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

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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.

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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.
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.
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.
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.
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.
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.

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