ROUNDWORMS: CAENORHABDITIS ELEGANS

Aging is a complex deteriorative process affecting the survival of both living and nonliving things. To understand the underlying molecular and physiological processes of human aging, it is necessary to study a system that is less complex than humans—one where experiments can be easily performed. In response to these needs, a number of invertebrate models have been identified. Such models invariably are quite short-lived; in fact, the species described here, the nematode Caenorhabditis elegans, (see Figure 1) lives for only three weeks under normal conditions.

Overview of C. elegans.

During the first three days of life, the worm grows from an egg into an immature larval form that molts four times before finally becoming an adult. Most adults are hermaphrodites, producing both sperm and eggs, and producing about three hundred offspring over the next five days of life. By ten days of age, this species is finished with reproduction, but goes on to live for another ten days.

A great deal of research has been carried out since Dr. Sydney Brenner began his studies of the humble worm around 1965. Most research has concentrated on the development of the animal, but an increasing amount of interest into the aging process in C. elegans is apparent, with a dozen or more high-profile articles on genes that slow the aging process appearing around the turn of the century.

Gerontogenes. Genes are DNA-based entities that code for proteins (and RNA), which function to carry out all of the biological needs of the organism. Geneticists discovered many years ago that disruption of these genes (called mutations) are inherited by offspring of all living things. Moreover, by careful comparisons of mutant and normal genes, geneticists can infer the normal function of the protein encoded by the disrupted gene. One can think of this process by analogy with a mechanic who knows nothing about how a car functions, but pulls one part at a time to see what function is changed as a result. Thus, removing the battery stops electrical function while removing the radiator makes the car overheat.

Nematode geneticists began looking for mutations in genes that affected aging (so-called gerontogenes) around 1980. In particular, the doctors Tom Johnson and Mike Klass genetically manipulated worms so as to lengthen their life span. They reasoned that by increasing longevity they could be assured that the basic aging process is affected. (Most short-lived mutants would probably be merely dysfunctional in some key process, rather than aging rapidly.) Indeed, these searches for longevity mutants have turned out to be quite productive, and many gerontogenes (close to sixty) have been identified. At first glance, it is counterintuitive that altering a gene can lead to increased longevity—this implies that the normal gene is somehow shortening the life span. It must be remembered that evolution does not care about postreproductive longevity and that only the individual, not the species, benefits from increased longevity. All longevity mutants found so far decrease evolutionary fitness by decreasing reproductive capacity or slowing development.

The first gerontogene identified was age-1. A combined effort of both the Johnson and Klass labs resulted in identifying this gene in 1988, which was ultimately cloned in 1996 by Gary Ruvkun. (When a gene is cloned, it is isolated from all other genes so that its DNA sequence can be ascertained and the proposed molecular function of the protein encoded by that gene can be predicted.) In the case of age-1 (and other gerontogenes in the same molecular pathway), the sequence suggested that the gene was a signaling element and should function to regulate another gene, daf-16, which encodes a protein that has a sequence similar to a type of transcription factor in humans. (Transcription factors regulate the amount and types of RNA synthesized.) In fact, this nematode pathway has a very strong relationship to that encoding the mammalian insulin-response pathway and has revealed previously unknown mammalian genes involved in insulin signaling. Clearly, function can be highly conserved between species that have been separated by over a billion years of evolution.

More than sixty gerontogenes have been identified. These fall into multiple different classes, including age-1 (about fifteen mutants), ‘‘clock’’ slow development (about ten mutants), decreased fertility (two mutants), and reduced food intake (five mutants), among others.

By 2001, the entire worm sequence had become known. Some large labs, and even entire companies, have been formed to harvest the results of this sequence, and hopes are high that the nematode can be used to find proteins in humans that can be targeted by drugs with the goal of retarding and even eliminating aging. The first study on this possibility by doctors Simon Melov and Gordon Lithgow appeared in September 2000. They showed that a drug could increase the life span of the worm by 60 percent. The drug has not yet been tested in humans (see Figure 2).

Stress, Biomarkers, and Molecular Changes

Nematodes show many of the same signs of aging that are seen in humans. They accumulate a fluorescent pigment in their cells that is called lipofuscin. They move slower and slower and finally stop moving altogether a few days before they die. They eat less and less (and defecate less and less too), as they near death. They get wrinkled. They show a lot of other pathological changes associated with aging. However, all tissues do not change at the same rate. The gonad changes quite rapidly but neurological tissue seems to remain quite intact.

Among the most consistent changes associated with increased longevity of the mutants is the increased resistance to many forms of environmental stress (see Figure 3). Johnson’s lab has found that heat, UV, reactive oxidants, etc. are all less toxic to the long-lived mutants. Although not all agree, it seems likely that the increased stress resistance plays a key role in the life prolongation of these mutants. Indeed, the drug that prolonged life in the worms was an antioxidant designed to mimic the effect of a normal protein found at higher levels in age-1 mutants. This is a very exciting and extremely competitive area of research but may well yield secrets that will result in doubling the human life span within the life times of our children, if not ourselves.

Thomas E. Johnson

BIBLIOGRAPHY

Brenner, S. ‘‘The Genetics of Caenorhabditis Elegans. ’’ Genetics 77 (1974): 71–94.

Friedman, D. B., and Johnson, T. E. ‘‘A Mutation in the Age-1 Gene in Caenorhabditis Elegans Lengthens Life and Reduces Hermaphrodite Fertility.’’ Genetics 118 (1988): 75–86.

Johnson, F. B.; Sinclair, D. A.; and Guarante, L. ‘‘Molecular Biology of Aging.’’ Cell 96 (1999): 291–302.

Johnson, T. E. ‘‘The Increased Life Span of Age-1 Mutants in Caenorhabditis Elegans Results from Lowering the Gompertz Rate of Aging.’’ Science 249 (1990): 908–912.

Johnson, T. E., and Wood, W. B. ‘‘Genetic Analysis of the Life-Span of Caenorhabditis Elegans. ’’ Proceedings of the National Academy of Sciences USA 79 (1982): 6603–6607.

Klass, M. R. ‘‘A Method for the Isolation of Longevity Mutants in the Nematode Caenorhabditis Elegans and Initial Results.’’ Mechanisms of Ageing and Development 22 (1983): 279–286.

Martin, G. M.; Austad, S. N.; and Johnson, T. E. ‘‘Genetic Analysis of Aging: Role of Oxidative Damage and Environmental Stresses.’’ Nature Genetics 13 (1996): 25–34.

Riddle, D. L.; Blumenthal, T.; Meyer, B. J.; and Priess, J. R. C. elegans II. Cold Spring Harbor, N.Y.: Cold Spring Harbor Press, 1997.

Wood, W. B., ed. The Biology of Caenorhabditis elegans. Cold Spring Harbor, N.Y.: Cold Spring Harbor Press, 1988.