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Serum samples were prepared from trunk blood at decapitation between 9:00 and 12:00. Data represent means ± SD (mg/dL) of 3 to 7 rats. 2-f ANOVA analyzed the main effects of rat group and diet and their interaction. AL, groups of rats fed ad libitum. CR1 and CR2, groups of rats subjected to 30% calorie restriction, while sacrificed in the first day and the second day of 2-day feeding cycle, respectively (see the rat husbandry for the CR regimen, a modified alternate-day-feeding, used in the present study).

while not in CR rats. Our preliminary experiment did not confirm the upregulation of phosphorylated AMPK in transgenic rats (data not shown).

Stress response

Stress resistance is linked to retardation of aging and an extended lifespan. CR rodents exhibit resistance to many types of stressors including toxic substances, inflammatory stimuli, ambient temperature, and surgery (Masoro, 2003). Some long-lived mice also show high survival rates after intraperitoneal injection of paraquat, a herbicide that generates reactive oxygen species (ROS) (Migliaccio et al., 1999; Holzenberger et al., 2003).

We therefore examined the resistance of the transgenic mice included here to lipopolysaccharide (LPS)-induced inflammatory challenge, which causes cellular injury by generating ROS and reactive nitrogen species (RNS). Six-month-old male Wistar (—/—), (tg/—), and (tg/tg) rats fed ad libitum were administered LPS (1.6 mg/ kg body weight) through the tail vein, then sacrificed 0-, 1-, 4-, and 8-h later. A preliminary study indicated that this dose of LPS induced necrotic foci in the liver at 8-h in 50% of (—/—) rats. Serum aspartate aminotransferase (AST) levels, an index of LPS-induced tissue damage, were consequently measured. The preliminary results at 4- and 8-h (Figure 31.6) indicated that serum AST levels were greater in (—/—) rats compared with (tg/—) and (tg/tg) rats, with no difference between (tg/—) and (tg/tg) rats.

Our previous study using a similar experimental protocol with F344 rats showed that CR rats resisted LPS-challenge (Tsuchiya et al., 2005). Thus, common stress response machinery is thought to be elicited with reduced GH-IGF-1 and CR, respectively.

Figure 31.6. Stress response to lipopolysaccharide (LPS)-induced inflammation. Rats were sacrificed 0-, 1-, 4-, and 8-h after intravenous injection of 1.6 mg/kg body weight (BW) of LPS. Serum aspartate aminotransferase (AST) levels were measured as an index of LPS-induced tissue injury. Values represent the mean ± SD of 3 to 10 rats. AST levels at 0- and 1-h are not shown because levels were not significantly elevated. 2-f ANOVA was used to analyze the main effects of rat group and time and their interaction on AST levels.

Time after LPS injection

Figure 31.6. Stress response to lipopolysaccharide (LPS)-induced inflammation. Rats were sacrificed 0-, 1-, 4-, and 8-h after intravenous injection of 1.6 mg/kg body weight (BW) of LPS. Serum aspartate aminotransferase (AST) levels were measured as an index of LPS-induced tissue injury. Values represent the mean ± SD of 3 to 10 rats. AST levels at 0- and 1-h are not shown because levels were not significantly elevated. 2-f ANOVA was used to analyze the main effects of rat group and time and their interaction on AST levels.

Conclusions

When fed ad libitum, transgenic (tg/—) rats displayed several phenotypes similar to those of wild-type rats subjected to CR. For example, profiles of blood glucose, insulin and other hormones during the feeding cycle or after glucose load and an enhanced stress response were seen in both. These findings suggest that this rat model is suitable for analyses of the mechanisms underlying the effect of CR, particularly with regard to the role of the somatotropic axis in the regulation of lifespans and aging. Another merit of this model is that the reduced level of the GH-IGF-1 axis was moderate and less severe than in Ames or GHR/BP-KO mice whose GH-IGF-1 signaling was almost totally deficient. Thus, experiments using the transgenic mini rats can be conducted within physiological ranges.

The (tg/tg)-AL rats resembled (tg/—)-AL rats as well as (—/—)-CR rats with regard to glucose and insulin levels and the stress response. However, these (tg/tg) rats died earlier of neoplastic diseases. Although immunological dysfunction was noted in (tg/tg) rats, further studies are needed to determine whether severe suppression of the somatotropic axis results in negative effects on aging and longevity, because mice models with deficient GH signals were shown to live longer.

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