by Dallas Clouatre, Ph.D. and Sid Shastri
Most of us, when we think
about the signs of aging,
think about wrinkles, sagging
skin, sun damage,
aches and pains, perhaps
weight gain. Biochemists and medical
researchers see those same signs, but to these
scientists the important changes are structural.
To their eyes the significant changes are
those that alter the nature of cell membranes,
change DNA expression, oxidize fats and
make proteins less usable. These changes
alter the body’s repair mechanisms.
In the dance of life, the body is continuously
making and remaking itself. Aging ultimately
is the failure of the body to renew
itself. One of the primary ways in which this
happens is through damage done to proteins
when molecules of sugar and a few other
compounds become inappropriately
attached. In fact, glucose, the sugar the body
uses for fuel, is so often a culprit in aging that
some authors refer to molecules of sugar as
being the body’s “sands of time.”
How does sugar do this damage? Let’s
look first at another common source of
damage to tissues. The image of a cut apple
browning on exposure to air is a familiar one.
This example is often used to illustrate the
damage that oxygen can do to cells and how
antioxidants can help to protect health.
However, the picture is a little more complicated
than this image suggests. Antioxidants
are useful, but they are only one of the body’s
resources in the battle against time. This is
largely a result of the fact that oxygen is not
the only villain when it comes to tissue
damage. Damage such as that seen with the
cut apple is often due to the cross-linking of
sugar to protein.
Sugar in the form of glucose and related
molecules is used not only as a source of fuel
but also as a building block for cartilage and
other tissues. However, sugar molecules can
act in ways that are less desirable, as well.
Much of the body is made up of proteins,
especially collagen, and these proteins can be
modified not just by oxidation but by interactions
with sugars. Fructose (“fruit sugar”)
is notorious in this regard. Another class of
villains is the the aldehydes, such as acetaldehyde,
which is produced as an aspect of the
metabolism of alcohol. Many environmental
toxins involve aldehydes.
There are several other different sources of
damage to proteins. Aside from oxidation
and free radical damage, there is a process
known as carbonylation, the attachment of
6 groups (consisting of a carbon and an
oxygen bound together and written as CO-)
to proteins. As we grow older, proteins collect
more and more 6 groups. These misplaced
groups interfere with necessary
chemical interactions, weaken the structure
of tissues and act as a source of “drag” on the
normal metabolism of the body. Protein
molecules collecting 6 groups is somewhat
analogous to a ship collecting barnacles.
Normal interactions are slowed, made more
cumbersome or even prevented from being
completed. Some authorities estimate that in
older adults one third of all proteins may
become carbonylated with a resulting decline
in a variety of cellular functions.
A related type of damage is glycation.
Glycation refers to the oxidation of protein
by glucose, including the cross-linking
already mentioned. In chemistry this damage
is sometimes called a “browning” reaction
and in fact, it is seen whenever meats are
“browned” in cooking. Browning makes protein
tough and resistant to penetration by
water. This reaction also is called the
Maillard reaction, so named for the French
scientist who first described it in 1912. The
result is a cross-linking of glucose or another
sugar molecule to the protein, an operation that effectively prevents the protein from
acting properly. Aldehydes and a number of
other chemicals similarly can link to proteins.
Technically, glycation, damage by aldehydes
and also certain types of peroxidation are all
classed as forms of carbonylation.
The most serious of these types of carbonylation
is the formation of advanced glycation
end products (AGEs). The prolonged exposure
not only of proteins but also of lipids and cell
nucleotides (chiefly DNA and RNA) to glucose
results in reactions that synthesize AGEs. These
AGEs bind to special receptors and this binding
induces intracellular oxidative stress. The
related cellular activation and generation of
assorted cytokines (immune system components),
growth factors and transcription factors
such as nuclear factor kappa-beta can have
quite negative effects. AGEs are found in large
amounts in diabetics. For instance, glycation
leading to AGEs occurs in the blood fragment
known as Hemoglobin A1 and converts it into
Hemoglobin A1C for the life of the molecule.
This latter blood fragment is elevated in diabetes.
Not just diabetics, but anyone suffering
from Syndrome X (the insulin resistance syndrome)
will form AGEs at a heightened rate.
This includes a substantial percentage of all
Americans. The third National Health and
Nutrition Examination Survey indicated that
greater than 22 percent of the U.S. populace
shows the signs of the metabolic syndrome,
including three or more of these symptoms:
apple-shaped fat distribution, high serum
triglycerides, low ratio of high density lipoprotein
(HDL) cholesterol, elevated blood pressure
and elevated blood glucose.
Diabetics constitute advanced cases of a
type of damage that afflicts all of us. The difference
in the production of AGEs between
diabetics and non-diabetics is merely one of
degree. AGEs eventually accumulate in the
nerve tissue and are suspected of reducing
nerve conduction and activity. Similarly they
are linked to changes in the ability of blood
vessels to relax (leading to hypertension) and
to damage to the kidneys. Reduced nerve
activity, the tendency toward hypertension
and decreased health of the kidneys are all typical
developments in old age.
L-Carnosine: Stopping the Formation of
AGEs and Brain Protein Carbonylation
The body, of course, has some powerful
weapons to use in its battle against glycation.
The amino acid derivative L-carnosine is one
of these. Chemically it is a dipeptide (made up
of two amino acids) constructed from betaalanine
and l-histidine, hence its chemical
name alanylhistidine. L-carnosine is found
throughout the body but it is particularly
abundant in those cells which are long-lived,
such as the nerve cells (neurons) and the cells
of the muscles (myocytes). Similarly,
L-carnosine, as is true of the antioxidant
enzyme superoxide dismutase (SOD), is one of
a handful of compounds which are present in
tissues at levels that correlate strongly with the
maximum life spans of animal species.
Research interest in L-carnosine is focused on
a number of issues arising from the ability of
the compound to rejuvenate cells approaching
senescence (failure due to advancing age).
Muscle levels of L-carnosine, which are relatively
easily checked, decline approximately
63 percent between the ages of 10 and 70.
Brain levels of L-carnosine begin high and
remain high in comparison with the levels
found in most other tissues. Scientists have
speculated that this may be one reason that
brain functioning is stable into old age despite
the brain’s dependence upon glucose for
energy metabolism and the unusually high
ratio of fructose to glucose in the brain.
L-carnosine, however, performs more than
just one role. Experiments have shown that
aside from being a powerful antioxidant, it
helps to prevent glycation. L-carnosine has
been shown to “sacrifice” itself as a substitute
victim to glycating agents, thus sparing the
proteins and membranes which otherwise
would have been the targets of glycation.
Furthermore, there is evidence that L-carnosine
reacts with and removes the 6 groups of
glycated proteins. As yet another benefit, it
detoxifies aldehydes and related compounds
and it chelates metal ions which otherwise
might be available to cause damage by generating
free radicals.
Promoting Cellular Rejuvenation
The ultimate test of cellular rejuvenation is the
way in which an animal ages. A Russian study
tested the effect of carnosine on life span and
indicators of senescence in age-accelerated
mice by giving half the mice carnosine in their
drinking water starting at two months of age.
L-carnosine did not alter the 15 month maximum
life span of this mouse strain, but the
mice given carnosine were about twice as likely
to reach the “ripe old age” of 12 months as
were untreated mice. L-carnosine extended
the life span of the treated mice by 20 percent
on average.
The L-carnosine treated mice displayed
glossier coats, fewer skin ulcers and quite dramatically
retained normal behavioral reactivity
when compared with the untreated mice. Tests
used to determine brain aging showed signifi-
cant protection against several standard
markers for decline. The mice therefore were
“more resistant to the development of features
of aging.”
Tuning Up Your Sugar Metabolism
Remember, the more excess glucose that is
available in the blood, the more opportunity
for cross-linking with proteins. L-carnosine
may be a star player in defending against
glycation, but every player still needs a team.
Other supplements help. Trivalent chromium
is important primarily to those individuals
whose diets are deficient in chromium.
Contemporary research has identified compounds
which have much stronger effects
directly upon glucose transport, such as
alpha-lipoic acid (which doubles as an
incredible antioxidant) and colosolic acid.
Phytonutrients also pitch in. The compounds
found in herbs such as green tea, bilberry and
eucalyptus leaf have proven efficacy in
reducing glycation. Some products, such as
Jarrow Formulas’ Glucose Optimizer, have
been carefully formulated to include these and
other nutrients for a harmony of synergy.
So, if you are worried about sugar being the
body’s “sand of time,“ do something about it.
Eating less sugar and more phytonutrients is a
start. Supplements, however, can help bolster
your defenses against glycation. L-carnosine
and sugar-regulating nutrients may not stop
the clock, but they might help to slow
it down.
Selected references
- Boldyrev, A., Song, R., Lawrence, D., et al. “Carnosine protects against excitotoxic cell death independently of effects on reactive oxygen species.” Neuroscience (1999). Vol. 94(2) pp. 571–7.
- Ford, E. S., et al. “Prevalence of the metabolic syndrome among U.S. adults: findings from the third National Health and Nutrition Examination Survey.” JAMA (Jan 16, 2002). Vol. 287(3) pp. 356–9.
- Wang, A. M., Ma, C., Xie, Z. H., et al. “Use of carnosine as a natural anti-senescence drug for human beings.” Biochemistry (Moscow). (2000). Vol. 65(7) pp. 869–71.
- Yuneva, M. O., Bulygina, E. R., Gallant, S. C., et al. “Effect of carnosine on age-induced changes in senescence-accelerated mice.” J Anti-Aging Med. (1999). Vol. 2(4) pp. 337–42.
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