[
1996]
Species with short life spans have been the primary targets for studies into the genetic basis of the aging process(es). Almost all genetic studies of aging and longevity have been performed on invertebrates. Invertebrates often have very short life spans, and this fact, together with the excellent genetic systems available for some yeasts, Drosophila melanogaster, and the nematode Caenorhabditis elegans, make them almost the only choice for studying the genetics of aging. The mouse, with its 2-year life span, is an exception to this rule; several genetic studies, including the analysis of short-lived mice, have been performed and used in an attempt to infer causal relationships. The mouse is the focus of a recent NIA initiative on mammalian models of aging. Recently human marker association" studies, where longevity is shown to be associated with defined regions of the human genome by characterizing molecular markers at certain candidate loci, have started to appear. Genetic approaches have been used also to identify the processes causing replicative senescence in human tissue culture. Two fundamentally distinct but overlapping questions have been the focus of genetic studies. What are the molecular mechanisms limiting life span? How does the process of evolution lead to aging and senescence? Although the answer to the latter question has been obtained to the satisfaction of most in the field, studies into the molecular basis continue. The details of the mechanisms leading to senescence and aging have not been forthcoming. Genetic approaches promise to fill this gap.
[
2005]
RNA interference (RNAi) is a recently discovered phenomenon in which doublestranded RNA (dsRNA) silences endogenous gene expression in a sequencespecific manner (Fire et al., 1998). Since its discovery, the use of RNAi has become widely employed in many organisms to specifically knock down gene function. RNAi shares a remarkable degree of similarity with silencing phenomena in other organisms (Cogoni et al., 1999a; Sharp, 1999). For instance, RNAi, posttranscriptional gene silencing in plants and cosuppression in fungi can all be activated by the presence of aberrant RNAs (Maine, 2000; Tijsterman et al., 2002a). Additionally, plant, worm, and fly cells or extracts undergoing RNA-mediated interference all contain small dsRNAs, around 25 nucleotides in length, identical to the sequences present in the silenced gene (Baulcombe, 1996; Hammond et al., 2000; Zamore et al., 2000; Catalanotto et al., 2000). The high degree of similarity between these RNA-mediated silencing phenomena supports the notion that they were derived from an ancient and conserved pathway used to regulate gene expression, presumably to eliminate defective RNAs and to defend against viral infections and transposons. (Zamore, 2002). Components of RNAi have also been implicated in developmental processes, suggesting that RNAi may play a broader role in regulating gene expression (Smardon et al., 2000; Knight et al., 2001; et al., Ketting et al., 2001). Although we have learned much about the general mechanisms underlying RNAi, a detailed understanding of how RNAi works remains to be elucidated. In this chapter we will discuss first the biology of RNAi, then the genes required for its function, and we will end with a discussion on recent findings that have implicated chromatin silencing in the mechanism of RNAi.