Effects of rapamycin on growth hormone receptor knockout mice.
Yimin Fang,Cristal M. Hill,Justin Darcy,Adriana Reyes-Ordoñez,Edwin Arauz,Samuel McFadden,Chi Zhang,Jared M. Osland,John Gao,Tian Zhang,Stuart J. Frank,Martin A. Javors,Rong Yuan,John J. Kopchick,Liou Y. Sun,Jie Chen,Andrzej Bartke +16 more
TLDR
It is reported that mTORC2 plays a positive role in regulating longevity via maintenance, or enhancement, of whole-body homeostasis in GHR-KO mice, and drastic reduction of mTORc2 plays important roles in impaired longevity in G HR- KO mice via disruption of entire-bodyHomeostasis.Abstract:
It is well documented that inhibition of mTORC1 (defined by Raptor), a complex of mechanistic target of rapamycin (mTOR), extends life span, but less is known about the mechanisms by which mTORC2 (defined by Rictor) impacts longevity. Here, rapamycin (an inhibitor of mTOR) was used in GHR-KO (growth hormone receptor knockout) mice, which have suppressed mTORC1 and up-regulated mTORC2 signaling, to determine the effect of concurrently decreased mTORC1 and mTORC2 signaling on life span. We found that rapamycin extended life span in control normal (N) mice, whereas it had the opposite effect in GHR-KO mice. In the rapamycin-treated GHR-KO mice, mTORC2 signaling was reduced without further inhibition of mTORC1 in the liver, muscle, and s.c. fat. Glucose and lipid homeostasis were impaired, and old GHR-KO mice treated with rapamycin lost functional immune cells and had increased inflammation. In GHR-KO MEF cells, knockdown of Rictor, but not Raptor, decreased mTORC2 signaling. We conclude that drastic reduction of mTORC2 plays important roles in impaired longevity in GHR-KO mice via disruption of whole-body homeostasis.read more
Citations
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Journal ArticleDOI
The Genetics of Aging: A Vertebrate Perspective.
TL;DR: Advances in the genetic regulation of aging in vertebrates from work in mice, humans, and organisms with exceptional lifespans are discussed and challenges for the future are highlighted, including sex-dependent differences in lifespan and the interplay between genes and environment.
Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity
Dudley W. Lamming,Lan Ye,Pekka Katajisto,Marcus D. Goncalves,Maki Saitoh,Deanna Stevens,James G. Davis,Adam B. Salmon,Arlan Richardson,Rexford S. Ahima,David A. Guertin,David M. Sabatini,Joseph A. Baur +12 more
TL;DR: It is demonstrated that rapamycin disrupted a second mTOR complex, m TORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis and was sufficient to extend life span independently from changes in glucose homeostasis.
Journal ArticleDOI
Regulation and metabolic functions of mTORC1 and mTORC2
TL;DR: In this article, the authors discuss the key discoveries and recent findings on the regulation and metabolic functions of the mTOR complexes, highlighting findings from cancer models but also discuss other examples of mTOR-mediated metabolic reprogramming occurring in stem and immune cells, type 2 diabetes/obesity, neurodegenerative disorders and aging.
Journal ArticleDOI
Growth Hormone Deficiency: Health and Longevity
TL;DR: It is thought that low, but detectable, residual GH secretion combined with life-long reduction of circulating IGF-1 and with some tissue levels of IGF- 1 and/or IGF-2 preserved may account for the normal longevity and apparent extension of healthspan in these individuals.
Journal ArticleDOI
Effect of rapamycin on aging and age-related diseases—past and future
TL;DR: It is concluded that it is time that pre-clinical studies be focused on taking rapamycin to the clinic, e.g., as a potential treatment for Alzheimer’s disease.
References
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mTOR Signaling in Growth Control and Disease
TL;DR: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis as mentioned in this paper, and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration.
Journal ArticleDOI
mTOR signaling in growth control and disease.
TL;DR: Recent advances in understanding of the mTOR pathway are reviewed and pharmacological approaches to treat human pathologies linked to mTOR deregulation are discussed.
Journal ArticleDOI
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
David E. Harrison,Randy Strong,Zelton D Sharp,James F. Nelson,Clinton M. Astle,Kevin Flurkey,Nancy L. Nadon,J. Erby Wilkinson,Krystyna Frenkel,Christy S. Carter,Christy S. Carter,Marco Pahor,Marco Pahor,Martin A. Javors,Elizabeth Fernandez,Richard A. Miller +15 more
TL;DR: It is reported that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age.
Journal ArticleDOI
mTOR is a key modulator of ageing and age-related disease
TL;DR: Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies in humans.
Journal ArticleDOI
Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span
Colin Selman,Jennifer M. A. Tullet,Daniela Wieser,Elaine E. Irvine,Steven J. Lingard,Agharul I. Choudhury,Marc Claret,Hind Al-Qassab,Danielle Carmignac,Faruk Ramadani,Angela Woods,Iain C. A. F. Robinson,Eugene Schuster,Rachel L. Batterham,Sara C. Kozma,George Thomas,David Carling,Klaus Okkenhaug,Janet M. Thornton,Linda Partridge,David Gems,Dominic J. Withers,Dominic J. Withers +22 more
TL;DR: It is shown in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity.
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Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span
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Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice
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