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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
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[
1981]
This chapter is in part a review of the work of others and in part a summary of recent results from our own laboratory. It attempts to cover the currently available information on apparent neurotransmitters in the small soil nematode Caenorhabditis elegans, whose advantages of genetic manipulability and cellular simplicity have recently gained it some favor in investigations of genetic control mechanisms in neural development (for review, see Riddle, 1978). Particular attention is given to mutants that affect either the level or the action of apparent neurotransmitters, since it seems likely that such mutants may have the most to offer toward the understanding of human genetic neuropathies. The general features of C. elegans are described briefly at the outset, then each apparent neurotransmitter is considered in turn, and finally a few potential implications for other organisms
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[
1977]
Radiochemical assays based on the selective extraction of either substrate or product from an aqueous reaction volume into an organic scintillator have been developed for acetylcholinesterase and choline acetyltransferase. These rapid, convenient assays have made it possible to screen large numbers of mutant lines for potential enzymatic defects. One mutant with a partial acetylcholinesterase defect and two more with choline acetyltransferase defective mutants have been identified. The acetylcholinesterase defective mutant lacks two of the four isozymic forms of acetylcholinesterase found in wild type C. elegans. Behaviorally, it is selectively defective in the propagation of contractile waves in the body region. Of the two mutants with choline acetyltransferase defects, one is remarkabley paralyzed and uncoordinated, while the other is behaviorally nearly normal.
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[
1985]
Studies of aging in nematodes are based largely on the hope that there are some general mechanisms of aging which can be expeditiously revealed in simple multicellular organisms. Although differing greatly from mammals in size, body plan, and some organ systems, nematodes nontheless strongly resemble other metazoans at the cellular, subcellular, and biochemical levels. Moreover, nematodes do exhibit some rather widespread aging phenomena, such as nutritional prolongation of life span, accumulation of age pigments, and enzyme alterations, and their short life span, cellular simplicity, and genetic manipulability can be real advantages in studying the mechanisms underlying these phenomena.
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[
1987]
The concept of developmentally programmed senescence has been outlined by Leonard Hayflick (this volume), and examples from development have been used as exemplars of "developmentally programmed senescence" (Richard Russell, this volume). Unlike development, senescence has probably evolved in the absence of direct selection for increased longevity, perhaps as a direct result of the absence of such selection. (For an excellent review see Charlesworth.) A popular evolutionary model that has received experimental support suggests that senescence may result from pleiotropic effects of selection for adaptive life history characteristics. In the literature on aging, less rigorous arguements have been used to suggest that in human evolution, a delay in the age of senescence has been indirectly selected for by means of so-called longevity assurance or longevity-determinant genes. However, all explanations for the evolution of senescence are theoretical, and, with few exceptions, remain largely untested. Like Dr. Hayflick and Russell, I will assume that by developmental programming we mean genetic specification. I will use a general definition so as not to preclude examples that fail to meet one or more of the rigid criteria defined by Russell (this volume). This less rigid definition of programmed aging is necessary, because unlike development, where genetics has been successfully applied for 50 years, examples of genetic specification of senescent processes are quite few. In the literature on aging, it is still not widely accepted that mutants can alter fundamental patterns of senescent events in well-defined ways. One purpose of this presentation is to outline a few examples. In senescence, large batteries of new genes are not differentially regulated; this is quite unlike development, where many genes are differentially regulated. The molecular etiology of senescence is unknown in almost every instance and, as such, makes the study of aging a fascinating area for inquiry. If senescence is unlike development in lacking differential gene regulation, what are the approaches that are likely to yield useful results in the analysis of senescence and the aging process? The developmental genetic paradigm is a useful, indeed essential, theoretical construct for approaching the aging process in an experimental context. The lack of a suitable model organism in which classical and molecular genetics can be productively combined with other experimental techniques has impeded our understanding of senescence. Despite a general lack of evidence for genetic specification, there are instances where genetic specification is clearly evident; the analysis of mutational events that alter normal senescence in well-defined ways demonstrates this point. These instances also provide experimental models for dissecting the aging