Rapamycin-induced metabolic defects are reversible in both lean and obese mice

Liu, Yuhong; Diaz, Vivian; Fernández, Elízabeth; Strong, Randy; Ye, Lan; Baur, Joseph A.; Lamming, Dudley W.; Richardson, Arlan; Salmon, Adam B.

doi:10.18632/aging.100688

Cited by 63 publications

(64 citation statements)

References 45 publications

(87 reference statements)

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“…We treated 9‐week‐old male C57BL/6J mice for 2 weeks with vehicle or 2 mg/kg rapamycin every day (1×/day) or weekly (1×/7 days), and analyzed the effect on glucose tolerance. We performed a fasting glucose tolerance test 7 days after the most recent rapamycin treatment of the weekly (1×/7 days) group; the effects of chronic rapamycin treatment on glucose tolerance persist for 2 weeks (Yang et al ., 2012; Liu et al ., 2014). …”

Section: Resultsmentioning

confidence: 99%

“…The effect of chronic rapamycin treatment on AKT S473 phosphorylation can be difficult to observe and is time sensitive (Schreiber et al ., 2015), and so we may have only observed this effect in skeletal muscle due to the time point utilized. The impact of chronic rapamycin on AKT S473 phosphorylation is also influenced by diet (Liu et al ., 2014). The current study utilized a different chow (LabDiet 5001) than we utilized in our previous studies (ProLab RMH 3000), yet the phenotypes of rapamycin‐treated mice were identical.…”

Section: Discussionmentioning

confidence: 99%

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Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

et al. 2015

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SummaryInhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA‐approved drug rapamycin has been shown to promote lifespan and delay age‐related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long‐term prophylactic use of rapamycin as a therapy for age‐related diseases. While the beneficial effects of rapamycin are largely mediated by the inhibition of mTOR complex 1 (mTORC1), which is acutely sensitive to rapamycin, many of the negative side effects are mediated by the inhibition of a second mTOR‐containing complex, mTORC2, which is much less sensitive to rapamycin. We hypothesized that different rapamycin dosing schedules or the use of FDA‐approved rapamycin analogs with different pharmacokinetics might expand the therapeutic window of rapamycin by more specifically targeting mTORC1. Here, we identified an intermittent rapamycin dosing schedule with minimal effects on glucose tolerance, and we find that this schedule has a reduced impact on pyruvate tolerance, fasting glucose and insulin levels, beta cell function, and the immune system compared to daily rapamycin treatment. Further, we find that the FDA‐approved rapamycin analogs everolimus and temsirolimus efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance. Our results suggest that many of the negative side effects of rapamycin treatment can be mitigated through intermittent dosing or the use of rapamycin analogs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

et al. 2015

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“…(164) The mechanisms of the effect of rapamycin are pleiotropic, including inhibition of protein synthesis, alteration of transcriptomes, modulation of inflammation, and improvement of cerebral blood flow, in addition to regulation of autophagy, mitophagy and thereby mitochondrial function. (157,161,(165)(166)(167)(168)(169)(170)(171)(172)(173)(174)(175)(176)(177) Taken together, these examples provide strong support for the concept that autophagy plays a critical role in maintaining a normal lifespan and healthy neuronal aging, and that its decline is inexorably tied to age related pathologies ( Figure 5). (178) Degradation of dysfunctional mitochondria is carried out by the autophagy-lysosomal pathway.…”

Section: Mitochondrial -Lysosomal Dysfunction In Nddmentioning

confidence: 55%

New Insight in The Molecular Mechanisms of Neurodegenerative Disease

2018

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B ACKGROUND:Redox and proteotoxic stress contributes to age-dependent accumulation of dysfunctional mitochondria and protein aggregates, and is associated with neurodegeneration. The free radical theory of aging inspired many studies using reactive species scavengers such as alpha-tocopherol, ascorbate and coenzyme-Q to suppress the initiation of oxidative stress. However, clinical trials have had limited success in the treatment of neurodegenerative diseases (NDDs). CONTENT:The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of NDDs. In Alzheimer's disease, the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism, corruptive protein templating. The accumulation of redox modified proteins or organelles cannot be reversed by oxidant intercepting antioxidants and must then be removed by alternative mechanisms. Autophagy serves this essential function in removing damaged or dysfunctional proteins and organelles thus preserving neuronal function and survival.SUMMARY: Senescent cells and their senescenceassociated secretory phenotypes (SASPs) may constitute a novel, understudied, and potentially important contributor to neuro-inflammation and subsequent neurodegeneration. Characterization of cellular senescence in the brain could uncover novel therapeutic targets for the prevention and treatment of chronic age-related NDDs. KEYwORDS

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“…33,38,43 These metabolic changes are reversible. 44 Like so called "starvation-diabetes," this condition may be benevolent and associated with longevity. 45 Also, "starvation-like" benevolent diabetes seems to be achieved only at high everyday doses and in some strains like C57BL/6NCr.…”

Section: Introductionmentioning

confidence: 99%

“…44 It may seem paradoxical that intermittent administration (by i.p.) is more effective than everyday administration (by oral gavash).…”

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confidence: 99%

Comparison of rapamycin schedules in mice on high-fat diet

2014

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At a wide range of doses, rapamycin extends life span in mice. It was shown that intraperitoneal injections (i.p.) of rapamycin prevent weight gain in mice on high-fat diet (HFD). We further investigated the effect of rapamycin on weight gain in female C57BL/6 mice on HFD started at the age of 7.5 months. By the age of 16 and 23 months, mice on HFD weighed significantly more (52 vs 33 g; p D 0.0001 and 70 vs 38 g; p < 0.0001, respectively) than mice on low fat diet (LFD). The i.p. administration of 1.5 mg/kg rapamycin, 3 times a week every other week, completely prevented weight gain, whereas administration of rapamycin by oral gavash did not. Rapamycin given in the drinking water slightly decreased weight gain by the age of 23 months. In addition, metabolic parameters were evaluated at the age of 16 and 23 months, 6 and 13 days after last rapamycin administration, respectively. Plasma leptin levels strongly correlated with body weight, (P < 0.0001, rD0.86), suggesting that the difference in weight was due to fat tissue mass. Levels of insulin, glucose, triglycerides and IGF1 were not statistically different in all groups, indicating that these courses of rapamycin treatment did not impair metabolic parameters at least after rapamycin discontinuation. Despite rapamycin discontinuation, cardiac levels of phospho-S6 and pAKT(S473) were low in the i.p.-treated group. This continuous effect of rapamycin can be explained by prevention of obesity in the i.p. group. We conclude that intermittent i.p. administration of rapamycin prevents weight gain without causing gross metabolic abnormalities. Intermittent gavash administration minimally affected weight gain. Potential clinical applications are discussed.

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Rapamycin-induced metabolic defects are reversible in both lean and obese mice

Cited by 63 publications

References 45 publications

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

New Insight in The Molecular Mechanisms of Neurodegenerative Disease

Comparison of rapamycin schedules in mice on high-fat diet

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