InsulinIGFI Signaling Pathway and Stress Resistance

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To investigate the relationship between lifespan-extension and oxidative-stress resistance, we screened the oxidative-stress resistance phenotype in various mutants (6,23). We examined the survival period of each mutant under experimentally induced, acute oxidative stress. We used paraquat, an intracellular superoxide O2 generator, under hyperoxia for acute oxidative stress. The daf-2 mutants with an extended lifespan, survived for a longer period of time than wild-type animals in the presence of paraquat under hyperoxic or normoxic conditions. The daf-2 mutant is also more resistance to menadione, another intracellular O2 generator, under hyperoxia, than wild-type animals. The mutants in the TGF-^ pathway and cGMP pathway do not show oxidative-stress resistance. The oxidative-stress resistance seen in the daf-2 mutants is suppressed by mutations in daf-18 or daf-16 indicating that daf-16 and daf-18 act downstream of daf-2 to confer oxidative-stress resistance, as well as extended lifespan. Vanfleteren (22) and Larsen (21) showed that the lifespan-extension mutant age-1 is more resistant to oxidative stress in old age than wild-type animals at the same age. We showed that the age-1 mutants of young adults also display the oxidative-stress resistance. The oxidative-stress resistance in age-1 mutants is suppressed by daf-16 mutation, indicating that daf-16 is located downstream of age-1 in the pathway for regulating oxidative-stress resistance.

On the other hand, oxidative-stress resistance in two alleles of age-1 mutants (m333 and mg44) is not fully suppressed by daf-18 mutation, indicating that daf-18 does not act downstream of age-1. daf-16 and daf-18 act downstream of daf-2 in the insulin/IGF-I signaling pathway for oxidative-stress resistance (23). Taken together, we postulate the following pathway for oxidative-stress resistance:

daf-2 —> daf-18 —> age-1 —> daf-16 —> Oxidative-stress resistance

This pathway is essentially identical to the pathway regulating longevity (63), suggesting a strong association between lifespan-extension and oxidative-stress resistance. However, Dorman and Canyon (65) demonstrated that the daf-18 mutation suppressed the lifespan-extension phenotype of another allele of age-1 (hx546) indicating that daf-18 acts downstream of age-1. Such differences could be attributed to the differences in severity of the age-1 alleles used.

Two alleles of age-1 mutants (m333 and mg44) display the Daf phenotype, which is completely suppressed by daf-18 or daf-16 mutations, indicating the following pathway for dauer formation:

daf-2 —> age-1 —> daf-18 —> daf-16 —> dauer formation

Thus, oxidative-stress resistance is closely associated with longevity but not with dauer formation. The PIP3 level is maintained under a balance between generation by AGE-1 PI3 kinase and degradation by DAF-18 PTEN, which could determine the impact of this pathway. The loss or reduction of function mutations in age-1 could reduce PI3 kinase activity to drop this second messenger level. When DAF-18 is reduced, only the preexisting pool of the second messenger may be insufficient to inhibit longevity and oxidative-stress resistance but sufficient to inhibit dauer formation. Dillin et al. (66) found that the inactivation of daf-2 during adulthood by RNAi extends lifespan and increases oxidative-stress resistance. Since dauer formation is switched in the early larval stage, the insulin/IGF-I pathway controls the dauer switch and oxidative-stress resistance/longevity independently.

There are several genes in C. elegans that encode SOD enzymes: sod-1 encodes cytosolic CuZnSOD (21), sod-2 and sod-3 each encodes mitochondrial MnSOD (67-69), and sod-4 encodes extracellular CuZnSOD (70). The level of sod-3 mRNA in daf-2 mutants is higher than that in the wild-type animals (23). The levels of mRNA transcripts of sod-1, sod-2, and catalase in the daf-2 are similar to those in the wild-type animals. The level of sod-3 mRNA in daf-2 mutants increases as it develops from the egg to the L2 larval stage coinciding with increased in oxidative-stress resistance. The elevated level of sod-3 mRNA in the daf-2 mutants is suppressed by daf-16 and daf-18 mutation (23). The level of sod-3 mRNA in the age-1 mutants is higher than that in wild-type animals (6). The elevated level of sod-3 mRNA in age-1 mutants is suppressed by daf-16 mutation but is not fully suppressed by daf-18 mutation. These results provide further evidence that the insulin/IGF-I signaling pathway regulates extended lifespan, oxidative-stress resistance and sod-3 expression in a similar way. These results suggest that the extended lifespan is correlated with the efficient withdrawal of ROS generated in mitochondria during normal metabolism.

Murakami and Johnson (19) showed that the insulin/IGF-I pathway confers resistance to UV exposure. Lithgow (71) indicated that the insulin/ IGF-I pathway also confers increased Cd- and Cu-ion resistance. Metallothio-neins are metal-binding proteins that are induced in response to a wide variety of stresses including metal ions and oxidative stress. In C. elegans, there are two isoforms of metallothioneins. Metallothionein-1 (MTL-1) is induced by Cd and heat in intestinal cells. Levels of mtl-1 mRNA are high in daf-2 mutants compared with wild-type animals under normal conditions. Cd challenge induces mtl-1 and mtl-2 in daf-2 mutants more greatly than in wild-type animals.

The daf-2 mutant is resistant to hypoxia. Scott et al. (72) showed that daf-2 is important for preventing hypoxic death in myocyte and neurons. The signaling pathway for hypoxia resistance is somewhat distinct from insulin/IGF-I signaling for longevity.

The age-1 and daf-2 mutants survive longer in acute thermal stress than wild-type animals (5,64). The age-1 mutant has elevated levels of HSP-16 at normal temperature, and when challenged by heat shock, accumulates greater levels of HSP16 compared with wild-type animals (41). The hsp-16 transgene induces heat-stress resistance and extended lifespan both in wild-type and age-1 mutant animals. The DAF-16 transcription factor is essential for maximal hsp-16 expression and for lifespan-extension induced by the hsp-16 transgene (44). DAF-16 translocates into the nucleus upon heat and oxidative stress (73). Taken together, these results suppose that molecular chaperons play an important role in the extension of lifespan by preventing the accumulation of conformation-ally altered protein associated with aging. Munoz and Riddle (74) isolated ther-motolerant mutants of C. elegans, and 80% of these mutants exhibit an extended lifespan, suggesting a strong correlation between stress resistance and lifespan extension.

From the overall screening of RNAi inactivation of chromosome I genes, Garigan et al. (18) found that the inactivation of HSF-1, a transcription factor regulating the response to heat and oxidative stress, shortens the lifespan and causes premature aging. These findings raise the possibility that the activation of thermal and oxidative stress response mechanisms may slow down the rate of aging. Hsu et al. (42) introduced extra-copies of the hsf-1 gene into animals, resulting in resistance to heat and oxidative stress (paraquat) and lifespan extension. The lifespan extension by hsf-1 extra-copies requires daf-16, suggesting that DAF-16 and HSF-1 may act together to promote longevity. DAF-16 also appears to act independently of HSF-1, because hsf-1 RNAi does not prevent DAF-16 from accumulating in the nucleus of daf-2 mutants or activating two known DAF-16-downstream genes, mtl-1 and sod-3. The expression of several shsp genes, hsp-16.1, hsp-16.49, hsp-12.6, and sip-1 is increased in daf-2 mutants and decreased in daf-16 mutants. HSF-1 is required for increased shsp gene expression in daf-2 mutants, thus, HSF-1 functions in the insulin/IGF-1 system. DAF-16 as well as HSF-1 is required to activate shsp expression after heat shock. Furthermore, both the DAF-16 binding site (GTAAAc/tA) and HSF-1 binding site (TTCTa/cGAA) are located at the regulatory regions of the shsp genes. The RNAi inactivation of each shsp genes partly shortens the lifespan of daf-2 mutant and HSF-1 overexpressed animals. These results suggest that DAF-16 from insulin/IGF-I signals and stress, and HSF-1 from stress, act together to activate the transcription of a variety of genes inducing lifespan extension (Fig. 4.1). The RNAi inactivation of shsp accelerates the onset of polyglutamine-expansion protein aggregation in a C. elegans model for triplet repeat disease. This result suggests that SHSPs may influence the aging rate and polyglutamine aggregation coordinately by in part, preventing the improper association of oxidized or abnormally folding proteins.

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