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

Vincent Hurez, Vinh Dao, Aijie Liu, Srilakshmi Pandeswara, Jonathan Gelfond, Lishi Sun, Molly Bergman, Carlos J. Orihuela, Veronica Galvan, Álvaro Padrón, Justin Drerup, Yang Liu, Paul Hasty, Zelton Dave Sharp, Tyler J. Curiel

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)945-956
Number of pages12
JournalAging cell
Volume14
Issue number6
DOIs
StatePublished - Dec 1 2015

Keywords

  • Immune cell differentiation
  • Immunology
  • Longevity
  • Mammalian (mechanistic) target of rapamycin
  • Metagenomics
  • Microarray
  • Rapamycin
  • Transcriptomics

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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