Aging Research Gains Respect Via Molecular Biology Studies

The study of aging has had a long reputation of quackery and wild speculative theories. Francis Bacon took note of this problem in 1645 in his Historia Vitae et Mortis: "With regard to the length and shortness of life in animals, the information to be had is small, observation careless, and tradition fabulous." But by applying the tools of molecular biology to the question of the causes of aging and death, researchers have lately been pulling the field into mainstream respectability and potential applicability. Today, researchers are searching not for a fountain of youth but rather for the genes of youth. And a number of the genes governing key aging processes have so far been uncovered--at least in fruit flies, yeast, and roundworms. Moreover, scientists say these genes are just the beginning and herald a golden era of research in a field that should yield solid information on the biochemical mechanisms that govern aging and, with that, the possibility of extending the average human life span to 120 years. Michal Jazwinski, a molecular geneticist at Louisiana State University in New Orleans, is using brewer's yeast as his model for studying aging. While this single-celled organism clearly is not as complex as a mammal, its very simplicity has its virtues. "It's a stripped-down version of aging," he says. Since yeast organisms don't have livers, kidneys, and nervous systems, and have about one-third fewer genes than mammals, the hunt for the mechanisms that lead to aging is not cluttered by a pantheon of confusing physiological changes. Jazwinski has cloned a total of 13 genes that are differentially expressed as yeast cells age, but he has singled out one in particular for extensive study and dubbed it the longevity assurance gene (lag-1). Jazwinski says that when he first began working with lag-1, mutated and therefore dysfunctional copies of the gene were inserted into yeast. "The yeast looked normal and happy, but when we looked at the life spans, they had half the number of divisions," he says. Because the number of days a yeast cell lives varies with temperature, Jazwinski uses the total number of times an individual cell divides, forming a daughter cell, as an accurate measure of longevity. When an excessive amount of unmutated lag-1 was inserted into the yeast, causing overexpression of the trait the gene codes for, half the cells died but the other half lived considerably longer. In ongoing experiments, Jazwinski is fine-tuning his approach and has found that expressing the gene at moderately elevated levels will allow all the cells to live and to increase their life span by about 30 percent. Lag-1 appears to be a cell membrane protein, and recently Jazwin-ski found that it appears to have a human homolog, as determined by comparison to cDNA. But at this point, it is still unclear where the lag-1 protein is located within the cell and whether it's a receptor, an ion channel, or even a mitochondrial protein. "We're using the yeast system to be able to very thoroughly study this protein. Then we can ask very pointed questions about the gene and protein in human cells," Jazwinski says. "Presumably, lag-1 will have some effect on cell longevity in humans." And that "effect," expressed at the cellular level, could lead to longer overall life span, since an organism is but a collection of many cells, he says. Other genes Jazwinski has overexpressed in yeast are the v-ras and ras-2 oncogenes, which double the maximum life span of yeast. Obviously, overexpression of oncogenes in humans could have negative consequences--namely, cancer. But Jazwinski finds it intriguing that research is showing not only that yeast cells and human cells have many genes in common, but also that oncogenes, tumor suppressor genes, and longevity genes have closely related roles in the complex balancing act of cell life and death. The roundworm Caenorhabditis elegans is the organism being studied by molecular geneticist Thomas Johnson at the University of Colorado in Boulder. By mutating the age-1 gene, Johnson has doubled the normal three-week life span of the worms. Age-1 appears to cause cells to produce increased levels of two enzymes: superoxide dismutase, which intercepts free radicals before they can cause damage to DNA and other cell components; and catalase, which converts hydrogen peroxide to water, he says. This finding falls in line with the "oxidative stress" theory of aging, whereby accumulated damage to DNA and other cell structures causes organs to lose function over time. Johnson hopes that within the next three months he and his colleagues will have age-1 cloned and will learn more about the mechanism by which the gene is producing the longer life span. Johnson is optimistic that similar "gerontogenes" may be found in humans: "In the most optimistic scenario, it's possible that pharmaceutical intervention could someday slow the aging process in humans." It's conceivable that the average human life span could climb to about 130 years as more is discovered about the molecular mechanisms of aging, he says. Michael Rose, an evolutionary biologist at the University of California, Irvine, and the author of The Evolutionary Biology of Aging (New York, Oxford University Press, 1991), is working on extending the life span of fruit flies using a top-down approach. That is, rather than searching for specific genes and changing their expression, he is selecting flies that reproduce at an older age and crossing them with other late breeders. The result is fruit flies that live 100 percent longer, and with continued breeding, Rose says, he will have developed a fly that lives 200 percent longer than the wild type. Rose says that the advantage of his breeding approach is that he's able to change the distribution of a large number of genes at once, instead of zeroing in on a specific gene in yeast or roundworms that may later prove to be useless in prolonging human aging. Jazwinski, however, says he is critical of Rose's approach because you create a "bag of genes" that are hard to sort through. But Rose says that creating this bag of genes--not molecular biology--is his business. "What I do is create the organisms that contain the information that people want." It's then up to collaborators such as biologist James Fleming of the Linus Pauling Institute of Science and Medicine in Palo Alto, Calif., to hunt for the mechanisms behind the longevity that has been bred into the flies. Using two-dimensional gel electrophoresis, Fleming has found seven proteins in the long-lived flies that are expressed at different concentrations from normal-lived flies. He is now trying to identify the genes responsible for those proteins and determine causality. Fleming is a proponent of the oxidative damage notion of aging. "What happens in aging is a fancy sort of `rusting' process that goes on in mitochondria," he says. Years of oxidative damage seem to yield an accumulation in mitochondria of lipofuscin, an insoluble lipid-protein complex found in the cells of older organisms that apparently shuts down cellular function. He expects that the fruit fly proteins he is working with will turn out to be anti-oxidants. Although Rose says funding for the fruit fly work has been readily available from the National Institute on Aging (NIA), he has been unable so far--despite eight years' worth of applications--to obtain the $10 million he needs to take his work up to the next rung, to the breeding of long-lived mice. Until work begins on mammalian systems, scientists will have no idea whether this molecular approach to aging research has any potential toward extending the human life span. Jazwinski agrees that funding is constrained and believes that NIA should double the $40 million currently devoted to molecular biology to take advantage of the promise offered by cutting-edge gerontogene research. Whether the funding situation changes or not, he feels that further discoveries in the field will soon yield an "explosion of interest and understanding." He says that evidence of this explosion could be seen at the April 22-26 conference on Molecular Biology of Aging at Cold Spring Harbor Laboratory on Long Island, N.Y. There were "a lot of new faces" at the meeting that were not present at a similar symposium in Santa Fe, N.Mex., in 1989. He also found that "there really is a lot of very-high-quality work going on now."

Aging Research Gains Respect Via Molecular Biology Studies

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