Clear Eyes with N-Acetylcarnosine

N-Acetylcarnosine Delivers the Goods

Clear Eyes with
N-Acetylcarnosine

It delivers carnosine to the lenses of our eyes,
providing protection to the lenses’ own protectors
By Hyla Cass, M.D.

emember chaperones, and how annoying it was to have to be under their watchful eye all the time when we were just trying to have some fun? They were there to keep us out of trouble, of course—knowing full well that, to kids, trouble and fun are pretty much the same thing. Whatever happened to chaperones, anyway?

They’re still with us, actually. Chaperones of a certain kind have, in fact, been with us, in every living cell, doing their thing, for millions of years. But what are these chaperones, and what is their thing?

Molecular Chaperones Protect Proteins

In cellular biology, molecular chaperones are a special kind of protein that’s a little less vulnerable to degradation by factors such as ionizing radiation, chemical attack, or excessive heat than most other proteins. There are many different varieties of chaperones, and one of their main functions is to protect other, more sensitive proteins from harm; some of them even repair proteins that have become damaged. That’s pretty remarkable, if you think about it (please do). It’s the molecular equivalent of a human “surgeon-chaperone” who would not only try to prevent you from going joyriding in a car, but would also put you back together again if you managed to do it anyway and got into an accident.

Just as human chaperones might welcome some help from a friend if their unruly charges were getting out of control, molecular chaperones can receive assistance from “friendly” molecules that are able to modify the chaperones’ actions and provide them some protection from harm. One such molecule is carnosine, which assists chaperones called α-crystallins in the lenses of our eyes. We’ll get to that, but first, we need to know more of the basics, such as how proteins are built.

Protein Folding Is Complex and Crucial


Simple computer-graphic diagram of the small digestive enzyme α-amylase (about 500 amino acids) showing the intricate folding of the polypeptide chain. The strings represent simple end-to-end linkages of amino acids. The ribbons represent more complex linkages, in which the chains adopt a configuration called the α-helix; some of these α-helical segments form supercoils, as shown here. The colors represent different functional domains of the protein.
All human proteins (of which there are tens of thousands) start out as polymers called polypeptide chains, which are made up of 20 different kinds of amino acids. There can be anywhere from a few dozen to about 27,000 amino acids in a polypeptide chain; most are in the range of several hundred to several thousand. The exact sequence of amino acids in every such polymer is determined by our genes, which are DNA segments that encode this information. It’s our RNA, however, that directs the actual synthesis of the protein molecules.

Proteins are immensely complex, not just because of their sheer size and number of atoms, but because of the intricate manner in which the polypeptide chain folds in on itself to form a more or less globular protein structure (this is true of most proteins, but not all—some have a fibrous structure). The folding process is crucial to the ultimate structure and function of the protein. (For more on this, see the sidebar below.)

How to Unboil an Egg

Imagine a 50-foot-long piece of wet spaghetti (the egg comes later) that you scoop up and dump into a spherical shell: it will wind up as a random, tangled mess. When a polypeptide chain, however, folds up into the shape of a ball (more or less), the process is not random. Instead, it’s governed by the laws of quantum mechanics and chemical thermodynamics, which collaborate, so to speak, in finding the optimal 3-dimensional conformation of the molecule in terms of minimizing its chemical free energy.

OK, that sounds pretty arcane, so think of it this way: if you tossed a bunch of refrigerator magnets into a bag, they would wind up clumping together in a particular way, owing to the net effect of all the attractive and repulsive forces between any one magnet and every other magnet that was near it. It’s somewhat like that with all the atoms in the protein: they attract each other or repel each other through electric and magnetic forces that depend on … well, a lot of different factors that chemists and physicists spend their lives studying.

There is a catch, though: in the magnet experiment, the clump would come out randomly every time. With proteins, as we’ve just learned, it’s not random at all: the process leads inexorably to one optimal conformation every time (well, not every time, but almost), owing to those laws of nature we mentioned. Figuring out how this works was one of the most formidable challenges in the history of chemistry. Many great scientists worked on it, with Linus Pauling, as usual, leading the way; a key breakthrough was made in 1959 by Walter Kauzmann, a distinguished physical chemist at Princeton University.

When polypeptide chains are synthesized in our cells, some of them spontaneously fold themselves into their correct protein conformation, called the native state. Others, however, require assistance, which is provided by molecular chaperones. Once this process is complete, the protein is ready to fulfill its biological role, whatever that may be. In many cases, the protein’s function depends critically on its exact conformation—even the tiniest deviation from it (a single chemical bond broken, a single amino acid replaced by a slightly different one) can damage or destroy the protein’s functionality, by inducing it to assume a different conformation; this is called misfolding.

Such flaws are most likely to occur when the protein is subjected to harmful physical or chemical conditions, such as intense radiation, damaging free radicals, or excessive heat (“heat shock”). And here’s where chaperones, also called heat-shock proteins, come in again. Via mechanisms that seem like magic but that can be deduced from experimental data and explained by the principles of chemistry, the chaperones can often repair the damage, inducing the protein to refold itself properly and regain its functionality. Without this vital “Mr. Fix-It” service, life as we know it could not exist.

When a protein becomes more or less totally unfolded, it’s said to be denatured, and the polypeptide chain is highly vulnerable to chemical changes that make the process irreversible. This occurs, e.g., when digestive juices in the stomach attack and degrade the proteins in our foods. The proteins in cooked foods, of course, are already irreversibly denatured by the heat of cooking—as, e.g., when we boil an egg, which turns the aqueous solution of albumins (the egg white) into a solid.

In our cells, however (and in laboratory experiments), denaturation is not necessarily irreversible. Indeed, the damage can often be undone, either through spontaneous refolding or with the aid of chaperones. When the idea that denaturation might be a reversible process was first put forth in the 1920s (at a time when there was virtually no knowledge of protein structure, let alone the existence of chaperones), some scientists laughed it off derisively as “unboiling the egg.” They eventually wound up with egg on their faces.

Protein Misfolding Can Lead to Disease

Just as the correct folding in a protein is essential for good health, any misfolding is a potential source of cellular dysfunction or systemic disease. There are many ways in which this can occur. One way is for an enzyme (all enzymes are proteins) to lose its catalytic activity (all enzymes are catalysts), which will suppress the biochemical function it was designed for. Sometimes such damage can be repaired, and sometimes it cannot be. Another example: some kinds of incompletely or incorrectly folded proteins tend to cross-link to each other, forming large molecular aggregates that can disrupt (chemically or physically, or both) various aspects of cellular function, thereby accelerating the aging process. At worst, such aggregates can cause tissue degeneration and cell death.

More than a dozen diseases have been traced to such protein defects. Among the best known is Alzheimer’s disease, which involves the formation of two kinds of pathological proteins: amyloid-beta, the culprit in neuritic plaques (which are intercellular), and hyperphosphorylated tau, the culprit in neurofibrillary tangles (which are intracellular). Abnormalities in protein folding also underlie the brain-wasting disease called bovine spongiform encephalopathy (mad cow disease) and its human equivalent, variant Creutzfeldt-Jakob disease; they’re examples of diseases caused by prions, which are infectious protein particles containing no DNA.

Free Radicals Underlie Cataracts


Three computer-graphic representations of one portion of the enzyme triose phosphate isomerase. Left: all-atom view color-coded by atom type. Center: schematic view showing the folding of the supercoiled α-helical segments. Right: surface view color-coded by different types of chemical interactivity with other molecules.
Free radicals were mentioned in the sidebar as one factor that can damage proteins in such a way as to cause misfolding. These destructive entities are implicated, in fact, in countless human diseases and disorders. One of them is cataracts, an age-related disease that sends about 1.5 million Americans to the operating room every year. Cataract surgery is the most common operation there is. It’s quick, easy, painless, and almost always successful. But, like most surgeries, it should always be the last resort.

The first resort, of course, is prevention—especially through the avoidance of free radical-induced oxidative stress. That means no smoking, minimal exposure of the eyes to the sun’s harmful ultraviolet rays, and a healthy diet with plenty of antioxidant-rich fruits and vegetables. These should be supplemented with a multivitamin/multimineral/multiantioxidant formulation, which is beneficial for countless aspects of your health. Beyond that, there are certain nutrients known to be good for your eyes, such as the alkaloid vinpocetine, the carotenoids lutein and zeaxanthin, and the flavonoid quercetin.

Carnosine Helps Prevent and Treat Cataracts

Another nutrient, N-acetylcarnosine, plays a special role in eye health because it’s a good delivery vehicle (in the form of eye drops) for its parent compound, carnosine, which does not enter the eye as readily as does the N-acetyl derivative. Carnosine is a dipeptide (two joined amino acids) that is found naturally in the body (as is N-acetylcarnosine). Much research in Russia, where carnosine was discovered in 1900, indicates that it’s helpful in both the prevention and treatment of cataracts, providing tangible improvements in visual acuity and glare sensitivity. (See N-Acetylcarnosine May Help with Cataracts” in the August 2003 issue.)

Carnosine
Other research, primarily in England, has shown that carnosine helps protect an important class of lens proteins called α-crystallins. These are structural proteins that are responsible for the transparency of our lenses. Carnosine protects them by inhibiting a pernicious cellular process called glycation, in which sugars (primarily glucose) react with various proteins, causing the latter to become chemically cross-linked. This produces large molecular aggregates called AGEs (advanced glycation end products), which foul the cellular machinery of life in myriad ways and contribute to a variety of chronic degenerative diseases of aging—including cataracts and complications of diabetes. (See “Fighting Cataracts with N-Acetylcarnosine” in the April 2006 issue.)

Carnosine Helps Protect Chaperones

The British research team about whom we wrote previously (one author is now in China) has reported on and contributed to a body of research demonstrating carnosine’s antioxidant and antiglycation properties, which account in large measure for its beneficial effects on cataracts.1 Now they have published a study showing that one of the ways in which carnosine may protect our lenses’ α-crystallins is by inhibiting chemical attacks that tend to degrade … are you ready? … the α-crystallins’ chaperone activity!2

That’s right: in addition to being structural proteins in our lenses, the α-crystallins help protect other lens proteins from aggregation and inactivation brought about by oxidative stress and glycation. But molecular chaperones can themselves be damaged, so they need help too. Fortunately, as the new research shows, carnosine can provide that help (in lab experiments with cow lenses, at least).


Much research in Russia,
where carnosine was discovered in
1900, indicates that it’s helpful in
both the prevention and
treatment of cataracts, providing
tangible improvements in
visual acuity and glare sensitivity.


The researchers suggested that the role of α-crystallins as chaperones may help explain why our lenses remain transparent for as long as they do. (Bear in mind, in case you’d forgotten, that lenses are the body’s only tissue that never regenerates its cells, so the cells must remain chemically “fit” and functional incomparably longer than any other cells; it’s amazing that they last as long as they do.) When the α-crystallins themselves become degraded, however, our lenses become clouded by protein aggregates that scatter the incoming light rays rather than transmitting them straight to the retina. The result is the blurred vision of cataracts, which eventually lead to blindness if they’re not properly treated or removed.

The authors concluded,

… this is the first report describing the protective effect of carnosine on glycation-induced decreased chaperone activity of α-crystallin. In addition, our results further support the notion that carnosine can disaggregate cross-linking mediated by glycation … These results shed new light on the properties of carnosine and have important implications for understanding the mechanism by which carnosine may be of benefit in preventing lens opacity in humans.

The Vision Thing

Back in 1987, when someone suggested to President George Bush the Elder that he turn his attention from short-term campaign objectives and look to the longer term, he famously responded, “Oh, the vision thing.” We too are committed to “the vision thing,” but in the literal sense. Now that you know something about how the proteins in your lenses work, and how they might be protected from harm by supplements such as N-acetylcarnosine, perhaps you will have the vision to take appropriate action.

References

  1. Yan H, Harding JJ. Carnosine protects against the inactivation of esterase induced by glycation and a steroid. Biochim Biophys Acta 2005;1741:120-6.
  2. Yan H, Harding JJ. Carnosine inhibits modifications and decreased molecular chaperone activity of lens a-crystallin induced by ribose and fructose 6-phosphate. Molec Vision 2006;12:205-14.


Dr. Hyla Cass is a nationally recognized expert in integrative medicine, an assistant clinical professor of psychiatry at the UCLA School of Medicine, and the author or coauthor of several popular books, including Natural Highs: Supplements, Nutrition, and Mind-Body Techniques to Help You Feel Good All the Time and 8 Weeks to Vibrant Health: A Woman’s Take-Charge Program to Correct Imbalances, Reclaim Energy, and Restore Well-Being.

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