Science
Scientists weigh facts, theories on aging Biological time clock for certain cells, on-off switches for genes are among explanations offered at AAAS symposium Even if man is freed of all the debilitating diseases that reduce his longevity, his life span probably will not stretch much beyond 90 years until much more is learned about the specific biological happenings that contribute to the aging process. This conclusion ran through a symposium on biomedical aspects of aging held in San Francisco at the 140th annual meeting of the American Association for the Advancement of Science. An impressive array of facts and theories on aging along with a scattering of suggestions for reversing the process were exposed and dissected. In support of the idea that the study of aging somehow should be separated from the study of diseases that lead to an early death, Dr. Leonard Hayflick of Stanford University's school of medicine pointed out that "even if the current effort to understand and cure all human cancers was to be successful, life expectancy at birth would be increased by about two years. "Furthermore, if heart disease and stroke were to be miraculously eliminated in the United States, then about seven more years of life could be expected. Thus, a generation of humans in which the two current major causes of death were eliminated would surprisingly enjoy nine to 10 years additional life. "Indeed, regardless of the state of technological progress within a country, the human life span of 90 years or so is similar in all societies and appears to be fixed. What has changed is the probability of dying in younger age groups." Just as men and other organisms seem to have their own species-specific life spans, the cells that compose them seem to be similarly limited, Dr. Hayflick told the symposium. Ten years ago, he had determined that normal human embryonic cells, when sustained in tissue culture, can double their population an average of 50 times before they die. Others have found that the cells of mice double no more on the average than 28 times, and chicken embryo cells double a maximum of 35 14
C&EN March 18, 1974
times. As they age, the cells appear to run down and take longer to divide than when they are young. The Stanford researchers also have found that human cells seem to have a built-in time clock that seems to tell them how many times to divide within a lifetime. Whether that clock is regulated from outside the cell or from within still is not clear. In any event, when Dr. Hayflick stopped the clock by freezing the cells, then returned them to normal tissue culture temperature, they started up where they left off until they had reached an average of 50 duplications. Similarly, cells from adult humans doubled in cell cultures an average of 20 times, compared to embryo cells, the number of doublings being related to the age of the adult donor. Backing up Dr. Hayflick's findings, Dr. Charles Daniel of the University of California, Santa Cruz, noted that the same type of growth limitation occurred "in vivo," when mammary cell tissue was taken from one mouse and serially transplanted in other mice. After a series of four such transplantations covering a 12-month period, the cells eventually began to decline and lose their ability to be transplanted into other young mice. Dr. Daniel says his work suggests that aging may result when the hormonal processes that trigger deoxyribonucleic acid (DNA) synthesis and cell division somehow break down in aging cells. As evidence, he cites an experiment in which he serially transplanted mammary cell tissue into virgin mice for a number of times until the cells stopped proliferating. Yet, when the same mice were bred and became pregnant, the cells began to proliferate again, presumably because of the effect of newly formed reproductive hormones on DNA synthesis and cell proliferation. Because each organism seems to have its own specific life span, the issue of whether the biological time clock resides in all cells or in a specific organ was widespread at the AAAS symposium. According to Dr. Caleb E. Finch of the gerontology center of the University of Southern California, the brain, with its role as an overseer for hormone production, may contain the clock that defines the length of life, while other cells do not. As evidence, he notes that when the ovary of an old rat is transplanted to a young female, it again will produce estrogenic hormones and begin to function normally,
even though it had ceased to do so in the older female. In addition, researchers at Michigan State University have found that the ovaries of old rats can be reactivated by stimulating the rats' brains electrically or by administering the drugs L-dopa or iproniazid. Both drugs are known to build up levels of substances that transmit nerve impulses (catecholamines), Dr. Finch explains. As such, they can regulate the production of hormones elsewhere in the body. "According to current models, catecholamines are released at nerve endings in the hypothalamic section of the
Hayflick: a built-in time clock brain and then trigger the discharge of hypothalamic releasing factors, which, in turn, act on the pituitary to cause the secretion of its hormones. "The fact that electrical stimulation or pharmacological stimulation of the brain neurotransmitters can reawaken the ovaries in old female rats at least shows us that the brain is a key locus of aging in reproductive senescence," Dr. Finch says. Dr. Finch has found recently that the rate of catecholamine metabolism is slowed down in the hypothalamus of old mice. "This finding provides a basis for interpreting many age-related changes of hormones as the result of changes in the parts of the brain which control hormone production," he says. In addition, he and his coworkers find that levels and turnover of dopamine (a catecholamine neurotransmitter) are reduced in the corpus striatum of older mice. Because that area of the brain, with its role as a regulator of body coordination, is greatly affected in Parkinson's disease, Dr.
Finch believes that his findings could lead to a better understanding of the effects of aging on the progress of that disease. Dr. Robert R. Kohn of Case Western Reserve University medical school ar gued at the AAAS symposium that "there is no generalized loss of cells, necessary for life, associated with aging." So stated, his views conflict with those of others who maintain that aging begins when the cell population begins to decline in number in the brain and other organs. As an alterna tive, Dr. Kohn suggests that the aging process could be the result of the accu mulation of a growing number of cells that for various reasons can no longer carry out their normal functions. As a model for this type of change, he focused on collagen, a fibrous pro tein found in lung, muscle, bone, carti lage, skin, and other tissue. As a per son ages, tissue containing the collagen tends to stiffen and become less func tional. Presumably this occurs when the protein of the collagen molecules
Finch: brain may be a key begins to cross-link. The result is a de crease in lung activity, reduced trans port of substances across cell mem branes, a decline in muscular activity, and similar occurrences. In his laboratory, Dr. Kohn has found that the relative toughness of collagen tissue, as determined by di gestion with the enzyme collagenase and other techniques, is directly relat ed to the age of the donor. On that basis, he says, increased toughness of vascular tissue could contribute to hy pertension and atherosclerosis, each of which is associated with aging. This argues, he says, for giving a high prior ity to the study of connective tissue aging and the chemistry of collagen cross-linking agents with age. Other insights to the aging process come from studies with some 10,000 fruit flies carried out by Dr. Jaime Miquel and his coworkers at the National Aeronautics and Space Administra tion's Ames Research Center at Moffett Field, Calif. Their work suggests that although atomic radiation may
damage cells and shorten life, it proba bly has no effect on aging processes per se. In the NASA experiments, the mat ing activity of young fruit flies (Drosophila melanogaster) treated with 50,000 roentgens of gamma radiation from a cobalt source was sharply re duced, and in older flies chemical and physical disruptions were obvious in the cytoplasm and nuclei of their cells. The mating changes result from an "acute, irreversible injury and a chron ic syndrome that eventually results in death," Dr. Miquel says. "Our histo logical and fine structure observations [of the cells of the older flies] support the view that the life-shortening effects of 50 kiloroentgens of gamma radiation on Drosophila are the consequence of a radiation syndrome unrelated to aging." On the other hand, if the tempera ture of the environment in which the fruit fly lives is raised, accelerated aging does occur, Dr. Miquel says. The mean life span of flies raised at 21° C. was 116 days; those raised at 24° C , 82
Strehler: off-switch genes days; and those raised at 27° C , 67 days. Flies raised under the same high oxygen pressure conditions as were en dured by the Apollo astronauts suf fered brain damage and lived 10% shorter lives than control flies, accord ing to the NASA scientist. Again, in this case, the life shortening process did not appear to be related to any in nate aging process enhanced by the oxygen, he notes. Following up an earlier suggestion that aging results from the accumula tion of free radicals and the observa tion that the life span of certain mice increases when they are fed antioxi dants, Dr. Miquel has found that the natural antioxidant vitamin Ε extends fruit fly life about 13%. On this basis, even though he admits the danger of extrapolating from fruit fly studies to aging in mammals, Dr. Miquel ob serves that further studies on the ef fects of antioxidants on life span seem warranted. Dr. Bernard L. Strehler, now on sab
batical leave from the University of Southern California, proposed to the AAAS symposium that many of the aging theories that surfaced during the two-day proceedings could be unified if the aging process is programed by the action of "on-off switches" that reside in the genetic machinery. The effect, he said, would be to cause first one set of genes, then another, to produce spe cial products (enzymes, hormones, an tibodies, structural proteins, and the like) as the individual matures, ages, and eventually dies. In some cases, says Dr. Strehler, these genes may be switched off prematurely by accidents that attack the individual at many lev els, from single molecules to function ing organs. "From this, the important conclu sion follows that even the cells of an aged human still retain the informa tion needed to undo the damage im posed by molecular and more massive accidents. But unfortunately for the survival of the individual, much of this gene-coded information is no longer available for use once the 'off-switch' genes have been activated," Dr. Strehler says. He adds that a specific off-switch that appears to be central is that which prevents key body cells, found in the heart, brain, and endo crine system, from dividing once matu rity has been attained. Many studies of genetic transcription and translation processes suggest to Dr. Strehler that the switch is turned off through faulty translation of the ge netic information relayed via messen ger ribonucleic acid (RNA) to transfer RNA molecules, ribosomes, or the enzymic machinery responsible for at taching specific amino acids to tRNA molecules. For example, Dr. Strehler's own recent work indicates that the rate of message translation is reduced by a decrease of ribosomes in older nondividing dog brain and muscle cells over a period of 10 years. In these studies, a 30 to 40% decrease in the number of genes that produce ribosomal RNA was observed. "Quite recently a similar reduction in ribosomal DNA gene dosage has been found in preliminary studies on aging human heart muscle, suggesting a generality to the phenomenon," he says. Like other participants in the sym posium, Dr. Strehler made a strong pitch for increased public and federal support of aging research, now that the research appears to be taking hold. "With even moderate funding," he says, "the key gerontological questions should yield within the next five years or less. For the long-range future, a real possibility, even a probability, ex ists that some means of restoring at least some lost functions by reactivat ing switched-off genes will be devel oped, probably no more than five to 10 years after the mechanism of the off switches are understood and docu mented." March 18, 1974 C&EN
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