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, Vishwa Deep Dixit

Research output: Contribution to journalArticle

39 Citations (Scopus)

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 agerelated 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.

Original languageEnglish (US)
Pages (from-to)1026-1031
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number4
DOIs
StatePublished - Jan 26 2016

Fingerprint

Hormones
T-Lymphocytes
Caloric Restriction
Hematopoietic Stem Cell Transplantation
Epithelial Cells
Lipids
Fibroblast Growth Factor Receptors
Brown Adipose Tissue
Thymocytes
Stromal Cells
Mental Competency
Thymus Gland
fibroblast growth factor 21
Immune System
Wounds and Injuries
Neoplasms

Keywords

  • Aging
  • FGF21
  • Inflammation
  • Metabolism
  • Thymus

ASJC Scopus subject areas

  • General

Cite this

Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. / Youm, Yun Hee; Horvath, Tamas L.; Mangelsdorf, David J.; Kliewer, Steven A.; Dixit, Vishwa Deep.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 4, 26.01.2016, p. 1026-1031.

Research output: Contribution to journalArticle

@article{87c28008d2e14e8da22d3976c8735a14,
title = "Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution",
abstract = "Age-related thymic degeneration is associated with loss of na{\"i}ve 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 agerelated 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 na{\"i}ve 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.",
keywords = "Aging, FGF21, Inflammation, Metabolism, Thymus",
author = "Youm, {Yun Hee} and Horvath, {Tamas L.} and Mangelsdorf, {David J.} and Kliewer, {Steven A.} and Dixit, {Vishwa Deep}",
year = "2016",
month = "1",
day = "26",
doi = "10.1073/pnas.1514511113",
language = "English (US)",
volume = "113",
pages = "1026--1031",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "4",

}

TY - JOUR

T1 - Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution

AU - Youm, Yun Hee

AU - Horvath, Tamas L.

AU - Mangelsdorf, David J.

AU - Kliewer, Steven A.

AU - Dixit, Vishwa Deep

PY - 2016/1/26

Y1 - 2016/1/26

N2 - 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 agerelated 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.

AB - 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 agerelated 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.

KW - Aging

KW - FGF21

KW - Inflammation

KW - Metabolism

KW - Thymus

UR - http://www.scopus.com/inward/record.url?scp=84955481171&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955481171&partnerID=8YFLogxK

U2 - 10.1073/pnas.1514511113

DO - 10.1073/pnas.1514511113

M3 - Article

C2 - 26755598

AN - SCOPUS:84955481171

VL - 113

SP - 1026

EP - 1031

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 4

ER -