Reduce Your Wrinkles and Age Less Through Tissue Engineering

Obviously, a big sign of aging is wrinkles. Turns out, wrinkles and sagging skin are outward manifestations of something called “advanced glycation end products” (“AGE”). You can fight back with so-called chelating agents and AGE blockers. Find out how.

Tissue engineering reduce wrinkles

 

EVERYBODY DOES it, but no one completely knows precisely why we age. If you present the question to aging experts, you may hear different answers about what is aging and why it happens.

Aubrey-de-Grey

Aubrey de Grey

Despite that, led by the brilliant and irrepressible anti-aging gerontologist, Aubrey de Grey, the SENS Research Foundation basically declares that a precise, all-encompassing definition of aging isn’t necessary to make great strides in slowing it down and then reversing it, because eight things are very clearly known:

  1. Our bodies (including the brain) ages due to the burden of decades of unrepaired damage to the cellular and molecular structures that make up the functional units of our tissues; and
  2. There are no more than seven major classes of such cellular and molecular damage, which together with #1 above, constitute the eight things about aging that we know.

When you examine the table below, note that the seven categories of aging have been known about for at least 33 years. What’s not fully known, but getting closer day by day, are the rejuvenation biotechnologies that — at least in Aubrey de Grey’s mind — will someday reverse the damage caused by aging.

Seven Major Classes of Cellular and Molecular Damage (source)
Aging Damage Year Discovered Rejuvenation Biotechnology
Cell loss, tissue atrophy 19551 Stem cells and tissue engineering: RepleniSENS
Cancerous cells 19592, 19823 Removal of telomere-lengthening machinery: OncoSENS
Mitochondrial mutations 19724 Allotopic expression of 13 proteins: MitoSENS
Death-resistant cells 19655 Targeted ablation: ApoptoSENS
Extracellular matrix stiffening 19586, 19817 AGE-breaking molecules; tissue engineering: GlycoSENS
Extracellular aggregates 19078 Immunotherapeutic clearance: AmyloSENS
Intracellular aggregates 19599 Novel lysosomal hydrolases: LysoSENS

Table Content References

1. Brody H. Organization of the cerebral cortex III. J Comp Neurol 1955; 102:511-556.

2. Szilard L. On the nature of the ageing process. Proc Natl Acad Sci USA 1959; 45:35-45.

3. Cutler RG. The dysdifferentiation hypothesis of mammalian aging and longevity. In: The Aging Brain: Cellular and Molecular Mechanisms of Aging in the Nervous System (Gicobini E et al., eds), Raven (New York), 1982, pp. 1-19.

4. Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc 1972;20:145-147.

5. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 1965; 37:614-636.

6. Movat HZ, More RH, Haust DM. The diffuse intimal thickening of the human aorta with aging. Am J Pathol 1958;34:1023-1031.

7. Monnier VM, Cerami A. Nonenzymatic browning in vivo: possible process for aging of long-lived proteins. Science 1981;211:491-493.

8. Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie und psychisch-gerichtliche Medizin Berlin 1907; 64: 146-148.

9. Strehler BL, Mark DD, Mildvan AS, Gee MV. Rate and magnitude of age pigment accumulation in the human myocardium. J Gerontol 1959; 14:430-439.

 

“SENS” is an acronym for Strategies for Engineered Negligible Senescence. The term “negligible senescence” was first used in the early 1990s by professor Caleb Finch to describe organisms such as lobsters and hydras, which do not show symptoms of aging.

The term “engineered negligible senescence” first appeared in print in Aubrey de Grey’s book The Mitochondrial Free Radical Theory of Aging, and was later prefaced with the term “strategies” in the article Time to Talk SENS: Critiquing the Immutability of Human Aging. (1)

De Grey called SENS a “goal-directed rather than curiosity-driven” approach to the science of aging, and “an effort to expand regenerative medicine into the territory of aging”. To this end, SENS identified the seven categories of aging “damage” and a specific regenerative medical proposal for treating each. (2)

Click on any of the links in the above table to learn more about the seven definitions of “Aging Damage” and the corresponding “Rejuvenation Biotechnology” currently underway.

The rest of the blog posts takes a deep dive into one of those seven, “Extracellular matrix stiffening”

What you’ll discover in this post:
  • The major factor behind aging
  • What causes wrinkles
  • What you can do about it

Why bother reading about this?

Because “AGE” is about the most simple of the seven classes of cellular and molecular damage associated with aging to understand… you see one of its manifestations every time you peer in the mirror – wrinkles!

Another reason to bother reading this is because there are proven foods, supplements and pharmaceuticals that can slow down and even reverse AGE.

To tell the tale, I’m going to move from Aubrey de Grey to Dr. Ward Dean, a world-renowned expert in anti-aging and life extension science, who in answer to a question asked him about the glycation theory of aging (aka “AGE”), gave a very detailed answer. (3)

Dr. Ward DeanThe rest of this blog post summarizes Dr. Dean’s take on AGE and preventative measures, as published on the site Antiaging-Systems.com, along with my inevitable commentary. We’ll take a look at the work done by the scientists responsible for discovering the impact of glycation on the aging process, and those supplements and pharmaceuticals that mighty be helpful.

I’d like to underscore that with the exceptions of Berberine and Carnosine, I have no direct experience with any of the products reviewed here.  Also, know that most of the assertions here made are backed by a long list of references you may explore at the bottom of this page where much of this content (minus my commentary and edits) first appeared.

With all that said, let’s read what Dr. Ward Dean has to say about AGE, it’s prevention and reversal, along with some products made with the chelators, herbs and other stuff he mentions that I pulled from Antiaging-Systems.com and Amazon.com.  If you want his unadulterated version, go here.

Search for cross-linkage inhibitors to protein cross-linking

The glycation theory of aging is a modern outgrowth of the venerable cross-linking theory of aging, first proposed in 1942 by a chemist from Finland named Johan Bjorksten. The crosslinkage theory stated that the principal cause of aging was the linking together of two or more large molecules (macromolecules), which progressively linked with other molecules, impairing the functioning of cells, tissues, and organs, resulting in the aging of the organism.

Bjorksten spent his entire career searching for the cause and cure of crosslinks, which he believed would result in the reversal of aging and maintenance of prolonged youth. He believed that one cause of the crosslinks was heavy metal poisoning, (especially aluminum), which could be prevented and reversed with chelation therapy. He also identified the loss of fluidity of cell membranes as a contributing factor, and supported the use of membrane fluidizers such as centrophenoxine, phosphatidylserine, choline and lecithin.

Bjorksten focused on a potential means of preventing and breaking up crosslinkages by using chelating agents that attach to metals within the body, enabling them to be excreted. One of the most commonly used chelators is called EDTA (short for “ethylene-diamine-tetra-acetic acid”), a synthetic amino acid that removes metal-based crosslinkages by chelation.

Chelating agents in current clinical practice besides EDTA (which is approved for use in the treatment of lead poisoning) are deferoxamine (Desferal® for acute iron intoxication), and DMSA (used to treat lead and mercury intoxication). Physician members of the American College for Advancement in Medicine (ACAM) are proponents of intravenous chelation therapy with EDTA as a treatment for many chronic degenerative diseases, like atherosclerosis, hypertension, diabetes, and Alzheimer’s disease. Chelation with oral EDTA chelation is also becoming more widely used.

{Products of interest: BCI®, Beyond Clean 2® and Beyond Fiber®}

Natural chelators include garlic, chlorella, cilantro, lactic acid, citric acid, and malic acid. Bjorksten demonstrated that lithium was also an effective aluminum chelator and crosslinkage inhibitor, stating that “lithium continues to be the most effective electrolyte for aluminum detachment.”

{Product of interest: Lithium orotate }

Chelators as life-extending substances

A number of studies confirm that chelating agents, particularly, EDTA — may have life-extending properties. Scientists demonstrated the life-extending effects of EDTA on small multi-celled animals found in freshwater lakes and ponds. In the Soviet Union in the 1970s, Dr. T.L. Dubina performed a series of studies with EDTA on the life span of rats. In most of the studies, the mean life span of female rats treated with EDTA was increased by nearly 50%, and in one study the maximum lifespan increased 18-25% over the control animals.

{Product of interest: EDTA is available in BCI®, EDD® and in Beyond Clean2® bath salts}.

Aluminum—a powerful cross-linker

Aluminum is a highly reactive metal that occurs freely in nature, and comprises over 8% of the earth’s crust. In humans, aluminum is highly toxic, even in extremely small amounts. Scientists now know that aluminum accumulation may contribute to Parkinson’s disease, Down’s syndrome and Alzheimer’s disease.

In 1955, during a talk on gelatin crosslinkages and aging at the Gerontological Society in Baltimore, Bjorksten discussed the relationship of aluminum to crosslinking. One of the attendees, Prof. H.H. Zinsser of Columbia University, was so interested in the concept that he and Bjorksten began a fruitful collaboration that was to last for seven years.

Using spectrographic analysis, they examined the aluminum content of 84 persons, ranging in age from 10 to 90 years (Fig. 3).

Aluminum concentration versus increasing age in aortic tissue. Bjorksten, J. The crosslinking reaction in relation to aging, Life Chemistry Reports, 1988, 6:367-385.

They found peak levels at age 40-50, followed by a drop and then leveling off, indicating that those whose aluminum accumulation peaked in middle age most likely did not survive the next ten years.

Zinsser’s data were confirmed independently by scientists who demonstrated a progressive increase of aluminum concentrations in the brain (Fig. 4).

Brain aluminum concentrations as a function of age. Bjorksten, J. The role of aluminum and age dependent decline, Environmental Health Perspectives. 1989, 31, 241-242.

Bjorksten came to believe that the deleterious health effects of progressive increases of aluminum with age were so profound that it alone could limit lifespan even if no other cause of death intervened. Testing an assortment of chelating agents to remove aluminum-containing stains from the aortas of hogs, he found that EDTA was the most effective (Fig. 5).

Comparison of the ability of various chelating agents to remove aluminum from hog aorta

Lactic acid, similar to blood concentrations generated by exercise, were moderately effective. Procaine (0.5 %), the active ingredient of Gerovital® (or GH3, the Romanian anti-aging drug), was also moderately effective in reducing the aluminum.

{Products of interest: Original Gerovital-H3® and generic GH3-Pro® are available, as is centrophenoxine as Cent-Pro®}

Lithium is used clinically to treat manic depressive illness (MDI), and recent studies indicate that it may offer benefit in the prevention and treatment of Alzheimer’s disease, as well. Dr. Ward thinks that  long-term treatments with low doses of lithium may be an effective way to displace crosslinked/protein bound aluminum in animals and humans. Lithium orotate as a dietary supplement is the safest, most effective form of lithium available.

 

Advanced Glycation End Products of Aging (AGEs)

In 1965, Dr. H.B. Bensusan proposed that a process known as the Maillard reaction, (the non-enzymatic chemical reactions between proteins and carbohydrates that cause cooked foods to turn brown) was what caused all long-lived proteins in the body to turn brown and become fluorescent (under UV light), become more cross-linked, less soluble, less elastic, and less digestible by the naturally occurring enzymes in our body.

In 1985, Monnier, Kohn and Cerami provided further details of the role of the Maillard reaction, and further developed the idea that the Maillard reaction causes premature aging and degenerative diseases such as diabetes and heart disease.

The Maillard reaction involves a chemical reaction between a sugar with a protein, into a complex known as a Schiff base. With continued exposure to the sugar, the Schiff base undergoes a ‘rearrangement’ known as non-enzymatic glycosylation that results in a more stable, less reversible substance, known as an Amadori product. In the human body, this process reaches equilibrium over several weeks.

The Amadori product further degrades irreversibly into a number of highly reactive carbonyl compounds called Advanced Glycation End products, designated by the acronym AGE, which reflects the proposed relationship of these reactive substances to aging and age-related diseases. AGEs can further react with other fats, proteins and nucleic acids to form largely indissoluble crosslinks. The age-related accumulation of these AGE products has been demonstrated in many tissues of the body (Fig. 7).

Increased accumulation of AGEs (carboxymethyllysine [CML]) with age in human lens protein and skin collagen

Note in the above graph that the density of AGE factors increase with age in skin collagen, the result of which we know too well — wrinkles.

During long-term hyperglycemia (elevated blood sugar), as in diabetics, glycation and AGE formation may be quadrupled which explains why diabetics suffer the premature onset of a wide range of age-related complications including cataracts, retinopathy, neuropathy, nephropathy, atherosclerosis and osteoporosis.

 

AGE Breakers (and inhibitors)

There are a number of substances that have been used to delay and reverse glycation-induced crosslinkages (AGEs). Khalifah and his colleagues proposed a schematic of the formation of AGEs, and illustrates a number of specific therapeutic targets (Fig.8).

Schematic of Maillard Reactions and potential sites of intervention

Metformin (Glucophage®): Metformin is an anti-diabetic biguanide that was derived from the herb, Goat’s rue (Galega officinalis). Metformin is an insulin receptor sensitizer, capable primarily of lowering blood sugar and insulin, and has many other beneficial properties, including optimizing lipid profile, reducing body fat, maintaining levels of growth hormone, stimulating immunity, and extending the maximum lifespan of experimental animals.

Despite these benefits, Metformin is a drug with side effects, and there may be a better substitute, such as the herb, Berberine, which I profiled in Control Your Blood Sugar With These 4 Tricks and Supplements.

{Product(s) of interest: Metaformin and Berberine}

Aminoguanidine (Pimegedine): It’s structurally very similar to guanidine, the active ingredient in Goat’s rue (the herbal prototype for metformin), and has aroused a great deal of interest in the last twenty years, due to its demonstrated ability to block the formation of AGEs and AGE-induced crosslinkages in both animal and human clinical studies. Aminoguanidine inhibits AGE formation, preventing AGE-induced crosslinks in collagen and other tissues. Fortunately, aminoguanidine does not interfere with the formation of normal collagen crosslinks, which are required for structural integrity. Another mechanism by which aminoguanidine is believed to act is by enhancing the action of nitric oxide (the same mechanism by which Viagra functions). Aminoguanidine also reduces the formation of lipofuscin (age pigment) and prevents or reduces cataracts, atherosclerosis, diabetic retinopathy, nephropathy and neuropathy (Fig. 9).

Effect of aminoguanidine on prevention of structural abnormalities of long-term diabetics in the eye (retina) and kidney (glomerulus).

In a study of diabetic patients, after four weeks of therapy with aminoguanidine, LDL (the “bad”) cholesterol decreased almost 30%, and total cholesterol and triglycerides both decreased almost 20%. Hemoglobin-AGE levels, a circulating marker of the degree of glycosylation, also decreased dramatically (13.8 U/mg Hb at the beginning of therapy, to 10.0 U/mg Hb after only four weeks).

Aminoguanidine is very safe, as indicated by short-term human studies which used the astronomical dose of 1200 mg daily. (This is in comparison with a usual human dose of 100-300 mg daily). The dose required to cause death in half the animals (mice) to which it was administered was 1800 mg/kg, equivalent to a human dose of almost 300 grams!

{Product of interest: Aminoguanidine}

Pyridoxal-5-Phosphate (P5P): P5P, the active form of vitamin B6, has been found to significantly reduce the non-enzymatic glycosylation (formation of AGEs) of bovine serum albumin (BSA) with radioactive-labeled sugar. Of the substances tested, P5P was exceeded only by aminoguanidine in its ability to inhibit AGE formation (Fig. 10).

. In vitro (“test tube”) test comparing the formation AGEs on bovine serum albumin when exposed to glucose

Combining P5P with metformin or aminoguanidine may enhance their AGE-inhibiting actions even more.

{Product of interest: Pyridoxal-5-Phosphate}

Vitamin B1 (Thiamine) and Benfotiamine: In their book, Life Extension, Durk Pearson and Sandy Shaw reported that thiamine was an effective crosslink inhibitor. They were at that time consuming two grams of thiamine each day in their personal antiaging regimens. Thiamine may ultimately also prove to be an effective crosslinkage breaker as well as inhibitor. Another thiamine derivative is the fat-soluble Benfotiamine. Benfotiamine is very helpful in the treatment of diabetic neuropathy at a dose of 300 mg twice daily.

{Products of interest: Vitamin B1 and Benfotiamine}

Carnosine: Dr. Alan Hipkiss of the Division of Biomolecular Sciences, King’s College London, reviewed the antiaging effects of carnosine and aminoguanidine.46 Dr. Hipkiss believes that one of the major mechanisms of the antiaging effects of carnosine is its powerful effects as a crosslink inhibitor and breaker, and that the use of these substances might help to control age-related molecular dysfunction. Carnosine has been used in doses generally ranging from 500-2,000 mg/day.

{Product of interest: Carnosine}

Your Takeaway

Whew, yes, that was a lot of information to chew on, and I have more homework to do because I want to try some of those chealtors and supplements.  If you’ve used them or intend to, let us know in the Comments below.

Before you click away, remember these three things:

  1. Aging is accumulating, unrepaired damage to the cellular and molecular structures that make up the functional units of our tissues.
  2. Damage is intensified by various toxic heavy metals, such as aluminum, which specifically adds to the bodies glycation burden over time.
  3. Detoxification can occur by various agents that bind to (chelate) and remove toxins.

 

P.S. For more articles about detoxification on this site, click here.

P.P.S. Much of this article focused on the damages wrought by aluminium toxicity. Mercury, however, is typically a bigger problem for most of us. Lots of surprises and solutions in this article:

What You Absolutely Must Know About Detox Cleanses (But Don’t)

 

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Joe Garma
 

I help people live with more vitality and strength. I'm a big believer in sustainability, and am a bit nutty about optimizing my diet, supplements, hormones and exercise. To get exclusive Updates, tips and be on your way to a stronger, more youthful body, join my weekly Newsletter. You can also find me on LinkedIn, Twitter and Instagram.

Click Here to Leave a Comment Below 4 comments
Jean Marie Lescohier - October 15, 2016

Hello Joe, the aminoguanidine sounds like it may have great potential. I ordered some from antitaging-systems.com $46.98 w/shipping – I’ll try it at 2 a day & proceed for about 6 months. I enjoy “listening” to your blog & share the info with friends.
Thank you!
Jean Marie L.

Reply
Joe Garma - October 15, 2016

Please let us know what you think of it, Jean, once you’ve used it for awhile.

Reply
februadi bastian - August 7, 2018

Thank you for the nice article. If possible, could you send me the article about fig 8.? thank you very much

Reply
Joe Garma - August 8, 2018

Februadi, I could not find the original source for Figure 8. I got it from a piece written by Dr. Ward Dean and he did not cite where he got it. I did, however, look for it on Google Images to no avail. You might try doing this using terms specific to your point of inquiry. I did find an interesting illustration: Figure 1: Schematic representation of AGEs formation and of their biological effects, found in this article — https://www.omicsonline.org/open-access/advanced-glycation-end-products-ages-in-food-focusing-on-mediterranean-pasta-2155-9600-1000440.php?aid=63980

Hope this helps.

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