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Short-Term Treatment With Rapamycin and Dietary Restriction Have Overlapping and Distinctive Effects in Young Mice

Address correspondence to Viviana I Pérez, Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University, 307 Linus Pauling Science Center, Corvallis, OR 97331.Email: .
The Journals of Gerontology Series A Biological Sciences and Medical Sciences (Impact Factor: 4.98). 05/2012; 68(2). DOI: 10.1093/gerona/gls127
Source: PubMed

ABSTRACT Because rapamycin, an inhibitor of the nutrient sensor mammalian target of rapamycin, and dietary restriction both increase life span of mice, it has been hypothesized that they act through similar mechanisms. To test this hypothesis, we compared various biological parameters in dietary restriction mice (40% food restriction) and mice fed rapamycin (14 ppm). Both treatments led to a significant reduction in mammalian target of rapamycin signaling and a corresponding increase in autophagy. However, we observed striking differences in fat mass, insulin sensitivity, and expression of cell cycle and sirtuin genes in mice fed rapamycin compared with dietary restriction. Thus, although both treatments lead to significant downregulation of mammalian target of rapamycin signaling, these two manipulations have quite different effects on other physiological functions suggesting that they might increase life span through a common pathway as well as pathways that are altered differently by dietary restriction and rapamycin.

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    • "There is also evidence that rapamycin is toxic to pancreatic b-cells both in vitro and in vivo (Barlow et al., 2013). As increased insulin sensitivity is a notable feature of longevity extension in pituitary dwarf mutants (Dominici et al., 2002) and in DR rodents (Barzilai et al., 1998; Fok et al., 2013), the deficit in glucose homeostasis consistently seen in rapamycin-treated mice is unexpected and suggests that the lifespan benefit of this drug might be extended still further by combination of rapamycin with an insulin sensitizing agent like metformin. On the other hand, it is interesting to note that we found the dose of rapamycin that extends lifespan to the greatest degree (42 ppm) is also associated with the largest deficits in glucose metabolism. "
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    ABSTRACT: Rapamycin, an inhibitor of mTOR kinase, increased median lifespan of genetically heterogeneous mice by 23% (males) to 26% (females) when tested at a dose three-fold higher than that used in our previous studies; maximal longevity was also increased in both sexes. Rapamycin increased lifespan more in females than in males at each dose evaluated, perhaps reflecting sexual dimorphism in blood levels of this drug. Some of the endocrine and metabolic changes seen in diet-restricted mice are not seen in mice exposed to rapamycin, and the pattern of expression of hepatic genes involved in xenobiotic metabolism is also quite distinct in rapamycin-treated and diet restricted mice, suggesting that these two interventions for extending mouse lifespan differ in many respects. This article is protected by copyright. All rights reserved.
    Aging cell 12/2013; 13(3). DOI:10.1111/acel.12194 · 5.94 Impact Factor
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    • "Because rapamycin is known to inhibit the mTOR signaling pathway, we measured mTOR signaling (ratio of phosphorylated S6 compared to the total S6) in the livers of the four groups of mice (Fig. S1, Supporting information). The Rapa and DR groups showed significant decreases (34% and 60%, respectively, comparing the means of each group) in mTOR signaling when compared with AL, which we have previously observed (Fok et al., 2012). We found that the Rapa + DR group had a 68% decrease in mTOR signaling relative to AL; however, mTOR signaling was not significantly different from either the DR or Rapa group. "
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    ABSTRACT: Rapamycin (Rapa) and dietary restriction (DR) have consistently been shown to increase lifespan. To investigate whether Rapa and DR affect similar pathways in mice, we compared the effects of feeding mice ad libitum (AL), Rapa, DR, or a combination of Rapa and DR (Rapa + DR) on the transcriptome and metabolome of the liver. The principal component analysis shows that Rapa and DR are distinct groups. Over 2500 genes are significantly changed with either Rapa or DR when compared with mice fed AL; more than 80% are unique to DR or Rapa. A similar observation was made when genes were grouped into pathways; two-thirds of the pathways were uniquely changed by DR or Rapa. The metabolome shows an even greater difference between Rapa and DR; no metabolites in Rapa-treated mice were changed significantly from AL mice, whereas 173 metabolites were changed in the DR mice. Interestingly, the number of genes significantly changed by Rapa + DR when compared with AL is twice as large as the number of genes significantly altered by either DR or Rapa alone. In summary, the global effects of DR or Rapa on the liver are quite different and a combination of Rapa and DR results in alterations in a large number of genes and metabolites that are not significantly changed by either manipulation alone, suggesting that a combination of DR and Rapa would be more effective in extending longevity than either treatment alone.
    Aging cell 12/2013; 13(2). DOI:10.1111/acel.12175 · 5.94 Impact Factor
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    • "Surprisingly, and in contrast to these results, we found that dietary rapamycin did not induce insulin resistance in HET3 mice as measured by ITT in either young (Fig. 2A) or old (Fig. 2B) mice, even when given to mice over a 3-month period. Interestingly, Fok et al., (2012) have recently reported that dietary rapamycin caused glucose intolerance in the absence of any effect on insulin tolerance in C57BL/6 mice, suggesting that the delivery method, rather than the strain, may be the major determinant of whether mice develop overt insulin resistance. In concurrence with our previous study in C57BL/6 mice, HET3 mice treated with rapamycin are hyperglycemic after refeeding and when young and treated with rapamycin for 3 months, also display fasting hyperglycemia (Fig. 2C). "
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    ABSTRACT: Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, extends the lifespan of yeast, worms, flies, and mice. Interventions that promote longevity are often correlated with increased insulin sensitivity, and it therefore is surprising that chronic rapamycin treatment of mice, rats and humans is associated with insulin resistance (Johnston et al. 2008; Houde et al. 2010; Lamming et al. 2012). We examined the effect of dietary rapamycin treatment on glucose homeostasis and insulin resistance in the genetically heterogeneous HET3 mouse strain, a strain in which dietary rapamycin robustly extends mean and maximum lifespan. We find that rapamycin treatment leads to glucose intolerance in both young and old HET3 mice, but in contrast to the previously reported effect of injected rapamycin in C57BL/6 mice, HET3 mice treated with dietary rapamycin responded normally in an insulin tolerance test. To gauge the overall consequences of rapamycin treatment on average blood glucose levels, we measured HBA1c. Dietary rapamycin increased HBA1c over the first three weeks of treatment in young animals, but the effect was lost by three months, and no effect was detected in older animals. Our results demonstrate that the extended lifespan of HET3 mice on a rapamycin diet occurs in the absence of major changes in insulin sensitivity, and highlight the importance of strain background and delivery method in testing effects of longevity interventions. This article is protected by copyright. All rights reserved.
    Aging cell 05/2013; 12. DOI:10.1111/acel.12097 · 5.94 Impact Factor
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