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Crosslinkage Theory of Aging: Part I

New Life for an Old Theory

By Ward Dean, M.D.

The oldest still-viable molecular-based theory of aging is the Cross-linkage Theory of Aging, conceived by Dr. Johan Bjorksten in 1942. Bjorksten was a true ‘Renaissance Man’ who spoke seven languages, was a profound philosopher, a creative storyteller (using entertaining parables to explain profound scientific concepts), and a successful businessman. And although he was considered somewhat of a maverick by his colleagues, he was also a highly respected and innovative scientist.

Bjorksten was born in Finland in 1907. He earned a Ph.D. in protein chemistry in 1931 from the University of Helsingfors, Finland, and immigrated to the US in 1931, where he continued post-doctoral work at the University of Minnesota. From 1936 to 1941, he was the Chief Chemist for Ditto, Inc., which at that time was the world’s largest manufacturer of hectograph films and equipment. The Hectograph was a low-tech forerunner of today’s photocopying machines. The Hectograph utilized a flexible gel as the primary copy medium. From 1941 to 1944 he was Chemical Director for Quaker Chemical Products Corporation in Conshohocken, Pennsylvania. In 1944, he established his own research organization in Chicago – Bjorksten Research Laboratories – which he moved to Madison, Wisconsin, in 1948. It was there that his main office and laboratories were situated, on a 168-acre tract of land.

In addition to the research organization for which he served as Chairman of the Board, Bjorksten was also Vice President and Director of the ABC Pack-aging Machine Corporation of Tarpon Springs, FL (which he founded in 1941); President and Board Chairman of Bee Chemical Company in Chicago (which he founded in 1945); Director of Ircon International, Chicago, Griffolyn Co., Houston, Texas, and International Plastics, Inc., of Wichita, Kansas. In 1953, he founded Bjorksten Research Foundation, a non-profit foundation devoted exclusively to fundamental research on aging, with a view to finding new paths toward control of degenerative disease and extending the human lifespan.

Protein Reaction Clue to Aging

While at Ditto Corporation, one of the main problems Bjorksten faced was to develop a way to increase the ability of the hectograph films to withstand summer temperatures, exposure to water, mechanical stretching and friction, and to prevent their drying out and cracking. Bjorksten noted the apparent resemblance between the aging of the hectographic film and the aging of the human body.

Crosslink1_Figs_1_and_2 Both processes involved protein reactions, leading to drying out and loss of elasticity. The aging of hectograph films was due to the cross-linking of protein molecules. Bjorksten believed that this phenomenon was the cause of aging in humans.1,2 In fact, this was confirmed in a crude way, by comparing the similarity between the shape of the mortality curve for humans (Fig. 1) with a viscosity curve of gelatin during a cross-linking reaction (Fig. 2).3,4 Bjorksten interpreted this similarity as support for his theory that the immobilization of large molecules is a controlling factor of the aging process.

The Effects of Crosslinking

Crosslinking has many industrial uses. Whenever one wishes to make something more rigid and less elastic, crosslinking is the way to do it. Tanning of leather is due to the formation of crosslinkages, as is the drying of paint. However, in the case of our own cells, crosslinking can be catastrophic when it happens without control, by pure chance. We can recognize some of the effects of crosslinking in our outward appearance.

For example, the effect of solar radiation on the fats in our skin, combined with oxygen, forms crosslinking substances which then tan the collagen and other protein in the skin, thus making the skin age faster. This explains why exposure to the sun ages the skin faster than if sun exposure were minimized. Unfortunately, the effects of crosslinking under the surface go unnoticed until they manifest themselves as diseases, which are often irreversible.

A Deadly Sequence of Events

Bjorksten believed that the obvious anatomical and psychological changes that take place with aging develop from changes on a cellular level, and that these cellular changes, in turn, originate on a molecular level.5 He reasoned that if we want to find the origin of aging, we must ask, Which chemical reaction initiates the sequence of events that ends in functional impairment, degeneration, senility and death? He determined that those molecules which are carriers of vital processes – proteins and nucleic acids – were the keys to understanding the aging process. The next thing to identify was the way in which these molecules were damaged. He concluded that crosslinking was the specific process that initiated the sequence of events that ultimately led to aging, senility and death.

The crosslinkage theory stated that the principal cause of aging was the linking together of two or more large molecules (macromolecules). Once the two macromolecules were linked, the molecular motion causes them to make further contacts with each other, thereby increasing the likelihood of additional crosslinkages forming between them, as well as forming crosslinkages with other molecules. As this progresses, the cells become increasingly burdened with an accumulation of malfunctioning or inert large molecules which cannot be removed.

Floating Inert Islands

The main premise of the crosslinkage theory of aging is that the crosslinking of large molecules within cells occurs regularly and unavoidably wherever large molecules (having at least two reactive sites) and crosslinking agents co-exist. And they do co-exist in every living cell.

Bjorksten confirmed that crosslinkage is the principal mechanism in the aging of collagen, and that it causes a number of adverse effects on proteins, nucleic acids, and possibly other vital macromolecules, causing them to gradually lose their function by:

1. Creating a deficiency of one or more irreplaceable molecules;

2. Forming tangled molecular chains or nets, which progressively impede intra- and intercellular transport;

3. Progressively reducing the volume of space available for vital molecules within the organism;

4. Causing loss of elasticity of all tissues, thereby increasing susceptibility for rupture;

5. Increasing the lipophilicity of proteins causing crosslinkages of hydrophilic areas;

6. Converting essential molecules into inert aggregates; and

7. Inactivating vital molecules.6

Eventually, these hindrances will lead to the death of the cell. Some large muscles like the heart can counteract crosslinking by repeated stretching and relaxing. This orients the crosslinkers and therefore keeps the arteries and heart muscle from becoming hard, losing elasticity, or becoming otherwise non-functional.7 The concept of crosslinking is illustrated in Figs. 3 and 4.

Crosslink_Figs_2and3

Goal-Oriented Research Strategy

linkBjorksten doggedly devoted 50 years of his life to the pursuit and elaboration of his theory. He was a goal-oriented scientist, determined to unlock the mysteries of aging, and extend the human lifespan. He believed that gerontological research should be goal-directed towards extending the human life-span, and that the primary objectives in gerontological research should be to gain time for (1) enjoying a pleasant life, (2) adding new disciplines of knowledge and creativity, (3) completing specific tasks to which one is committed, (4) any other pursuits one may desire.7

Consequently, he outlined a general research strategy, based on four principles:

1. De-emphasize gerontological work with any animal which has a substantially shorter lifespan than humans, because he believed that chemical reactions which underlie human aging are different from those which act on shorter-lived animals;

2. Studies should be performed on humans old enough to give meaningful results, but not so old that secondary damage overshadows basic aging effects;

3. Do research in countries where it can be done with a minimum of government intervention and harassment; and,

4. Do not sacrifice speed of research for the sake of accuracy greater than the situation permits or requires.

In other words, don’t study something to death before moving on to the next step. If gerontological research is to benefit those who are currently in the field, we cannot afford to work with higher precision than needed, when this leads to major loss of time. We must move on with a belief that the target can be achieved and with a firm resolve to succeed in time to reap the rewards of a greatly extended life span in good health.8

Bjorksten believed that sequential tests should be started as soon as the previous tests have given a fair indication of which way to go. The price we would pay for speed is perhaps a 20% risk that a serious flaw may have been overlooked, and that we must backtrack a bit – at worst, all the way to the beginning. However, the time that may be gained should justify the risk. We have to adopt a strategy of concentrating support on work which will be clearly relevant to the extension of the human lifespan.

Bjorksten illustrates the difference between action-oriented gerontologists and academic gerontologists in a parable of two prisoners:

link.cartoon.2“Both prisoners were held in prison, awaiting their execution by hanging. Their crime was daring to teach theories that did not agree with the conventional wisdom. Three days before their execution, each of them had a visit from a supernatural being who appeared to each of the condemned men in their cells, and said: ‘A higher Power who commands me will give you one more chance. I am to give you one and only one of the two things I hold.

In my right hand is a knife, which is invisible to everyone except you. In the last moment, you might be able to cut your rope and escape in the commotion. In my other hand, I hold an electron microscope and a piece of the rope that will be used to hang you. If you choose the microscope, you will have the satisfaction of examining to the utmost detail the structure of the rope which will end your days. Choose, and may your choice be wise.”

We are all under a sentence of death. Only the date is uncertain. Many of us [gerontologists] have received the strange visitor and have heard his offer. I chose the knife. Many of my colleagues chose the microscope, and are spending their remaining time in pursuits which could not in any event give them longer life.”

Always the practical scientist, Bjorksten believed that in order to decide on a strategy for any game, business venture, or other purpose, one must know the maximum potential gain, as well as any potential losses. He reasoned that only when the potential winnings were known, could we judge what risks we could afford. Although the maximum human lifespan has been estimated to be about 120 years, Bjorksten was interested in knowing if it could be increased by a significant amount.

Crosslink1_Fig_5Dr. Henry Simms calculated that if we could maintain the same resistance to dying throughout our lifespans that we had when mortality was the least (i. e., between the ages of 10-12), we could achieve a theoretical maximum lifespan of 800 years!9 Donald Carpenter re-evaluated Simms’ data, using even more selected methods, and calculated a projected mean lifespan of 2,400 years for men, and 3,800- 4,300 years for women (Fig. 5)!10 Bjorksten reviewed the above two evaluations, in conjunction with added data, and independently calculated ultimate attainable mean longevity values of 640-940 years for men and 2220-3450 years for women!

References

  1. Bjorksten, Johan. Recent developments in protein chemistry, Chem Industries, 1941,48: 746-751.
  2. Bjorksten, Johan, and Champion, William J. Mechanical influence upon tanning, J American Chemical Society, 1942, 64: 868-869.
  3. Bjorksten, Johan. A common molecular basis for the aging syndrome. J American Geriatrics Society, 1958, 6: 740-747.
  4. Bjorksten, Johan, and Andrews, Fred. Fundamentals of aging: A comparison of the mortality curve for humans with a viscosity curve of gelatin during the cross-linking reaction. J American Geriatrics Society, 1960, 8: 632-637.
  5. Bjorksten, Johan. The crosslinkage theory of aging, Finska Kemists Medd, 1971, 80:23-38.
  6. Bjorksten, Johan. The time factor in gerontological research. Rejuvenation, 1980, 8: 84-85.
  7. Bjorksten, Johan. Longevity 2-Past, Present, Future, 1987, JAB Publishing, Charleston, SC.
  8. Bjorksten, Johan. Possibilities and limitations of chelation as a means for life extension. Rejuvenation, 1980, 8: 67-72.
  9. Simms, Henry. Logarithmic increase in mortality as a manifestation of aging J. Gerontol, 1946, 1: 13-26.
  10. Carpenter, Donald. Correction of biological aging. Rejuvenation, 1980,7: 31-49.
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