title: Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune-deficient mice.
abstract: The mammalian (mechanistic) target of rapamycin (mTOR) regulates critical immune processes that remain incompletely defined. Interest in mTOR inhibitor drugs is heightened by recent demonstrations that the mTOR inhibitor rapamycin extends lifespan and healthspan in mice. Rapamycin or related analogues (rapalogues) also mitigate age-related debilities including increasing antigen-specific immunity, improving vaccine responses in elderly humans, and treating cancers and autoimmunity, suggesting important new clinical applications. Nonetheless, immune toxicity concerns for long-term mTOR inhibition, particularly immunosuppression, persist. Although mTOR is pivotal to fundamental, important immune pathways, little is reported on immune effects of mTOR inhibition in lifespan or healthspan extension, or with chronic mTOR inhibitor use. We comprehensively analyzed immune effects of rapamycin as used in lifespan extension studies. Gene expression profiling found many and novel changes in genes affecting differentiation, function, homeostasis, exhaustion, cell death, and inflammation in distinct T- and B-lymphocyte and myeloid cell subpopulations. Immune functions relevant to aging and inflammation, and to cancer and infections, and innate lymphoid cell effects were validated in vitro and in vivo. Rapamycin markedly prolonged lifespan and healthspan in cancer- and infection-prone mice supporting disease mitigation as a mechanism for mTOR suppression-mediated longevity extension. It modestly altered gut metagenomes, and some metagenomic effects were linked to immune outcomes. Our data show novel mTOR inhibitor immune effects meriting further studies in relation to longevity and healthspan extension.
authors: Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Vincent
authors: http://orcid.org/0000-0003-0271-4157
authors: V
authors: Hurez
authors: Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Vinh
authors: V
authors: Dao
authors: Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Aijie
authors: A
authors: Liu
authors: Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Srilakshmi
authors: S
authors: Pandeswara
authors: Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Jonathan
authors: J
authors: Gelfond
authors: Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Lishi
authors: L
authors: Sun
authors: Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Molly
authors: M
authors: Bergman
authors: Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Carlos J
authors: CJ
authors: Orihuela
authors: Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, TX, USA.|Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX, USA.|Department of Physiology, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Veronica
authors: V
authors: Galvan
authors: Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Álvaro
authors: Á
authors: Padrón
authors: Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Justin
authors: J
authors: Drerup
authors: Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Yang
authors: Y
authors: Liu
authors: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX, USA.|Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Paul
authors: P
authors: Hasty
authors: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Zelton Dave
authors: ZD
authors: Sharp
authors: Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.|Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, TX, USA.|Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX, USA.|Cancer Therapy & Research Center, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Tyler J
authors: TJ
authors: Curiel
mesh_terms: D000375:Aging / Q000187:drug effects; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005408:Flagellin / Q000276:immunology; D000069196:Gastrointestinal Microbiome; D020869:Gene Expression Profiling; D007156:Immunologic Memory / Q000276:immunology; D007378:Interleukins / Q000378:metabolism; D008136:Longevity / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D020123:Sirolimus / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D000903:Antibiotics, Antineoplastic; D005408:Flagellin; D007378:Interleukins; D061026:Programmed Cell Death 1 Receptor; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000097043:Interleukin-22; C491383:Pdcd1 protein, mouse; C546843:mTOR protein, mouse
keywords: immune cell differentiation; immunology; longevity; mammalian (mechanistic) target of rapamycin; metagenomics; microarray; rapamycin; transcriptomics