1. Cancer Biology
Download icon

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

Research Article
  • Cited 149
  • Views 10,959
  • Annotations
Cite this article as: eLife 2016;5:e16351 doi: 10.7554/eLife.16351

Abstract

The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. We also define a dose in female mice that does not extend lifespan, but is associated with a striking shift in cancer prevalence toward aggressive hematopoietic cancers and away from non-hematopoietic malignancies. These data suggest that a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome.

Data availability

The following data sets were generated

Article and author information

Author details

  1. Alessandro Bitto

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Takashi K Ito

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Victor V Pineda

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Nicolas J Letexier

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Heather Z Huang

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Elissa Sutlief

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Herman Tung

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Nicholas Vizzini

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Belle Chen

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Kaleb Smith

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Daniel Meza

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Masanao Yajima

    Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Richard P Beyer

    Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Kathleen F Kerr

    Department of Biostatistics, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Daniel J Davis

    Department of Veterinary Pathobiology, University of Missouri, Columbia, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Catherine H Gillespie

    Department of Veterinary Pathobiology, University of Missouri, Columbia, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Jessica M Snyder

    Department of Comparative Medicine, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Piper M Treuting

    Department of Comparative Medicine, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Matt Kaeberlein

    Department of Pathology, University of Washington, Seattle, United States
    For correspondence
    kaeber@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1311-3421

Funding

Samsung

  • Matt Kaeberlein

National Institute on Aging (P30AG013280)

  • Matt Kaeberlein

University of Washington

  • Daniel J Davis

National Institute on Aging (T32AG000057)

  • Alessandro Bitto

Japan Society for the Promotion of Science

  • Takashi K Ito

Uehara Memorial Foundation

  • Takashi K Ito

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#4359-01) of the University of Washington.

Reviewing Editor

  1. Amy J Wagers, Harvard University, United States

Publication history

  1. Received: March 24, 2016
  2. Accepted: August 3, 2016
  3. Accepted Manuscript published: August 23, 2016 (version 1)
  4. Version of Record published: August 24, 2016 (version 2)

Copyright

© 2016, Bitto et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 10,959
    Page views
  • 1,699
    Downloads
  • 149
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    2. Neuroscience
    Susu Pan et al.
    Research Article

    Emerging evidence suggests that the nervous system is involved in tumor development in the periphery, however, the role of central nervous system remains largely unknown. Here, by combining genetic, chemogenetic, pharmacological and electrophysiological approaches, we show that hypothalamic oxytocin (Oxt)-producing neurons modulate colitis-associated cancer (CAC) progression in mice. Depletion or activation of Oxt neurons could augment or suppress CAC progression. Importantly, brain treatment with celastrol, a pentacyclic triterpenoid, excites Oxt neurons and inhibits CAC progression, and this anti-tumor effect was significantly attenuated in Oxt neuron-lesioned mice. Furthermore, brain treatment with celastrol suppresses sympathetic neuronal activity in the celiac-superior mesenteric ganglion (CG-SMG), and activation of β2 adrenergic receptor abolishes the anti-tumor effect of Oxt neuron activation or centrally administered celastrol. Taken together, these findings demonstrate that hypothalamic Oxt neurons regulate CAC progression by modulating the neuronal activity in the CG-SMG. Stimulation of Oxt neurons using chemicals, eg. celastrol, might be a novel strategy for colorectal cancer treatment.

    1. Cancer Biology
    2. Cell Biology
    Lauren K Williams et al.
    Research Article Updated

    The abscission checkpoint regulates the ESCRT membrane fission machinery and thereby delays cytokinetic abscission to protect genomic integrity in response to residual mitotic errors. The checkpoint is maintained by Aurora B kinase, which phosphorylates multiple targets, including CHMP4C, a regulatory ESCRT-III subunit necessary for this checkpoint. We now report the discovery that cytoplasmic abscission checkpoint bodies (ACBs) containing phospho-Aurora B and tri-phospho-CHMP4C develop during an active checkpoint. ACBs are derived from mitotic interchromatin granules, transient mitotic structures whose components are housed in splicing-related nuclear speckles during interphase. ACB formation requires CHMP4C, and the ESCRT factor ALIX also contributes. ACB formation is conserved across cell types and under multiple circumstances that activate the checkpoint. Finally, ACBs retain a population of ALIX, and their presence correlates with delayed abscission and delayed recruitment of ALIX to the midbody where it would normally promote abscission. Thus, a cytoplasmic mechanism helps regulate midbody machinery to delay abscission.