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.

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

  • 20,098
    views
  • 2,277
    downloads
  • 318
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Alessandro Bitto
  2. Takashi K Ito
  3. Victor V Pineda
  4. Nicolas J Letexier
  5. Heather Z Huang
  6. Elissa Sutlief
  7. Herman Tung
  8. Nicholas Vizzini
  9. Belle Chen
  10. Kaleb Smith
  11. Daniel Meza
  12. Masanao Yajima
  13. Richard P Beyer
  14. Kathleen F Kerr
  15. Daniel J Davis
  16. Catherine H Gillespie
  17. Jessica M Snyder
  18. Piper M Treuting
  19. Matt Kaeberlein
(2016)
Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice
eLife 5:e16351.
https://doi.org/10.7554/eLife.16351

Share this article

https://doi.org/10.7554/eLife.16351

Further reading

    1. Cancer Biology
    Fan Sun, Pengrong Yan ... Zhaoxia Qu
    Research Article

    Immune checkpoint inhibitors (ICIs) and their combination with other therapies such as chemotherapy, fail in most cancer patients. We previously identified the PDZ-LIM domain-containing protein 2 (PDLIM2) as a bona fide tumor suppressor that is repressed in lung cancer to drive cancer and its chemo and immunotherapy resistance, suggesting a new target for lung cancer therapy improvement. In this study, human clinical samples and data were used to investigate PDLIM2 genetic and epigenetic changes in lung cancer. Using an endogenous mouse lung cancer model faithfully recapitulating refractory human lung cancer and a clinically feasible nano-delivery system, we investigated the therapeutic efficacy, action mechanism, and safety of systemically administrated PDLIM2 expression plasmids encapsulated in nanoparticles (nanoPDLIM2) and its combination with PD-1 antibody and chemotherapeutic drugs. Our analysis indicate that PDLIM2 repression in human lung cancer involves both genetic deletion and epigenetic alteration. NanoPDLIM2 showed low toxicity, high tumor specificity, antitumor activity, and greatly improved the efficacy of anti-PD-1 and chemotherapeutic drugs, with complete tumor remission in most mice and substantial tumor reduction in the remaining mice by their triple combination. Mechanistically, nanoPDLIM2 increased major histocompatibility complex class I (MHC-I) expression, suppressed multi-drug resistance 1 (MDR1) induction and survival genes and other tumor-related genes expression in tumor cells, and enhanced lymphocyte tumor infiltration, turning the cold tumors hot and sensitive to ICIs and rendering them vulnerable to chemotherapeutic drugs and activated tumor-infiltrating lymphocytes (TILs) including those unleashed by ICIs. These studies established a clinically applicable PDLIM2-based combination therapy with great efficacy for lung cancer and possibly other cold cancers.

    1. Cancer Biology
    2. Cell Biology
    Zijing Wang, Bihan Xia ... Jilin Yang
    Research Article

    Bestrophin isoform 4 (BEST4) is a newly identified subtype of the calcium-activated chloride channel family. Analysis of colonic epithelial cell diversity by single-cell RNA-sequencing has revealed the existence of a cluster of BEST4+ mature colonocytes in humans. However, if the role of BEST4 is involved in regulating tumour progression remains largely unknown. In this study, we demonstrate that BEST4 overexpression attenuates cell proliferation, colony formation, and mobility in colorectal cancer (CRC) in vitro, and impedes the tumour growth and the liver metastasis in vivo. BEST4 is co-expressed with hairy/enhancer of split 4 (HES4) in the nucleus of cells, and HES4 signals BEST4 by interacting with the upstream region of the BEST4 promoter. BEST4 is epistatic to HES4 and downregulates TWIST1, thereby inhibiting epithelial-to-mesenchymal transition (EMT) in CRC. Conversely, knockout of BEST4 using CRISPR/Cas9 in CRC cells revitalises tumour growth and induces EMT. Furthermore, the low level of the BEST4 mRNA is correlated with advanced and the worse prognosis, suggesting its potential role involving CRC progression.