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Carnosine: Nature's Pluripotent Life Extension Agent

January 2001

By Karin Granstrom Jordan, M.D.

Glycation and AGE formation

One of the processes that carbonylates proteins, glycation, is itself recognized as a major cause of aging and degenerative disease. Glycation occurs when proteins react with sugars. Then, through a series of reactions including oxidation, advanced glycation end products (aptly called AGEs) form.

AGEs accelerate aging processes and promote degenerative disease. This is not surprising when one considers that AGE formation in the body is the chemical equivalent of the browning of food in the oven—and equally irreversible. When proteins accumulate AGEs they do in fact turn brown. The “slow oven” of AGE formation turns proteins fluorescent, and cross- links them to a point where the body cannot break them down. As AGEs build up, tissues lose tone and resiliency and organ systems degenerate. For example, AGEs are now recognized as an important factor in atherosclerosis (Bierhaus A et al., 1998), cataracts, Alzheimer's disease (Munch G et al., 1998), and loss of skin elasticity (see “Skin Aging” in the article “Carnosine and Cellular Senescence” in this issue).

AGEs exert their harmful effects on two levels. Most obviously, they physically impair proteins, DNA and lipids, altering their chemical properties. They also act as cellular signals, triggering a cascade of destructive events when they attach to their cellular binding sites (see sidebar titled “AGEs and RAGE”). One consequence is a 50-fold increase in free radical generation. Since oxidative stress is often described as a “fixative” of AGE formation, a vicious cycle can ensue of oxidative stress and AGE accumulation.

Carnosine is by far the safest and most effective natural anti-glycating agent. Studies in a wide variety of experimental models demonstrate that carnosine inhibits protein glycation and AGE formation (see Table 1).

Through its structural resemblance to the sites that glycating agents attack in proteins, carnosine is thought to act as a “sacrificial sink.” When carnosine becomes glycated, it spares proteins from the same fate. Glycated carnosine is not mutagenic, in contrast to amino acids such as lysine which becomes mutagenic when glycated, according to the well-known Ames test (Hipkiss AR, Michaelis J, Syrris P, et al., 1995).

Carnosine not only inhibits the formation of AGEs, it can also protect normal proteins from the toxic effects of AGEs that have already formed. An elegant experiment carried out at King's College, University of London, made this point (Brownson C et al., 2000; Hipkiss AR et al., 2000). The scientists employed a glycating agent called methylglyoxal (MG) that reacts with lysine and arginine residues in body proteins.

The scientists used MG to glycate ovalbumin (egg white protein). This produced a brown colored solution typical of the “browning” effect of glycation. They then incubated the glycated albumin with a normal protein, a-crystallin, from the lens of the eye. The glycated albumin formed cross-links with the crystallin, but this was inhibited by carnosine.

The study demonstrated that carnosine can stop protein damage from spreading to healthy proteins. It also found evidence that carnosine reacts with and removes the carbonyl groups in glycated proteins. This study reinforces the body of research demonstrating carnosine's unique three-stage protection against accumulation of aberrant proteins: carnosine protects against protein carbonylation, inhibits damaged proteins from damaging healthy proteins, and helps the proteolytic system dispose of damaged and unneeded proteins.


The main binding site for AGEs is appropriately called RAGE (receptor for AGEs). The binding of AGEs to RAGE induces cellular activation and intracellular oxidative stress, which lead to generation of assorted cytokines, growth factors and transcription factors such as nuclear factor kappa beta (Schmidt AM et al., 1999).

AGE binding to RAGE tends to be self-amplifying, since the more AGEs bind to RAGE, the more RAGE binding sites develop. This creates a “positive feedback loop” leading to spreading waves of cellular activation and tissue damage (Schmidt AM et al., 1999).

The implications of the discovery of RAGE become revolutionary when one considers that amyloid-beta, the senile plaque material in Alzheimer's disease, also binds to RAGE with similar effects (Yan SD et al., 1996). Scientists do not yet know how AGEs and amyloid-beta might interact in stimulating the RAGE response in Alzheimer's disease.

Genome protection

DNA is organized into chromosomes, each of which contains a double helical DNA structure carrying the genes. Oxidative stress causes breaks and other aberrations in the chromosome that accumulate with age. A fascinating experiment shows the paradoxical effects of antioxidants on oxidative damage to chromosomes (Gille JJ et al., 1991). This study used hyperoxia, exposure to nearly pure oxygen (90%), as a physiologically natural oxidative stressor. Hyperoxia is thought to generate free radicals at the same intracellular sites where they normally form over time.

The scientists tested the ability of several antioxidants—including vitamin C, n-acetylcysteine (NAC), vitamin E, carnosine and a form of glutathione—to protect the chromosomes in Chinese hamster ovary cells from oxidative damage. Some of the antioxidants tested acted instead as pro-oxidants: they increased chromosomal damage, aggravating the effects of hyperoxia. It is a well known phenomenon that single antioxidants can sometimes exert a pro-oxidant effect in the body, which is the reason people take multiple antioxidants. In this study, only one antioxidant, carnosine, significantly reduced chromosomal damage. Cells cultured without any antioxidant exhibited 133 chromosomal aberrations per 100 cells. Carnosine reduced this level of damage by two-thirds, to only 44 chromosomal aberrations per 100 cells. Carnosine preserved 68% of cells fully intact, as compared to 46% of the control cells.

Membrane lipid peroxidation

A major source of oxidative damage and cellular dysfunction in the brain is the oxidation of polyunsaturated lipids in the membranes of brain cells and their extensions such as axons. This chain reaction spreads oxidative damage and generates highly neurotoxic byproducts such as HNE and other aldehydes which are quenched by carnosine.

In Alzheimer's disease, lipid peroxidation products are thought to interfere with critical membrane proteins involved in cellular signaling and in transporting ions, glucose and glutamate. Their impairment leads to membrane depolarization, metabolic deficit, excitotoxicity and increased vulnerability to oxidative assault (Mark RJ et al., 1997; Butterfield DA, 1999).

As we have seen, carnosine feeding suppressed lipid peroxidation in the brains of old senescence-accelerated mice. Another mouse study tested the effects of carnosine on mice stressed with electric shocks for two hours (Gulyaeva NV et al., 1989). Carnosine protected brain cells from damage by lipid peroxidation products while increasing the “flowability” of cell membranes.

The study found that mice pretreated with carnosine displayed brain and blood levels of lipid peroxidation products more than 85% lower than in the untreated mice, and more than 70% lower even than in control mice who did not receive shocks. Brain SOD (superoxide dismutase) antioxidant activity was six times higher in the carnosine treated mice. Essential membrane phospholipid levels dropped by 9% in the untreated mice, but carnosine treatment actually raised them by 26%.


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, protein-sugar interactions leading to AGE formation (see above), lipid peroxidation, and copper and 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. We will survey carnosine's neuroprotective actions, with special attention to Alzheimer's disease.

Brain aging and degeneration are marked by protein carbonylation. A highly sensitive and specific assay was recently developed for protein carbonyls. Applied to human brain tissue, this assay reveals that the carbonyl content of neurons is several times as high in Alzheimer's disease patients as in control subjects similar in age (Smith MA et al., 1998).

Advances in cell culturing techniques permit scientists for the first time to maintain neurons in culture for extended periods. Scientists at the University of Kentucky used these techniques to study “aging in a dish” (Aksenova MV et al., 1999). They found that cultured neurons from the hippocampus of the rat fetus begin to rise in protein carbonyl content about a week before noticeable changes in neuronal viability appear. At a point when only 10% to 20% of neurons are no longer viable, protein carbonyl levels have already doubled. They observed swollen, unhealthy cell bodies in many of the cells with high carbonyl levels.

The Kentucky study also reinforced earlier findings correlating protein oxidation with declining activity of the energy-transfer enzyme creatine kinase, which is very sensitive to oxidation. This leads to diminished energy metabolism in the brain, a hallmark of Alzheimer's disease.

Animal studies demonstrate that brain protein carbonylation is associated with cognitive and behavioral dysfunctions. A study in senescent mice found that protein carbonyl levels in the brain cortex correlate with the degree of cognitive impairment, while levels in the cerebellum correlate with motor deficits (Forster MJ et al., 1996). An earlier study in aged gerbils showed increased protein carbonyl levels are associated with spatial memory loss (Carney JM et al., 1991, 1994).