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

Aging Cell. 2015 Dec;14(6):945-56. doi: 10.1111/acel.12380. Epub 2015 Aug 28.

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.

Keywords: immune cell differentiation; immunology; longevity; mammalian (mechanistic) target of rapamycin; metagenomics; microarray; rapamycin; transcriptomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects
  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • B-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / drug effects
  • Dendritic Cells / immunology*
  • Female
  • Flagellin / immunology
  • Gastrointestinal Microbiome
  • Gene Expression Profiling
  • Immunologic Memory / immunology
  • Interleukins / metabolism
  • Longevity / drug effects*
  • Longevity / immunology
  • Male
  • Melanoma, Experimental
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / immunology*
  • Programmed Cell Death 1 Receptor / biosynthesis
  • Sirolimus / pharmacology*
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / immunology

Substances

  • Antibiotics, Antineoplastic
  • Interleukins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Flagellin
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Sirolimus
  • interleukin-22