|LE Magazine January 2001 |
Nature's pluripotent life extension agent
by: Karin Granstrom Jordan, M.D.
Page 1 of 5
A substance that protects and extends the functional life of the body's key building blocks—cells, proteins, DNA, lipids—can be fairly called an agent of longevity. When that agent is safe, naturally present in the body and in food, and has demonstrated prolongation of life span in animals and cultured human cells, it is fundamental to any life extension program. Mounting research suggests that carnosine has just such anti-aging potential.
Carnosine is a multifunctional dipeptide made up of a chemical combination of the amino acids beta-alanine and l-histidine. Long-lived cells such as nerve cells (neurons) and muscle cells (myocytes) contain high levels of carnosine. Muscle levels of carnosine correlate with the maximum life spans of animal species (Hipkiss AR et al., 1995).
Laboratory research on cellular senescence (the end of the life cycle of dividing cells) suggests that these facts may not be coincidences. Carnosine has the remarkable ability to rejuvenate cells approaching senescence, restoring normal appearance and extending cellular life span.
How does carnosine rejuvenate cells? We do not yet know the full answer, but carnosine's properties may point up key mechanisms of tissue and cell aging, as well as the anti-aging measures that counteract them.
Carnosine addresses the biochemical paradox of life: the elements that make and give life—oxygen, glucose, lipids, protein, trace metals—also destroy life in ways that are inhibited by carnosine. Carnosine protects against their destructive sides through potent antioxidant, anti-glycating, aldehyde quenching and metal chelating actions (Quinn PJ et al., 1992; Hipkiss AR, Preston JE et al., 1998). A prime beneficiary is the body's biggest target—its proteins.
The body is made up largely of proteins. Unfortunately, proteins tend to undergo destructive changes as we age, due largely to oxidation and interactions with sugars or aldehydes. These interrelated protein modifications include oxidation, carbonylation, cross-linking, glycation and advanced glycation endproduct (AGE) formation. They figure prominently not only in the processes of aging but also in its familiar signs such as skin aging, cataracts and neurodegeneration. Studies show that carnosine is effective against all these forms of protein modification.
As an antioxidant, carnosine potently quenches that most destructive of free radicals, the hydroxyl radical, as well as superoxide, singlet oxygen and the peroxyl radical. Surprisingly, carnosine was the only antioxidant to significantly protect chromosomes from oxidative damage due to 90% oxygen exposure.
Carnosine's ability to rejuvenate connective tissue cells may explain its beneficial effects on wound healing. In addition, skin aging is bound up with protein modification. Damaged proteins accumulate and cross-link in the skin, causing wrinkles and loss of elasticity. In the lens of the eye, protein cross-linking is part of cataract formation. Carnosine eye drops have been shown to delay vision senescence in humans, being effective in 100% of cases of primary senile cataract and 80% of cases of mature senile cataract (Wang AM et al., 2000).
Carnosine levels decline with age. Muscle levels decline 63% from age 10 to age 70, which may account for the normal age-related decline in muscle mass and function (Stuerenberg HJ et al., 1999). Since carnosine acts as a pH buffer, it can keep on protecting muscle cell membranes from oxidation under the acidic conditions of muscular exertion. Carnosine enables the heart muscle to contract more efficiently through enhancement of calcium response in heart myocytes (Zaloga GP et al., 1997).
The body is made up largely of proteins. Unfortunately, proteins tend to undergo destructive changes as we age, due largely to oxidation and interactions with sugars or aldehydes.
The high levels of carnosine in the brain may serve as natural protection against excitotoxicity, copper and zinc toxicity, protein cross-linking and glycation, and especially oxidation of cell membranes. Animal studies show broad protective effects in simulated stroke.
New research shows that copper and zinc dramatically stimulate senile plaque formation in Alzheimer's disease. Chelators of these metals dissolve plaques in the laboratory. Carnosine can also inhibit the cross-linking of amyloid-beta that leads to plaque formation. A signature of Alzheimer's disease is impairment of brain microvasculature. Carnosine protected the cells that line brain blood vessels (endothelial cells) from damage by amyloid-beta (senile plaque material) as well as by products of lipid oxidation and alcohol metabolism in laboratory experiments.
Now that many are cutting down on meat—the main dietary source of carnosine—supplementation becomes especially important. Carnosine is safe, with no toxicity even at dosages above 500 mg per kilogram of body weight in animal studies (Quinn PJ et al., 1992). It is most fortunate that carnosine is safe at high dosages because the body would neutralize lesser amounts of carnosine. The enzyme carnosinase (Quinn PJ et al., 1992) must be saturated with more carnosine than it is able to neutralize in order to make free carnosine available to the rest of the body.
There are thought to be many mechanisms responsible for aging. Consequently, an agent must work along many basic pathways of the aging process in order to control it. Scientists have described carnosine as “pluripotent”—active in a multitude of ways, in many tissues and organs (Hipkiss AR, Preston JE et al., 1998). Carnosine's pluripotent life extension potential places it on a par with CoQ10 as a cornerstone of longevity nutrition.
It is well known that cells have only a limited capacity to continue to divide through the course of life. For example, human fetal fibroblasts (connective tissue cells) divide no more than about 60 to 80 times in laboratory cultures. By young adulthood, fibroblasts have 30 to 40 divisions left, while in old age no more than 10 to 20 remain.
The limited capacity of the cell to perpetuate itself through division is called the Hayflick Limit, after the scientist who discovered it nearly four decades ago (Hayflick L et al., 1961; Hayflick L, 1965). In concert with telomeres, which count off the rounds of cell division, the Hayflick Limit caps life span at the cellular level. With each division a cell becomes less likely to divide again, until finally it stops dividing altogether and becomes senescent.
As cultured cells approach the Hayflick Limit they divide less frequently and take on strikingly irregular forms. They no longer line up in parallel arrays, assume a granular appearance, and deviate from their normal size and shape (McFarland GA et al., 1994). This distorted appearance, called the senescent phenotype, normally ushers in a twilight state called cellular senescence that until recently was thought to be irreversible (see the article “Carnosine and Cellular Senescence” in this issue).
Extending cell life span
In a remarkable series of experiments, scientists at an Australian research institute have shown that carnosine rejuvenates cells as they approach senescence (McFarland GA, 1999; McFarland GA, 1994). The scientists cultured human fibroblasts (connective tissue cells) from the lung and the foreskin. Fibroblasts that went through many rounds of division, known as late-passage cells, displayed a disorganized, irregular appearance before ceasing to divide. Fibroblasts cultured with carnosine lived longer, retaining youthful appearance and growth patterns.
What is most exciting is the ability of carnosine to reverse the signs of aging in cells approaching senescence. 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. They again grew in the characteristic whorled growth patterns of young fibroblasts, and resumed a uniform appearance. But when they transferred the fibroblasts back to a medium lacking carnosine, the signs of senescence quickly reappeared.
The scientists switched late-passage fibroblasts back and forth several times between the culture media. They consistently observed that the carnosine culture medium restored the juvenile cell phenotype within days, whereas the standard culture medium brought back the senescent cell phenotype.
The carnosine medium also increased life span, even for old cells. The number of PDs, or population doublings, provides a convenient measure of cell division. When late-passage lung fibroblasts at 55 PDs (population doublings) were transferred to the carnosine medium, they lived to 69 to 70 PDs, compared to 57 to 61 PDs for the fibroblasts that were not transferred. Moreover, the fibroblasts transferred to the carnosine medium attained a life span of 413 days, compared to 126 to 139 days for the control fibroblasts. Carnosine increased chronological life span more dramatically than PDs in the Australian series of experiments.
When cells in the carnosine medium eventually enter into cellular senescence, they nevertheless retain a normal or less senescent morphology. Carnosine's ability to retain or restore the juvenile phenotype suggests that it may help maintain cellular homeostasis.