Ward Dean, MD
Introduction: Sixty years ago Dr. Johan Bjorksten introduced his theory on the role of protein crosslinking as a process involved in many of the debilitating effects of human aging. In Part I of The Crosslinkage Theory of Aging we examined this theory and explained its relevance to ongoing anti-aging research. In Part II we examined ground-breaking research into compounds that can potentially repair the effects of protein cross-linking and reverse some of the most debilitating effects of aging at the molecular level.
Aluminum is a highly reactive metal that occurs freely in nature, and comprises over 8% of the earth’s crust. Although it also occurs very widely in human nutrition (most people ingest 10-100 mg of aluminum daily), it does not play a role in any known metabolic process. Since the human digestive system rejects all but traces of ingested aluminum, aluminum has historically been regarded as a relatively non-toxic substance. However, we are now learning that aluminum is highly toxic, even in extremely small amounts.
The neurotoxic effects of aluminum have been known for many years. (1) More recently, scientists have shown that aluminum accumulation may contribute to Parkinson’s disease (2,3) Down’s syndrome4 and Alzheimer’s disease. Crapper, et al injected 100 nanamoles of aluminum chloride into cats’ brains. (5) Ten days after the aluminum injections, the cats’ short term memories were completely gone, causing a condition similar to Alzheimer’s disease in humans.
There are a number of reasons which explain the toxic effects of aluminum. First, aluminum is a powerful flocculant (an agent that precipitates suspended solids in turbid water) commonly used in municipal water treatment processes to “purify” drinking water. These properties also cause shrinkage of colloids (suspended microscopic particles). Since the human brain contains large amounts of colloidal gels as essential constituents, abnormal coagulation of these gels will cause shrinkage — and possibly sever interneuronal connections — in a process similar to ones known to occur in aging. If aluminum “de-flocculates” our brains, however slowly, it might be a high price to pay for absolute clarity of our drinking water.
Second, aluminum is a powerful crosslinking agent. The reason for this is that the aluminum atom has a very small diameter (Fig. 1), and a very high surface binding energy. Therefore aluminum can penetrate almost everywhere and displace any of the other common metals in soluble compounds. In particular, aluminum readily displaces calcium, which is present in every living cell. The mechanism of how aluminum can cause crosslinkages and age-related changes becomes clear when we consider a critical property of aluminum in relation to calcium. Calcium atoms have only two binding sites. Aluminum atoms, on the other hand, possess three binding sites (Fig. 2).
With only two binding sites calcium is restricted to combining in straight lines only (Fig. 3). Thus, when calcium combines with anything else with two binding sites, there is no way in which branching (crosslinking) can occur. However, when even the smallest trace of aluminum displaces anything with two binding sites, there is no way in which branching can be avoided! This is because aluminum has an extra valence, or “hook,” which can combine with an unsatisfied binding site in another bi-valent (two binding sites) chain. Therefore each aluminum replacement of calcium results in a new branching (crosslinking). Repeated branching, coupled together with growth, makes tangling unavoidable (Fig. 4).
Our bodies have five defenses against aluminum. These are:
Despite these barriers, nothing works perfectly, and a small amount of aluminum is still absorbed. Using another one of his charming stories, Bjorksten (6) described how this might happen: “If I were an aluminum atom and wanted to get into the nucleus of a neuron, past the body’s defenses, I would watch for a calcium transport and board it. Calcium is needed in every cell, so calcium has (relatively) free access. I, as aluminum, am only half as big as the calcium, but have 50% more strength, and, as an “ace in the hole,’ I have a third arm! So I would board the calcium transport, occupy a calcium compartment, and use my totally unsuspected resource, the third arm, either to hold camouflage or to defend my place against all comers. The calcium shuttle might be chosen from any of the four groups of calcium-binding proteins. I might slip out inconspicuously once inside the last defense, or I might even use my third free arm to kidnap the entire transport, converting it to a free radical by the force in my third arm, and then maneuver the entire unit to combine with literally anything it happened to hit.” Unfortunately, our defenses against aluminum were not designed to last much more than the 60 years or so required for the average human to have children and help them get a good start in life.
In 1955, during a talk on gelatin crosslinkages and aging at the Gerontological Society in Baltimore, Bjorksten discussed the probable 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. 5). 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 did not survive the next ten years. (7)
Zinsser’s data were confirmed independently by Markesbery and colleagues, who demonstrated a progressive increase of aluminum concentrations in the brain (Fig. 6). (8) Extrapolating from these values, Bjorksten concluded that the finding of progressive increases of aluminum with age were of great theoretical importance, and indicate that humans, in their natural state, will die between 110-120 years of age as a result of the aluminum mechanism alone, even if no other cause of death intervenes. (9) Bjorksten is so convinced of the profound toxicity of aluminum in contributing to the aging process, that he predicted that even if cancer and atherosclerosis were completely eliminated as causes of death, aluminum accumulation would be the foremost cause of age-related human disease.
Clearly, it is important to reduce our exposure to aluminum. The most obvious steps are to drink only filtered water, and to avoid aluminum cookware, aluminum foil-wrapped food, beverages in aluminum cans, aluminum-containing anti-acids, aluminum-containing anti-perspirants, and foods made with aluminum, like baking powder and most non-dairy coffee creamers.
However, when preventive methods are not enough — and Dr. Zinsser’s data cited above indicate that they obviously are not enough — we must consider ways to remove as much accumulated aluminum as possible.
Bjorksten and his staff evaluated the ability of chelating agents to remove aluminum from the aortas of 5-6 month-old hogs, which had previously been stained with an aluminum-containing stain (Fig. 7). (10) It can be seen that EDTA was the most effective. Lactic acid, similar to blood concentrations generated by exercise were moderately effective. Of interest was the fact that 0.5 % procaine — the active ingredient of Gerovital (the Romanian anti-aging drug) — was also moderately effective in reducing the aluminum. This raises the question whether the metabolites of GH3 — DMAE and PABA — might also have some effect in this regard.
Other benefits of DMAE/PABA were described in a previous issue of Vitamin Research News. (11) Drs. Imre Zs.-Nagy and Katalin Nagy demonstrated that both dimethylaminoethanol (DMAE) and centrophenoxine (CPH) are indeed able to diminish the extent of crosslinking in old rats. (12) Professor Zs.-Nagy’s membrane hypothesis of aging, and his studies with Idebenone and DMAE were also described in a previous issue of Vitamin Research News. (13)
In another series of innovative studies, (14,15) Bjorksten’s team evaluated the ability of various concentrations of lithium to remove tightly bound aluminum from tanned leather baseball covers. Using a 0.05M concentration of lithium citrate, they were able to displace 100% of the protein bound aluminum in the baseball covers. They found that it took approximately three months to completely demetalize the leather. Lithium is used to treat manic depressive illness (MDI) — but recent studies indicate that it may offer benefit in the prevention and treatment of Alzheimer’s disease, as well. (16) Safe blood lithium levels are about 1.0 mEq/liter — about 1/50th of the concentration used to displace aluminum from the baseball covers. Nevertheless, it is intriguing to consider that perhaps long-term treatment with low doses of lithium may be an effective way to displace protein bound aluminum in animals and humans. Lithium orotate as a dietary supplement is the safest, most effective form of lithium available.
In another series of experiments, using himself as a guinea pig, Bjorksten applied a low voltage current to his head, in an attempt to demetalize his own brain. (17) His parents both died from Alzheimer’s disease, and he believed that he was beginning to show some early signs. After much trial and error, he designed an electrical “skull cap,” which was moistened with a solution of sodium chloride to enhance conduction. He hypothesized that at the rate of 1/2 hour every day, it should be possible to remove the aluminum present in the neural chromatin in the brain in 1,538 days (4.3 years). However, he realized that only a part of the energy may have been applied to aluminum removal, and that a longer time may be required.
Another theoretical approach to removing aluminum is by the intravenous, oral, or topical use of dimethylsulfoxide (DMSO). Bjorksten and colleagues extracted a substantial part of the aluminum present in human cadaver brains with DMSO. (18) DMSO is approved for human use as a bladder irrigant in patients with interstitial cystitis, and for use in dogs and horses as a topical anti-inflammatory agent. However, it is also widely used topically, intravenously, and orally to treat a wide range of clinical conditions, including arthritis, sprains, atherosclerosis, burns, scleroderma, and many other conditions. (19-21) MSM (methylsulfonylmethane) is the active metabolite of DMSO, and shares most of its properties, without the somewhat objectionable odor of DMSO. An effective dose of MSM is generally in the range of 3-5 gm daily.
Despite the sound theoretical and experimental basis, and the apparent promise of the Crosslinkage Theory of Aging, Bjorksten’s contributions have been largely ignored by present-day gerontologists. Although Bjorksten remained fully active until his death in 1996 (He published his last book in 1991, and co-authored a yet-unpublished paper with his last collaborator, Dr. Don Kleinsek, shortly before passing away at the age of 89) (22) little has been written about the crosslinkage theory since that time.
Nevertheless, Bjorksten’s work remains solid. He suggested (and validated) the value of a number of potential anti-crosslinking nutritional substances, with primary emphasis on EDTA. Bjorksten, in his later years focused primarily on the crosslinks caused by aluminum (largely, I think, because this was something which he discovered could be prevented). In recent years, much has been written about the process of enzymatic browning and glycation, resulting in production of advanced glycation end products of aging (AGEs) which result in crosslinked proteins, just as Bjorksten predicted. I believe the currently popular approach of preventing and breaking AGE-induced cross-links is in reality an outgrowth and development of Bjorksten’s theory.
The next installment of the Crosslinkage Theory will address the glycation of proteins in detail, and suggest specific anti-aging approaches based on preventing and eliminating these AGE-induced crosslinks.
1. Spira, L. Clinical Aspects of Chronic Poisoning by Aluminum and its Alloys, 1933, Bale and Sons, London.
2. La Presle, J. , Duckett, S. , Galle, P. , and Cartier, L. Documents cliniques, anatomiques et biophysiques dans une encephalopathie avec presence de depots d’aluminum, Biol, 1975, 2: 282.
3. Galle, P. , and Duckett, S. X-ray microanalysis of pallidal arteries in Parkinson Disease, Sixth European Congress on Electron Microscopy, 1976, Jerusalem, 210-211.
4. Crapper, D.R., Kalrik, S., and DeBoni, U. Aluminum and other metals in senile (Alzheimer) dementia, in: Alzheimer’s Disease: Senile Dementia and Related Disorders, by Katzman, R., Terry, R.D., and Bick, K.L. (eds), 1978, Raven Press, New York.
5. Crapper DR, Krishnan SS, Quittkat S. Aluminium, neurofibrillary degeneration and Alzheimer’s disease. Brain. 1976 Mar;99(1):67-80.
6. Bjorksten, Johan. Longevity 2 – Past, Present, Future, 1987, JAB Publishing, Charleston, SC.
7. Zinsser, H., Bjorksten, I., Bruck, E.M., Baker, R.F., et al. The freezing pool: A unified sequence of the aging process, in: Medical and Clinical Aspects of Aging, by Blumenthal, H. T. (ed), in: Proc 5th Int Assn Gerontology, 1962, Columbia U Press, 1962,482-505.
8. Markesbery, W.R. , Ehmann, W.D. , Alauddin, M. , and Nossain, T.I.M. Brain element concentrations in aging. Neurobiology of Aging, 1984,5: 19-28.
9. Bjorksten, Johan, Yaeger, Luther L. , and Wallace, Terri. Control of aluminum ingestion and its relation to longevity. Internat J Vit Nutr Res, 1988,58: 462-465.
10. Schenk, Roy U. , Bjorksten, Johan, Lipert, Robert, and Mortell, Molly. Extraction of aluminum from aorta tissues by chelating agents and lactic acid. Rejuvenation, 1981, 9: 4-10.
11. Dean, W. DMAE and PABA — An alternative to Gerovital (GH3), the “Romanian Youth Drug,” Vitamin Research News, 2001, 15: 9, 1 7.
12. Zs.-Nagy, I., and Nagy, K. On the role of cross-linking of cellular proteins in aging. Mech Aging Dev, 14: 245-251, 1980.
13. Dean, W. Imre Nagy, Anti-Aging Pioneer — Key Developer of Centrophenoxine and Idebenone. Vitamin Research News, 2001, 15: 2, 1-14.
14. Yaeger, Luther L. Electrolytic scission of hexadentate aluminum bonds. Rejuvenation, 1983, 11: 76-80.
15. Yaeger, Luther L. , and Bjorksten, Iohan. Displacement of protein bound aluminum. Rejuvenation, 1984, 12: 12-14. 16.
Fugate, L. Potential Role for Lithium in Preventing Alzheimer’s Disease. Vitamin Research News, 2002, 16: 2, 1-7.
17. Bjorksten, Johan. The possibility of removing covalently bound aluminum from the living human brain. Rejuvenation, 1984, 12: 24-27.
18. Bjorksten, Johan, Sundholm, Franciska, and Tenhu, Heikki. Aging, crosslinking and Alzheimer’s disease. Rejuvenation, 1984, 12: 3 and 4, 43-46.
19. Herschler, Robert, and Jacob, Stanley. DMSO Patent, U.S. Patent Office, 3,549,770, 22 December, 1970.
20. Jacob, Stanley, and Herschler, Robert. DMSO-The True Story of a Remarkable Pain-Killing Drug. 1981, William Morrow and Company, New York.
21. McGrady, Pat. The Persecuted Drug-The Story ofDMSO, 1980, Charter Books, New York.
22. Bjorksten, J. and Kleinsek, D. Synopsis of Prospective Longevity Research, 1991, JAB Publishing, Madison, WI.