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The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging

Published on Jun 1, 2016in Cell Metabolism22.41
· DOI :10.1016/j.cmet.2016.05.009
Brian K. Kennedy64
Estimated H-index: 64
(Buck Institute for Research on Aging),
Dudley W. Lamming32
Estimated H-index: 32
(UW: University of Wisconsin-Madison)
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Abstract
Since the discovery that rapamycin, a small molecule inhibitor of the protein kinase mTOR (mechanistic target of rapamycin), can extend the lifespan of model organisms including mice, interest in understanding the physiological role and molecular targets of this pathway has surged. While mTOR was already well known as a regulator of growth and protein translation, it is now clear that mTOR functions as a central coordinator of organismal metabolism in response to both environmental and hormonal signals. This review discusses recent developments in our understanding of how mTOR signaling is regulated by nutrients and the role of the mTOR signaling pathway in key metabolic tissues. Finally, we discuss the molecular basis for the negative metabolic side effects associated with rapamycin treatment, which may serve as barriers to the adoption of rapamycin or similar compounds for the treatment of diseases of aging and metabolism.
  • References (171)
  • Citations (141)
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References171
Newest
Published on Dec 1, 2016in Skeletal Muscle4.00
Maitea Guridi4
Estimated H-index: 4
(University of Basel),
Barbara Kupr5
Estimated H-index: 5
(University of Basel)
+ 4 AuthorsMarkus A. Rüegg58
Estimated H-index: 58
(University of Basel)
Background The mammalian target of rapamycin complex 1 (mTORC1) is a central node in a network of signaling pathways controlling cell growth and survival. This multiprotein complex integrates external signals and affects different nutrient pathways in various organs. However, it is not clear how alterations of mTORC1 signaling in skeletal muscle affect whole-body metabolism.
Published on Sep 1, 2016in Nature Communications11.88
Yuefeng Tang5
Estimated H-index: 5
,
Martina Wallace15
Estimated H-index: 15
+ 6 AuthorsDavid A. Guertin29
Estimated H-index: 29
Adipose tissue de novo lipogenesis (DNL) positively influences insulin sensitivity, is reduced in obesity, and predicts insulin resistance. Therefore, elucidating mechanisms controlling adipose tissue DNL could lead to therapies for type 2 diabetes. Here, we report that mechanistic target of rapamycin complex 2 (mTORC2) functions in white adipose tissue (WAT) to control expression of the lipogenic transcription factor ChREBPβ. Conditionally deleting the essential mTORC2 subunit Rictor in mature ...
Published on Aug 1, 2016in Mammalian Genome2.34
Matt Kaeberlein53
Estimated H-index: 53
(UW: University of Washington),
Kate E. Creevy7
Estimated H-index: 7
(UGA: University of Georgia),
Daniel E. L. Promislow30
Estimated H-index: 30
(UW: University of Washington)
Studies of the basic biology of aging have identified several genetic and pharmacological interventions that appear to modulate the rate of aging in laboratory model organisms, but a barrier to further progress has been the challenge of moving beyond these laboratory discoveries to impact health and quality of life for people. The domestic dog, Canis familiaris, offers a unique opportunity for surmounting this barrier in the near future. In particular, companion dogs share our environment and pl...
Sebastian I. Arriola Apelo5
Estimated H-index: 5
(UW: University of Wisconsin-Madison),
Dudley W. Lamming32
Estimated H-index: 32
(UW: University of Wisconsin-Madison)
Sebastian I. Arriola Apelo5
Estimated H-index: 5
(UW: University of Wisconsin-Madison),
Cassidy P. Pumper2
Estimated H-index: 2
(UW: University of Wisconsin-Madison)
+ 2 AuthorsDudley W. Lamming32
Estimated H-index: 32
(UW: University of Wisconsin-Madison)
Inhibition of the mTOR (mechanistic target of rapamycin) signaling pathway by the FDA-approved drug rapamycin promotes life span in numerous model organisms and delays age-related disease in mice. However, the utilization of rapamycin as a therapy for age-related diseases will likely prove challenging due to the serious metabolic and immunological side effects of rapamycin in humans. We recently identified an intermittent rapamycin treatment regimen-2mg/kg administered every 5 days-with a reduce...
Published on Jun 1, 2016in Molecular metabolism6.18
Peter L. Lee3
Estimated H-index: 3
(UMMS: University of Massachusetts Medical School),
Yuefeng Tang5
Estimated H-index: 5
(UMMS: University of Massachusetts Medical School)
+ 1 AuthorsDavid A. Guertin29
Estimated H-index: 29
(UMMS: University of Massachusetts Medical School)
Abstract Objective Normal adipose tissue growth and function is critical to maintaining metabolic homeostasis and its excess (e.g. obesity) or absence (e.g. lipodystrophy) is associated with severe metabolic disease. The goal of this study was to understand the mechanisms maintaining healthy adipose tissue growth and function. Methods Adipose tissue senses and responds to systemic changes in growth factor and nutrient availability; in cells mTORC1 regulates metabolism in response to growth facto...
Published on Apr 1, 2016in Diabetes7.20
Cassie M. Tran1
Estimated H-index: 1
(UPenn: University of Pennsylvania),
Sarmistha Mukherjee4
Estimated H-index: 4
(UPenn: University of Pennsylvania)
+ 6 AuthorsJoseph A. Baur41
Estimated H-index: 41
(UPenn: University of Pennsylvania)
Rapamycin extends life span in mice, yet paradoxically causes lipid dysregulation and glucose intolerance through mechanisms that remain incompletely understood. Whole-body energy balance can be influenced by beige/brite adipocytes, which are inducible by cold and other stimuli via β-adrenergic signaling in white adipose depots. Induction of beige adipocytes is considered a promising strategy to combat obesity because of their ability to metabolize glucose and lipids, dissipating the resulting e...
Published on Apr 1, 2016in Cell Metabolism22.41
Deborah C.I. Goberdhan20
Estimated H-index: 20
(University of Oxford),
Clive Wilson25
Estimated H-index: 25
(University of Oxford),
Adrian L. Harris143
Estimated H-index: 143
(University of Oxford)
Cell metabolism and growth are matched to nutrient availability via the amino-acid-regulated mechanistic target of rapamycin complex 1 (mTORC1). Transporters have emerged as important amino acid sensors controlling mTOR recruitment and activation at the surface of multiple intracellular compartments. Classically, this has involved late endosomes and lysosomes, but now, in a recent twist, also the Golgi apparatus. Here we propose a model in which specific amino acids in assorted compartments acti...
Published on Apr 1, 2016in Nature Communications11.88
Constantinos Demetriades5
Estimated H-index: 5
(DKFZ: German Cancer Research Center),
Monika Plescher2
Estimated H-index: 2
(DKFZ: German Cancer Research Center),
Aurelio A. Teleman27
Estimated H-index: 27
mTORC1 promotes cell growth and is therefore inactivated upon unfavourable growth conditions. Signalling pathways downstream of most cellular stresses converge on TSC1/2, which serves as an integration point that inhibits mTORC1. The TSC1/2 complex was shown to translocate to lysosomes to inactivate mTORC1 in response to two stresses: amino-acid starvation and growth factor removal. Whether other stresses also regulate TSC2 localization is not known. How TSC2 localization responds to combination...
Published on May 2, 2016in Journal of Clinical Investigation12.28
Dianxin Liu11
Estimated H-index: 11
,
Marica Bordicchia10
Estimated H-index: 10
+ 7 AuthorsSheila Collins55
Estimated H-index: 55
A classic metabolic concept posits that insulin promotes energy storage and adipose expansion, while catecholamines stimulate release of adipose energy stores by hydrolysis of triglycerides through β-adrenergic receptor (βARs) and protein kinase A (PKA) signaling. Here, we have shown that a key hub in the insulin signaling pathway, activation of p70 ribosomal S6 kinase (S6K1) through mTORC1, is also triggered by PKA activation in both mouse and human adipocytes. Mice with mTORC1 impairment, eith...
Cited By141
Newest
Published on Dec 1, 2019in Nature Communications11.88
Katherine H. Schreiber6
Estimated H-index: 6
(Buck Institute for Research on Aging),
Sebastian I. Arriola Apelo5
Estimated H-index: 5
(UW: University of Wisconsin-Madison)
+ 13 AuthorsDawn S. Sherman3
Estimated H-index: 3
(UW: University of Wisconsin-Madison)
Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vi...
Published on 2019in Nature Communications11.88
Thomas Venables2
Estimated H-index: 2
(Scripps Research Institute),
Ann V. Griffith5
Estimated H-index: 5
(Scripps Research Institute)
+ 1 AuthorsHoward T. Petrie38
Estimated H-index: 38
(Scripps Research Institute)
T lymphocytes must be produced throughout life, yet the thymus, where T lymphocytes are made, exhibits accelerated atrophy with age. Even in advanced atrophy, however, the thymus remains plastic, and can be regenerated by appropriate stimuli. Logically, thymic atrophy is thought to reflect senescent cell death, while regeneration requires proliferation of stem or progenitor cells, although evidence is scarce. Here we use conditional reporters to show that accelerated thymic atrophy reflects cont...
Published on Feb 12, 2019in Nature Communications11.88
T.M. Zaved Waise3
Estimated H-index: 3
(TGH: Toronto General Hospital),
Mozhgan Rasti2
Estimated H-index: 2
(TGH: Toronto General Hospital)
+ 4 AuthorsTony K.T. Lam37
Estimated H-index: 37
Glucose homeostasis is partly controlled by the energy sensor mechanistic target of rapamycin (mTOR) in the muscle and liver. However, whether mTOR in the small intestine affects glucose homeostasis in vivo remains unknown. Here, we first report that delivery of rapamycin or an adenovirus encoding the dominant negative acting mTOR-mutated protein into the upper small intestine is sufficient to inhibit small intestinal mTOR signaling and lower glucose production in rodents with high fat diet-indu...
Published on May 24, 2019in Scientific Reports4.01
Joseph M. Schinaman1
Estimated H-index: 1
(UCLA: University of California, Los Angeles),
Anil Rana10
Estimated H-index: 10
(UCLA: University of California, Los Angeles)
+ 2 AuthorsDavid W. Walker9
Estimated H-index: 9
(UCLA: University of California, Los Angeles)
The FDA approved drug rapamycin can prolong lifespan in diverse species and delay the onset of age-related disease in mammals. However, a number of fundamental questions remain unanswered regarding the mechanisms by which rapamycin modulates age-related pathophysiology and lifespan. Alterations in the gut microbiota can impact host physiology, metabolism and lifespan. While recent studies have shown that rapamycin treatment alters the gut microbiota in aged animals, the causal relationships betw...
Published on Dec 1, 2019in Scientific Reports4.01
Matthew Tillman (Emory University), Manoj Khadka1
Estimated H-index: 1
(Emory University)
+ 2 AuthorsEric A. Ortlund25
Estimated H-index: 25
(Emory University)
The lysosome plays a crucial role in the regulation of longevity. Lysosomal degradation is tightly coupled with autophagy that is induced by many longevity paradigms and required for lifespan extension. The lysosome also serves as a hub for signal transduction and regulates longevity via affecting nuclear transcription. One lysosome-to-nucleus retrograde signaling pathway is mediated by a lysosome-associated fatty acid binding protein LBP-8 in Caenorhabditis elegans. LBP-8 shuttles lysosomal lip...
Published on Dec 1, 2019in Neurochemistry International3.99
Shuang Lu (CSU: Central South University), Lvshuang Liao4
Estimated H-index: 4
(CSU: Central South University)
+ 7 AuthorsJie Yan5
Estimated H-index: 5
(CSU: Central South University)
Published on 2019in Nature Communications11.88
Zhi-Xiang Xu1
Estimated H-index: 1
(Scripps Research Institute),
Jiwei Tan1
Estimated H-index: 1
(Scripps Research Institute)
+ 4 AuthorsBaoji Xu35
Estimated H-index: 35
(Scripps Research Institute)
Caspase-2 is the most evolutionarily conserved member in the caspase family of proteases and is constitutively expressed in most cell types including neurons; however, its physiological function remains largely unknown. Here we report that caspase-2 plays a critical role in synaptic plasticity and cognitive flexibility. We found that caspase-2 deficiency led to deficits in dendritic spine pruning, internalization of AMPA receptors and long-term depression. Our results indicate that caspase-2 deg...
Published on Jan 1, 2019in BMC Veterinary Research1.79
Lynne Cassimeris32
Estimated H-index: 32
(Lehigh University),
Julie B. Engiles14
Estimated H-index: 14
(UPenn: University of Pennsylvania),
Hannah Galantino-Homer12
Estimated H-index: 12
(UPenn: University of Pennsylvania)
Background Laminitis is often associated with endocrinopathies that cause hyperinsulinemia and is also induced experimentally by hyperinsulinemia, suggesting that insulin initiates laminitis pathogenesis. Hyperinsulinemia is expected to activate pro-growth and anabolic signaling pathways. We hypothesize that chronic over-stimulation of these pathways in lamellar tissue results in endoplasmic reticulum stress, contributing to tissue pathology, as it does in human metabolic diseases. We tested thi...
Published on May 23, 2019in Scientific Reports4.01
Kun Wang2
Estimated H-index: 2
(Guangzhou University of Chinese Medicine),
Jianyong Xiao3
Estimated H-index: 3
(Guangzhou University of Chinese Medicine)
+ 12 AuthorsBonan Chen (Guangzhou University of Chinese Medicine)
Systemic or local inflammation drives the pathogenesis of various human diseases. Small compounds with anti-inflammatory properties hold great potential for clinical translation. Over recent decades, many compounds have been screened for their action against inflammation-related targets. Databases that integrate the physicochemical properties and bioassay results of these compounds are lacking. We created an “Anti-Inflammatory Compounds Database” (AICD) to deposit compounds with potential anti-i...
Published on 2019in Aging Cell7.35
Karthikeyani Chellappa4
Estimated H-index: 4
(UPenn: University of Pennsylvania),
Jacqueline A. Brinkman2
Estimated H-index: 2
(UW: University of Wisconsin-Madison)
+ 7 AuthorsCole S. Purdy (UPenn: University of Pennsylvania)
View next paperRapamycin fed late in life extends lifespan in genetically heterogeneous mice