1. Cell Biology
  2. Stem Cells and Regenerative Medicine
Download icon

Recurrent turnover of senescent cells during regeneration of acomplex structure

  1. Maximina H Yun  Is a corresponding author
  2. Hongorzul Davaapil
  3. Jeremy P Brockes
  1. University College London, United Kingdom
Research Article
  • Cited 187
  • Views 5,910
  • Annotations
Cite this article as: eLife 2015;4:e05505 doi: 10.7554/eLife.05505

Abstract

Cellular senescence has been recently linked to the promotion of age-related pathologies, including a decline in regenerative capacity. While such capacity deteriorates with age in mammals, it remains intact in species such as salamanders, which have an extensive repertoire of regeneration and can undergo multiple episodes through their lifespan. Here we show that, surprisingly, there is a significant induction of cellular senescence during salamander limb regeneration, but that rapid and effective mechanisms of senescent cell clearance operate in normal and regenerating tissues. Furthermore, the number of senescent cells does not increase upon repetitive amputation or ageing, in contrast to mammals. Finally, we identify the macrophage as a critical player in this efficient senescent cell clearance mechanism. We propose that effective immunosurveillance of senescent cells in salamanders supports their ability to undergo regeneration throughout their lifespan.

Article and author information

Author details

  1. Maximina H Yun

    Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom
    For correspondence
    maximina.yun@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  2. Hongorzul Davaapil

    Institute of Ophthalmology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Jeremy P Brockes

    Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All procedures for care and manipulation of adult newts (Notophthalmus viridescens) and axolotls (Ambystoma mexicanum) were performed in compliance with the Animals (Scientific Procedures) Act 1986, approved by the United Kingdom Home Office and University College London (Institutional License: 70-2716). All surgical procedures were carried out under anesthesia (0.1% Tricaine) followed by treatment with analgesics (Butorphanol tartrate). Every effort was made to minimise suffering.

Reviewing Editor

  1. Margaret Buckingham, Institut Pasteur, France

Publication history

  1. Received: November 6, 2014
  2. Accepted: May 3, 2015
  3. Accepted Manuscript published: May 5, 2015 (version 1)
  4. Version of Record published: May 18, 2015 (version 2)

Copyright

© 2015, Yun 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

  • 5,910
    Page views
  • 1,364
    Downloads
  • 187
    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. Cell Biology
    Laura Le Pelletier et al.
    Research Article Updated

    Aging is associated with central fat redistribution and insulin resistance. To identify age-related adipose features, we evaluated the senescence and adipogenic potential of adipose-derived stromal cells (ASCs) from abdominal subcutaneous fat obtained from healthy normal-weight young (<25 years) or older women (>60 years). Increased cell passages of young-donor ASCs (in vitro aging) resulted in senescence but not oxidative stress. ASC-derived adipocytes presented impaired adipogenesis but no early mitochondrial dysfunction. Conversely, aged-donor ASCs at early passages displayed oxidative stress and mild senescence. ASC-derived adipocytes exhibited oxidative stress, and early mitochondrial dysfunction but adipogenesis was preserved. In vitro aging of aged-donor ASCs resulted in further increased senescence, mitochondrial dysfunction, oxidative stress, and severe adipocyte dysfunction. When in vitro aged young-donor ASCs were treated with metformin, no alteration was alleviated. Conversely, metformin treatment of aged-donor ASCs decreased oxidative stress and mitochondrial dysfunction resulting in decreased senescence. Metformin’s prevention of oxidative stress and of the resulting senescence improved the cells’ adipogenic capacity and insulin sensitivity. This effect was mediated by the activation of AMP-activated protein kinase as revealed by its specific inhibition and activation. Overall, aging ASC-derived adipocytes presented impaired adipogenesis and insulin sensitivity. Targeting stress-induced senescence of ASCs with metformin may improve age-related adipose tissue dysfunction.

    1. Cell Biology
    2. Medicine
    Richard Nakamura et al.
    Research Article

    Background: Blinding reviewers to applicant identity has been proposed to reduce bias in peer review.

    Methods: This experimental test used 1200 NIH grant applications, 400 from Black investigators, 400 matched applications from White investigators, and 400 randomly selected applications from White investigators. Applications were reviewed by mail in standard and redacted formats.

    Results: Redaction reduced, but did not eliminate, reviewers' ability to correctly guess features of identity. The primary, pre-registered analysis hypothesized a differential effect of redaction according to investigator race in the matched applications. A set of secondary analyses (not pre-registered) used the randomly selected applications from White scientists and tested the same interaction. Both analyses revealed similar effects: Standard format applications from White investigators scored better than those from Black investigators. Redaction cut the size of the difference by about half (e.g. from a Cohen's d of 0.20 to 0.10 in matched applications); redaction caused applications from White scientists to score worse but had no effect on scores for Black applications.

    Conclusions: Grant-writing considerations and halo effects are discussed as competing explanations for this pattern. The findings support further evaluation of peer review models that diminish the influence of applicant identity.

    Funding: Funding was provided by the NIH.