1. Developmental Biology
Download icon

Targeting senescent cells enhances adipogenesis and metabolic function in old age

Research Article
  • Cited 244
  • Views 8,291
  • Annotations
Cite this article as: eLife 2015;4:e12997 doi: 10.7554/eLife.12997

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.

Article and author information

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.

Reviewing Editor

  1. Andrew Dillin, Howard Hughes Medical Institute, University of California, Berkeley, United States

Publication history

  1. Received: November 13, 2015
  2. Accepted: December 18, 2015
  3. Accepted Manuscript published: December 19, 2015 (version 1)
  4. Version of Record published: February 4, 2016 (version 2)
  5. Version of Record updated: September 22, 2016 (version 3)

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.

Metrics

  • 8,291
    Page views
  • 2,108
    Downloads
  • 244
    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. Developmental Biology
    Soyeon Lim et al.
    Research Article

    Retinal progenitor cells (RPCs) divide in limited numbers to generate the cells comprising vertebrate retina. The molecular mechanism that leads RPC to the division limit, however, remains elusive. Here, we find that the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) in an RPC subset by deletion of tuberous sclerosis complex 1 (Tsc1) makes the RPCs arrive at the division limit precociously and produce Müller glia (MG) that degenerate from senescence-associated cell death. We further show the hyperproliferation of Tsc1-deficient RPCs and the degeneration of MG in the mouse retina disappear by concomitant deletion of hypoxia-induced factor 1-a (Hif1a), which induces glycolytic gene expression to support mTORC1-induced RPC proliferation. Collectively, our results suggest that, by having mTORC1 constitutively active, an RPC divides and exhausts mitotic capacity faster than neighboring RPCs, and thus produces retinal cells that degenerate with aging-related changes.

    1. Developmental Biology
    2. Neuroscience
    Tania Moreno-Mármol et al.
    Research Article Updated

    The vertebrate eye primordium consists of a pseudostratified neuroepithelium, the optic vesicle (OV), in which cells acquire neural retina or retinal pigment epithelium (RPE) fates. As these fates arise, the OV assumes a cup shape, influenced by mechanical forces generated within the neural retina. Whether the RPE passively adapts to retinal changes or actively contributes to OV morphogenesis remains unexplored. We generated a zebrafish Tg(E1-bhlhe40:GFP) line to track RPE morphogenesis and interrogate its participation in OV folding. We show that, in virtual absence of proliferation, RPE cells stretch and flatten, thereby matching the retinal curvature and promoting OV folding. Localized interference with the RPE cytoskeleton disrupts tissue stretching and OV folding. Thus, extreme RPE flattening and accelerated differentiation are efficient solutions adopted by fast-developing species to enable timely optic cup formation. This mechanism differs in amniotes, in which proliferation drives RPE expansion with a much-reduced need of cell flattening.