: the more carnosine the longer intervals between divisions, and more divisions are in place.

Carnosine extends the average life of fibroblasts in culture, destroys their transformed (mutated) forms, protects against aldehydes and formation of ß-amyloide fragments (characteristic for Alzheimer’s disease), and against creation of α-synukleinu (Parkinson’s disease). At the same time suppresses, at least in vitro, glycation of proteins, and formation of dangerous cross links DNA/protein.

Recent research proves that patients taking carnosine quite objectively after some time (some 6 to 12 months) appear younger than before use. This supports findings from “in vitro” experimental trials and experimental works confirming that carnosine is able to rejuvenate cells in cultures, and also “in vivo”, performed on laboratory animals where carnosine suppresses visible signs of aging. During these trials carnosine significantly delayed development of skin ulceration in eye area, vertebral lordokyphosis, typical manifestation of old age. Moreover mice suplemented with carnosine not only “looked” younger than mice in control group (i.e. without carnosine), but achieved average life extension by 20 %. As a curiosity – a rumor circulates that Boris Yeltsin had been taking the “Russian supervitamin”, i.e. carnosine for some time, so that he looked 10 years younger.

9. Carnosine rejuvenates skin.Normal cells are aging also in their replication abilities, it is the number of division repetition. Shortening of DNA telomeres occurs at every division (telomere = marginal DNA complex with protein protecting the chromosome edges). This DNA shortening after each division

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causes creation of a so called DNA – damage signal in a certain moment, and p53 is activated. Some chemotherapeutics induce such of rapid cell aging in malignant, and healthy cells. Carnosine on the contrary has a very effective impact on reverting signs of aging in skin cells (fibroblasts) already in process of aging, and restore their functionality together with extension of their lifetime. These functions are typical for effect of carnosine to prevent all forms of harmful changes in protein and phospholipid molecules, and also to significantly limit cutting of DNA telomeres, i.e. to prevent damage to the DNA. Limited number of cell divisions is called Hayflick limit. It is the maximum number of cell divisions before its destruction. Hayflick limit refers to the mortality of cells. Majority of the cells in fact regenerate in division into two daughter cells. Since 1961 Dr. Leonard Hayflick proved that cells can achieve a limited number of divisions, and later lose their dividing ability. His well known experiments demonstrated that cultures of human fibroblasts (cells of joint tissue) are able to divide maximum 60 to 80 times, while fibroblasts of young people were able to divide 30 to 40 times, and fibroblasts of older ones only 10 to 20 times. When cells achieve this “Hayflick limit”, the twilight called cell senescence arrives, i.e. aging. Cells in senescence are still alive, but they do not divide anymore, and are damaged in structure and functionality. Human fibroblasts are very suitable for performing cultivation and experimental trials in laboratories. Fibroblast cultures in senescence cannot be exchanged with young one because they are quite uniform and create groups of parallel fibres. Senescent fibroblasts on a contrary are granular, are variable in size, do not group, and their fibres are irregular and differ in length – they lose their ability to organise regular forms. These important features of old cells are called as senescent phenotype (young cells then represent a juvenile phenotype).

Remarkable set of experiments was performed by Australian scientists under lead of Dr. McFarland, who has proven that carnosine rejuvenates cells heading to senescence. The most exciting fact in these experiments is that they’ve proven the ability of carnosine to reverse signs of aging. Namely when the aging cells were put in a culture enriched with carnosine, they showed not only phenotype change from senescent to juvenile, but also increased ability to divide. They again exhibited ability of organisation, became uniform, and built organised fibre groups. Once they were moved back in the culture without carnosine the signs of senescence returned rapidly. The same cells were again put into the carnosine culture, and again they showed juvenile phenotype. This was repeated with the same cells many times, and in medium with carnosine the phenotype was changed to juvenile, in culture without carnosine the phenotype was senescent. Moreover, carnosine significantly extended lifetime of old cells. These experiments were later confirmed also by British scientists under the lead of Dr. Alan Hipkiss, mainly the ability to prolong the lifetime of human fibroblasts.Carnosine delays processes of aging in cultures of human fibroblasts, and is able to change senescent phenotype to a juvenile phenotype. Anyhow the positive properties of antioxidants in removal of free radicals may be, they never prove features against aging process like carnosine does. These are just associated, next features of carnosine, its attributes in process of senescence. It is especially notable that carnosine is able to react with carbonyl groups to form “carnosinylated” polypeptides

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(adducts) which suppress aging process, and reduce formation of protein damages typical for these processes.

Revitalising effect of carnosine on fibroblasts is also explaining the reason of significantly improved heeling of wounds after surgical interventions.

What in fact causes wrinkles on the skin? Aging (senescent) skin cells, keratinocytes and fibroblasts after protein changes start to “behave” abnormally, and accumulate in human skin in the course of time. They produce more metal-proteinase-like enzymes, which damage proteins in surrounding matrix (extracellular mass where cells, lymphatic nodes, vessels, and other skin structures are placed).

They also produce adhesive molecules which cause thickening of vessel walls and their stiffness (arteriosclerosis). Senescent cells produce more other degradative enzymes and anti-inflammatory cytokines with action in distant areas of the body (transport by blood). That way can a relatively small amount of senescent cell cause relatively extensive changes in function, and integrity of the skin. Senescent cells accumulate in all organs and tissues where they withstand so called apoptosis (programmed cell death), and invoke degenerative aging processes. Moreover: disruption of microscopic environment by the accumulated senescent cells may be the reason behing increased incidence of malignant diseases in the elderly.

10. Muscle aging, muscle disorders.From 20 to 70 years of age the muscle mass drops by 20 %, equally does the power and endurance, so the total reduction of muscle efficiency is higher than 20 % and approaches 40 %.

Concentration of carnosine and its antioxidative effect drops to the half of original values during this period. This reduction of carnosine content in muscles is most probably also influenced by reduction of muscle mass, power, and endurance due to age.

Active, strong so called fast muscle fibres contain big amount of carnosine, while the weak and atrophic ones contain significantly less carnosine. Russian scientist Severin proved already in the fifties that supplying carnosine to the liquid where incubated isolated exhausted muscles were kept caused almost immediately recovery of the full muscle energy.

Australian team of Dr. MacFarlane has recently proven that supplying carnosine increases power and endurance of tired muscles. It is interesting that supplementation with carnosine is directly related to the final effect on the muscle: the more carnosine is supplied, the higher its content in muscles and consequently the power and endurance increases comparably. Role of carnosine was also scientifically investigated in various neuro-muscular disorders. Results of those trials recommend supplementation of carnosine in these disorders. Obviously curing of these severe diseases is not expected, but oxidative stress accompanying these diseases can be reduced, contractility of muscles can be increased, and power and endurance can be donated. Muscles of patients with Duchenne muscle dystrophy contain just half of the carnosine levels compared to the muscles of healthy people, so the supplementation with carnosine is plausible.

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Carnosine plays an important role in the following neurological disorders:● ALS (amyotrophic lateral sclerosis)● Duchenne muscle dystrophy● FSH muscle dystrophy● Myasthenia gravis● Polymyositis● Muscle disorders induced by drugs (e.g. statins, cholesterol reducing medication)● Mitochondrial myopathy (late stages)

11. Carnosine in sport.Russian scientist E. S. Severin proved already in 1953 that carnosine significantly contributes To physio-chemical balancing of acidity (buffering) in skeletal muscles by keeping acidobasic balance during the intensive muscle work where surpluses of H+ produced in relation with accumulation of lactic acid take place – whereas significant increase of acidity in muscles causing muscle tiredness, reduced power and endurance appears together with regeneration slowdown. Carnosine represents 30 % of total buffering capacity of organism. Recent studies confirmed that increased concentration of carnosine leads to increased buffering capacity for H+, i.e. carnosine regulates (buffers) intracellular acidity (pH). It is important that carnosine has this feature also supplied before exercise.

It is generally known that accumulation of lactic acid in working muscle causes decrease of pH, i.e. increase of acidity which results in muscle tiredness, and even exhaustion.

Reduction of carnosine concentration in the course of life leads to suppression of muscle power and endurance. Supplementation with carnosine leads to its increased concentration, thus recovery and increase of power, resistance, endurance, and accelerated regeneration.

Carnosine also helps the function of so called calcium pump in sarcoplasmatic reticulum of muscle cells, and maintains the calcium channels opened. The pump stops working at lack of carnosine, calcium channels are closing as a consequence of acidity increase, lipid peroxidation increase, and accumulation of malondialdehydes (MDA). Carnosine prevents development of these harmful reactions, and represents an ideal physiologic additive in sport. Carnosine is not declared as a doping substance.

In sport and body-building, carnosine is participating on detoxication of reactive aldehydes formed by lipid peroxidation during the muscle work. That way carnosine protects muscles against damaging, increases their power, resistance, endurance, and accelerates regeneration – this was confirmed by a proven number of trials. Above mentioned features of carnosine were also investigated from the view of quantity that is able to provide those features. Studies proved that minimum quantity is 2.5 mM to stop lipid peroxidation, and 1.0 mM to suppress carbonylation. These concentrations are reachable at carnosine supplementation after several months (even after 13 months according to one trial). Food containing 1.8 % carnosine provided concentration growth in muscles up to 5 times yet after 8 weeks. Carnosine represents an ideal supply for athletes.

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12. Disorder of potency.Production of nitrate oxide (NO) in penis is a precondition to initiate and maintain erection. Carnosine is a natural source of NO, in another words, body creates NO from carnosine. Carnosine supplementation automatically improves potency.

13. Cataract.Carnosine not only suppresses AGEs – one of the main processes leading to cataract, but also protects normal proteins against toxic effect of AGEs already developed. This knowledge is rather new, since 2000, when papers from King‘s College, University of London (C. Brownson, A. R. Hipkiss et al.) on effects of carnosine were published. Experiments were based on the following: glycated ovalbumine was created (proteinof egg white was impaired by effect of a known glycating substance, methylglyoxale). This way impaired ovalbumine was mixed with cristaline, eye lens protein, and caused formation of cross-linings in cristaline, and thereafter its opacity. Carnosine not only prevented cristaline from impairment, but also recovered its structure, and transparency.

Next studies confirmed positive effects of carnosine on developed glaucoma, and its prevention. This finding is very important also for patients suffering with Alzheimer’s and Parkinson’s disease, where glaucoma has an increased incidence. Effect of carnosine eye drops in delaying of aging process of eye and sight, has been definitely proven, and it has been found to be almost 100 % effective in cases of primary senile cataract, and in 80 % cases of developed senile cataract. These drops penetrate aqueous and lipid eye parts, where carnosine acts preventively and correctively on light induced DNA. Carnosine drops are administered regularly as a medication for several eye diseases in some countries.

14 . Diabetes and its complications.Diabetics excrete increased quantity of sugar and other substances such as proteins, amino acids(arginine, carnosine, taurine, etc.), and magnesium with urine. Obviously they impoverish their body with those necessary substances. Diabetes intensifies processes of glycation concomitantly with growing deficiency of carnosine, which is one of the reasons (not the only one however) for arteries of diabetics to be more prone to thickening of their walls, thus developing atherosclerosis. Incidence of atherosclerosis in diabetics is three times higher (including incidence of myocardial infarction, and cerebrovascular disorders) as in nondiabetics.

Carnosine is a substance that controls levels of blood sugar via H3-receptors of autonomous (vegetative) nervous system. Tests on animals have proven that pregnant rats with the lack of carnosine have significantly higher risk to bear diabetic offspring. This is explained by the effect of carnosine which improves glucose tolerance of the fetus. This way carnosine can be a valuable additive for diabetic mothers as it reduces risk of their children falling ill with diabetes.

Carnosine is suitable for all types of diabeties because it reduces the risk of diabetic complication development, i.e. heart disease, cerebrovascular events, atherosclerosis, kidney damages, and eye complications.

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15. Cardiovascular disorders.Healthy myocardium naturally contains a certain amount of carnosine.Supplementation of carnosine however increases very significantly (even by 30 %) power and endurance of the heart muscle. Loss of contractility of myocardial cells is a common reason of death caused by damages from ischemic heart disease. Based on recent pharmacologic trials carnosine improves contractility of myocardium even in the course of ischemia equally well as verapamil (medicine - blocker of calcium channels), often prescribed as a medicine of heart diseases. This way carnosine opens brand new horizons in treatment of heart insufficiency. beneficial effects of carnosine on cardiovascular disorders can be summarized based on performed trials:● increased power of contractions of myocardium● reduced high blood pressure● protection against oxygen deficit (hypoxia, ischemia) in tissues at ischemic heart disease● prevention of LDL-cholesterol oxidation, and atherosclerosis development

Carnosine can be broadly used to treat all forms of reduced heart pumping efficiency. Moreover, carnosine reduces level of leptine, hormone of obesity. This hormone is several times higher in blood of diabetics, and lifts the blood pressure, too.

Interesting experiments were performed with aim to explain the effect of carnosine on rats with programmed hypoxia (lack of oxygen), i.e. exposed to environment with such oxygen deficiency as to cause inability to move. Revitalisation was performed by adding oxygen to their environment. Rats treated with carnosine were able to get up after 4,3 minutes, untreated ones only after 6,3 minutes, which is a statistically significant difference.

Next study was performed with animals with artificially induced brain stroke. Carnosine indicated significant neuroprotective effects (protection of nerve cells against damage) in ischemized brains (brain with insufficient oxygen supply). Rats supplemented with carnosine had normal ECG readings, less accumulated lactic acid (general indicator of damage severity), and demonstrated better parameters of brain blood circulation.

Finally it is possible to state that carnosine is an outstanding nutrition additive in prevention and treatment of almost all cardiovascular disorders.

16. Neurologic and mental disorders – carnosine’s role in nerve protection.

– Alzheimer’s disease and mild cognitive impairment– Parkinson’s disease– Epilepsy and schizophrenia– Autistic disorders– Vascular brain disorder, vascular brain events (stroke)Carnosine is a versatile neuroprotectant. Evolution ensured that healthy and young nerve cells of brain contain sufficient amount of carnosine for protection of very valuable cells against damage, and degenerative changes. Protective features refer mainly to antioxidative effects of carnosine, and prevention of glycation and carbonylation, as mentioned above. Moreover, carnosine protects proteasoma, which plays a central role

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in removal of harmful carbonylated proteins. Carnosine simply stops the process of protein deformation, and “paves” the way to prevention, and delays the progression of Alzheimer’s disease and next types of dementia, and mild cognitive impairment.

At chronic disorders of brain, Alzheimer’s and Parkinson’s diseases, epilepsy, depressive disorders, schizophrenia – everywhere oxidative stress is prevailing, and the above mentioned concomitant harmful degenerative processes are ongoing at these diseases at an alarming rate. Glycation denaturates proteins and phospholipids followed by production of AGEs, which are “fuel” for oxidation of cell membrane lipids.

Oxidative stress increases activity of enzyme phospholipase A2 (PLA2) that disrupts fatty acids of cell membranes, which causes violation of membrane integrity, and heavy function failure of cells until death. All these harmful reactions disturb the function of neurotransmitters at the same time. Carnosine not only reduces the oxidative stress, but reduces the damage from the following or concomitant processes (glycation, carbonylation, AGEs). Carnosine also acts directly as a neurotransmitter, anticonvulsive agent, and chelating substance (binding heavy metals). This way it becomes a versatile substance protecting against neurologic and mental syndromes and disorders.

Alzheimer’s disease and MCI - mild cognitive impairment. Alzheimer’s disease is a degenerative disease of brain causing progressive memory disturbance and cognitive abilities.

Disease slowly and mercilessly attacks nerve cells in all parts of brain cortex, and surrounding structures resulting in the inability of the patient to control emotions, differentiate errors, mistakes, patterns, coordinate movements, and ability to remember. Patient in the final stage completely loses memory and all mental functions. Cure has not yet been found, and medication used currently yields insufficient results.

Apart from the progressive nerve cell destruction it is possible to detect broad spectrum of other abnormalities in dead patients on Alzheimer’s disease including extracellular deposit of amyloide and microscopic bunches of fibres intracelularly – inside nerve cells. Experimental works have found that carnosine is able to reduce or completely avoid cell damage, where the reason is toxic impact of amyloide, protein typical for Alzheimer’s disease. Beta-amyloid reacts with certain RAGE receptors, and causes damage to nerve cells and brain arteries. Carnosine blocks and inactivates beta-amyloid, and so protects nerve tissue against dementia developing.

Moreover, carnosine protects brain cells with its neutralizing effect against highly toxic substance – alfa-beta-unsaturated aldehyde of acroleine – formed during peroxidation of multi-unsaturated lipids (PUFA). This substance very likely acts as “toxicological second messenger” during oxidative (i.e. free radicals) destruction of cell membranes. Recent research has found that also toxic unsaturated crotonaldehyde (CA) participates in the following process of protein and phospholipid destruction (mainly of cell membranes) – by carbonylation influenced by lipid peroxidation. Due to the fact that carnosine fights all aldehydes, explanation of next action is offered as an important preventive factor of Alzheimer’s disease and other diseases associated with oxidative stress.

Carnosine acts preventively also on next mechanisms accompanying Alzheimer’s disease. Some studies on this disorder have found increased concentration of zinc

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and copper ions in brains of the patients. These ions probably change the chemical construction of normal beta-amyloide, and are reason of its toxicity. This change demands slightly acidic environment to make it happen, i.e. to bind the zinc and/or copper ion with beta-amyloid. These conditions (acidic medium and increased concentration of zinc and copper ions) are generally present as a part of inflammatory reaction on site of the damage.

Carnosine as an exceptional “chelator” of zinc and copper (and other metals) is able to remove these metals from the body (as described above). This may imply another important function of carnosine in prevention and delay of progress in Alzheimer’s disease and other degenerative brain diseases .

Mild cognitive impairment – MCI.This disorder is currently described as transition between healthy aging of cognitive function and dementia. Studies dealing with the issue of MCI, assume important role of multiplicity of this disorder together with statement that the role of some causal processes are underestimated, such as cerebrovascular illness. At such multiplicity it is very difficult to correctly identify the prevalence, prognosis, and possible benefit and advantage of treatment. Carnosine with its powerful neuro-protective effect is offered as an ideal supplement for persons in suspicion on developing MCI or its initial stages.

Parkinson’s disease.Final cause on the atomic level are toxic free radicals and their toxic metabolites, that destroy certain brain cells. H2 O2 and TCA (tetracanoylphorbolacetate) are such free radicals and are able to early destroy brain cells. Carnosine is able to avoid formation of these radicals and therefore protects brain cells against damage. Next, the so called Lewy particle in brain of Parkinson’s patients accumulates a substance called alfa-synuclein, which accelerates the process of disease. Alfasynuclein is created in oxidative stress – and carnosine is able to reduce the oxidative stress, and accumulation of alfa-synuclein. Therefore carnosine is already recommended as additional treatment of Parkinson’s disease.

Epilepsy and schizophrenia.These chronic disorders also belong to the big group of diseases, where on damaging of brain cells oxidative stress and carbonylation is participating. Because carnosine effectively suppresses both forms of reaction, it becomes a suitable nutrition additive to the treatment of those patients. Carnosine has important anticonvulsive effect, as it was proved in trials lately.

Vascular brain events.Laboratory experiments have proven that supplementation with carnosine protects brain cells against damage from oxygen insufficiency (ischemia which is demonstrated at or after sudden closure of some brain arteries (stroke, ictus). The result of one of the trials has found mortality in rats after ischemic stroke as high as 67 % . In the group treated with carnosine (i.e. supplementation with carnosine had been initiated before the ictus) the mortality was 30 %. Another trial finished with similar results – mortality after ischemic attack dropped from 55 % to 17 %. Therefore a growing number of

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researchers share the opinion that carnosine is a beneficial supplement for secondary prevention of vascular brain events.

Disorders of autistic spectrum.It was quite an excitement when Dr. Michael Chez, neurologist, published treatment results of autistic diseases (autism and Asperger’s syndrome). Since 2001, he has treated almost 1 000 autistic children with carnosine. He claims that in 80 to 90 % of cases, the condition has significantly improved as early as 8 weeks after the start of the treatment. According to Dr. Chez, carnosine acts in frontal parts of brain where it joins its effects with effects of neurotransmitters acting in deep parts of the brain. Remarkable results of this treatment were confirmed by parents of autistic children, even on the first week after treatment onset. Improvement has been observed not only in communication area, but also in behaviour and social contacts. Treatment of dyslectics treated by Dr. Chez also manifested improvement, mainly in the area of reading skills and level of attention. Beyond the report on treatment of mentioned number of autistic children Dr. Chez performed a double-blind study with 31 autistic children with similar results. He administered 400 mg carnosine daily, and no side effects were observed.

17. Further beneficial effects on health.Historically since 1936, carnosine has been used in treatment and prevention of stomach ulcers. Recent trials have found that carnosine very significantly suppresses forming of erosions and ulcerations in stomach and duodenum. Ulcer diseases and non-ulcerous digestive disorders (dyspepsia) impact millions of people worldwide. They are the reason behind the high morbidity and impose great financial expenses on diagnostics and treatment. One of the primary reasons is the Helicobacter pylori infection, which is present at nearly 75 % cases of disorders. Most infected are probably the carriers of this infection on next persons. Second main reason is using of nonsteroid antirheumatics (NSAID), including aspirin. These medicines suppress activity of cyclooxygenase (COX), a useful enzyme responsible for keeping integrity of mucosa in upper part of digestive tract, and for blood flow support to stomach. Despite deployment of modern nonsteroid antirheumatics with activity mainly against another form of cyclooxygenase (inhibitors COX-2), which is placed mainly in the joint cartilage, these medicines remain dangerous, however smaller for digestive tract as far as the ulcerations.

Further beneficial effects of carnosine are:– support of immune system and suppression of inflammatory processes,– significant support of wound healing, and protection against radiation, including

suppressing of post-radiation syndrome,– prevention of malignancies

18. Carnosine for longevity.Quite a broad research documents that carnosine has important anti-aging potential given its exceptional abilities to protect and extend functional viability of key building

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units of organism, i.e. cells, proteins, DNA, and lipids. Carnosine can be quite frankly called a substance of longevity. And since this substance is safe, naturally occurring in organism and food, and found to extend life in animals and cultures of human cells, it becomes the fundamental substance for life extension program.

How does carnosine extend life?Answer to this question is not fully known, but features of carnosine point to mechanisms of aging of cells and tissues, and to anti-aging propertiex, which suppress these processes. Interesting experiments have been carried out by Russian experts by the end of 1990s, which tested effects of carnosine against aging in mice –average life time and signs of senescence (aging) in mice with accelerated aging process was tested. Half of the mice were given drinking water with carnosine since second month of life Here carnosine extended life in average by 20% compared to the control group fed without carnosine. Moreover, these mice with accelerated aging with average life of 15 months, show signs of aging in average in10th month. Mice fed with the addition of carnosine were still without signs of aging in 12th month.

Their fur has shown quite visible signs of “youth” in this age – glossy fur (44 % versus 5 %), a lower occurrence of skin ulceration (typical sign of age in these mice) (14 % versus 36 %).

Carnosine also significantly reduced occurrence of spinal lordokyphosis (pathologic spine curving as next aging sign), and skin lesions around eyes, but had no impact on occurrence of corneal opacity. However the sharpest contrast was observed in behaviour – just 5 % mice without carnosine showed normal behaviour in old age, compared to 58 % with carnosine.

Biochemical indicators of brain aging were tested as well. Membranes of brain cells of carnosine mice had statistically significant lower content of malodialdehyde (MDA), highly toxic product of oxidative (free radicals) damaged membrane lipids. Activity of monoaminooxidase B was lower by 44 % in carnosine mice, what points to maintenance of dopamine production (neurotransmitter whose lack leads to Parkinson’s disease). Glutamate bound to its cell receptors double in carnosine mice. As glutamate is the main excitation transmitter, it can explain normal behaviour of mice fed with carnosine. This trial has found that carnosine significantly improves signs of aging given the physiologic health, behaviour, and brain biochemical indicators, including life extension in genetically altered mice with accelerated aging. Authors of this trial modestly conclude that mice fed with carnosine could be characterized as being more resistant to the development of signs of aging.

19. Carnosine as a medicine and a nutrition additive.For many years, this remarkable substance has beeb recommended with a broad range of treatment options. For example in 1935 as medicament for polyarthritis, in1936 to treat ulcer diseases of stomach and duodenum. Some recent studies recommend combination of zinc and carnosine, which has important protective effect against various mucosa triggering substances, and shows healing effect even with existing ulcers of digestive tract.

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Carnosine has a strange property, it is able to regulate cell and enzymatic processes, when “out of order”: when the processes are in excess, they are suppressed (down- regulation), when they are insufficient, they are supported (up-regulation) – e.g. carnosine represents antiagregating features (reduction of increased blood clotting, i.e. risk of thromboembolic events, “blood dilution”) in patients with increased clotting, vice-versa increases aggregating features of thrombocytes in people with increased bleeding. Carnosine has protective and stabilizing effect on cell membranes, increases their resistance and period of survival in adverse conditions, and does offer possibility of medicinal use in chemically induced haemolytic anaemia.

20. Posology.It has been found that doses from 50 mg carnosine effectively reduce concentration of malodialdehyde (MDA – sign of oxidative stress) excreted by urine. Currently recommended dosage:– for preventive purposes, and as component of anti-senescence programs (i.e. against

aging) suitable doses are 100 – 200 mg/day, without interruption, permanently– as additional treatment of chronic conditions like autism, muscle dystrophy, etc. 300 –

800 mg/day– 1 500 – 2 000 mg daily are not recommended despite they do not prove adverse effects

nor complications, from the reason that those mega doses do not significantly increase its favourable effects. Sportsmen are exception, for those are mega doses very useful – particularly during limited period of sporting event.

21. Conclusion.Effects of carnosine result from previous text. Several most important properties are mentioned:– safe, naturally occurring in body and food– anti-inflammatory and anticancer effect– universal antioxidant and aldehyde sweeper– absorbs toxic effects of hydroxyl, superoxyl and peroxyl radicals– perfect protector of chromosomes (DNA) against damage by free radicals– suppresses effective lipid peroxidation– significantly absorbs (natural way) glycation processes– inhibitor of AGEs formation, protects proteins against damage by AGEs– suppresses formation of protein cross-linking– represents multifunctional protection of proteins and phospholipids– protects proteins against damage by carbonylation– inhibits processes of damaging healthy proteins by their denaturised forms– helps recycling damaged proteins by protecting proteasoma– helps to preserve normal protein recovery– significantly positive effect in autistic diseases– protects brain cells against damage– protects brain proteins and biochemical parameters

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– acts as neurotransmitter– rejuvenates cultivated human cells in senescence– extends life time– protects against toxic impact of heavy metals, chelates zinc and copper, chelates of zinc

and copper created by carnosine then resolve plaques at Alzheimer’s disease (positive effect of these chelates)

– suppresses formation of cross-linking of beta-amyloide at Alzheimer’s disease and their penetration into plaques.

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183. Suh YH, Checler F. Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer‘s disease. Pharmacol Rev. 2002 Sep;54(3):469-525. Sunderman FW Jr. Nasal toxicity, carcinogenicity, and olfactory uptake of metals. Ann Clin Lab Sci. 2001;31(1):3-24. Review. Suslina ZA, Federova TN, Maksimova MIu et al. [Antioxidant therapy in ischemic stroke] Zh Nevrol Psikhiatr Im S S Korsakova. 2000;100(10):34-8

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Effective dipeptide,For a more colorfull life.

Unique composition of Carnosine EXTRA assures:

• longer action of carnosine in organism (8 to 12 hours),

• guarranteed action of carnosine in cell mitochondria,

• formation of healthy cells and suspension of damaged cells.

1 capsule contains: % RDD

carnosine 125 mg —d-alfa-tocoferyl succinate,corresponding to 16 mg vitamin E 20 mg 130 %

L-carnitine 13,6 mg —coensyme Q10 20 mg 33,33 %extrakt from blueberries 20 mg —extrakt from wine grapes 20 mg —

% RDD = % recommended daily dose

Ordering is simple:

�call 0850 555 001�mail to objednavky@carnomed.sk�visit our internet shop www.shop.carnomed.sk

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CarnoMed, s.r.o.Partizánska 2811 03 Bratislava

0850 555 001

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