Prolonged Rapamycin treatment led to beneficial metabolic switch

Fang, Yimin; Bartke, Andrzej

doi:10.18632/aging.100554

Cited by 22 publications

(18 citation statements)

References 8 publications

(11 reference statements)

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“…*P<0.05 et al 1997). Similarly, rapamycin treatment extends longevity and suppresses rather than increases insulin sensitivity and glucose tolerance indicating that suppression of insulin signaling or parts of the signal can be also beneficial at some stages of life for healthy aging (Fang and Bartke 2013;Kurosu et al 2005;Kuro-o et al 1997;Bartke 2006). We speculate that the adaptation to low glucose uptake in df/df brain could resemble the condition present during CR or starvation which may be necessary to preserve the healthy function of the brain during long life and aging.…”

Section: Discussionmentioning

confidence: 90%

“…Interestingly, it is also shown that this pro-longevity treatment does not improve insulin sensitivity (Miller et al 2008) but may rather promote glucose intolerance and insulin resistance (Blagosklonny 2011). However, prolonged treatment with rapamycin promotes beneficial adaptations and metabolic switching by increasing insulin sensitivity and also extending longevity (Fang and Bartke 2013). All of these observations suggest healthy insulin and glucose metabolism as a key factor for longevity, but it is not yet determined if whole-body insulin sensitivity or just tissue-specific action is crucial for healthy aging.…”

Section: Introductionmentioning

confidence: 99%

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Insulin sensitivity in long-living Ames dwarf mice

Wiesenborn

Ayala

King

et al. 2014

AGE

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Long-living Ames dwarf mice (df/df) characterized by growth hormone (GH) deficiency are widely used in aging research because of their 40-60 % lifespan extension compared to normal (N) littermates. Importantly, these mice not only live longer but are also protected from age-related diseases including insulin resistance. Several studies demonstrate that df/df mice have enhanced insulin signaling in different insulin-sensitive tissues and suggest that this is a mechanism for extended lifespan. However, it is unknown whether the enhanced insulin signaling in df/df mice translates to improved insulin action on hepatic glucose production and tissue glucose uptake. We performed hyperinsulinemic-euglycemic clamps to assess tissue-specific insulin action in vivo for the first time in these small long-living dwarfs. Our results demonstrate that the glucose infusion rate required to maintain euglycemia was ∼2-fold higher in df/df mice compared to N controls. Insulin-mediated glucose production was completely suppressed in dwarf mice, and stimulation of gastrocnemius and vastus muscle and adipose tissue glucose uptake was also enhanced in df/df mice (100, 86, and 65 %, respectively). These findings show that improved insulin signaling in df/df mice is associated with enhanced tissue-specific insulin action in vivo. This improved functionality of insulin action and glucose homeostasis may play a key role in promoting healthy aging and longer lifespan in df/df mice.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Insulin sensitivity in long-living Ames dwarf mice

Wiesenborn

Ayala

King

et al. 2014

AGE

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“…In certain strains of mice, rapamycin causes some symptoms of starvation-like insulin-resistance, erroneously viewed as real diabetes [ 11 ]. These metabolic alterations are reversible [ 12 , 13 ]. MTOR-centric model predicts that this reversible insulin resistance is benevolent and is associated with increased longevity because longevity is promoted not via increased insulin sensitivity, but instead via decreased mTOR pathway signaling [ 9 ].…”

Section: Triumph Of Mtor-centric Modelmentioning

confidence: 99%

Rejuvenating immunity: “anti-aging drug today” eight years later

Blagosklonny

2015

Oncotarget

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“…Upon entering a cell, rapamycin binds to 12-kDa FK506-binding protein (FKBP12), and then this complex suppresses the kinase activity of mTORC1 [24]. Although it is believed that rapamycin imposes its inhibition on mTOR via mTORC1 complex [11,28], but there is evidence showing a more complex mechanism of action which is determined based on the temporal properties of rapamycin treatment [24,[29][30][31]. For example, short-term treatment with rapamycin renders cells more sensitive to insulin via mTORC1 while long-term exposure increases the insulin resistance which happens via affecting mTORC2 [31].…”

Section: Introductionmentioning

confidence: 99%

Dynamic Modeling of Signal Transduction by mTOR Complexes in Cancer

Dorvash

Farahmandnia

Mosaddeghi

et al. 2019

Preprint

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Signal integration in the mTOR pathway plays a vital role in cell fate decision making in cancer cells.As a signal integrator, mTOR shows a complex dynamical behavior which determines the cell fate at different cellular processes levels including cell cycle progression, cell survival, cell death, metabolic reprogramming, and aging. The dynamics of the complex responses to rapamycin in cancer cells have been attributed to its differential time-dependent inhibitory effects on mTORC1 and mTORC2, the two main complexes of mTOR. Two explanations were previously provided for this phenomenon: 1-Rapamycin does not inhibit mTORC2 directly, whereas it prevents mTORC2 formation by sequestering free mTOR protein. 2-Components like Phosphatidic Acid further stabilize mTORC2 compared with mTORC1. To understand the mechanism by which rapamycin differentially inhibits the mTOR complexes, we present a mathematical model of rapamycin mode of action based on the first explanation, i.e., Le Chatelier's principle. Translating the interactions among components of mTORC1 and mTORC2 into a mathematical model revealed the dynamics of rapamycin action in different doses and time-intervals of rapamycin treatment. The model shows that rapamycin has stronger effects on mTORC1 compared with mTORC2, simply due to its direct interaction with free mTOR and mTORC1, but not mTORC2, without the need to consider other components that might further stabilize mTORC2. Based on our results, even when mTORC2 is less stable compared with mTORC1, it can be less inhibited by rapamycin.

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Prolonged Rapamycin treatment led to beneficial metabolic switch

Cited by 22 publications

References 8 publications

Insulin sensitivity in long-living Ames dwarf mice

Insulin sensitivity in long-living Ames dwarf mice

Rejuvenating immunity: “anti-aging drug today” eight years later

Dynamic Modeling of Signal Transduction by mTOR Complexes in Cancer

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