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rusting - TRENDS IN BlOLOGY WHY DO WE AGE by Ricki L...

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Unformatted text preview: TRENDS IN BlOLOGY WHY DO WE AGE? by Ricki L. Rusting, Staff writer To a great extent, the answer is written in our genes. But which ones? New research offers tantalizing clues. of California at Irvine, sounds like a proud parent when he talks about his extraordinary fruit flies. By successively breeding ever longer-lived females and males, he has created stocks of Drosophila melanogaster that he says survive almost twice as long as their standard laboratory-reared counterparts. Longevity is just one of the remarkable traits of these minute Methuselahs. They are, Rose boasts, “superior flies" that are “more robust at every age and better able to resist stress." Even when they are old, many are stronger than ordinary young specimens. Rose has every reason to be pleased. Profoundly extending life and health in any Species is an impressive achievement. Moreover, having developed unusually robust stocks, Rose and his collabora- tors can now begin to identify the alleles, or variants of genes, that may account for the differences between the superflies and their mundane relatives. One such allele has already been pinpointed. Rose's fruit-fly work is part of a broader effort to ultimately ex- plain why humans age—why we inevitably deteriorate and die. His findings along with other recent discoveries from a variety of dis- ciplines are encouraging optimism that the question, which once seemed impenetrable, will yield to scrutiny. “We're still groping," says Huber R. Warner of the National Institute on Aging. "but in a dimly lit room instead of in a dark one." A number of scientists engaged in the struggle say they hope their endeavors will result in ways to slow what they believe is an internally controlled aging process—one that would eventually lead to death even in the absence of accidents, violence and infec- tion. If this intrinsic process does in fact exist and can be slowed, the achievement could help delay or prevent much of the cancer, heart disease and other disabling and deadly conditions to which adults become increasingly vulnerable as they grow older. Any therapy that retards aging will almost certainly extend life in the bargain, although few scientists seem willing to admit that pro- longation of life is a priority for its own sake. “The ideal," says S. Michal Jazwinski of the Louisiana State University Medical Center at New Orleans, “would be to live a long and healthy life and then undergo a rapid demise—to die with your boots on, as they say in cowboy movies.” Rose and others are becoming confident that a full understand- ing of aging is within reach. “Only in the 19803 have we seen how easy it is to postpone aging.“ he says. “ That’s what makes the field very exciting now—we are doing things that wor " indeed, as re— cently as 15 years ago, most of the available data were descriptive, the notable exception being evidence that caloric restriction could D 1 ichael R. Rose, an evolutionary biologist at the University ELDERLY WOMAN is among the more than a million Americans older than 65 years who live in nursing facilities. Researchers are now begin- ning to tease out the reasons people generally lose vigor and become prone to an array of disorders in the later years. ScnzN‘riFIc AMERICAN December 1992 1:51 prolong the lives of rodents and many other animals. (How diet restriction works is still unclear.) And theories about aging were almost as common as fruit flies. Senescence was caused by a strict genetic program for death. Or by random damage to DNA or to some of the critical enzymes that keep the body running. Or by changes in hormone lev- els. a decline in the functioning of the immune system or the relentless activity of highly reactive. potentially desuucn've molecules called oxygen free radicals. The swarm of opinions prompted Alex Comfort. a pioneer in the field. to write in 1979 that “throughout its history the study of aging has been ruinously obscured by theory." Today consensus is still elusive. but investigators gener- ally concur that aging does not have a single cause. Mounting evidence points to a multitude of parallel and often in- teracting processes. many of them ge- netically controlled. that combine to en- sure eventual decrepitude. Nature Loses Interest A number of workers. including Rose. also agree that an understanding of why aging has evolved is a prerequisite to uncovering the physiological bases of senescence. Evolutionary theory. these researchers say. provides a much need- ed framework for knowing how the body functions and fails—and for iden— tifying the genes involved in controlling life span. “Biochemistry is a valuable part of what we do.“ Rose says of re- search on aging in general. “but it doesn't provide an intellectual foundation." Basic evolutionary theory holds that individuals who are most fit—whose particular mix of alleles best equips them to survive and reproduce in their environment—exert the most influence on the gene pool of future generations. Genetic alterations that enhance fitness (for instance. by enabling one to run faster from danger) will be selected for. CHANGES COMMON BY THE MIDDLE THIRD OF THE BY THE FINAL .‘ _ strum om ’ .;..; lungs. ; d; SOURCE: Carob E. Finch. University or Southern Califomia 132 LIFE SPAN _ - . i ' CHANGES common Ability of heart. Edna ‘ 5' or retained. and become common with- in several generations. Traits are select- ed because bearers are most likely to survive and reproduce more abundant- ly. contributing large numbers of off- spring to the next generation. likewise. natural selection will eliminate muta- tions that are invariably lethal before sexual maturity is attained; thus. affect- ed individuals “ill leave no offspring to pass along the deadly traits. Since the late 18005. many scientists have subscribed to the idea that senes- cence has arisen because removal of el- ders increases the fitness of younger in- dividuals. perhaps by reducing the drain on available resources. This scenario suggests that aging is programmed in genes whose sole purpose is to destroy the organism. But the proposition is los- ing favor. partly because most animals do not survive in the wild long enough to have the chance to become senes- cent. During the bulk of human history. we. too. died young. The average person born in an industrialized nation today can expect to live about 73 years; for most of our history. life expectancy was closer to 30 or ~10 years. Alternative evolutionary hypotheses hold that genes control senescence but that the unwelcome alleles were not se lected specifically for that purpose. The genes of aging—sometimes called ge- rontogenes—have become ensconced in human chromosomes. these theories as- sert. because natural selection could not prevent their spread. Alleles that were strictly harmful would persist in a spe- cies if the bad effects did not kick in un- til long after reproduction had begun. What is worse. as George C. Williams of the State University of New York at Stony Brook proposed in the 1950s. al- leles that were destructive late in life would be adopted readily if they some- how improved fitness to any extent ear- ly in life—a duality known as antago- nistic pleiotropy. Genes that specify the instructions for synthesizing reproduc- " - Girl. Capacity for coping ._.Bo_d_y's power to combat Male fertility ‘ {on degllgsg‘auto. decli - -' . with #1519935 10.6““ * summit??? . -- «L Scniv'rtrtc AMERICAN December 1992 Selected Changes of Age Some of the more common physiological and anatomic alterations that actur as people grow older are listed below. Interestingly. certain monkeys and other mammals. including rodents. undergo many of the same changes. ORGAN FUNCTION THERMOREGULATION IMMUNITY NORMAL FIBROBLASTS (blue) or connec- tive tissue cells. extracted from human tissue (fem. become larger as they grow old in a culture dish {right}. At the same time. their rate of proliferation slows unli]. ultimately. replication ceases. in- tive hormones could well be among those in the traitorous group. Steven Austad of Harvard University posits that the rising risk of breast cancer with age in women might be an exam- ple: long-term exposure to the estrogen women require for fertility could pre- dispose breast tissue to malignancy. Similarly. Caleb E. Pinch of the Univer- sity of Southern California finds that a variety of normal hormones and other regulatory molecules may harm the cells and tissues they influence. The hypo- HEPRODUCTlON Women undergo menopause VISlC vestigators in several laboratories have now identified many of the genes that seem to control the loss of replicative ca- pacity. What those findings say about how the human body as a whole ages is not yet clear, however. thalamus and the pituitary gland con- trol ovarian function but also seem to contribute to aging of the ovary. at least in rodents. At the same time. the ovary, which itself sends signals to the hypothalamus and pituitary. seems to promote aging of those organs. Finch further sees these pleiotropic proper ties as evidence that aging stems to some extent from the activity of—and interactions between—the nervous and endocrine systems. The genes that enhance early fitness need not be directly destructive late in life in order to cause eventual deterio- ration. Thomas B. L. Kirkwood of the Medical Research Council in London and Richard G. Cutler of the National Institute on Aging have each proposed that senescence would arise in a popu- lation if the body’s maintenance sys- tems. which are under genetic control. were good enough to ensure that an or- ganism survived to perpetuate the spe— cies but were not able to keep the body going forever. A Disposable Soma Kirkwood suggests most animals have not evolved maintenance systems that ensure immortality because doing so would squander energy that could be better put toward reproduction. Since environmental hazards are likely to kill individuals within a reasonably predict- able time. a species should invest in protective systems that will guarantee youthful vigor for the expected period but no longer. The rest of an organ- ism‘s energy supply can then go into maximizing fertility. In an analogy to industry's practice of investing little in the durability of goods that will be used for only a limit- ed tlme. Kirkwood calls his model the disposable some theory. In this case. it is the somatic cells—the nonreproduc— tive cells of the body—that finally are expendable. In contrast. some percent- age of germ cells must retain the ability to repair themselves perfectly. or the species would die out. Kirkwood estimates that the invest~ ment humans have made in protecting the some provides enough defensive capacity to assure zest for perhaps 40 years—the period we might have ex- pected to survive during much of our evolution. That investment would in- clude some backup capacity, in case of accidental damage. Presumably. we muddle through mid—life and late life by taking advantage of our reserves. As these backups gradually give out on us. we lose the ability to respond to environmental stress. and, eventually. we die. The disposable some hypothesis lends theoretical support to proposals that aging results from destruction caused by molecules produced in the normal course of living, including oxygen free radicals. The idea that free radicals play a role in aging was put forward in the mid-19505 by Denham Harman of the University of Nebraska. Many biological reactions generate free radicals. Because they carry an unpaired electron, such radicals can oxidize—and thereby dam» age—DNA. proteins. lipids and other molecules throughout the body. They can also give rise to more radicals and to related oxidants. such as hydrogen peroxide. consequently triggering long chains of destructive activity. Hannah proposed that an accumulation of irre- versible oxidative damage to cells and tissues throughout the body could re- sult in aging. The disposable some concept also ac- commodates Anthony Cerami's propos- al that glucose, the human body’s main fuel, is another major factor in aging [see “Glucose and Aging," by Anthony Cerami. Helen Vlassara and Michael Brownies; Scu—zmn‘tc AMERICAN. May 1987]. Cerami. now at the Picower In- stitute for Medical Research in Manhas- set. N.Y.. has shown that glucose slowly alters long-lived proteins, such as colla— gen. causing them to become cross-.inked. or shackled. to one another. He contends that this glycosylation proba- bly has a part in the stiffening of con- nective tissue and of the heart muscle that occurs over time. According to the disposable some model. these and other wear-and-tear processes could all contribute to aging if they outpaced the capacity of our prevention and repair systems to com- bat them. But the true test of this and CORONARY LARGE AND NEURONS REACTION GROWTH CEREBRAL IN TIMES TUMORS HORMONE FAT ARTERIES BONE JOINTS BRAIN Cancers become Storage Some degree of In women. common in repro- increases atherosclerosis osteoporosis . ductive organs usually appears sets in J; ,_ . .I. .. .. , “gm.“ . . . . ‘mm ental and physn- "Frequency _ _ _ . 7 -' f ' ;; Arthritlc Somelgrow I ll responses ; ‘ fir pf secretion-i '_-.' -- . . _ , ‘ _ 'Fhfipges I. large: ‘ in“ specific stimuli v ' '- ' idflfllnes ”2'3. . ‘ cur If ' . W SCIENTIFIC Amcm December 1992 133 other evolutionary hypotheses will lie in identifying the genes. perhaps hun- dreds of them. that actually control the molecules that thwart or promote se- nescence. Many laboratories are now busy attempting to tease out some of the more influential genes. Genetic Clues Several investigators—among them Rose. Jazvvinski and Thomas E. john- son of the University of Colorado—are meeting that challenge by seeking genes that can prolong life in relatively sim- ple organisms. “Aging is a puzzle you can understand only if you can compare normal with postponed aging." Rose says. “That tells you what the normal animals are missing. With humans. you don't have a control group." After Rose created his hardy fruit flies. he and his colleagues compared the proteins made by the experimental and normal insects. One clear difference turns out to be that many of the long- lived flies produce an unusually active version of the antioxidant enzyme su- peroxide dismutase. which means they harbor a variant of the normal enzyme- specit‘ying gene. Specifically. they pro- duce a highly efficient version of the form of the enzyme typically found in the cytoplasm of cells. In fruit flies, as in humans and other organisms. super- oxide dismutases defend against oxida- tive damage by helping to neutralize a dangerous free radical called superox- ide. The genetic difference implies that one reason normal fruit flies age more quickly is that their free radical defens- es are not as effective as those of the specially bred files. of course. the variant of superoxide dismutase manufactured by fruit flies is sure to he just one of many factors that influence how quickly such flies age. Rose and joseph L. Graves and their co-workers at Irvine have found. for in- stance. that the long-lived flies are more resistant to starvation because they 134 MICHAEL R. ROSE of the University of California at Irvine has significantly extend- ed the life span of the fruit fly Drasophila melanognster (far left) by selective breeding. The insect here. shown in flight. was tethered to fishing line by a drop of Duco Cement for an experiment in which Joseph L. Graves. now at irvine. demon- strated that the long-lived flies are stronger than normal specimens: they can keep themselves airborne longer under a range of temperatures and humidity levels. store more fat. (Rose says the insects are so hefty that they spray fat in all di- rections if they are touched even light- ly.) The flies are also less likely to dehy- drate. in part because they stow more of the carbohydrate glycogen. “The work on Drosophilu is trial~run stuff for doing the same thing in mice." Rose says. “If we can create long-lived mice. specific genes. enzymes and cell processes involved in longevity should be revealed.“ As mammals. mice are ge- netically closer to humans than are fruit flies. and so they should have more to reveal about how people age. Mouse research should be more informative. that is. if someone will foot the bill for long-term studies. which Rose estimates would cost about $10 million. Findings related to Rose's are coming out ot‘ Johnson‘s laboratory at Colora- do. Johnson and his colleagues have wielded selective breeding to produce long-surviving versions of a tiny soil- dwelling worm known as c'ucnorhuhdi- tis eleguns. They have also managed to Scnmmc AMERJCAN December my: prolong life in the species by generat- ing random genetic mutations. Like Rose's group. Johnson's team is attempting to identify the genes that are differentially expressed in long-lived and normal groups (differentially tran- scribed from DNA into messenger RNA. which is then translated into protein). In “)88 he reported that mutation of a single gene called age-l can increase the average life span of C. elegans by about 70 percent. Strikingly. the mu- tant worms produce elevated levels of antioxidants (both cytoplasmic super— oxide dismulase and an enzyme called catalase) and are more resistant to the toxic effects of paraquat. a herbicide that leads to generation of the superox- ide radical. The mutation in the age-l gene seems to inactivate that gene, which means the encoded protein is no longer made. If the protein‘s elimination leads to in- creased production of antioxidants. then it is possible that the normal protein inhibits production or those substances. THOMAS E. JOHNSON of the University of Colorado. who is examining pen-i dishes with a technician in his laboratory. has prolonged the life of another multicellular organism: the small. soil-dwelling worm Caenorhabditis elegans (far right). John— son and his colleagues achieved the feat in two independent ways-—by selectively breeding for longevity and by introducing a mutation in a single gene. called age-1. The group is now attempting to clone the age—l gene. Why would an organism deliberately inhibit synthesis of such critical com- pounds? “i don't think its purpose is to kill the worm at a certain age." Johnson says. Rather he speculates that the in- hibition may well be an undesirable ef- fect of some other important function that has not yet been discovered. In oth- er words. he thinks antagonistic pleio- tropy is probably operating. Once Johnson has cloned the age-l gene—which he hopes to accomplish soon—he plans to search for a counter- part in mice. If mice harbor a similar stretch of DNA. he might be on the track of a specific gene that could also be involved in human aging. johnson is fond of a line from Thus Spoke Zara- thustra. by Friedrich Nietzsche: “You have made your way from worm to man. and much in you is still worm." He is hoping Nietzsche's observation extends literally to the genetics of aging. although he realizes that the causes of senes- cence in C. elegant maybe quite differ- ent from those in humans. Jazwinski. aware that we have many genes in common with an even more primitive. single-celled organism, has focused his attention on baker's. or brewer’s. yeast (Succhuromyces cerevisi— ae). He has identified several genes that prolong the yeast's life. The best stud- ied of these. LAGI (longevity assurance gene 1). is more active in young cells than in old ones. inducing extra LAGI activity in older cells. after expression has normally declined. extends their life by about a third. Most important. elderly yeast cells bearing the extra-ac- tive gene do not become immortal (as cancerous cells in multicellular organ- isms do); they simply operate youthful- ly longer. Jaawinski does not know the func- tion of the corresponding protein yet. Nevertheless. he has discovered that...
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