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Research Article

Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution

Yun-Hee Youm, Tamas L. Horvath, David J. Mangelsdorf, Steven A. Kliewer, and Vishwa Deep Dixit
PNAS first published January 11, 2016; https://doi.org/10.1073/pnas.1514511113
Yun-Hee Youm
aSection of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06520;
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Tamas L. Horvath
aSection of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06520;
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David J. Mangelsdorf
bDepartment of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
cHoward Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390;
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Steven A. Kliewer
bDepartment of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
dDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
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Vishwa Deep Dixit
aSection of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06520;
eDepartment of Immunobiology, Yale School of Medicine, New Haven, CT 06520
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  • For correspondence: vishwa.dixit@yale.edu
  1. Edited by Ruslan Medzhitov, Yale School of Medicine, New Haven, CT, and approved December 16, 2015 (received for review July 22, 2015)

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Significance

Liver-derived metabolic hormone fibroblast growth factor 21 (FGF21) improves insulin sensitivity and extends lifespan in mice. Aging also compromises the adaptive immune system by reducing T-cell production from the thymus. In this paper, we describe a new immunological function of FGF21 as a regulator of T-cell production from thymus in aging. The overexpression of FGF21 prevents thymic lipoatrophy, which protects the mice from age-induced loss of naïve T cells. FGF21 expression in thymic epithelial cells and signaling in thymic stromal cells support thymic function in aging. Loss of FGF21 in mice increases lethality postirradiation and delays the reconstitution of thymus. Hence, we highlight FGF21 as an immunometabolic regulator that can be harnessed to delay immune senescence.

Abstract

Age-related thymic degeneration is associated with loss of naïve T cells, restriction of peripheral T-cell diversity, and reduced healthspan due to lower immune competence. The mechanistic basis of age-related thymic demise is unclear, but prior evidence suggests that caloric restriction (CR) can slow thymic aging by maintaining thymic epithelial cell integrity and reducing the generation of intrathymic lipid. Here we show that the prolongevity ketogenic hormone fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily, is expressed in thymic stromal cells along with FGF receptors and its obligate coreceptor, βKlotho. We found that FGF21 expression in thymus declines with age and is induced by CR. Genetic gain of FGF21 function in mice protects against age-related thymic involution with an increase in earliest thymocyte progenitors and cortical thymic epithelial cells. Importantly, FGF21 overexpression reduced intrathymic lipid, increased perithymic brown adipose tissue, and elevated thymic T-cell export and naïve T-cell frequencies in old mice. Conversely, loss of FGF21 function in middle-aged mice accelerated thymic aging, increased lethality, and delayed T-cell reconstitution postirradiation and hematopoietic stem cell transplantation (HSCT). Collectively, FGF21 integrates metabolic and immune systems to prevent thymic injury and may aid in the reestablishment of a diverse T-cell repertoire in cancer patients following HSCT.

  • aging
  • thymus
  • metabolism
  • inflammation
  • FGF21

Footnotes

  • ↵1To whom correspondence should be addressed. Email: vishwa.dixit{at}yale.edu.
  • Author contributions: Y.-H.Y. and V.D.D. designed research; Y.-H.Y. and V.D.D. performed research; D.J.M. and S.A.K. contributed new reagents/analytic tools; Y.-H.Y., T.L.H., D.J.M., S.A.K., and V.D.D. analyzed data; and Y.-H.Y., S.A.K., and V.D.D. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1514511113/-/DCSupplemental.

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FGF21 protects against thymic aging
Yun-Hee Youm, Tamas L. Horvath, David J. Mangelsdorf, Steven A. Kliewer, Vishwa Deep Dixit
Proceedings of the National Academy of Sciences Jan 2016, 201514511; DOI: 10.1073/pnas.1514511113

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FGF21 protects against thymic aging
Yun-Hee Youm, Tamas L. Horvath, David J. Mangelsdorf, Steven A. Kliewer, Vishwa Deep Dixit
Proceedings of the National Academy of Sciences Jan 2016, 201514511; DOI: 10.1073/pnas.1514511113
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