Abstract

Senescent cells accumulate in fat with aging. We previously found genetic clearance of senescent cells from progeroid INK-ATTAC mice prevents lipodystrophy. Here we show that primary human senescent fat progenitors secrete activin A and directly inhibit adipogenesis in non-senescent progenitors. Blocking activin A partially restored lipid accumulation and expression of key adipogenic markers in differentiating progenitors exposed to senescent cells. Mouse fat tissue activin A increased with aging. Clearing senescent cells from 18-month-old naturally-aged INK-ATTAC mice reduced circulating activin A, blunted fat loss, and enhanced adipogenic transcription factor expression within 3 weeks. JAK inhibitor suppressed senescent cell activin A production and blunted senescent cell-mediated inhibition of adipogenesis. Eight weeks-treatment with ruxolitinib, an FDA-approved JAK1/2 inhibitor, reduced circulating activin A, preserved fat mass, reduced lipotoxicity, and increased insulin sensitivity in 22-month-old mice. Our study indicates targeting senescent cells or their products may alleviate age-related dysfunction of progenitors, adipose tissue, and metabolism.

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Author details

  1. Ming Xu

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
  2. Allyson K Palmer

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    Competing interests
    Allyson K Palmer, This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.
  3. Husheng Ding

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
  4. Megan M Weivoda

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
  5. Tamar Pirtskhalava

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    Competing interests
    Tamar Pirtskhalava, This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.
  6. Thomas A White

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
  7. Anna Sepe

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
  8. Kurt O Johnson

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
  9. Michael B Stout

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
  10. Nino Giorgadze

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    Competing interests
    Nino Giorgadze, This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.
  11. Michael D Jensen

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
  12. Nathan K LeBrasseur

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
  13. Tamar Tchkonia

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    Competing interests
    Tamar Tchkonia, This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.
  14. James L Kirkland

    Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States
    For correspondence
    Kirkland.James@mayo.edu
    Competing interests
    James L Kirkland, This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.

Ethics

Animal experimentation: Experimental procedures (A21013, A37715 and A16315) were approved by the IACUC at Mayo Clinic

Human subjects: The protocol (10-005236) was approved by the Mayo Clinic Foundation Institutional Review Board for Human Research. Informed consent and consent to publish was obtained from all human subjects.

Copyright

© 2015, Xu 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.

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