zarkovAging, diabetes, toast, and roast beef all have something in common: crosslinking.

To a chemist, this means that sugars – from carbohydrates, starches, and natural sources – have reacted with cellular components like amino acids, fats, proteins, and DNA.

To a chef, it means that the Maillard reaction (See article in this issue) has browned a roast or caramelized onions.

To a doctor, it means that your arteries, organs, and cells have been hardened or damaged, causing cardiovascular disease, neurological disorders, vision loss, kidney problems, and chronic inflammation.

To you, it means premature aging, diabetes, and lowered quality of life.

Joined at the Hip

The basis of crosslinking is what chemists call intermolecular bonding. This means that molecules bond to other molecules. (Bonding inside the same molecule is called cyclization.)

Crosslinking is very useful: leather is tanned (crosslinked) skin, paint is cured (crosslinked) polymer films, plastics are polymerized (crosslinked) oils, and tires are made from vulcanized (crosslinked) rubber. Many of the natural products that we enjoy – fibers, wool, fur, and feathers, to name just a few – depend upon crosslinking.

Nearly anything can crosslink, which creates both opportunities and problems for the body.

A Double-Edged Sword

Crosslinking is a lot like Janus, the two-faced Roman god of doorways. With it we age, but without it we can’t live at all. Consider collagen, a critical protein in connective tissue, tendons, ligaments, cartilage, skin, bone, and even the cornea of the eye.

Crosslinked collagen is hard, which creates a host of problems: skin deterioration (wrinkles, sagging, stiffness), connective tissue rigidity (often misdiagnosed as arthritis), bone problems, organ stiffening (heart problems, bladder incontinence, lung issues), etc. But collagen is an example of the two faces of crosslinking; while unwanted bonds destroy collagen, they are also crucial for connective tissue strength. Without this web of interlocking we’d fall apart.

Our hair and fingernails are a type of crosslinked protein called keratin. (Hair straightener and depilatories rely on breaking crosslinks.)

Any solution to the crosslinking problem must target the unwanted type causing damage, while leaving the remainder alone. This is not always so easy to do, and considering how crosslinking originates will explain why.

Literally Tied Up in Knots

Consider a strand of protein as a flexible piece of rope. Imagine two adjacent strands of rope (protein) fixed only at the ends, such that each has total freedom to bend and move, independent of the other.

As more and more horizontal pieces of twine are tied from one rope to the other, the flexibility of movement declines until the two have become somewhat rigid. As the joining twine contracts, as it often does in crosslinked molecules, the ropes pull together simplifying adding new crosslinks.

This is exactly what happens in the body, as proteins and other molecules bind together. This changes their shapes, and thus their biological properties, preventing normal functioning.

Chemists call changes like these ‘denaturing’, since the original properties of the molecule have been altered. This isn’t always bad; cooking a steak denatures the proteins, making them far more digestible, and much tastier, too.

The idea that crosslinking causes aging is hardly a new one; back in 1941, Dr. Johan Bjorksten, a Wisconsin chemist, first proposed that undesirable bonding gradually damages proteins, fats, DNA, vitamins, etc.

These damaged molecules bind together into sticky tangles; over time, these blobs grow and wrap around other molecules, growing and posing more and more of a problem.

Leather, Hectographs, & Aging

Bjorksten came to his discovery because of his background in leather chemistry and his work on hectograph films, which were used to duplicate pages prior to the invention of the photocopier.

This wet process, which dates back to the late 19th century, uses a gelatin film to transfer ink to paper, much like a printing press. It was good for about fifty copies of the same sheet. (Remember this the next time you use fast, inexpensive, and dry copier technology.)

The problem plaguing Bjorksten was how to stop the gelatin films from hardening with age and use. He quickly identified the culprit as protein crosslinking, and noticed that the hard gelatin films were remarkably similar to damaged skin. He concluded that the same chemical processes must be at work in both cases and that inhibiting crosslinking would prevent any human diseases and disorders, and thus extend life.

Cracking Bonds With Enzymes

Bjorksten began taking vitamin E, the only anti-crosslinking agent available to him, and began searching for a means to crack the strong bonds with proteins.

The first approach used soil bacteria a rich source of raw material for pharmaceuticals fed crosslinked protein, exclusively. (Many antibiotics, like the potent streptomycin, originated with bacteria from dirt.)

The bacteria that survived would, of necessity, produce enzymes capable of breaking protein bonds. Bjorksten felt that these enzymes could then be used in humans.

The Real World Intrudes

Facing him were two big problems: science and funding. Every single enzyme he found that could break protein crosslinks was so toxic it couldn’t be used in lab animals, let alone humans. Beyond science, however, the debate over extending human lifespan was as contentious as today’s debates over stem cell research, and this made funding his work controversial.

Bjorksten also contributed to the controversy, including a proposal that the United States Department of Defense fund development of a “rapid-aging spray” to be used against enemy soldiers during wartime. The military’s reaction was, needless to say, not enthusiastic.

Running out of money and deciding the search for enzymes was hopeless, at least in any time frame that would benefit him – both of Bjorksten’s parents died from Alzheimer’s Disease, which exhibits a great deal of crosslinking – he abandoned breakers for other approaches.

Cracking Bonds With Chelation

Moving into chelation agents like Ethylenediaminetetracetic acid (EDTA), Bjorksten reasoned that if these compounds can break bonds with metals that they would prevent, or even break down, the protein tangles in the body.

There is evidence that copper and iron catalyze reactions between sugars and proteins, particularly in cataracts and Alzheimer’s disease, Johan Bjorksten and that eliminating excess metalions may slow crosslinking. This is, of course, a topic so big it needs to be covered in its own article.

A Theory Now Accepted as Fact

Bjorksten’s work on the ‘crosslinking theory of aging’ provides an explanation for aging and diabetes making perfect sense; the body’s proteins do harden over time. One example is the leathery skin of cowboys and habitual beach goers. His theory is accepted today as a crucial component in aging and disease, especially diabetes.

Origins of the Ties That Bind

Crosslinking is caused by such diverse factors as: inter-molecular bonding (metabolic by-products), ultraviolet light (sun, tanning salons), ozone (pollution), acetaldehyde (alcohol, cigarette smoke, pollution), ketones (diabetics, high-protein/low-carb diets), metal ions (lead, cadmium, mercury, copper, iron, aluminum), x-rays, and free radicals (normal metabolism, rancid or overheated oils and fats).

It wasn’t until 1965, however, that one of the leading culprits in crosslinking and aging was identified: sugar bonding to protein via the “maillard reaction”. (See the article in this issue.) This is why diabetics age prematurely and why otherwise healthy people need to protect themselves from even typical blood-sugar levels.

Other types of crosslinking, such as between proteins, lipids (fats) or involving metals like copper and iron, are very important as well. So are the sulfur-sulfur (disulfide) bonds made between the sulfur bearing amino acids in proteins. Sugar, however, seems to be the leading cause of damage and aging, even in non-diabetics.

Increases in blood-sugar happen after consuming starches and carbohydrates – these are broken down into simple sugars – as well as fruits and vegetables which also contain sugars and carbohydrates.

The problem is that sugar is a biochemical straight jacket: before it can be broken down and metabolized it locks up molecules needed for routine cellular function and creates toxic compounds.

Marrying Sugar to Protein

The overall process is very simple, but sounds a little complicated because of terminology. All you really need to know is in the next two paragraphs.

It all begins when sugar oxidizes, giving it a reactive carbon-oxygen (carbonyl) group that binds to proteins in a process called glycation. These glycated, or sugared, proteins eventually form stable, long-lived, and highly damaging Advanced Glycation End-products (AGE). This is the key phrase to remember, because the crosslinking theory of aging is basically all about AGEs.

Similar results occur when fats and proteins bond together. Reactions between proteins, sugars, and fats explain why sautéed food is tastier than steamed, and why sauces are made from browned bones (reacted proteins, fats, and sugars), roasted vegetables (caramelized carbohydrates and natural sugars), and butter (fat). (See the article on the “Maillard Reaction”.)

How Sweet It Isn’t

Arteries and the fine capillaries in the retina and kidney are particularly vulnerable to sugar protein reactions because, unlike other cells, they cannot break down some forms of sugar like sorbitol. These then attack the proteins in the blood-vessel walls, leading to damage and AGEs.

Artery-clogging plaque is nothing more than globs of crosslinked AGEs made from a variety of material sugars, proteins, lipids and fats like cholesterol, metals, fibrin, etc.

You’re Showing Your AGE

Over time, AGEs crosslink the inside of your body like a browned roast, causing diseases like cardiovascular hardening and heart attacks, retinal deterioration, cataracts, glaucoma, peripheral nerve damage, kidney failure, osteoarthritis, stroke, scleroderma, and atherosclerosis.

Once a long-lived protein, such as those in the eye s lens or the collagen in skin and joint cartilage, is damaged it usually remains so. This is why levels of the AGE product pentosidine in the joint cartilage of an eighty-year old have been measured as being over thirty times those of a twenty-year old.

Implicated in many diseases, AGEs are known to activate a variety of inflammatory cytokines, or messenger molecules, including tumor necrosis factor alpha (TNF-a) and interleukin, even in otherwise healthy people.

Stop Doing That Right Now!

A variety of prescription drugs and nutritional supplements with anti-crosslinking effects are readily available. (See “Which of the Crosslinking Inhibitors and Breakers Are Right For You” in this blog.)

Nearly a thousand such compounds are known, but many of them, as Bjorksten discovered a long time ago, are completely unsuitable for use in the body.

Crosslinking inhibitors – available as both prescription and supplements – typically interfere with the binding of the carbonyl groups (just a carbon-oxygen bond) on sugars to amino acids and other molecules. Some inhibitors are sacrificial, binding to an active site on the sugar before it can disrupt an amino acid in a protein.

The aptly-named crosslinking breakers crack the bond between the sugar and the protein, undoing some of the damage and allowing repair. This is more difficult, and many of the breakers target bonds – like those giving cartilage its strength – that must remain untouched.

Breaking Sugar’s Hammerlock

Supplement-based compounds are known to break existing AGE bonds without serious side effects. Prescription drug breakers are still relatively new, however, and have limited safety histories. Until their long-term, and even short term, effects are well known and understood, supplements are generally a safe, effective, and very affordable alternative.

Conclusion

Toast, roasts, and caramelized onions can be delicious, but you certainly don’t want the same reactions occurring in your body. So, if you have diabetes or just want to put the brakes on your age-related deterioration, you’ll definitely want to add crosslinking inhibitors and breakers to your supplement list. Before your body gets tied up in knots!

For a more information on Aging & Diabetes see:

http://www.ilifelink.com/

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