Article

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: 5.42). 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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    • "In particular, mTORC1 has been considered as a key modulator of several processes related to ageing and age-related disease. Indeed, inhibition of mTOR by rapamycin had been found to extend life span in a number of species, including mammals, with biologic effects similar, but not necessarily identical, to those found following calorie/nutrient restriction (Fok et al., 2013; Johnson et al., 2013; Lamming et al., 2013). The mechanism(s) behind extended life span are still under investigation; however, a number of possible mechanisms have been proposed, including anticancer effects, reduced translation, increased autophagy, support of functional stem cells, modulation of immune response, reduced inflammation, and improved mitochondrial function. "
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    ABSTRACT: The mammalian target of rapamycin (mTOR) is a protein kinase that shows key involvement in age-related disease and promises to be target for treatment of cancer. In the present study the elimination of potent ATP-competitive mTOR inhibitor 3-(6-amino-2-methylpyrimidin-4-yl)-N-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-amine (compound 1) is studied in bile duct cannulated rats, and the metabolism of compound 1 in liver microsomes is compared across species. Compound 1 was shown to undergo extensive N-glucuronidation in bile duct catheterized (BDC) rats. N-glucuronides were detected on positions N1 (M2) and N2 (M1) of the pyrazole moiety as well as on the primary amine (M3). All three N-glucuronide metabolites were detected in liver microsomes of the rat, dog and human, while primary amine glucuronidation was not detected in non-human-primate (NHP). In addition N1 and N2-glucuronidation showed strong species selectivity in vitro, with rats, dogs and humans favoring N2-glucuronidation and NHPs favoring N1-glucuronide formation. Formation of M1 in NHP liver microsomes also followed sigmoidal kinetics, singling out NHP as unique among the species with regard to compound 1 N-glucuronidation. In this respect, NHP might not always be the best animal model for N-glucuronidation of UGT1A9 or UGT1A1 substrates in humans. Impact of N-glucuronidation of compound 1 could be more pronounced in higher species such as NHP and human leading to high clearance in these species. While compound 1 shows promise as a candidate for investigating the impact of pan-mTOR inhibition in vivo, opportunities may exists through medicinal chemistry effort to reduce metabolic liability with the goal of improving systemic exposure.
    Preview · Article · Jan 2014 · Drug metabolism and disposition: the biological fate of chemicals
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    • "We found that the levels of blood Rapa measured in 10-month-old males and females were significantly different, while the Rapa levels in the livers of males and females measured at 25-months were not significantly different (Figure 2A and 2B). Interestingly, we observed no difference in mTORC1 signaling in mice (either males or females) fed the control or Rapa diets for 21 months as measured by the ratio of phosphorylation of S6 to total S6 (Figure S3 in File S1), which is in contrast to what we observed when Rapa is given to mice for 6 months [13], [20]. Several other groups have reported that Rapa does not alter mTOR signaling when given chronically over a long period of time [21], [22]. "
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    ABSTRACT: Rapamycin was found to increase (11% to 16%) the lifespan of male and female C57BL/6J mice most likely by reducing the increase in the hazard for mortality (i.e., the rate of aging) term in the Gompertz mortality analysis. To identify the pathways that could be responsible for rapamycin's longevity effect, we analyzed the transcriptome of liver from 25-month-old male and female mice fed rapamycin starting at 4 months of age. Few changes (<300 transcripts) were observed in transcriptome of rapamycin-fed males; however, a large number of transcripts (>4,500) changed significantly in females. Using multidimensional scaling and heatmap analyses, the male mice fed rapamycin were found to segregate into two groups: one group that is almost identical to control males (Rapa-1) and a second group (Rapa-2) that shows a change in gene expression (>4,000 transcripts) with more than 60% of the genes shared with female mice fed Rapa. Using ingenuity pathway analysis, 13 pathways were significantly altered in both Rapa-2 males and rapamycin-fed females with mitochondrial function as the most significantly changed pathway. Our findings show that rapamycin has a major effect on the transcriptome and point to several pathways that would likely impact the longevity.
    Full-text · Article · Jan 2014 · PLoS ONE
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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.
    Full-text · Article · Dec 2013 · Aging cell
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