Evolutionary Conserved Pro Aging Pathways

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Research conducted in the last decade has shown that aging is genetically regulated. More importantly, similar pro-aging pathways have been identified in all model organisms, suggesting that a strategy to regulate life span may have appeared early during evolution (Kenyon, 2001; Longo and Finch, 2003) (Figures 19.2-19.3).

As described in The Genetics of Chronological Aging: Yeast Methuselah Genes, two glucose-sensing pathways are responsible for the regulation of chronological aging in yeast: the Sch9 and the Ras/PKA pathways (Figure 19.2). Down-regulating the activity of these pathways promotes life-span extension by increasing thermotolerance and oxidative stress resistance and possibly by reducing cell metabolism (Fabrizio et al., 2003; Fabrizio et al., 2001).

Research conducted in C. elegans has identified the insulin/IGF-1-like pathway as a major pro-aging pathway (Figure 19.2). The similarities between yeast and worm aging pathways are remarkable. Analogously to the yeast Ras/PKA pathway, the insulin/IGF-1-like pathway senses the presence of nutrients and regulates entry into a hypometabolic stage (dauer larva) (Kimura et al., 1997). Worm life span can be extended up to three times by reducing the activity of some of the components of the insulin/IGF-1-like pathway such as the cellular receptor DAF-2 and PI-3 kinase AGE-1 (Kimura et al., 1997; Morris, 1996). Importantly, AGE-1 activates kinase Akt/ PKB, which was shown to be homolog of yeast Sch9 and can also be activated by PDK-1, homolog of yeast Pkh1 (Figure 19.2) (Paradis et al., 1999). Life-span extension in both daf-2 and age-1 mutants requires the activity of stress resistance transcription factor DAF-16, which belongs to the FOXO family transcription factors, and of the heat-shock transcription factor HSF-1, a highly conserved heat-shock protein (Hsu et al., 2003; Ogg et al., 1997). The mediators of longevity extension downstream of DAF-16 are also partially conserved between yeast and worms and include mitochondrial superoxide dismutase, catalase, and several heat-shock proteins (Figure 19.2). Long-lived mutants of both species store carbon in the form of glycogen (yeast and worm) or fat (worm).

The insulin-IGF-1 pathway has also been linked to the regulation of aging in Drosophila (Figures 19.2-19.3).

Reducing the activity of this pathway by mutating the insulin receptor (InR) or the insulin receptor substrate (chico) extends the life span of fruit fly by up to 85%. This life-span extension is associated with increased levels of superoxide dismutase activity and fat accumulation (Figure 19.2) (Clancy et al., 2001; Tatar et al.,

2001). Notably, as shown in yeast, the mitochondrial enzyme aconitase is oxidatively modified and inactivated in old flies (see The Genetics of Chronological Aging: Yeast Methuselah Genes) (Yan et al., 1997). Thus, impairing mitochondrial respiration by inactivating aconitase appears to be an age-dependent phenomenon shared between species, increasing superoxide dismu-tase activity—a common mechanism that contributes to longevity extension. Consistently, the overexpression of SOD1/SOD2 in yeast and flies causes a modest but significant extension of life span (Fabrizio et al., 2003; Orr and Sohal, 1994; Parkes et al., 1998; Sun and Tower,

1999). The life span of Drosophila is also extended by overexpressing dFOXO, homolog of the worm DAF-16, in the peripheral fat body (Giannakou et al., 2004; Hwangbo et al., 2004).

Mammals have separate receptors for IGF-1 and insulin. Research in mice has connected both receptors to life-span regulation. Dwarf mice with defective pituitary gland, consequently deficient in growth hormone (GH), IGF-1, and insulin, live up to 65% longer than the wild type and are stress resistant (Brown-Borg et al., 1996; Flurkey et al., 2002) (Figures 19.2-19.3). The effect of dwarf mutations on life span appears to be caused by reduction in GH and IGF-I signaling. In fact, mice lacking the GH receptor are long-lived (Coschigano et al.,

2000), and IGF-1 receptor heterozygous knock-out mice live 30% longer than the wild type (Holzenberger et al., 2003). Furthermore, mice lacking the insulin receptor in the adipose tissue live 18% longer than the wild type (Bluher et al., 2003). Stress resistance also appears to be regulated by GH and IGF-I. In fact, the activities of superoxide dismutases and catalase are decreased after exposure of murine hepatocytes to GH or IGF-1 and in transgenic mice overexpressing GH (Brown-Borg and Rakoczy, 2000; Brown-Borg et al.,

2002). Like the worm daf-2 and the fly InR mutants, dwarf mice accumulate fat, suggesting that the accumulation of reserve carbon sources is an important and conserved portion of a maintenance mode aimed at slowing down aging and surviving through periods of starvation. Analogously, long-lived yeast mutants accumulate glycogen, their main reserve carbon source during starvation. Mammalian FOXOs transcription factors, homologs of the life-span extending DAF-16 and dFOXO transcription factors, have not been conclusively linked with life-span regulation in mammals. However, FOXO activity is associated with increased stress resistance and elevated mitochondrial superoxide dismutase activity in quiescent cells (Figure 19.2) (Kops et al., 2002).

Taken together, the remarkable similarities between the life-span regulatory pathways of organisms ranging from yeast to mice suggest that they may have originated from a common ancestral pathway that regulated mechanisms of cell maintenance, protection against stress, and carbon storage in order to minimize aging during periods of starvation.

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