Indoles from commensal bacteria extend healthspan
- aDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
- bEmory Vaccine Center, Emory University, Atlanta, GA 30329;
- cDepartment of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322;
- dYerkes National Primate Research Center, Lawrenceville, GA 30043;
- eDepartment of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322;
- fDepartment of Biology, McMaster University, Hamilton, ON, Canada L8S 4K1;
- gImmunology and Molecular Pathogenesis Graduate Program, Emory University School of Medicine, Atlanta, GA 30322;
- hDepartment of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322;
- iDivision of Geriatric Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322
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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)

Significance
Increases in human life expectancy over the next century will be accompanied by increased frailty and massive and unsustainable health care costs. Developing means to extend the time that individuals remain healthy and free of age-related infirmities, called healthspan, has therefore become a critical goal of aging research. We show that small molecules produced by the microbiota and related to indole extend healthspan in geriatric worms, flies, and mice, without attendant effects on lifespan. Indoles act via the aryl hydrocarbon receptor and cause animals to retain a youthful gene expression profile. Indoles may represent a new class of therapeutics that improve the way we age as opposed to simply extending how long we live.
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.
Footnotes
- ↵1To whom correspondence should be addressed. Email: dkalman{at}emory.edu.
Author contributions: 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; and R.S. and D.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The raw RNA-Seq data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE101910).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1706464114/-/DCSupplemental.
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