C&EN Special Report/Part I
The Enigma of
HUMAN AGING The skin wrinkles. The hair turns gray. The hands grow gnarled. The eyes no longer can focus sharply on nearby objects. Bones become brittle. And most serious of all, the body, its vigor slowly ebbing, loses its capacity to withstand stresses. An illness that in a younger person would be sloughed off as minor now becomes catastrophic. Why? Why does man develop the tell-tale signs of age? What causes the human mechanism gradually to unwind and eventually stop? These and related questions on aging have now become the consuming interest of hundreds of scientists in
This is Part I of C&EN's two-part special report on the chemistry of human aging. The second section, to appear next week, will discuss the effect of genetics, radiation, hormones, diet, and other factors on the aging process. It will also analyze what scientists are really attempting to accomplish by their recently stepped-up attack on the important problem of aging. 138
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the U.S. and hundreds more abroad. Biochemists, physicians, physiologists, biologists, biophysicists, and others are probing the basic questions: • What specific changes—in organisms, in cells, in molecules—occur during aging? • What causes these changes? • How might such changes be significantly delayed? In the past 10 years, interest in aging research has grown rapidly. So has the number of research programs in this field. Among the biggest impetuses behind this trend has been the National Institutes of Health, which estimates that it is currently supporting about 75% of all U.S. research in aging. In 1960, NIH sponsored 700 research projects directly or indirectly related to aging, at a cost of $16.2 million. In 1961, NIH supported 879 projects, at a cost of $30.4 million. This is in sharp contrast to the 274 projects, costing $4.6 million, that NIH financed when it began stressing this program only six years ago. Of course, not all of these projects have
dealt with the fundamental causes of aging. In 1960, somewhat less than half were concerned directly or indirectly with the biochemical and physiological factors in aging. The remaining projects dealt with everything from research on the social aspects of aging to studies of improved graduate training in public health. Mounting interest in the aging problem has also shown itself in other ways. In December 1959, the American Association for the Advancement of Science held a special two-day symposium on aging. In January 1961, nationwide attention was drawn to a four-day White House Conference on Aging. Several weeks ago, a Bahamas Conference on the causes of aging was held in Nassau. Next month, the American Chemical Society's Division of Biological Chemistry will sponsor a symposium on the molecular biology of collagen, with emphasis on its structure and agerelated changes, And this coming June, a Gordon Research Conference on the basic chemistry of aging will be held in Tilton, N.H. A mere 30 years ago, if a research
Rapid Increase in Number of Older People in U.S. Emphasizes Importance of Aging Research Number of People 60 Years Old and Over
Population
As Percentage of Total U.S. Population
35
Percent 14
30
12
25
10
20
8
15
6
10
4
5
2
Millions
0
0' 1900 1920 ^Estimated.
1940
1960*
man announced that he was planning to take up the study of human aging, his colleagues might have viewed him with withering scorn. They might have concluded that the old boy, finally going off the deep end, was all set to become one of those crazy monkey-gland quacks in pursuit of the mystic elixir of perpetual youth. In those days, research workers in aging, with some notable exceptions, were practically scientific outcasts. But all that has changed. I n , t h e past decade or so, aging research, like cancer research, has finally become respectable. Not only respectable, but essential. Heightened
Urgency
The importance of aging research has been underscored by the fastgrowing number of aged in the U.S. population. Back in 1900, only about 4.9 million Americans (6.4% of the total population) were 60 years old or over. In 1960, about 23.0 million (12.8%) were in this age bracket. And the figures keep climbing. By 1980, an estimated 34.5 million (13.3% of the population) will be in this age group. With their steadily rising numbers, the aged have become 140
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1980*
1900
1920
1940
1960*
an ever-increasing social and economic factor in the U.S. Despite the great strides made in recent years in reducing infant mortality and the diseases of youth and middle age, relatively little has been done for the aged. In 1900, a person at age 65 could expect to live, on the average, about 12 more years. Now, he can expect to live about 14 years—a modest gain of only two years. Gradually, the public is recognizing the importance of the aging problem. More money is being channeled into aging research. And more of the nation's scientists are taking up the challenge. Today, aging studies are being carried out in dozens of universities, medical schools, hospitals, government laboratories, and research institutes across the country. Almost none of this research, however, is being done by private industry. For years, many pharmaceutical companies have been actively investigating the diseases of the aged—heart disease, cancer, arthritis, mental illness. Some companies, such as Lederle Laboratories, say that their research programs in nutrition, cell metabolism, steroid chemistry, and other areas touch on the basic problems of aging,
1980*
although they do not directly attack the question of aging's fundamental causes. Progress to Date How much do we really know about aging? Relatively little. Of course, there are a few scientists who are inclined to state unequivocally that they have "the answer," or something closely resembling it. They promote their special theories of aging with a vehemence that suggests that they have finally latched on to ultimate truth. But most research workers in aging are a cautious, conservative lot. They speak in terms of possibilities. They shy away from sweeping generalizations. They agree that, although progress is being made, aging continues to be what it has always been— one of the great biological and biochemical mysteries. Discussing the current status of aging research, Dr. Norman G. Anderson of Oak Ridge National Laboratory says, "Research on human aging is obviously in a very primitive state. Human aging is not fully described, much less understood in terms of
At Western Reserve University, Dr. Robert R. Kohn (left) shows William True the way to prepare an enzymatic digest of human collagen on filter paper for separation of its peptides by electrophoresis. Variation in the peptides obtained may indicate the sites of chemical change with increasing age
chemical mechanisms. At this point, we can only seek to gather additional basic data." Dr. Quentin B. Deming of Albert Einstein College of Medicine in New York City says, "We are in a terribly early stage of research on aging. Considering our present state of ignorance, it would be sheer arrogance to point to any one phenomenon as the sole cause of aging." If you ask the average scientist in this field what he thinks is the fundamental cause of human aging, he will most likely dodge the question or freely admit that he doesn't know. Many will start talking about their own work—but with no presumption that it is the final answer. Many will say they prefer to keep an open mind, even though obviously they consider their own research important and are inclined, at times, to be scathingly critical of the work of others. No Shortage of
Theories
Needless to say, scientists, philosophers, and armchair pundits have managed over the years to spawn a vast multitude of theories to explain human aging. Not long ago, one author listed over 120 different theories. Of
late, some scientists have been crying out against the great welter of "explanations." Says Dr. Alex Comfort of University College in London, "Throughout its history, the study of aging has been ruinously obscured by theory—particularly by theory that begets no experimental hypotheses." The problem with all these theories is that probably aging has no single cause but results from a chain of causes or a variety of causes. Anyone who claims, for example, that aging is produced by a disruption of pituitary function can always have thrown in his face the blunt remark, "Yes, but you still haven't told us what disrupts the pituitary." Further confusion results when one scientist says that aging is caused by basic changes in the cell nucleus, while someone else says that aging is produced by gene mutations and yet another points to the "progressive fraying of the template of deoxyribonucleic acid." They may all be talking about the same thing. Of the bewildering array of theories already suggested to explain aging, are any more valid than any others? Can any be discarded as useless? Is research in any one specific area of the aging field likely to yield more
valuable information than research in any other? Questions such as these can, of course, arouse vigorous controversy. However, many people in the field say that almost no theory of human aging has either been proved or disproved. In other words, relatively little can be discarded. Says Dr. Nathan W. Shock of the National Institutes of Health and Baltimore City Hospitals, "Although some theories of human aging, especially among those put forth prior to 1900, are no longer taken seriously, very few critical experiments have ever been done to rule out any theory of aging." Stressing the importance of a broadscale attack on aging, Dr. Deming says, "We need all types of research. Virtually any good research in biology or biochemistry today is worthwhile and potentially relevant to aging. Some day, we may be able to focus on more limited areas of research—but certainly not now." Says Dr. David A. Hall of the University of Leeds in England, "As long as scientists can be dissuaded from claiming that their own approach is 'the one and only,' there can be nothing but gain from having research groups cover as many diverse fields as posFEB. 12, 196 2 C&EN
141
Scientists today are learning more about the chemical changes that take place in collagen as it ages. Dr. Paul M. Gallop (left) of Albert Einstein College of Medicine discusses the amino acid analysis of a collagen sample with Dr. Quentin B. Deming
sible." Other scientists, while recognizing the immense value of the broad approach, emphasize that there is an even more urgent need for intensive research aimed squarely at the aging problem. Actually, the scientific study of human aging is relatively new. Although research in this field dates back to the work of Dr. Charles E. Brown-Sequard at the University of Paris in the 1880's and although some outstanding contributions were made in later decades, the really intensive study of human aging did not begin until about 1950. Because this research is so new, it is still largely descriptive. Scientists are learning more about what takes place in the organism as it ages. Understanding of why the changes occur is developing much more slowly. Research to date has been a continuous chipping away at the problem. Nothing remotely resembling a breakthrough has occurred. Says Dr. Comfort, "In the past 10 years, virtually nothing substantial has emerged that could be put honestly to a lay committee as evidence of 'definite progress/ . . . Yet a certain amount 142
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has been achieved in defining the problem, clearing away old errors, and raising a generation of scientists who know the possibilities and difficulties of aging research. . . . Although, this research has borne no fruit as yet in medicine, the work may later prove more important than it appears now." What Is Aging? Most scientists would agree that aging is an accumulation of adverse changes that decrease the ability of an organism to carry out various specialized functions. At the same time, these changes increase the probability that the organism will die. Primarily, aging is not caused by disease or other environmental stresses. And it may well be accelerated by processes inherent in all living organisms. A curious fact about aging is that practically nobody ever dies of it. Aging merely increases the chances that a person may die of any one of scores of diseases. This situation considerably complicates the research picture. Scientists have to separate out the changes that are caused by
disease and those produced by the fundamental processes of aging. Twenty years ago, many leading scientists believed, for example, that atherosclerosis was inherent in the aging process. Now, it is believed to be a potentially controllable diseaseone that occurs often enough among the young to suggest that other factors (including genetics and diet) may be at least as important as the deterioration of aging. Also complicating the aging picture is the fact that different organs of the body age at different rates. As a result, a 40-year-old man, biologically speaking, can have 37-year-old lungs and a 45-year-old heart. And this situation can vary markedly from person to person. Also significant is the fact that, although some bodily changes may seem to represent aging, they may actually be part of the body's healthful process of maturing. Over the years, scientists studying aging have probed, to a greater or lesser degree, just about every conceivable aspect of bodily function. They have given particular stress to the possible correlation between aging and: • Changes in connective tissue—specifically its collagen, elastin, and ground substance. • Cross-linking of proteins and nucleic acids. • Formation of free radicals. • Cenetics and the chemistry of the genes. • Ionizing radiation. • Accumulation of age pigments. • Enzymes and hormones. • Nutrition, especially underfeeding. Increasingly, the accent has been on what takes place on a molecular level. This is where chemists have made a vital contribution. And their role will be even more essential in the future. Alterations
in Connective
Tissue
Probably no area of aging research has received more attention than the study of connective tissue. Changes in connective tissue are among the most characteristic and most readily observable signs of aging. These are the changes that cause skin to lose its flexibility and wrinkle. They are the changes that give old people bent backs and creaking joints.
In the human body, connective tissue is ubiquitous. It is present in high concentration in tendons, which connect muscles to bones, and in ligaments, which hold bones together. It is present in skin and blood vessels. Scar tissue is a local deposit of connective tissue. With aging, the properties of connective tissue change markedly. And the total amount in the body increases. Connective tissue contains three types of fibrous material—collagen, elastin, and reticulin. All of these fibers are imbedded in an amorphous
material known a,s ground substance. Considerable research has been done on what happens to collagen as an animal ages. Collagen fibers are the strong, inelastic components of connective tissue. Also present in bones, collagen, the most abundant protein in the body, accounts for roughly 30% of all body protein. With aging, the amount of collagen in the body increases. In addition, the collagen becomes increasingly rigid and more definitely oriented (more crystalline). Tested in the laboratory, collagen from older animals
dissolves to a lesser extent in phosphate or citrate buffer solution than material from young animals. In 1954, Dr. F. Verzâr of the Institut fur Experimentelle Gérontologie in Basel, Switzerland, showed that various physical properties of collagen taken from rats, mice, and other animals change in direct relation to the animal's age. He found, for example, that, when collagen is heated to 60° C , the resulting contraction produces a tension proportional to age. This change he attributed to an agerelated increase in hydrogen cross-
With Aging, Collagen Forms Bonds Within and Between Molecules
αϊ
α2
OL\
YOUNG COLLAGEN WITH ESTER LINKING ONLY WITHIN EACH STRAND
OL\
«2
«1
COLLAGEN WITH SOME ESTER CROSS-LINKING BETWEEN TWO STRANDS
In highly schematic form, this shows the increasing cross-linking of collagen with age. Each collagen molecule, shown here in a shaded area, is composed of three polypeptide strands, two of which are the same chemically. Each strand contains four subunits, held together by pairs of ester bonds. After collagen is deposited into young collagen fibers or on the surface of older ones, switching of these ester bonds occurs. This forms bonds between strands of the same collagen molecule. On further aging, collagen also cross-links with adjacent collagen molecules. These cross-linking reactions have been suggested by Dr. Paul M. Gallop and co-workers at Albert Einstein College of Medicine
OLD COLLAGEN WITH ESTER CROSS-LINKING BOTH WITHIN AND BETWEEN MOLECULES FEB.
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linkages between the helixes of the collagen molecules. Structurally, collagen has been found to be a three-stranded helix with a molecular weight of about 360,000. As Dr. Karl Piez of the National Institute of Dental Research has shown, two of collagen's strands are the same chemically; the other has a slightly different amino acid composition. At Albert Einstein College of Medicine, Dr. Paul M. Gallop, Dr. Olga O. Blumenfeld, Dr. Carl Franzblau, and Dr. Sam Seifter have found that each strand of collagen is composed of four subunits, each of which is held together by a pair of ester bonds and perhaps a glycosidic linkage. As the material ages, the ester bonds of a collagen strand may gradually shift to form ester cross-linkages with another strand of the same molecule. This so-called intramolecular transesterification takes place with no increase in the total number of ester bonds. At the same time, some of collagen's ester bonds, says Dr. Gallop, may cross-link with a neighboring collagen molecule. This would not involve the action of an additional cross-linking agent. However, he says, it is possible (although it has not yet been shown experimentally) that collagen molecules may also cross-link with age through the action of separate crosslinking agents, such as polysaccharides and mucoproteins. Because of this increasing degree of cross-linking ("this greater cementing action/' as he describes it), collagen gradually becomes a tougher, more insoluble fiber with age. Other research workers have suggested that the progressive cross-linking of collagen may be caused, in part, by an aldehyde which acts in much the same way as a tanning agent. The aldehyde might diffuse into the collagen or might be formed by the action of oxidizing agents on collagen. Others have suggested that collagen's cross-linking is caused by an as-yet-undiscovered enzyme. Still others, such as Dr. Jerome Gross of Massachusetts General Hospital, have proposed that the cross-linking may actually be a very slow chemical reaction involving no enzyme. Allowing purified skin collagen to age in vitro in physiological buffered solution at body temperature, Dr. Gross has found that the material forms an increasing number of cross-links both within and between collagen mole144
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cules, without enzymes present. This process, he says, may be an example of a general phenomenon that occurs when large, sterically specific molecules of complementary structure are packed closely together. In this way, reactive groups on their surfaces may be in a position to form strong bonds. Elastin Gets Less Elastic Elastin, another important fiber in connective tissue, has also been subjected to intensive study. Like collagen, it is a protein. Unlike collagen, it is a rubbery, noncrystalline, elastic material. In fact, elastin is what gives blood vessels and lung tissue, for example, their typical flexibility. But elastin becomes less flexible with age. What causes this change is not too well understood. There lias been no evidence, for example, that the material increasingly cross-links with age. Dr. Karl Meyer of Columbia University College of Physicians and Surgeons has found that the ground substance in which the elastin fibers are embedded loses 50 to 70r/r of its hy-
aluronic acid by the time a person reaches the age of about 70. This acid, a mucopolysaccharide, normally acts as a lubricant for the elastic fibers. Loss of this lubricant, he says, decreases the slippage and thus the flexibility of the elastin molecule. Scientists find that the body's total amount of elastin decreases with age. In addition, the elastin fibers slowly break up into smaller pieces, probably because of mechanical stress. Elastin also changes in other ways with aging. Normally yellow (collagen is white), elastin gradually turns a darker yellow. The nature of the yellow pigment, as well as that of other pigments present, is still unknown. Possibly, as these pigments build up with age, they increasingly interfere with the flexibility of the elastin fibers. Scientists, such as Dr. David A. Hall of the University of Leeds, have found that the amount of such amino acids as aspartic acid, glutamic acid arginine, and lysine increases with age in elastin fiber taken from the walls of arteries. This change, he says, may cause an increased uptake of calcium, which would ultimately result in cal-
Clasiin fibers of connective tissue become less flexible with age. Dr. Karl Meyer of Columbia University says that decreased flexibility results from loss of lyaluronic acid in the ground substance on which the fibers-are embedded. Loss of this lubricant reduces fiber slippage
Some scientists believe that aging is caused by cross-linking of proteins and nucleic acids. Among the leading proponents of this theory is Dr. Johan A. Bjorksten of Bjorksten Research Laboratories, who says that some cross-linkages cause the body to accumulate materials that harmfully cannot be metabolized
cification and hardening of the arteries. It may also make the elastic fiber more susceptible to enzymatic breakdown and thus account, at least in part, for the body's decreased clastin content with age. Biochemists are also learning more about the nature of ground substance in connective tissue. A jelly-like material, ground substance consists primarily of four to six mucopolysaccharides. With aging, less of it is found in connective tissue as the amount of collagen increases. Ground substance also changes chemically with age. Studying the ground substance of human rib cartilage, Dr. Meyer finds that the total amount of the mucopolysaccharide, chondroitin sulfate, decreases almost linearly with age. It drops from about 6V< of the dry weight of cartilage at birth to less than V/< at age 75. He also finds that, as a person ages, the amount of the 4-sulfate form of chondroitin sulfate in this tissue decreases and is replaced by the 6-sulfate form. By the time a person reaches 50, only the 6-sulfate form is present. Dr. Meyer has also found that the amount of the mucopoly-
saccharide, keratosulfate, increases until a person is 20 to 30 and then remains constant. What specific effects these and other chemical changes have on the properties of ground substance are not known. However, they could influence the orientation of the collagen fibers formed in it. And they could also affect the ability of the ground substance to bind ions and retain water. These various changes could have major repercussions. They could alter the life processes of the cells. In connective tissue (the tissue that holds the cells in place), the ground substance provides the route through which the cells receive oxygen and nutrients. The ground substance is also the route through which the cells discard their waste products of metabolism. Interference with this flow could raise havoc with the functioning of the cells. Dr. Harry Sobel, now with the Veterans Administration Hospital in Sepulveda, Calif., has suggested that inadequate cell nutrition and eventual cell death may result, in part, from gradual chemical changes in the
ground substance. In addition, he says, the decrease in the amount of ground substance which accompanies the buildup of collagen with age might also make the flow of oxygen and nutrients more difficult and likewise promote cell destruction. Cross-Linking of Proteins Among the most widely debated theories of human aging is the one that says that aging is caused by the progressive, random cross-linking of proteins and nucleic acids. According to the theory, most of the cross-linkages are harmless. However, a small percentage of them are said to prevent enzymes from splitting some of these materials. Hence, these large molecules become irreversibly immobilized. The resulting accumulation of a "frozen metabolic pool" clogs the cells, interferes with their life processes, and ultimately destroys the cells. The most articulate spokesman for this theory is Dr. Johan A. Bjorksten of Bjorksten Research Laboratories. Dr. Bjorksten says he conceived the idea that cross-linking might be the FEB.
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According to one theory, aging is caused by the harmful effects of free radicals formed by the body's normal metabolism. Dr. Denham Harman (right) of the University of Nebraska weighs a mouse treated with a chemical that reacts rapidly with free radicals, while James E. Bare checks other experimental animals
fundamental process in human aging when, as chief chemist for Ditto, Inc., in the early 1940's, he was studying how cross-linking agents alter the properties of gelatin films. "The observed changes," he says, "almost precisely paralleled those occurring in tissue protein on aging." Cross-linking, Dr. Bjorksten points out, may be produced either by reactive groups already present in the long chains or through the action of separate cross-linking agents. Specifically, what agents in the body might promote cross-linking? Among the possibilities, he says, are the dibasic acids formed in the Krebs cycle. These might include malic acid, fumaric acid, and succinic acid. Other cross-linking agents, he says, might be quinones. Or they might be aldehydes formed by the oxidation of fats. Or they might be chelating compounds produced by the reaction of polyvalent metals (aluminum, copper, iron) with dibasic amino acids. Free radicals might also act as cross-linking agents. The cross-linking theory receives support—if only partial support—from several quarters. Dr. Verzar, Dr. Gallop, and others, while drawing no allencompassing conclusions from their work, believe that collagen ages by progressive cross-linking. Dr. Robert R. Kohn of Western Reserve University says, "Cross-linking, as well as thermal denaturation, probably occurs both in cells and connective tissue. These changes may alter the body's diffusion processes." Dr. Michael G. Mulinos of Commercial Solvents Corp. states that research on the cross-linking of 146
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proteins provides "the most plausible array of data to account for the occurrence of aging on the molecular level." Many research workers, however, are highly skeptical. They say that, apart from the work on collagen, there has not been enough evidence that cross-linkages do develop with time in biological systems. Furthermore, they say, tests in several laboratories have failed to show that cellular proteins become appreciably more resistant to enzymatic breakdown as the cell ages. Says Dr. F. Marott Sinex of Boston University School of Medicine, "While many substances in the body are capable of acting as cross-linking agents for collagen, elastin, RNA, DNA, and other materials, it is necessary to show that they are present in high enough concentration and that they do indeed produce cross-linking. Furthermore, it is necessary to show that such crosslinking is a significant factor in senescence, as distinguished from the body's normal maturing. We still lack the needed proof." Partly tied to the theory of crosslinking is the one that says that aging is caused by the harmful effects of free radicals formed by the body's normal metabolism. One of these adverse effects might be cross-linking. The free radicals might attack connective tissue or such cell components as nucleoproteins and nucleic acids. The resulting chemical changes might disrupt the functioning of the cell and also its ability to reproduce. According to Dr. Denham Harman of the University of Nebraska, the
free radicals involved include HO and H 0 2 . These might be formed in the body, he believes, by the interaction between oxidative enzymes and oxygen. They might also be formed by the attack of catalase on hydrogen peroxide or by the action of radiation. Dr. Harman has suggested that aging might be retarded if animals are fed compounds that react rapidly with free radicals. In one series of tests, he used such compounds as cysteine hydrochloride and 2-mercaptoethylamine hydrochloride to the extent of 1% in the diet of a special breed of short-lived mice. The chemical treatment, he found, extended the halfsurvival time of the mice to 10 months, compared to only eight months for the controls. "These results," he says, "are in conformity with the theory that aging may, in part, be due to the deleterious side effects of free radicals produced in normal metabolism."
COMBINED REPRINTS . . . . . . of this special report on aging, together with Part II to be published next week, will be available at the following prices: One to nine copies—$1.00 each 10 to 49 copies—15% discount 50 to 99 copies—20% discount 100 or more copies—rates on request Address orders to Reprint Department, ACS Applied Publications, 1155 16th St., N.W., Washington 6, D.C.
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For use with A S C O Pirani-type Vacuum Gauge only. The smallest and simplest strip chart recorder on the Only! W U market, it provides true rec tilinear recording free from inconvenient distortion. Operating at one inch per hour, a 63-foot chart roll records for 31 days. A galvanometer pointer swings free for maximum ac curacy, being clamped for marking briefly once every 2 seconds, generating a continuous line of many small dots. Scale length—25/i6;/. For portable use or panel mounting. 35/8 " wide χ 55/8 " high χ 4ι/β " peep. Range—.1 to 5000 microns Hg.
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