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Associations Between Plasma Growth and Differentiation Factor-15 with Aging Phenotypes in Muscle, Adipose Tissue, and Bone

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Abstract

Growth and differentiation factor 15 (GDF-15) is associated with muscle, fat, and bone metabolism; however, this association has not been well characterized. Plasma GDF-15, appendicular skeletal muscle mass (ASM), fat mass (FM), and bone mineral density (BMD) were measured in 146 postmenopausal women. GDF-15 levels were higher in subjects with low Body Mass Index (BMI)-adjusted ASM than in those without (median [interquartile range] 831.3 [635.4–1011.4] vs. 583.8 [455.8–771.1] pg/mL, p = 0.018). The GDF-15 level was inversely correlated with BMI-adjusted ASM (r =  − 0.377, p < 0.001) and BMD at femur neck (FN-BMD; r =  − 0.201, p = 0.015), and positively correlated with percent FM (pFM; r = 0.328, p < 0.001). After adjusting for confounders, the GDF-15 level was inversely associated with BMI-adjusted ASM (β = –0.250, p = 0.006) and positively associated with pFM (β = 0.272, p = 0.004), and tended to be inversely associated with FN-BMD (β = – 0.176, p = 0.076). The area under the receiver-operating characteristic curve of GDF-15 level > 618.4 pg/mL for sarcopenia was 0.706 (95% confidence interval (CI) 0.625–0.779) with a sensitivity of 83.3% and a specificity of 54.5%. Using a GDF-15 level of 618.4 pg/mL as a cut-off, the GDF-15 level was associated with a significantly greater likelihood of sarcopenia (odds ratio [OR] 2.35; 95% CI 1.00–5.51; p = 0.049), obesity (OR 3.28; 95% CI 1.48–7.27; p = 0.001), osteopenic obesity (OR 3.10; 95% CI 1.31–7.30; p = 0.010), and sarcopenic or osteosarcopenic obesity (OR 4.84; 95% CI 0.88–26.69; p = 0.070). These findings support the potential of GDF-15 as a biomarker for age-related changes in muscle, fat, and bone.

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Data Availability

Restrictions apply to the availability of data generated or analyzed during this study because they were used under license. The corresponding author will, on request, detail the restrictions and any conditions under which access to some data may be provided.

References

  1. Binkley N, Krueger D, Buehring B (2013) What’s in a name revisited: should osteoporosis and sarcopenia be considered components of “dysmobility syndrome?” Osteoporos Int 24:2955–2959. https://doi.org/10.1007/s00198-013-2427-1

    Article  CAS  PubMed  Google Scholar 

  2. Ilich JZ, Kelly OJ, Inglis JE (2016) Osteosarcopenic obesity syndrome: what is it and how can it be identified and diagnosed. Curr Gerontol Geriatr Res 2016:7325973. https://doi.org/10.1155/2016/7325973

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ilich JZ, Kelly OJ, Inglis JE, Panton LB, Duque G, Ormsbee MJ (2014) Interrelationship among muscle, fat, and bone: connecting the dots on cellular, hormonal, and whole body levels. Ageing Res Rev 15:51–60. https://doi.org/10.1016/j.arr.2014.02.007

    Article  CAS  PubMed  Google Scholar 

  4. Chen LK, Woo J, Assantachai P, Auyeung TW, Chou MY, Iijima K, Jang HC, Kang L, Kim M, Kim S, Kojima T, Kuzuya M, Lee JSW, Lee SY, Lee WJ, Lee Y, Liang CK, Lim JY, Lim WS, Peng LN, Sugimoto K, Tanaka T, Won CW, Yamada M, Zhang T, Akishita M, Arai H (2020) Asian Working Group for Sarcopenia: 2019 consensus update on sarcopenia diagnosis and treatment. J Am Med Dir Assoc 21(300–307):e302. https://doi.org/10.1016/j.jamda.2019.12.012

    Article  Google Scholar 

  5. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP, Rolland Y, Schneider SM, Topinková E, Vandewoude M, Zamboni M (2010) Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People. Age Ageing 39:412–423. https://doi.org/10.1093/ageing/afq034

    Article  PubMed  PubMed Central  Google Scholar 

  6. Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, Cooper C, Landi F, Rolland Y, Sayer AA, Schneider SM, Sieber CC, Topinkova E, Vandewoude M, Visser M, Zamboni M, Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), Extended Group for EWGSOP2 (2019) Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 48:16–31. https://doi.org/10.1093/ageing/afy169

    Article  PubMed  Google Scholar 

  7. Conte M, Martucci M, Mosconi G, Chiariello A, Cappuccilli M, Totti V, Santoro A, Franceschi C, Salvioli S (2020) GDF15 plasma level is inversely associated with level of physical activity and correlates with markers of inflammation and muscle weakness. Front Immunol 11:915. https://doi.org/10.3389/fimmu.2020.00915

    Article  PubMed  PubMed Central  Google Scholar 

  8. Herpich C, Franz K, Ost M, Otten L, Coleman V, Klaus S, Muller-Werdan U, Norman K (2021) Associations between serum GDF15 concentrations, muscle mass, and strength show sex-specific differences in older hospital patients. Rejuvenation Res 24:14–19. https://doi.org/10.1089/rej.2020.2308

    Article  CAS  PubMed  Google Scholar 

  9. Hofmann M, Halper B, Oesen S, Franzke B, Stuparits P, Tschan H, Bachl N, Strasser EM, Quittan M, Ploder M, Wagner KH, Wessner B (2015) Serum concentrations of insulin-like growth factor-1, members of the TGF-beta superfamily and follistatin do not reflect different stages of dynapenia and sarcopenia in elderly women. Exp Gerontol 64:35–45. https://doi.org/10.1016/j.exger.2015.02.008

    Article  PubMed  Google Scholar 

  10. Kim H, Kim KM, Kang MJ, Lim S (2020) Growth differentiation factor-15 as a biomarker for sarcopenia in aging humans and mice. Exp Gerontol 142:111115. https://doi.org/10.1016/j.exger.2020.111115

    Article  CAS  PubMed  Google Scholar 

  11. Kim M, Walston JD, Won CW (2021) Associations between elevated growth differentiation factor-15 and sarcopenia among community-dwelling older adults. J Gerontol A Biol Sci Med Sci. https://doi.org/10.1093/gerona/glab201

    Article  PubMed  PubMed Central  Google Scholar 

  12. Oba K, Ishikawa J, Tamura Y, Fujita Y, Ito M, Iizuka A, Fujiwara Y, Kodera R, Toba A, Toyoshima K, Chiba Y, Mori S, Tanaka M, Ito H, Harada K, Araki A (2020) Serum growth differentiation factor 15 level is associated with muscle strength and lower extremity function in older patients with cardiometabolic disease. Geriatr Gerontol Int 20:980–987. https://doi.org/10.1111/ggi.14021

    Article  PubMed  Google Scholar 

  13. Semba RD, Gonzalez-Freire M, Tanaka T, Biancotto A, Zhang P, Shardell M, Moaddel R, Consortium CHI, Ferrucci L (2020) Elevated plasma growth and differentiation factor 15 is associated with slower gait speed and lower physical performance in healthy community-dwelling adults. J Gerontol A Biol Sci Med Sci 75:175–180. https://doi.org/10.1093/gerona/glz071

    Article  CAS  PubMed  Google Scholar 

  14. Dostálová I, Roubícek T, Bártlová M, Mráz M, Lacinová Z, Haluzíková D, Kaválková P, Matoulek M, Kasalicky M, Haluzík M (2009) Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet. Eur J Endocrinol 161:397–404. https://doi.org/10.1530/EJE-09-0417

    Article  CAS  PubMed  Google Scholar 

  15. Kempf T, Guba-Quint A, Torgerson J, Magnone MC, Haefliger C, Bobadilla M, Wollert KC (2012) Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial. Eur J Endocrinol 167:671–678. https://doi.org/10.1530/EJE-12-0466

    Article  CAS  PubMed  Google Scholar 

  16. Vila G, Riedl M, Anderwald C, Resl M, Handisurya A, Clodi M, Prager G, Ludvik B, Krebs M, Luger A (2011) The relationship between insulin resistance and the cardiovascular biomarker growth differentiation factor-15 in obese patients. Clin Chem 57:309–316. https://doi.org/10.1373/clinchem.2010.153726

    Article  CAS  PubMed  Google Scholar 

  17. Westhrin M, Moen SH, Holien T, Mylin AK, Heickendorff L, Olsen OE, Sundan A, Turesson I, Gimsing P, Waage A, Standal T (2015) Growth differentiation factor 15 (GDF15) promotes osteoclast differentiation and inhibits osteoblast differentiation and high serum GDF15 levels are associated with multiple myeloma bone disease. Haematologica 100:e511-514. https://doi.org/10.3324/haematol.2015.124511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schafer MJ, Zhang X, Kumar A, Atkinson EJ, Zhu Y, Jachim S, Mazula DL, Brown AK, Berning M, Aversa Z, Kotajarvi B, Bruce CJ, Greason KL, Suri RM, Tracy RP, Cummings SR, White TA, LeBrasseur NK (2020) The senescence-associated secretome as an indicator of age and medical risk. JCI Insight 5:e133668. https://doi.org/10.1172/jci.insight.133668

    Article  PubMed Central  Google Scholar 

  19. Tanaka T, Biancotto A, Moaddel R, Moore AZ, Gonzalez-Freire M, Aon MA, Candia J, Zhang P, Cheung F, Fantoni G, CHI consortium, Semba RD, Ferrucci L (2018) Plasma proteomic signature of age in healthy humans. Aging Cell 17:e12799. https://doi.org/10.1111/acel.12799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev N (1994) The diagnosis of osteoporosis. J Bone Miner Res 9:1137–1141. https://doi.org/10.1002/jbmr.5650090802

    Article  CAS  PubMed  Google Scholar 

  21. Perkins NJ, Schisterman EF (2005) The Youden Index and the optimal cut-point corrected for measurement error. Biom J 47:428–441. https://doi.org/10.1002/bimj.200410133

    Article  PubMed  Google Scholar 

  22. Muñoz-Espín D, Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15:482–496. https://doi.org/10.1038/nrm3823

    Article  CAS  PubMed  Google Scholar 

  23. van Deursen JM (2014) The role of senescent cells in ageing. Nature 509:439–446. https://doi.org/10.1038/nature13193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Englund DA, Sakamoto AE, Fritsche CM, Heeren AA, Zhang X, Kotajarvi BR, Lecy DR, Yousefzadeh MJ, Schafer MJ, White TA, Atkinson EJ, LeBrasseur NK (2021) Exercise reduces circulating biomarkers of cellular senescence in humans. Aging Cell 20:e13415. https://doi.org/10.1111/acel.13415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Baker JF, Long J, Leonard MB, Harris T, Delmonico MJ, Santanasto A, Satterfield S, Zemel B, Weber DR (2018) Estimation of skeletal muscle mass relative to adiposity improves prediction of physical performance and incident disability. J Gerontol A Biol Sci Med Sci 73:946–952. https://doi.org/10.1093/gerona/glx064

    Article  PubMed  Google Scholar 

  26. Kim TN, Park MS, Lee EJ, Chung HS, Yoo HJ, Kang HJ, Song W, Baik SH, Choi KM (2017) Comparisons of three different methods for defining sarcopenia: an aspect of cardiometabolic risk. Sci Rep 7:6491. https://doi.org/10.1038/s41598-017-06831-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tang TC, Hwang AC, Liu LK, Lee WJ, Chen LY, Wu YH, Huang CY, Hung CH, Wang CJ, Lin MH, Peng LN, Chen LK (2018) FNIH-defined sarcopenia predicts adverse outcomes among community-dwelling older people in Taiwan: results from I-Lan longitudinal aging study. J Gerontol A Biol Sci Med Sci 73:828–834. https://doi.org/10.1093/gerona/glx148

    Article  PubMed  Google Scholar 

  28. Chen XK, Yi ZN, Wong GT, Hasan KMM, Kwan JS, Ma AC, Chang RC (2021) Is exercise a senolytic medicine? A systematic review. Aging Cell 20:e13294. https://doi.org/10.1111/acel.13294

    Article  CAS  PubMed  Google Scholar 

  29. He C, He W, Hou J, Chen K, Huang M, Yang M, Luo X, Li C (2020) Bone and muscle crosstalk in aging. Front Cell Dev Biol 8:585644. https://doi.org/10.3389/fcell.2020.585644

    Article  PubMed  PubMed Central  Google Scholar 

  30. LeBrasseur NK, de Cabo R, Fielding R, Ferrucci L, Rodriguez-Manas L, Viña J, Vellas B (2021) Identifying biomarkers for biological age: geroscience and the ICFSR task force. J Frailty Aging 10:196–201. https://doi.org/10.14283/jfa.2021.5

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by grants from the Asan Institute for Life Sciences, Seoul, Republic of Korea (Project No. 2019IP0862) and from the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (Project No. HI15C2792). The funding organization had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

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  1. Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea

    Seung Hun Lee, Jee Yang Lee, Kyeong-Hye Lim & Jung-Min Koh

  2. Asan Institute for Life Sciences, Seoul, 05505, Republic of Korea

    Young-Sun Lee

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Contributions

SHL and JMK contributed to the conception and design of the study. Material preparation and data collection were performed by SHL, JYL, KHL, YSL and JMK. Analysis and interpretation of the data were performed by SHL and JMK. The first draft of the manuscript was written by SHL, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Seung Hun Lee or Jung-Min Koh.

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Seung Hun Lee, Jee Yang Lee, Kyeong-Hye Lim, Young-Sun Lee, and Jung-Min Koh state that they have no conflicts of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Asan Medical Center Ethics Review Committee (no. 2018–0157).

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Lee, S.H., Lee, J.Y., Lim, KH. et al. Associations Between Plasma Growth and Differentiation Factor-15 with Aging Phenotypes in Muscle, Adipose Tissue, and Bone. Calcif Tissue Int 110, 236–243 (2022). https://doi.org/10.1007/s00223-021-00912-6

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  • DOI: https://doi.org/10.1007/s00223-021-00912-6

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