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

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 aging gut in Drosophila. The intestinal epithelium of the aging 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 aging females, and extends female lifespan more than male. By genetic sex reversal of a specific gut region, we induced female-like aging pathologies in males, associated with decreased lifespan, but also with a greater increase in longevity in response to dietary restriction. DOI: http://dx.doi.org/10.7554/eLife.10956.001

• Publication year

  2016

• Venue

  eLife

• Publication date

  2016-02-16

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.7554/eLife.10956PMID 26878754PMCID 4805549
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2015cited by this paper
• Macronutrient balance, reproductive function, and lifespan in aging mice

  2015cited by this paper
• Sex- and gender-specific disparities in colorectal cancer risk.

  2015cited by this paper
• Regional Cell Specific RNA Expression Profiling of FACS Isolated Drosophila Intestinal Cell Populations.

  2015cited by this paper
• Distinct Shifts in Microbiota Composition during Drosophila Aging Impair Intestinal Function and Drive Mortality.

  2015cited by this paper
• Niche Appropriation by Drosophila Intestinal Stem Cell Tumors

  2015influential reference
• Promoting health and longevity through diet: from model organisms to humans.

  2015cited by this paper
• Hemocytes control stem cell activity in the Drosophila intestine

  2015cited by this paper
• A Deregulated Intestinal Cell Cycle Program Disrupts Tissue Homeostasis without Affecting Longevity in Drosophila*

  2014cited by this paper
• Age and gender differences in the prevalence and patterns of multimorbidity in the older population

  2014cited by this paper
• PGRP-SC2 promotes gut immune homeostasis to limit commensal dysbiosis and extend lifespan.

  2014cited by this paper
• Microbiota-Induced Changes in Drosophila melanogaster Host Gene Expression and Gut Morphology

  2014influential reference
• Sexual antagonism for resistance and tolerance to infection in Drosophila melanogaster

  2014cited by this paper
• AMPK modulates tissue and organismal aging in a non-cell-autonomous manner.

  2014cited by this paper
• Promoting longevity by maintaining metabolic and proliferative homeostasis

  2014cited by this paper
• Gender and longevity: why do men die earlier than women? Comparative and experimental evidence.

  2013cited by this paper
• Morphological and molecular characterization of adult midgut compartmentalization in Drosophila.

  2013cited by this paper
• Organ-specific mediation of lifespan extension: more than a gut feeling?

  2013cited by this paper
• Increased longevity mediated by yeast NDI1 expression in Drosophila intestinal stem and progenitor cells

  2013influential reference
• Epidemiology of multimorbidity.

  2012cited by this paper
• Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study.

  2012cited by this paper
• Epidemiology of multimorbidity.

  2012cited by this paper
• Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila

  2012cited by this paper
• Senescence of the cellular immune response in Drosophila melanogaster.

  2011cited by this paper
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  2011cited by this paper
• Altered modes of stem cell division drive adaptive intestinal growth.

  2011influential reference
• dFOXO-independent effects of reduced insulin-like signaling in Drosophila

  2011cited by this paper
• Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog.

  2011cited by this paper
• Nonautonomous regulation of Drosophila midgut stem cell proliferation by the insulin-signaling pathway

  2011influential reference
• Sex determination in insects: a binary decision based on alternative splicing.

  2011cited by this paper
• Males use multiple, redundant cues to detect mating rivals.

  2011cited by this paper
• Lifespan Extension by Preserving Proliferative Homeostasis in Drosophila

  2010influential reference
• Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogaster

  2010cited by this paper
• Long-Range Activation of Systemic Immunity through Peptidoglycan Diffusion in Drosophila

  2009cited by this paper
• Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut.

  2009cited by this paper
• Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation.

  2009cited by this paper
• Pathogenic stimulation of intestinal stem cell response in drosophila

  2009cited by this paper
• The Relationship between Gravidity and Parity and Colorectal Cancer Risk

  2009cited by this paper
• JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut.

  2008cited by this paper
• Lifespan and reproduction in Drosophila: New insights from nutritional geometry

  2008cited by this paper
• Dietary composition specifies consumption, obesity, and lifespan in Drosophila melanogaster

  2008cited by this paper
• Age-related changes in Drosophila midgut are associated with PVF2, a PDGF/VEGF-like growth factor

  2008cited by this paper
• The physiological costs of reproduction in small mammals

  2008cited by this paper
• Regulatory peptides in fruit fly midgut

  2008cited by this paper
• Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis.

  2007cited by this paper
• The Drosophila amidase PGRP-LB modulates the immune response to bacterial infection.

  2006cited by this paper
• Evidence that stem cells reside in the adult Drosophila midgut epithelium

  2006cited by this paper
• The adult Drosophila posterior midgut is maintained by pluripotent stem cells

  2006cited by this paper
• A Direct Role for Dual Oxidase in Drosophila Gut Immunity

  2005cited by this paper
• Sex differences in the effect of dietary restriction on life span and mortality rates in female and male Drosophila melanogaster.

  2004influential reference
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  2002cited by this paper
• DOUBLESEX GENE EXPRESSION IN THE CENTRAL NERVOUS SYSTEM OF DROSOPHILA MELANOGASTER

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• A Mutant Drosophila Insulin Receptor Homolog That Extends Life-Span and Impairs Neuroendocrine Function

  2001influential reference
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  2000cited by this paper
• Body size and cell size in Drosophila: the developmental response to temperature.

  1998cited by this paper
• Adaptation of the Maternal Intestine During Lactation

  1997cited by this paper
• The effect of reproductive activity on the longevity of male Drosophila melanogaster is not caused by an acceleration of ageing

  1985cited by this paper
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  1930cited by this paper

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  2026cites this paper
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  2026cites this paper
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  2022influential citation
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