1. Developmental Biology
  2. Immunology and Inflammation

Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction

  1. Jennifer C Regan  Is a corresponding author
  2. Mobina Khericha
  3. Adam J Dobson
  4. Ekin Bolukbasi
  5. Nattaphong Rattanavirotkul
  6. Linda Partridge
  1. University College London, United Kingdom
https://doi.org/10.7554/eLife.10956
Share this article
Cite this article
  1. Jennifer C Regan
  2. Mobina Khericha
  3. Adam J Dobson
  4. Ekin Bolukbasi
  5. Nattaphong Rattanavirotkul
  6. Linda Partridge
(2016)
Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction
eLife 5:e10956.
https://doi.org/10.7554/eLife.10956
  2. Download BibTeX
  3. Download .RIS

Abstract

Women live on average longer than men, but have greater levels of late-life morbidity. We have uncovered a substantial sex difference in the pathology of the ageing gut in Drosophila. The intestinal epithelium of the ageing female undergoes major deterioration, driven by intestinal stem cell (ISC) division, while lower ISC activity in males associates with delay or absence of pathology, and better barrier function, even at old ages. Males succumb to intestinal challenges to which females are resistant, associated with fewer proliferating ISCs, suggesting a trade-off between highly active repair mechanisms and late-life pathology in females. Dietary restriction reduces gut pathology in ageing females, and extends female lifespan more than male. By genetic sex reversal of a specific gut region, we induced female-like ageing pathologies in males, associated with decreased lifespan, but also with a greater increase in longevity in response to dietary restriction.

Article and author information

Author details

  1. Jennifer C Regan

    Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, London, United Kingdom
    For correspondence
    j.regan@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

  2. Mobina Khericha

    Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. Adam J Dobson

    Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Ekin Bolukbasi

    Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Nattaphong Rattanavirotkul

    Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Linda Partridge

    Institute of Healthy Ageing, Department of Genetics, Evolution, and Environment, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

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

Version history

  1. Received: August 18, 2015
  2. Accepted: February 2, 2016
  3. Accepted Manuscript published: February 16, 2016 (version 1)
  4. Version of Record published: March 14, 2016 (version 2)

Copyright

© 2016, Regan 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

  • 8,431
    views
  • 1,676
    downloads
  • 186
    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. Jennifer C Regan
  2. Mobina Khericha
  3. Adam J Dobson
  4. Ekin Bolukbasi
  5. Nattaphong Rattanavirotkul
  6. Linda Partridge
(2016)
Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction
eLife 5:e10956.
https://doi.org/10.7554/eLife.10956

Share this article

https://doi.org/10.7554/eLife.10956

Categories and tags

Research organism

Further reading

  1. Gender divide: Listen to Jenny Regan talk about sex differences in aging

    Podcast

    The guts of male and female fruit flies age differently.

    1. Developmental Biology
    2. Physics of Living Systems

    Morphogenesis: The enigma of cell intercalation

    Raphaël Clément
    Insight

    Geometric criteria can be used to assess whether cell intercalation is active or passive during the convergent extension of tissue.

    1. Computational and Systems Biology
    2. Developmental Biology

    The MODY-associated KCNK16 L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

    Arya Y Nakhe, Prasanna K Dadi ... David A Jacobson
    Research Article

    The gain-of-function mutation in the TALK-1 K+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.