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Author Notes:

To whom correspondence should be addressed. Email: dkalman@emory.edu

Edited by Frederick M. Ausubel, Harvard Medical School and Massachusetts General Hospital, Boston, MA, and approved July 21, 2017 (received for review April 19, 2017)

R.S., A. Swimm, Y.M., H.Q., J.M.F., R.M.J., G.M.B., and D.K. designed research

R.S., A. Swimm, L.L., Y.M., Z.W., J.A.B., E.A.E., H.Q., D.N.P., and C.T.C. performed research

R.S. contributed new reagents/analytic tools

R.S., A. Swimm, A. Sahoo, L.L., A.R., H.Q., D.N.P., C.T.C., and D.K. analyzed data;

R.S. and D.K. wrote the paper.

We thank T. Cleverley and W. Kelly for helpful discussions, and C. Moreno, P. O’Lague, B. Shur, and B. Weiss for helpful discussions and for reviewing the manuscript.

The authors wish to acknowledge the memory of Vladimir Brezina (1958–2016), an old and dear friend.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

Subjects:

Research Funding:

This work was supported by grants from Bio-Merieux Foundation and NIH (2R01DK074731-04A1) (to D.K.). The Bloomington Drosophila Stock Centre, which provided Drosophila lines, is supported by NIH Grant P40OD018537.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • C. elegans
  • aging
  • frailty
  • aryl hydrocarbon receptor
  • microbiota
  • ARYL-HYDROCARBON RECEPTOR
  • CAENORHABDITIS-ELEGANS
  • LIFE-SPAN
  • ESCHERICHIA-COLI
  • GUT MICROBIOTA
  • C. ELEGANS
  • INTESTINE
  • DISEASE
  • CELL
  • TRANSPLANTATION

Indoles from commensal bacteria extend healthspan

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Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 114, Number 36

Publisher:

, Pages E7506-E7515

Type of Work:

Article | Final Publisher PDF

Abstract:

Multiple studies have identified conserved genetic pathways and small molecules associated with extension of lifespan in diverse organisms. However, extending lifespan does not result in concomitant extension in healthspan, defined as the proportion of time that an animal remains healthy and free of age-related infirmities. Rather, mutations that extend lifespan often reduce healthspan and increase frailty. The question arises as to whether factors or mechanisms exist that uncouple these processes and extend healthspan and reduce frailty independent of lifespan. We show that indoles from commensal microbiota extend healthspan of diverse organisms, including Caenorhabditis elegans, Drosophila melanogaster, and mice, but have a negligible effect on maximal lifespan. Effects of indoles on healthspan in worms and flies depend upon the aryl hydrocarbon receptor (AHR), a conserved detector of xenobiotic small molecules. In C. elegans, indole induces a gene expression profile in aged animals reminiscent of that seen in the young, but which is distinct from that associated with normal aging. Moreover, in older animals, indole induces genes associated with oogenesis and, accordingly, extends fecundity and reproductive span. Together, these data suggest that small molecules related to indole and derived from commensal microbiota act in diverse phyla via conserved molecular pathways to promote healthy aging. These data raise the possibility of developing therapeutics based on microbiota-derived indole or its derivatives to extend healthspan and reduce frailty in humans.

Copyright information:

© 2017, National Academy of Sciences. All rights reserved.

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