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Prolongevity Hormone FGF21 Protects Against Immune Senescence by Delaying Age-Related Thymic Involution

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Prolongevity Hormone FGF21 Protects Against Immune Senescence by Delaying Age-Related Thymic Involution Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution Yun-Hee Youma, Tamas L. Horvatha, David J. Mangelsdorfb,c, Steven A. Kliewerb,d, and Vishwa Deep Dixita,e,1 aSection of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06520; 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; dDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and eDepartment of Immunobiology, Yale School of Medicine, New Haven, CT 06520 Edited by Ruslan Medzhitov, Yale School of Medicine, New Haven, CT, and approved December 16, 2015 (received for review July 22, 2015) Age-related thymic degeneration is associated with loss of naïve T showed that FGF7/keratinocyte growth factor (KGF) adminis- cells, restriction of peripheral T-cell diversity, and reduced health- tration in aged mice partially reversed thymic involution (17–19). span due to lower immune competence. The mechanistic basis of Notably, unlike most FGFs, FGF21 lacks affinity for heparan age-related thymic demise is unclear, but prior evidence suggests sulfate in the extracellular matrix and thus can be secreted to act that caloric restriction (CR) can slow thymic aging by maintaining in an endocrine fashion (20). FGF21 is predominantly secreted thymic epithelial cell integrity and reducing the generation of from liver but is also expressed in thymus (21). FGF21 is a pro- intrathymic lipid. Here we show that the prolongevity ketogenic longevity hormone that elicits it biological effects by binding to β hormone fibroblast growth factor 21 (FGF21), a member of the Klotho in complex with FGF receptor (FGFR) 1c, 2c, or 3c, but endocrine FGF subfamily, is expressed in thymic stromal cells along not FGFR4 (16, 22, 23). FGF21 supports host survival during with FGF receptors and its obligate coreceptor, βKlotho. We found states of energy deficit by increasing ketogenesis and fuel utiliza- that FGF21 expression in thymus declines with age and is induced tion through mitochondrial fatty acid oxidation (16, 23, 24). In- by CR. Genetic gain of FGF21 function in mice protects against age- terestingly, energy deficit induced by the prolongevity intervention related thymic involution with an increase in earliest thymocyte of caloric restriction (CR) reduces ectopic thymic lipid and progenitors and cortical thymic epithelial cells. Importantly, FGF21 maintains thymopoiesis in aged mice (13). This raises the ques- tion of whether signals that stimulate mobilization of ectopic overexpression reduced intrathymic lipid, increased perithymic brown lipid mediate the salutary effects of CR on immune function. INFLAMMATION adipose tissue, and elevated thymic T-cell export and naïve T-cell fre- IMMUNOLOGY AND Here we present evidence that FGF21 and βKlotho are coex- quencies in old mice. Conversely, loss of FGF21 function in middle-aged pressed in TECs and maintain T-cell diversity in models of aging mice accelerated thymic aging, increased lethality, and delayed T-cell and hematopoietic stem cell transplantation (HSCT) by enhancing reconstitution postirradiation and hematopoietic stem cell transplan- thymic function. tation (HSCT). Collectively, FGF21 integrates metabolic and immune systems to prevent thymic injury and may aid in the reestablishment Results of a diverse T-cell repertoire in cancer patients following HSCT. FGF21 and βKlotho Are Expressed in Thymic Stromal Cells. Our initial microarray profiling studies revealed that thymic Fgf21 expres- aging | thymus | metabolism | inflammation | FGF21 sion declines with age. To confirm these findings, real-time PCR analysis showed that aging is associated with a reduction in thymic he degenerative changes in thymus precede age-related loss FGF21 mRNA expression, whereas CR significantly protected Tof function in other organs (1–4). As human lifespan con- against loss of Fgf21 expression in thymus (Fig. 1A). Consistent tinues to increase, it has been hypothesized that the ability to with prior studies (17, 21), Fgf21 and FGF receptors are expressed retain a functional level of thymic lymphopoiesis beyond the time in thymus along with βKlotho (Klb) (Fig. 1B). Interestingly, al- limit set by evolutionary pressures may be an important strategy though thymic FGF21 is reduced with age (Fig. 1C), Klb and Fgfr1 to extend healthspan (3, 4). Therefore, the ability to enhance thymic lymphopoiesis is thought to be central to the rejuvenation Significance of T-cell–mediated immune surveillance in the elderly (1–7). Aging is associated with marked perturbations in the stromal cell Liver-derived metabolic hormone fibroblast growth factor 21 microenvironment of the thymus (8, 9). This includes a reduction (FGF21) improves insulin sensitivity and extends lifespan in in thymopoiesis-supporting thymic epithelial cells (TECs) (10), mice. Aging also compromises the adaptive immune system by an increase in fibroblasts (11, 12), and emergence of adipocytes reducing T-cell production from the thymus. In this paper, we (4, 13) of unknown origin and function. Accordingly, recent ef- describe a new immunological function of FGF21 as a regulator forts have focused on targeting TECs for the rejuvenation of the of T-cell production from thymus in aging. The overexpression aging thymus (12, 14). Emerging evidence indicates that immune– of FGF21 prevents thymic lipoatrophy, which protects the mice metabolic interactions control several aspects of the thymic in- from age-induced loss of naïve T cells. FGF21 expression in volution process and age-related inflammation (13). We have thymic epithelial cells and signaling in thymic stromal cells shown that byproducts of thymic fatty acids and lipids result in support thymic function in aging. Loss of FGF21 in mice in- accumulation of “lipotoxic DAMPs” (damage-associated mo- creases lethality postirradiation and delays the reconstitution lecular patterns), which triggers innate immune-sensing mecha- of thymus. Hence, we highlight FGF21 as an immunometabolic nisms such as inflammasome activation that link aging to thymic regulator that can be harnessed to delay immune senescence. demise (15). Immune–metabolic interactions within the aging thymus produce a local proinflammatory state that directly com- Author contributions: Y.-H.Y. and V.D.D. designed research; Y.-H.Y. and V.D.D. performed promises the thymic stromal microenvironment, thymic lympho- research; D.J.M. and S.A.K. contributed new reagents/analytic tools; Y.-H.Y., T.L.H., D.J.M., poiesis, and serves as a precursor of systemic immune dysregulation S.A.K., and V.D.D. analyzed data; and Y.-H.Y., S.A.K., and V.D.D. wrote the paper. in the elderly (5, 8). Despite progress in the field, the thymic growth The authors declare no conflict of interest. factors that regulate thymic involution are incompletely understood. This article is a PNAS Direct Submission. The fibroblast growth factors (FGFs) constitute a family of 22 1To whom correspondence should be addressed. Email: [email protected]. proteins that regulate diverse biological processes such as growth, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. development, differentiation, and wound repair (16). Prior studies 1073/pnas.1514511113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1514511113 PNAS Early Edition | 1of6 Downloaded by guest on September 26, 2021 Thymus Immunostaining of thymic cryosections revealed that βKlotho is )egnahC dloF( A dloF( AB)egnahC + 3.5 * oht expressed in a subpopulation of Keratin8 cortical TECs (Fig. 2R 3R 4 1R 12FG R 3.0 olK FG FGF F FGF 1M), some of which seem to be thymic nurse cells (25). In GF 2.5 -b F F β 2.0 complementary studies, we also examined whether Klotho is * su 1.5 NRm 12FG NRm myhT expressed in TECs expressing FoxN1, a transcription factor that 1.0 Actin is critical for thymopoiesis (26). To do this, we used transgenic 0.5 mice harboring a fluorescent membrane dTomato/membrane F 0.0 Young Aging-AL Aging-CR EGFP (mT/mG) Cre reporter construct (27) that marks FoxN1 FGFR1 Cre excision by a heritable switch from membrane-targeted C FGF21 D Klotho E 6 1.4 12 * egna * e 5 egnahc tdTomato expression to membrane-targeted EGFP expression. g 1.2 10 nahc nahc 1.0 4 8 h 0.8 c 3 Examination of Foxn1-Cre:mT/mG mice thymi revealed that 6 d + loF dl 0.6 * dloF 2 β oF 4 Klotho is colocalized with Foxn1 TECs (Fig. 1N). In addition, 0.4 * 1 0.2 2 0 βKlotho was expressed in endothelial cells of double-walled 0 0 1m 7m 12m 26m 1m 7m 12m26m 1m 7m 12m 26m postcapillary venules (PCVs) in the corticomedullary junction of F G FGFR3 H FGFR4 FGFR2 4 3.5 egn 5 the thymus (Fig. 1O). PCVs are critical for import of hemato- e eg g 3.0 n 4 nahc a 3 ahc 2.5 hc dloF hc poietic stem cells into thymus and export of mature CD4 and 3 d 2.0 dloF 2 2 loF 1.5 CD8 cells. These data suggest that FGF21 may regulate thymic 1.0 1 1 0.5 function by acting on both TECs and PCVs. 0 0 0 1m 7m 12m 26m 1m 7m 12m 26m 1m 7m 12m 26m 0.70 ) FGF21 Overexpression Prevents Age-Related Thymic Involution. I 0.40 2 month KJ 2.00 L 2 month 5 0.60 24 month 1.80 )egn 24 month 0.35 * * * Given that Fgf21 expression in thymus decreases with aging, we 1.60 0.50 0.30 ah 4 c 1.40 next investigated thymic status in a line of Fgf21-transgenic (tg) d 0.40 0.25 loF 1.20 3 ( – 0.30 0.20 1.00 mice that compared with WT animals show 50 100 times higher A * N 2 ( 0.15 0.80 R 0.20 A m circulating FGF21 concentrations (28).
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