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[
1977]
The soil nematode Caenorhabditis elegans was selected 11 years ago by Sydney Brenner as an experimental organism suitable for the isolation of many behavioral mutants and small enough for anatomical analysis of such mutants with the electron microscope. Two distinct goals motivated the initial studies of this organism: first, the hope that some of the mutants would have simple anatomical alterations that could be directly correlated with their behavioral defects, allowing the assignment of specific functions to specific neurons, and second, the hope that the detailed analysis of the kinds of alterations induced by individual mutations and the classes of cells affected by given mutations would reveal general features of the genetic program that specifies the development of the organism. Over the past 11 years the number of investigators working on C. elegans has increased to about 75 and is still growing. Nearly 3,000 different mutants have been isolated and different investigators are pursuing their effects on different cells. My own research is in the development of the nervous system. In particular, I would like to learn something about the workings of the complex black box that connects individual genes to the determination of the morphology of developing neurons. Are there gene products whose specific function is to determine the morphology of cells? If so, what are these gene products and how do they act in the developing cell? One would anticipate that mutations in such hypothetical genes would cause specific morphological alterations in cells. Because the morphology of a neuron determines its function, by selecting behavioral mutants altered in the function of the nervous system one might commonly find mutants that alter the morphology of neurons, and some of these might be in specific morphological genes. It is my hope that it will be possible to compare such mutants to the wild type in order to identify the defective gene products and thereby learn something about the role of normal gene products in determining the development of neurons. In this paper I will first summarize the results of several years' work on one specific class of mutants in the nematode, sensory mutants, work performed both in my laboratory and that of my colleagues Jim Lewis and Jonathan Hodgkin. Second, I will discuss frankly some of the difficulties and frustrations we have experienced in trying to interpret the effects of these specific mutants. Some of these difficulties illustrate problems endemic to genetic studies of development. Third, I will describe the more recent work performed in my labortory that is being directed toward genetic analysis of the structure and function of a
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[
1960]
I would like to introduce my lecture on this subject with a brief consideration of meiosis in the female. The oogonial cells in the anterior part of the ovary in a nematode are small and multiply by mitosis. As they move down the ovary they increase in size with corresponding increase in the size of the nucleus. The chromatin is a single spherical mass located in the center of the nucleus. Eventually the chromatin mass is resolved into individual chromosomes. During prophase of meiosis the homologous chromosomes come together. All diploid cells possess identical chromosomes with the exception of the sex chromosomes and at synapsis these homologous chromosomes pair or come together. Paternal and maternal gametes each contribute a complement of identical chromosomes.
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[
Molecular Biology of Aging,
1999]
"Gerontogenes" (genes that affect the rate of aging) can be defined operationally to refer to genes that can be altered such that a longer than normal maximum lifespan is the result. The last two decades of research in aging have demonstrated overwhelmingly that gerontogenes exist and modulate the rate of aging. The first direct demonstration that genes play a role in the aging process was carried out in the nematode Caenorhabditis elegans. Despite original prejudices that the aging process is "ineluctable" or that genes controlling longevity cannot be selected for, these results and others have shown that the process of aging, just as other biological processes, is specified by the gene. This is not to say that aging is programmed. Statements by noted developmental biologists that aging must be programmed to prevent competition with offspring are untenable for the nematode C. elegans, which has billions of descendents by the time its hypothetical "death program" kicks in to kill it. In the text below I will provide an overview, first of work primarily from my laboratory having to do with the detection and study of gerontogene variants using multigenic approaches. Subsequent work on mutants, initially from my lab but more recently from a variety of other labs as well, showing the molecular nature of these gerontogenes will be subsequently reviewed. Finally, we will close with a discussion of the role of resistance to stress in determining life-extension: a hypothesis that is gaining increasing support from a wide variety of observations in both invertebrate and vertebrate
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[
1987]
To my knowledge, a theory of "developmentally programmed aging" has never been explicitly stated, although the notion that aging has some relationship to development has certainly been proposed many times. In the preceding chapter (36), Dr. Hayflick has made a brief description of the central idea of developmental programming within aging. In order to discuss relevant evidence in this chapter, I would like to propose the following, somewhat more specific and operational definition: The theory of developmentally programmed aging posits that aging involves events controlled in ways recognizably similar to those that operate during development. This definition is perhaps a little less extreme than it might have been, since it uses the phrase "aging involves events" rather than the phrase "aging is caused by events." However, I think it captures most of the usual connotations of "developmentally programmed aging," and it at least has the virtue of testability. Of course, to test the theory, as defined, requires evidence of several sorts. In particular, it requires (a) that we understand how some aging events are controlled, (b) that we understand how some developmental events are controlled, and (c) that we know how to recognize whether there is or is not similarity between the two. A central message of what follows is that we are really only at the beginning of being able to test this theory, although some lines of approach do appear