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SPECIAL REPORT
From The Life Extension Foundation

New Anti-Aging Mandate:
"PROTECT YOUR PROTEINS"

Research over the last decade points to protein degradation as a major pathway for aging and disease. Proteins are the substances most responsible for the daily functioning of living organisms. Destruction to proteins can be caused by oxidation (as by free radicals) and protein-sugar reactions (glycation).

Once too many proteins lose their ability to function, the body becomes prone to degenerative diseases and premature aging. Carnosine, an amino acid compound, has been shown to specifically protect against the age-related degradation of protein.

Laboratory research suggests that carnosine has the ability to rejuvenate cells and extend cellular life span.

Carnosine quenches the most destructive protein oxidizing agent (the hydroxyl radical). One study showed carnosine was the only antioxidant to significantly protect cellular chromosomes from oxidative damage.

Antioxidants, however, cannot completely protect proteins. Nature's second line of defense is to repair or remove damaged proteins. This is where carnosine demonstrates its most potent anti-aging effect.

Protein degradation occurs as a result of cross-linking and the formation of advanced glycation end products (AGE). These changes figure prominently in the processes of aging and its typical signs such as skin wrinkling and brain degeneration.

Studies show that carnosine is effective against cross linking and the formation of advanced glycation end products (AGE). Glycated proteins produce 50-fold more free radicals than nonglycated proteins and carnosine may be the most effective anti-glycating agent known.

An example of carnosine's defense against protein degradation is provided by MDA (malondialdehyde). MDA causes protein cross-linking and AGE formation. Carnosine has been shown to inhibit MDA-induced glycation in blood albumin and eye lens protein. Carnosine has also been shown to keep MDA from inducing protein cross-linking. One study showed that carnosine actually decreased MDA levels in mice.

Carnosine is highly concentrated in the brain. The reason is that the brain uses carnosine to protect against cross-linking, glycation, excitotoxicity and oxidation. Animal studies show that carnosine provides broad protective effects in simulated ischemic stroke.

Abnormal copper and zinc metabolism stimulates senile plaque formation in Alzheimer's disease. Chelators of these metals dissolve plaques in the laboratory. Carnosine is a potent copper-zinc chelating agent that can inhibit the cross-linking of amyloid-beta that leads to brain cell plaque formation. A signature of Alzheimer's disease is impairment of brain arterial and capillary system. Carnosine has been shown to protect the cells that line brain blood vessels from damage by amyloid-beta as well as by products of lipid oxidation and alcohol metabolism.

Carnosine extends cellular life span

Our bodies are in large part comprised of cells that replace themselves by dividing. There is a genetic limit as to how many times healthy cells will continue to replicate in tissue culture. There is evidence that cells taken from older people replicate less frequently than cells taken from younger people. Carnosine appears to extend the period of time that cells will continue to divide in a youthful manner.

Laboratory research suggests that carnosine has the ability to rejuvenate cells approaching senescence (the end of the life cycle of dividing cells), restoring normal appearance and extending cellular life span.

When scientists transferred late-passage fibroblasts (a type of skin cell) to a culture medium containing carnosine, they exhibited a rejuvenated appearance and often an enhanced capacity to divide. The carnosine medium increased life span, even for old cells. Cells transferred to the carnosine medium attained a life span of 413 days, compared to 126-139 days for the control cells. This study showed that carnosine induced a remarkable 67% increase in cellular life span.

These aged cells also grew in the characteristic patterns of young cells, and resumed a uniform appearance in the presence of carnosine. But when the scientists transferred the aged cells back to a medium lacking carnosine, the signs of senescence quickly reappeared. The scientists switched late-passage cells back and forth several times between the culture media. Carnosine consistently restored the youthful cell phenotype within days, whereas the standard culture medium (without carnosine) brought back the senescence cell phenotype.

How does carnosine revitalize cells in culture? Some researchers propose that carnosine may rejuvenate cells by reducing the formation of abnormal proteins, or by stimulating the removal of old proteins.

Carnosine extends organism life span

A study tested the effect of carnosine on life span and indicators of aging in senescence-accelerated mice. Carnosine extended the life span of the treated mice by 20% on average, compared to the mice not fed carnosine. The mice given carnosine were about twice as likely to reach the "ripe old age" of 12 months as untreated mice.

Carnosine did not alter the 15 month maximum life span of the senescence-accelerated mouse strain, but it did significantly raise the number of mice surviving to old age. Carnosine distinctly improved the appearance of the aged mice, whose coat fullness and color remained much closer to that of young animals. Significantly more carnosine-treated mice had glossy coats (44% vs. 5%), while fewer had skin ulcers (14% vs. 36%).

The researchers also measured biochemical indicators associated with brain aging. Carnosine treated mice had significantly lower levels of toxic MDA (malondialdehyde) in their brain cell membranes. MAO-B (monoamine oxidase B) activity was 44% lower in the carnosine-treated mice, indicating maintenance of youthful dopamine metabolism. Aging humans produce too much MAO-B, and this is thought to contribute to certain types of brain cell damage. Glutamate binding to its cellular receptors nearly doubled in the carnosine treated group, which may explain the more normal behavioral reactivity of the carnosine-fed mice.

This longevity study showed that carnosine significantly improved most measures of appearance, physiological health, behavior and brain biochemistry-as well as extending life span. The researchers concluded that "carnosine-treated animals can be characterized as more resistant to the development of features of aging."

Carnosine chelates copper and zinc

Copper and zinc are neurological double-edged swords. While the body cannot live without them, new research confirms that they can also be neurotoxic. Abnormal copper-zinc metabolism is implicated in Alzheimer's disease, stroke, seizures and many other diseases with neurological components.

Copper and zinc appear to be needed to modulate synaptic transmission, but can become neurotoxins at the concentrations reached when they are released from synaptic terminals. The brain must buffer these metals so that they can perform their functions without neurotoxicity. The new research on copper-zinc toxicity shows that carnosine provides that buffering action.

When scientists exposed rat neurons to physiological concentrations of copper or zinc the neurons died. However carnosine at a modest physiological concentration protected the neurons from the toxic effects of these metals.

A spate of recent research papers point to the role of abnormal copper and zinc metabolism in the development of Alzheimer's disease. This abnormal copper and zinc metabolism contributes to amyloid-beta formation and toxicity through a host of mechanisms.

These findings on copper and zinc as Alzheimer's disease promoters led scientists to investigate the effect of metal chelators on amyloid-beta plaques. A recent laboratory experiment by an international team of scientists found that chelators of copper and zinc solubilize (dissolve) aggregates of amyloid-beta in post-mortem human tissue samples from the brains of Alzheimer's disease patients. They hypothesize that:"Agents that specifically chelate copper and zinc ions but preserve magnesium and calcium may be of therapeutic value in Alzheimer's disease."

Carnosine fits this metal chelating profile, offering pH buffering and hydroxyl radical scavenging actions in addition. Not only does carnosine chelate copper and zinc, but the presence of copper and zinc ions enhances carnosine's potency as a scavenger of the superoxide radical.

Microvascular damage is the harbinger of Alzheimer's disease, preceding its other pathological features, possibly by impairing delivery of nutrients to the brain. An experiment on rat brain blood vessel walls shows that carnosine prevents this damage.

In another experiment carried out by the same British team, carnosine protected brain blood vessel cells from damage by MDA (malondialdehyde), a toxic product of lipid peroxidation. Carnosine inhibited protein cross-linking, while protecting cellular and mitochondrial function. A third experiment showed that carnosine also protects cells against the toxicity of acetaldehyde, which is produced when alcohol is metabolized.

Carnosine protects against excitotoxicity and stroke

Many neurological disorders are caused by excitotoxicity. 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.

Two further Russian studies tested carnosine in animal experiments designed to simulate stroke. In the first experiment, rats were exposed to low pressure hypoxia. 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.

Carnosine and skin aging

In the inner layer of the skin (the dermis), the population of fibroblasts (connective tissue cells) is cut in half by age eighty.

Protein degradation damages all components of the epidermis and dermis, leading to loss of elasticity, wrinkles, 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).

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.

Carnosine rejuvenates senescent fibroblasts (connective tissue cells). This helps to explain a series of research findings that carnosine significantly improves post-surgical wound healing.

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 art of the aging process.

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, 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, protecting cells from damage by lipid peroxidation toxins and increased the "flow-ability" 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.

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, 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, protecting cells from damage by lipid peroxidation toxins and increased the "flow-ability" 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.

How to use carnosine

It is critical to take the proper amount of carnosine each day in order to obtain a life extension effect. The reason for this is that the body produces an enzyme called carnosinase that degrades dietary carnosine. By taking at least 1000 mg a day of supplemental carnosine, you safely overwhelm the body's degradation enzymes and provide your cells enough carnosine to derive the benefits eluded to in the published research.

Commercial supplement companies offer carnosine in 50 mg strength tablets. This dose provides no benefit because the carnosine is degraded by the carnosinase enzyme before it can produce beneficial effects in the body.

The Life Extension Buyers Club is the first organization in the world to offer carnosine in 500 mg capsule strength. The suggested dose is one 500 mg capsule, twice or three times a day.

Even though the Buyers Club product is ten times more potent than commercial brands, Foundation members can obtain it at a fraction of the commercial price. The Buyers Club retails a bottle of 90 500 mg capsules of pure carnosine for $66.00. If a member buys four bottles during the SUPER SALE, the price is reduced to just $40.50 per bottle.

In 1999, The Life Extension Foundation introduced carnosine in a multi-nutrient formula called ChronoForte. The amount carnosine provided in the daily dose
of ChronoForte (six capsules) is 1000 mg.

In response to overwhelming evidence of the critical importance of carnosine, The Life Extension Buyers Club is pleased of offer low-cost Super Carnosine Caps that provide 500 mg of carnosine in each capsule.

Conclusion

Carnosine stands out as the most promising multi-modal life extension discovery of recent years. 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)

Carnosine is safe, with no toxicity even at dosages far above what humans would ever consume.

Many mechanisms have been identified as being responsible for aging. Consequently, an agent must work along multiple pathways of the aging process in order to control it.
Scientists have described carnosine as "pluripotent", i.e. active in a multitude of ways, in many tissues and organs. Carnosine's pluripotent life extension potential places it on a par with coenzyme Q10 as a cornerstone of longevity nutrition.

In the forthcoming issue of Life Extension magazine, two fully referenced dissertations about carnosine will be published that will enlighten the world to this breakthrough in the control of premature aging and its related diseases. In the meantime, carnosine is now available in pharmaceutical potency to Life Extension Foundation members.

Purchase Carnosine Here