The gene mutations extending the lifespan are more important in understanding molecular basis for aging than the mutations in genes resulting in shorter lifespans. This is because studies on shorter lifespans are debatable due to the fact that the observed effect could be due to pathological consequences of the mutations rather than a result of true aging. Over the past decade, information on the longevity genes has accumulated and now we have an impressive list of longevity genes provided by SAGE KE from yeast through mice. In C. elegans, daf and age-1 genes control the dauer state, an alternative larval state where these larvae are able to thrive despite the fact that food is scarcely available (Dorman et al., 1995; Kimura et al., 1997; Van Voorhies and Ward, 1999). These larvae could live up to two months in contrast to well-fed worms which live for about three weeks. Daf-2 is homologous to the insulin receptor. In this organism, an insulin-like hormone initiates a signaling cascade via daf-2 which ultimately activates AKT kinases to phosphorylate the forkhead transcription factor Daf-16 so that it is retained in the cytoplasm to favor the reproductive growth of the organism (Paradis and Ruvkun, 1998). When daf-2 is mutated, the forkhead transcription factor translocates to the nucleus and induces a group of stress resistance genes required for the dauer state, including super oxide dismutase gene. However, such a pathway may not be significant for vertebrates, because a mutation in an insulin receptor would develop insulin resistance and even diabetes—not a longer lifespan.
One of the best studies with known experimental evidence for extending life is dietary restriction, which extends life in every organism tested (Hursting et al., 2003). Studies to understand the basis of dietary restriction resulted in identification of altered expression of several genes using microarray analysis (Weindruch et al., 2001). However, deciphering the details of the molecular basis for extending the lifespan through restricting the diet is difficult and requires other approaches such as the use of genetics. Recently, Guarente and his colleagues have identified the sir-2 locus coding for NAD-dependent histone acetylase, which silences large regions of DNA and slows down aging in yeast (Guarente and Picard, 2005). Interestingly, caloric restriction, which produces more NAD, also slows down aging in other organisms, including humans. When an extra copy of the sir-2 homologue is placed in C. elegans and a similar homologue was placed in yeast, these organisms lived substantially longer (Tissenbaum and Guarente, 2001). Presently, this pathway seems to be common to organisms tested and also fits with dietary restriction, but it still remains to be tested in higher organisms.
In Drosophila, mutations like methuselah, and overexpression of Cu/Zn super oxide dismutase, can extend the maximum lifespan (Lin et al., 1998; Parkes et al., 1998). In mice, SHC gene product has been shown to respond to reactive oxygen species, and a mutation in this gene has been shown to increase the lifespan (Migliaccio et al., 1999). Several such examples support the theory of oxidative damage and appear to display a common theme, although exceptions exist.
Comparison of gene expression between phylogeneti-cally related organisms with different lifespans may reveal the critical differences between these organisms. Although this approach may produce the comprehensive differences between two organisms, it is difficult to pinpoint the genes which are responsible for lifespan differences since there may be tremendous variations in gene expression. Furthermore, a given pathway in an organism is more or less efficient depending upon the threshold levels of the factors involved in that pathway. The threshold levels of the factors may be different for different organisms, even though they are normal to the organism. Sifting for the true gene expression related to the lifespan differences over the background of normal threshold value differences will be difficult. Centenarian studies using SNPs to detect the longevity genes have yielded certain markers; however, this may not yield other possible genes affecting the lifespan (Perls et al., 2002). The above impressive list of genes and multiple theories imply that there are several mechanisms that may operate to prolong the lifespan. However, given the multifactorial nature of aging, the current list of genes may not be complete. Since vertebrate genes are more numerous, more novel genes that are not conserved in the lower model organisms that are specific to vertebrates may be identified. Therefore, a vertebrate genetic model that is amenable for large-scale genetic screens for aging is needed.
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