Carnosine is a multifunctional dipeptide made up of a chemical
combination of the amino acids betaalanine 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 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.
Biological
rejuvenation
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.
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.
|