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Life Extension Magazine

LE Magazine January 2001

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Two Japanese studies demonstrate carnosine's ability to stabilize and protect cultured fibroblasts. The first study shows that carnosine stimulates a factor called vimentin that promotes robustness in cultured fibroblasts (Ikeda D et al., 1999). Vimentin is a structural protein that imparts strength and stability to fibroblasts and endothelial cells.

The second Japanese study showed that carnosine preserves the integrity of rat fibroblasts in a nutritionally deficient culture medium (Kantha SS et al., 1996). Fibroblasts grown in this culture medium lost their characteristic form after one week, while those grown in the carnosine supplemented culture retained their healthy appearance. After four weeks those fibroblasts grown in the carnosine medium retained cellular integrity, while the others were no longer viable.

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When the scientists transferred late-passage fibroblasts to a culture medium containing carnosine, they exhibited a rejuvenated appearance and often an enhanced capacity to divide.

The study also examined levels of 8-hydroxydeoxyguanosine (8-OH dG), a marker of oxidative damage to DNA, in fibroblast cultures with and without carnosine. They found that carnosine significantly reduced 8-hydroxydeoxyguanosine levels in fibroblasts after four weeks of continuous culture. DNA oxidation is thought to contribute importantly not only to cellular senescence, but also to carcinogenesis, and indeed 8-hydroxydeoxyguanosine has been proposed as a marker for cancer risk (Kasai H, 1997).

Carnosine's revitalizing effects on cultured fibroblasts may explain why it improves post-surgical wound healing. Another Japanese study showed that carnosine enhances granulation, a healing process in which proliferating fibroblasts and blood vessels temporarily fill a tissue defect (Nagai K et al., 1986). A Brazilian study showed that granulation tissue developed and matured faster, with a higher level of collagen biosynthesis, in carnosine treated rats (Vizioli MR et al., 1983). The Japanese study also presented evidence that carnosine restores the body's regenerative potential suppressed by common drugs.

Extending organism life span

Do carnosine's rejuvenating effects on cells extend to the entire organism? Similar anti-senescence effects have now been demonstrated in mice. A new Russian study tested the effect of carnosine on life span and indicators of senescence in senescence-accelerated mice (Yuneva MO et al., 1999; Boldyrev AA et al., 1999). Half the mice were given carnosine in their drinking water starting at two months of age. Carnosine extended the life span of the treated mice by 20% on average, compared to the mice not fed carnosine.

Carnosine did not alter the 15 month maximum life span of the senescence-accelerated mice strain, but it did significantly raise the number of mice surviving to old age. The mice given carnosine were about twice as likely to reach the “ripe old age” of 12 months as untreated mice. It also improved indicators of senescence measured at the “old age” of ten months.

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 significantly fewer had skin ulcers (14% vs. 36%). However, carnosine did not affect the loss or texture of hair. Carnosine significantly reduced the rates of spinal lordokyphosis (spinal curvature) and periopthalmic lesions, but did not affect corneal opacities.

The sharpest contrast between the treated and untreated mice was seen in their behavior. Only 9% of the untreated mice displayed normal behavioral reactivity, compared to 58% of the carnosine treated mice.

The researchers also measured biochemical indicators associated with brain aging. Brain membranes of the carnosine treated mice had significantly lower levels of MDA (malondialdehyde), a highly toxic product of membrane lipid oxidation. MAO-B (monoamine oxidase B) activity was 44% lower in the carnosine-treated mice, indicating maintenance of dopamine metabolism. Glutamate binding to its cellular receptors nearly doubled in the carnosine treated group. Since glutamate is the main excitatory neurotransmitter, this may explain the more normal behavioral reactivity of the carnosine-fed mice.

This study showed that carnosine significantly improved most measures of appearance, physiological health, behavior, and brain biochemistry—as well as extended life span—in senescence-accelerated mice. The researchers therefore conclude that “carnosine-treated animals can be characterized as more resistant to the development of features of aging” (Boldyrev AA et al., 1999).

Protein carbonylation

The reason why older people—and animals—look different than younger ones has to do with changes in the proteins of the body. Proteins are the substances most responsible for the daily functioning of living organisms, which gives protein deterioration its dramatic impact on the body's function and appearance. Many lines of research over the last decade converge on protein modification as a major pathway for aging and degenerative disease. These modifications result from oxidation (as by free radicals) and interrelated processes such as protein-sugar reactions (glycation).

Modified proteins accumulate as we age, while carnosine levels are declining. Once a protein is modified it has lost its ability to function normally, and when a significant portion of the body's protein has reached this point, the body becomes more prone to degenerative diseases.

The telltale sign of destructive protein modification is the protein carbonyl group. Accumulation of proteins with carbonyl groups is a molecular indicator of cell aging. Protein carbonyl levels increase markedly in the last third of the life span, rising almost exponentially with age in a wide variety of animal species and tissues. In humans, about a third of proteins become carbonylated later in life. At that level, these aberrant proteins are considered likely to have deleterious effects on most aspects of cellular function (Stadtman ER et al., 2000).

Many pathways of protein modification produce carbonyl groups, including oxidation of amino acid side chains, glycation and reactions with aldehydes and lipid peroxidation products (Berlett BS et al., 1997; Stadtman ER et al., 2000, 1992). The multiplicity of mechanisms behind protein modification places this problem beyond the scope of simple antioxidants. A pluripotent agent is needed whose biochemical profile matches this array of mechanisms. Carnosine emerges as the most promising broad spectrum shield against protein modification.

Carnosine addresses the major pathways through which proteins become carbonylated through its antioxidant and anti-glycation actions, its ability to quench reactive aldehydes and chelate metals, and its effectiveness against lipid peroxidation. Carnosine's properties fit the mechanisms of protein carbonylation so well as to invite the speculation that evolution “designed” carnosine to protect proteins from carbonylation and other deleterious modifications.

An excellent example of carnosine's broad-spectrum defense against protein modification is provided by MDA (malondialdehyde). This noxious product of lipid peroxidation causes protein carbonylation, cross-linking, glycation and AGE formation (Burcham PC et al., 1997).

Carnosine inhibits MDA from carbonylating albumin (the main serum protein) and crystallin (eye lens protein) in a concentration-dependent manner. MDA glycates albumin leading to cross-linking and production of advanced glycation end products (AGEs), however these changes too were prevented by carnosine. Table 1 summarizes some of the many laboratory studies demonstrating that carnosine protects proteins against diverse protein damaging agents.

Study
Test Substance(s)
Protein Damaging Agent
Inhibited or Reversed Carbonylation?
Inhibited Cross-Linking or AGE Formation?
Hipkiss Preston,
et al., 1998
Serum albumin (the major plasma protein)
MDA
(lipid oxidation product)
X
X
Serum albumin (the major plasma protein)
Hypochlorite ions
(inflammatory response product)
X
X
DNA & histone
(DNA protein)
Formaldehyde or acetaldehyde
NA
X
Hipkiss Preston,
et al., 1997
Crystallin
(eye lens protein)
MDA
(lipid oxidation product)
X
X
Hipkiss & Chana, 1998;
Hipkiss & Brownson, 2000
Ovalbumin
(albumin from egg white)
Methylglyoxal
(promotes AGE formation)
X
X
Munch, Mayer,
et al., 1997
Amyloid beta
(forms senile plaques when cross-linked)
Fructose
NA
X
Hipkiss, Michaelis, Syrris, 1995
SOD
(key intercellular antioxidant)
Dihydroxyacetone
NA
X
Catalase
(enzyme that catalyzes breakdown of hydrogen peroxide)
Fructose
NA
X
Hipkiss, Michaelis, syrris, et al., 1995
Anti-thrombin III
(anticoagulant blood protein), serum albumin, or crystallin
Fructose
NA
X

Table 1. Protective effects of carnosine on protein carbonylation, cross-linking and AGE formation. NA = Not Applicable (not measured in study)

 

Continued on Page 3
References on Page 5


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