Crosslinkage Theory of Aging: Part II

New Life for an Old Theory

By Ward Dean, M.D.

Introduction: Part I of the Crosslinkage Theory of Aging was introduced in the January 2002 issue of Vitamin Research News. The Crosslinkage Theory was conceived by Prof. Johan Bjorksten, based on his observation that changes in aging skin and other tissues are similar to the observed hardening of gels and other flexible substances over time. Bjorksten determined that these changes, best exemplified by the tanning of leather, were due to permanent tissue alterations caused by the formation of intra- and inter-molecular crosslinking.

Prof. Bjorksten spent his life studying crosslinking in order to find a means to both delay the formation of crosslinkages and to dissolve those which had been formed. Prof. Bjorksten theorized that gaining control of the crosslinkage process could allow for the prevention of a number of age-related conditions, including Alzheimer’s disease, osteoporosis, cataracts, autoimmune diseases, atherosclerosis, cancer, endocrine dysfunctions, and the aging process itself.

Approaches to Eliminating Crosslinkages

By the end of the 1960s, Bjorksten believed that the evidence supporting the crosslinkage theory was so conclusive that he stopped working to prove the theory, and embarked on greater efforts toward specific applications to retard aging based on the theory. Bjorksten believed that if crosslinked aggregates are, in fact, a major factor in aging, then the removal of such aggregates should be beneficial, and would restore youthful characteristics to the tissues and would probably extend the lifespan.

Bjorksten proposed that safe, biological enzymes be found which could disrupt these pathological crosslinks. He believed that natural enzymes might be found in bacteria which were capable of surviving on a growth www.composed entirely of crosslinked biological proteins. He reasoned logically that if the microbes were able to survive with these highly crosslinked proteins or peptides as their sole nitrogen source, it would indicate that they possessed enzymes capable of digesting the crosslinks. These enzymes could then be isolated and tested for their ability to safely digest crosslinkages in intact experimental animals.

Bjorksten and his associates then set out in their search for these crosslinkage-dissolving enzymes. After four years of work, the team believed they had begun to make progress. They isolated numerous organisms capable of digesting insoluble crosslinked tissue, and selected seven of the most promising for further research. (1-4)

Unfortunately, at this point, the Food and Drug Administration set out on a vendetta against a number of small pharmaceutical companies, claiming that 70% of the output of the pharmaceutical industry was worthless. Consequently, the pharmaceutical company which was funding this long-term research redirected their funding priorities to protect themselves from the FDA attacks. Bjorksten then turned this promising approach over to other pharmaceutical firms in the U.S. (Worthington Biochemicals, later Micro-pore), and unnamed pharmaceutical firms in Sweden and Japan. (4)

Bjorksten then directed his primary efforts in another direction, but with the same objective. His idea was to feed pregnant rats huge amounts of radioactive nutrients several days before and several days after they gave birth to their litters. He used the radioactivity to track the paths of the nutrient in the body. Most of the radioactive material was excreted over a period of time by normal metabolic processes. However, a small fraction of these radioactive substances became bound by non-metabolizable gerogenic aggregates (crosslinked proteins and macro-molecules), and were permanently retained in the body. (5) Bjorksten then treated these animals with anti-crosslinking agents, and assayed their urine, to detect whether these radioactive substances were released. He reasoned that a sudden release of the radioactive substance would be due to the break-up of the crosslinkages in which they had been bound. (6) Unfortunately, funding for this project was also exhausted before any conclusive results were achieved. (7)

Inhibiting Metal-Based Crosslinking by Chelation Therapy

As the difficulties of finding a safe low-molecular-weight, anti-crosslinking enzyme increased, Bjorksten realized that at his current rate of progress, it would take a longer time to identify them than he had anticipated—or than he could afford to spend (he was then in his seventies). Consequently, he again switched his research priorities to find a more short-term age-retarding regimen that would give him the additional 10-20 years of good health which he needed to make his major breakthrough. (8)

Bjorksten focused on another potential means of breaking up crosslinkages, by using chelating agents. Chelating agents are molecules which are capable of attaching to metals within the body, enabling them to be excreted. Their mechanism of action is based on the simple fact that two or more attractive forces, acting simultaneously on a metal atom, are stronger than only one. Chelating agents contain molecules that contain at least two groups of polarity opposite to that of the metal it is wanted to remove. Ethylene-diamine-tetra-acetic acid (EDTA) is a synthetic amino acid that is capable of removing metal-based crosslinkages by chelation, thereby depolymerizing the gerogenic aggregates. (6) Examples of chelating agents in current clinical practice are EDTA (approved for use in the treatment of lead poisoning), 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 — and the International College of Integrative Medicine (ICIM, formerly GLACCM) are trained in the use of these agents. These physicians are also proponents of intravenous chelation therapy with EDTA as a treatment for many chronic degenerative diseases, like atherosclerosis, hypertension, diabetes, and Alzheimer’s disease. (9) Oral EDTA chelation is not yet as widely accepted as the intravenous route. Nevertheless, oral EDTA is rapidly gaining more adherents (see Oral Chelation Update).

Other natural chelators include garlic, (10) Chlorella, (11) 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. (12) Bjorksten (13) also believed that one of the benefits of exercise is that toxic heavy metals (especially aluminum) are chelated by the lactic acid that is generated. (14)

Chelators as Life-Extending Substances

A number of studies confirm that chelating agents — particularly, EDTA — may have life-extending properties. Many scientists demonstrated the life-extending effects of EDTA on lowly rotifers (small multi-celled animals found in freshwater lakes and ponds). (15-19) In the Soviet Union in the 1970s, Dr. T.L. Dubina performed a series of studies with EDTA on the life span of rats. (20) 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. Based on these and other studies, Bjorksten’s associate, Prof. Donald Carpenter, calculated that the widespread use of chelation therapy would result in an average lifespan increase of over fifteen years. (21)

Next Issue: In the third part of the Crosslinkage Theory of Aging, the use of chelating agents to reverse crosslinkages will be explained in more detail.


1. Bjorksten, Johan, Weyer, Elliott, and Ashman, Stephen M. Study of low molecular weight proteolytic enzymes, 1971, Finska Kemists Medd, 80: 70-87.

2. Schenk, Roy U., Bjorksten, Johan, Ashman, Stephen M., and Burrowbridge, George T. The search for microenzymes. Anomalous behavior of pronase. Suomen Kemistilehti B, 1972,45: 343-348.

3. Schenk, Roy U., and Bjorksten, Johan. The search for microenzymes: The enzyme of bacillus cereus, Finska Kemists Medd, 1973, 82: 26-46.

4. Bjorksten, Johan. Longevity 2-Past, Present, Future, 1987, JAB Publishing, Charleston, SC.

5. Zinsser, H. , Butt, E.M. , and Leonard, I. Metal content correlation in aging aorta. J Am Geriatrics Soc, 1957, 5: 20-26.

6. Bjorksten, Johan. Pathways to the decisive extension of the human specific lifespan, J American Geriatrics Soc, 1977 a, 25: 396-399.

7. Bjorksten, Johan. Aluminum in degenerative disease. Rejuvenation, 1981 b, 9: 11-19.

8. Bjorksten, Johan. Aluminum in degenerative disease. Rejuvenation, 1981 b, 9:p. 160

9. Chappell, L.T., Stahl, J.P., and Evans, R. EDTA Chelation treatment for vascular disease: A Meta-Analysis using unpublished data. J Adv Med, 1994, 7: 3, 131-142.

10. Lau, B. Garlic for Health, 1988, Lotus Light Publications, P.O. Box 2, Wilmot, Wisconsin 53192, pp. 31-32.

11. Wilkinson, S. Mercury removal by immobilized algae in batch culture systems, J Applied Phycology, 1990, 2: 223-230.

12. Yaeger, Luther L. , and Bjorksten, Johan. Displacement of protein bound aluminum. Rejuvenation, 1984, 12: 12-14.

13. Bjorksten, Johan. The crosslinkage theory of aging as a predictive indicator. Rejuvenation, 1980, 8: 59-66.

14. 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.

15. Tyler, A. Longevity of gametes: Histocompatibility, gene loss and neoplasia, in: Aging and Levels of Biochemical Organization, by Bruder, A.M., and Sacher, G.A. (eds), Section II, Part 11, 1965, U Chicago Press, Chicago, 50-86.

16. Tyler, A. Prolongation of life-span of sea urchin spermatozoa and improvement of the fertilization-reaction by treatment of spermatozoa and eggs with metal-chelating agents (amino acids, versene, DEDTC, Oxine, Cupron). Biol Bull, 1953, 104: 224.

17. Sincock, A.M. Calcium and aging in the rotifer Mytilina brevispina var redunca. J Gerontology, 1974, 29, 514-517.

18. Sincock, A.M. Life extension in the rotifer Mytilina brevispina var redunca by the application of chelating agents. J Gerontol, 1975, 30: 289.

19. Neigauz, B.M., and Ravin, V.K. Effect of physiologically active substances on the longevity of the nematode Caenorhabditis elegans. Zh. Obshch Biol, 1983, 44: 6, 835-841.

20. Komarov, L.V., and Bakaev, V.V. Means of the Life Prolongation, Rejuvenation, 1983, XI: 2-3, 46-51.

21. Carpenter, Donald. Correction of biological aging. Rejuvenation, 1980,7: 31-49.


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