Fasting levels of hepatic p-S6 are increased in old mice

Leontieva, Olga V.; Paszkiewicz, Geraldine; Blagosklonny, Mikhail V.

doi:10.4161/15384101.2014.949150

Cited by 21 publications

(17 citation statements)

References 58 publications

(57 reference statements)

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“…1A) and skeletal muscle (Fig. 1B), due to the conflicting previous reports (Sengupta et al ., 2010; Houtkooper et al ., 2011; Leontieva et al ., 2014). In agreement with the results seen by Houtkooper et al ., we observed a 30% decrease in S6 S240/S244 phosphorylation in the livers of Middle‐aged males and females compared to Young (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…6C, New Model). It is important to note that even the lower level of mTOR signaling found in tissues in which mTOR decreases with age could still ‘be inappropriately high for an aging organism’ (Leontieva et al ., 2014), and contribute to the pathophysiology of aging. The mechanistic basis for the varying impact of age and sex on mTOR signaling in different tissues is an important unanswered question that remains to be addressed.…”

Section: Discussionmentioning

confidence: 99%

“…The question of what happens to mTORC1 signaling during normal aging has therefore received significant attention. As reported in Table 1, numerous studies have reported increased mTORC1 signaling with age in HSCs (hematopoietic stem cells), hypothalamic POMC neurons, and in the liver and lung of mice (Chen et al ., 2009; Sengupta et al ., 2010; Yang et al ., 2012; Leontieva et al ., 2014; Calhoun et al ., 2015). …”

Section: Introductionmentioning

confidence: 99%

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Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

et al. 2015

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SummaryInhibition of the mTOR (mechanistic Target Of Rapamycin) signaling pathway robustly extends the lifespan of model organisms including mice. The precise molecular mechanisms and physiological effects that underlie the beneficial effects of rapamycin are an exciting area of research. Surprisingly, while some data suggest that mTOR signaling normally increases with age in mice, the effect of age on mTOR signaling has never been comprehensively assessed. Here, we determine the age‐associated changes in mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) signaling in the liver, muscle, adipose, and heart of C57BL/6J.Nia mice, the lifespan of which can be extended by rapamycin treatment. We find that the effect of age on several different readouts of mTORC1 and mTORC2 activity varies by tissue and sex in C57BL/6J.Nia mice. Intriguingly, we observed increased mTORC1 activity in the liver and heart tissue of young female mice compared to male mice of the same age. Tissue and substrate‐specific results were observed in the livers of HET3 and DBA/2 mouse strains, and in liver, muscle and adipose tissue of F344 rats. Our results demonstrate that aging does not result in increased mTOR signaling in most tissues and suggest that rapamycin does not promote lifespan by reversing or blunting such an effect.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

et al. 2015

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“…Although Tor activity was reported to increase with age in muscle, liver, lung, and stem cells (Chen et al ., 2009; Sandri et al ., 2013; Leontieva et al ., 2014; reviewed by Nacarelli et al ., 2015; Romero et al ., 2016; White et al ., 2016), other studies failed to confirm some of these findings (Baar et al ., 2016). It appears that phosphorylation of various Tor substrates is affected differentially during aging.…”

Section: Testing Predictions Of This Modelmentioning

confidence: 99%

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

Stern

2017

Aging Cell

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SummaryThe antagonistic pleiotropy (AP) theory posits that aging occurs because alleles that are detrimental in older organisms are beneficial to growth early in life and thus are maintained in populations. Although genes of the insulin signaling pathway likely participate in AP, the insulin‐regulated cellular correlates of AP have not been identified. The mitochondrial quality control process called mitochondrial autophagy (mitophagy), which is inhibited by insulin signaling, might represent a cellular correlate of AP. In this view, rapidly growing cells are limited by ATP production; these cells thus actively inhibit mitophagy to maximize mitochondrial ATP production and compete successfully for scarce nutrients. This process maximizes early growth and reproduction, but by permitting the persistence of damaged mitochondria with mitochondrial DNA mutations, becomes detrimental in the longer term. I suggest that as mitochondrial ATP output drops, cells respond by further inhibiting mitophagy, leading to a further decrease in ATP output in a classic death spiral. I suggest that this increasing ATP deficit is communicated by progressive increases in mitochondrial ROS generation, which signals inhibition of mitophagy via ROS‐dependent activation of insulin signaling. This hypothesis clarifies a role for ROS in aging, explains why insulin signaling inhibits autophagy, and why cells become progressively more oxidized during aging with increased levels of insulin signaling and decreased levels of autophagy. I suggest that the mitochondrial death spiral is not an error in cell physiology but rather a rational approach to the problem of enabling successful growth and reproduction in a competitive world of scarce nutrients.

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“…group. It was shown that obesity [56][57][58][59] and aging 60,61 can be associated with increased fasting p-S6 as a marker of increased mTOR activity. This suggests that prevention of obesity by rapamycin may decrease basal level of mTOR for a prolong time.…”

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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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Fasting levels of hepatic p-S6 are increased in old mice

Cited by 21 publications

References 58 publications

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

Comparison of rapamycin schedules in mice on high-fat diet

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