Mammalian Target of Rapamycin: A Target for (Lung) Diseases and Aging

Overview

Journal Ann Am Thorac Soc

Specialty Pulmonary Medicine

Date 2016 Dec 23

PMID 28005429

Citations 8

Authors

Brian K Kennedy

Juniper K Pennypacker

Affiliations

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Abstract

The mammalian target of rapamycin (mTOR) signaling pathway has been studied in the context of an impressive number of biological processes and disease states, including major diseases of the lung such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, as well as the rare condition lymphangioleiomyomatosis. The involvement of mTOR in so many disease states (in and out of the lung) raises the question how one signaling pathway can have overlapping but diverse roles seemingly everywhere. Findings in the last decade have placed the mTOR pathway in a new context as an important, conserved mediator of the aging process. This offers one explanation for the pleiotropic effects of mTOR: -that many chronic diseases are also diseases of aging and that pathways modulating aging will have widespread effects on associated disease. However, this may not be the entire story, because mTOR is also implicated in a large number of diseases not linked to aging. In this article, we discuss the current state of knowledge regarding mTOR, especially in the context of lung pathologies, and offer a potential explanation for its widespread involvement in human disease.

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References

Yates D . mTOR treatment in lymphangioleiomyomatosis: the role of everolimus. Expert Rev Respir Med. 2016; 10(3):249-60. DOI: 10.1586/17476348.2016.1148603. View

Tremblay F, Marette A . Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem. 2001; 276(41):38052-60. DOI: 10.1074/jbc.M106703200. View

Choi J, Muchir A, Wu W, Iwata S, Homma S, Morrow J . Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation. Sci Transl Med. 2012; 4(144):144ra102. PMC: 3700376. DOI: 10.1126/scitranslmed.3003875. View

Ramos F, Chen S, Garelick M, Dai D, Liao C, Schreiber K . Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci Transl Med. 2012; 4(144):144ra103. PMC: 3613228. DOI: 10.1126/scitranslmed.3003802. View

Kramer E, Hardie W, Mushaben E, Acciani T, Pastura P, Korfhagen T . Rapamycin decreases airway remodeling and hyperreactivity in a transgenic model of noninflammatory lung disease. J Appl Physiol (1985). 2011; 111(6):1760-7. PMC: 3290353. DOI: 10.1152/japplphysiol.00737.2011. View

Kennedy B, Lamming D . The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging. Cell Metab. 2016; 23(6):990-1003. PMC: 4910876. DOI: 10.1016/j.cmet.2016.05.009. View

Romero Y, Bueno M, Ramirez R, Alvarez D, Sembrat J, Goncharova E . mTORC1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts. Aging Cell. 2016; 15(6):1103-1112. PMC: 6398527. DOI: 10.1111/acel.12514. View

Orlova K, Crino P . The tuberous sclerosis complex. Ann N Y Acad Sci. 2010; 1184:87-105. PMC: 2892799. DOI: 10.1111/j.1749-6632.2009.05117.x. View

Miller R, Harrison D, Astle C, Fernandez E, Flurkey K, Han M . Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2013; 13(3):468-77. PMC: 4032600. DOI: 10.1111/acel.12194. View

10.

Mitani A, Ito K, Vuppusetty C, Barnes P, Mercado N . Restoration of Corticosteroid Sensitivity in Chronic Obstructive Pulmonary Disease by Inhibition of Mammalian Target of Rapamycin. Am J Respir Crit Care Med. 2015; 193(2):143-53. PMC: 4731710. DOI: 10.1164/rccm.201503-0593OC. View

11.

Bitto A, Ito T, Pineda V, LeTexier N, Huang H, Sutlief E . Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife. 2016; 5. PMC: 4996648. DOI: 10.7554/eLife.16351. View

12.

Jin X, Dai H, Ding K, Xu X, Pang B, Wang C . Rapamycin attenuates bleomycin-induced pulmonary fibrosis in rats and the expression of metalloproteinase-9 and tissue inhibitors of metalloproteinase-1 in lung tissue. Chin Med J (Engl). 2014; 127(7):1304-9. View

13.

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . The hallmarks of aging. Cell. 2013; 153(6):1194-217. PMC: 3836174. DOI: 10.1016/j.cell.2013.05.039. View

14.

Nho R, Hergert P . IPF fibroblasts are desensitized to type I collagen matrix-induced cell death by suppressing low autophagy via aberrant Akt/mTOR kinases. PLoS One. 2014; 9(4):e94616. PMC: 3984186. DOI: 10.1371/journal.pone.0094616. View

15.

Bartlett K, Kim K . Insight into Tor2, a budding yeast microdomain protein. Eur J Cell Biol. 2014; 93(3):87-97. DOI: 10.1016/j.ejcb.2014.01.004. View

16.

Buron F, Malvezzi P, Villar E, Chauvet C, Janbon B, Denis L . Profiling sirolimus-induced inflammatory syndrome: a prospective tricentric observational study. PLoS One. 2013; 8(1):e53078. PMC: 3538748. DOI: 10.1371/journal.pone.0053078. View

17.

Soefje S, Karnad A, Brenner A . Common toxicities of mammalian target of rapamycin inhibitors. Target Oncol. 2011; 6(2):125-9. DOI: 10.1007/s11523-011-0174-9. View

18.

Harrison D, Strong R, Sharp Z, Nelson J, Astle C, Flurkey K . Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009; 460(7253):392-5. PMC: 2786175. DOI: 10.1038/nature08221. View

19.

Chang W, Wei K, Ho L, Berry G, Jacobs S, Chang C . A critical role for the mTORC2 pathway in lung fibrosis. PLoS One. 2014; 9(8):e106155. PMC: 4146613. DOI: 10.1371/journal.pone.0106155. View

20.

Mannick J, Del Giudice G, Lattanzi M, Valiante N, Praestgaard J, Huang B . mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014; 6(268):268ra179. DOI: 10.1126/scitranslmed.3009892. View