Match!

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

Published on Jun 1, 2016in Cell Metabolism22.415
· DOI :10.1016/j.cmet.2016.05.009
Brian K. Kennedy66
Estimated H-index: 66
(Buck Institute for Research on Aging),
Dudley W. Lamming34
Estimated H-index: 34
(UW: University of Wisconsin-Madison)
Sources
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 (177)
📖 Papers frequently viewed together
200943.07Nature
2,139 Citations
201336.22Cell
3,490 Citations
4,357 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References171
Newest
#1Sebastian I. Arriola Apelo (UW: University of Wisconsin-Madison)H-Index: 6
#2Dudley W. Lamming (UW: University of Wisconsin-Madison)H-Index: 34
45 CitationsSource
#1Sebastian I. Arriola Apelo (UW: University of Wisconsin-Madison)H-Index: 6
#2Cassidy P. Pumper (UW: University of Wisconsin-Madison)H-Index: 2
Last. Dudley W. Lamming (UW: University of Wisconsin-Madison)H-Index: 34
view all 5 authors...
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...
36 CitationsSource
#1Peter L. Lee (UMMS: University of Massachusetts Medical School)H-Index: 3
#2Yuefeng Tang (UMMS: University of Massachusetts Medical School)H-Index: 5
Last. David A. Guertin (UMMS: University of Massachusetts Medical School)H-Index: 30
view all 4 authors...
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...
30 CitationsSource
#1Matt Kaeberlein (UW: University of Washington)H-Index: 55
#2Kate E. Creevy (UGA: University of Georgia)H-Index: 8
Last. Daniel E. L. Promislow (UW: University of Washington)H-Index: 31
view all 3 authors...
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...
26 CitationsSource
#1Yuefeng TangH-Index: 5
#2Martina WallaceH-Index: 15
Last. David A. GuertinH-Index: 30
view all 9 authors...
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 ...
52 CitationsSource
#1Cassie M. Tran (UPenn: University of Pennsylvania)H-Index: 1
#2Sarmistha Mukherjee (UPenn: University of Pennsylvania)H-Index: 4
Last. Joseph A. Baur (UPenn: University of Pennsylvania)H-Index: 44
view all 9 authors...
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...
30 CitationsSource
#1Deborah C.I. Goberdhan (University of Oxford)H-Index: 20
#2Clive Wilson (University of Oxford)H-Index: 25
Last. Adrian L. Harris (University of Oxford)H-Index: 148
view all 3 authors...
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...
90 CitationsSource
#1Dianxin LiuH-Index: 11
#2Marica BordicchiaH-Index: 11
Last. Sheila CollinsH-Index: 58
view all 10 authors...
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...
63 CitationsSource
#1Maitea Guridi (University of Basel)H-Index: 4
#2Barbara Kupr (University of Basel)H-Index: 5
Last. Markus A. Rüegg (University of Basel)H-Index: 60
view all 7 authors...
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.
11 CitationsSource
#1M. Kaeberlein (UW: University of Washington)H-Index: 1
A fundamental goal of research into the basic mechanisms of aging is to develop translational strategies that improve human health by delaying the onset and progression of age-related pathology. Several interventions have been discovered that increase life span in invertebrate organisms, some of which have similar effects in mice. These include dietary restriction and inhibition of the mechanistic target of rapamycin by treatment with rapamycin. Key challenges moving forward will be to assess th...
24 CitationsSource
Cited By177
Newest
#1Pradeep Ramalingam (Cornell University)H-Index: 9
#2Michael G. Poulos (Hackensack University Medical Center)H-Index: 10
Last. Jason M. Butler (Georgetown University)H-Index: 1
view all 7 authors...
Aging leads to a decline in hematopoietic stem and progenitor cell (HSPC) function. We recently discovered that aging of bone marrow endothelial cells (BMECs) leads to an altered crosstalk between the BMEC niche and HSPCs, which instructs young HSPCs to behave as aged HSPCs. Here, we demonstrate aging leads to a decrease in mTOR signaling within BMECs that potentially underlies the age-related impairment of their niche activity. Our findings reveal that pharmacological inhibition of mTOR using R...
Source
#1Si-Lan Han (ECNU: East China Normal University)H-Index: 2
#2Jing Wang (ECNU: East China Normal University)H-Index: 2
Last. Zhen-Yu Du (ECNU: East China Normal University)H-Index: 25
view all 7 authors...
Abstract High energy diets (HED) have been widely used in farmed fish, but HED also caused some metabolic diseases. The rapamycin-induced inhibition of mechanistic target of rapamycin (mTOR) signalling has been verified to alleviate metabolic syndromes in mammals, however, the functions of rapamycin in regulating metabolism in the fish fed with HED has not been well investigated. In the present 8-week feeding trial, Nile tilapia were fed with a normal diet with medium fat and medium carbohydrate...
Source
#1Sandip MukherjeeH-Index: 1
#2Jake HaubnerH-Index: 1
view all 3 authors...
In mammals, a family of three inositol hexakisphosphate kinases (IP6Ks) synthesizes the inositol pyrophosphate 5-IP7 from IP6. Genetic deletion of Ip6k1 protects mice from high fat diet induced obesity, insulin resistance and fatty liver. IP6K1 generated 5-IP7 promotes insulin secretion from pancreatic β-cells, whereas it reduces insulin signaling in metabolic tissues by inhibiting the protein kinase Akt. Thus, IP6K1 promotes high fat diet induced hyperinsulinemia and insulin resistance in mice ...
1 CitationsSource
#1Liangliang Xiang (YZU: Yangzhou University)H-Index: 1
#2Weimin Wang (YZU: Yangzhou University)H-Index: 2
Last. Yan Zhou (YZU: Yangzhou University)H-Index: 2
view all 10 authors...
Aim: Gastric cancer (GC) is one of the most common malignant tumors in the world. It is important to find accurate and reliable biomarkers in order to decrease whole morbidity and mortality. Results: We examined the expression of COX-2 and mTOR on GC tissue microarrays by immunohistochemistry. Multivariate COX regression analysis showed that the expression of COX-2 or mTOR was an independent factor in the prognosis of GC patients. In addition, COX-2 and mTOR had the potentially synergistic effec...
Source
#1Pradeep Ramalingam (Cornell University)H-Index: 9
#2Michael G. PoulosH-Index: 6
Last. Jason M. Butler (Georgetown University)H-Index: 1
view all 7 authors...
Aging leads to a decline in hematopoietic stem and progenitor cell (HSPC) function. We recently discovered that aging of bone marrow endothelial cells (BMECs) leads to an altered crosstalk between the BMEC niche and HSPCs, that instructs young HSPCs to behave as aged HSPCs. Here, we demonstrate aging leads to a decrease in mTOR signaling within BMECs that potentially underlies the age-related impairment of their niche activity. Our findings reveal that pharmacological inhibition of mTOR using Ra...
Source
#1Hongxia Zhang (University of North Texas Health Science Center)
#2Kunlin Jin (University of North Texas Health Science Center)H-Index: 64
People are living longer than ever. Consequently, they have a greater chance for developing a functional impairment or aging-related disease, such as a neurodegenerative disease, later in life. Thus, it is important to identify and understand mechanisms underlying aging as well as the potential for rejuvenation. Therefore, we used next-generation sequencing to identify differentially expressed microRNAs (miRNAs) in serum exosomes isolated from young (three-month-old) and old (22-month-old) rats ...
Source
#1Stephanie Deborah Fritsch (Medical University of Vienna)H-Index: 2
#2Thomas Weichhart (Medical University of Vienna)H-Index: 27
The intestinal epithelium is one of the most quickly dividing tissues in our body, combining the absorptive advantages of a single layer with the protection of a constantly renewing barrier. It is continuously exposed to nutrients and commensal bacteria as well as microbial and host-derived metabolites, but also to hazards such as pathogenic bacteria and toxins. These environmental cues are sensed by the mucosa and a vast repertory of immune cells, especially macrophages. A disruption of intesti...
Source
#1Piotr Chmielewski (Wrocław Medical University)H-Index: 5
Source
#1Malini Bhadra (Harvard University)H-Index: 1
#2Porsha R. Howell (Harvard University)H-Index: 2
Last. William Mair (Harvard University)H-Index: 24
view all 5 authors...
Alternative pre-mRNA splicing increases the complexity of the proteome that can be generated from the available genomic coding sequences. Dysregulation of the splicing process has been implicated in a vast repertoire of diseases. However, splicing has recently been linked to both the aging process itself and pro-longevity interventions. This review focuses on recent research towards defining RNA splicing as a new hallmark of aging. We highlight dysfunctional alternative splicing events that cont...
1 CitationsSource
#2Alberto Diaz-RuizH-Index: 6
Last. Rafael de CaboH-Index: 74
view all 7 authors...
Abstract Aging is a modifiable risk factor for most chronic diseases and an inevitable process in humans. The development of pharmacological interventions aimed at delaying or preventing the onset of chronic conditions and other age-related diseases has been at the forefront of the aging field. Preclinical findings have demonstrated that species, sex and strain confer significant heterogeneity on reaching the desired health- and lifespan-promoting pharmacological responses in model organisms. Tr...
2 CitationsSource