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  • Review Article
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The ageing thyroid: implications for longevity and patient care

Nature Reviews Endocrinology volume 20, pages 5–15 (2024)Cite this article

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Abstract

Thyroid hormones have vital roles in development, growth and energy metabolism. Within the past two decades, disturbances in thyroid hormone action have been implicated in ageing and the development of age-related diseases. This Review will consider results from biomedical studies that have identified the importance of precise temporospatial regulation of thyroid hormone action for local tissue maintenance and repair. Age-related disturbances in the maintenance of tissue homeostasis are thought to be important drivers of age-related disease. In most iodine-proficient human populations without thyroid disease, the mean, median and 97.5 centile for circulating concentrations of thyroid-stimulating hormone are progressively higher in adults over 80 years of age compared with middle-aged (50–59 years) and younger (20–29 years) adults. This trend has been shown to extend into advanced ages (over 100 years). Here, potential causes and consequences of the altered thyroid status observed in old age and its association with longevity will be discussed. In about 5–20% of adults at least 65 years of age, thyroid-stimulating hormone concentrations are elevated but circulating concentrations of thyroid hormone are within the population reference range, a condition referred to as subclinical hypothyroidism. Results from randomized clinical trials that have tested the clinical benefit of thyroid hormone replacement therapy in older adults with mild subclinical hypothyroidism will be discussed, as well as the implications of these findings for screening and treatment of subclinical hypothyroidism in older adults.

Key points

  • In line with the emerging role of thyroid hormone action in tissue maintenance and repair, studying local control of thyroid hormone in ageing is an area urgently in need of research.

  • The mechanisms contributing to altered thyroid status in old age are probably heterogeneous and comprise selective survival, transient age-related changes and persistent age-related changes.

  • Increased circulating levels of thyroid-stimulating hormone and/or reduced circulating levels of thyroid hormone is a heritable phenotype associated with exceptional longevity.

  • Subclinical hypothyroidism is a frequent diagnosis among older adults; in randomized clinical trials, levothyroxine therapy provided no apparent clinical benefits in older adults with mild subclinical hypothyroidism.

  • Older adults form a heterogeneous group, so future research should explore strategies for safe screening, initiation, continuation and/or discontinuation of treatment of subclinical hypothyroidism in specific subgroups of older adults.

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Fig. 1: Systemic regulation of thyroid hormone availability.
Fig. 2: Local regulation of thyroid hormone action.
Fig. 3: Possible causes and consequences of altered thyroid status in old age.
Fig. 4: Possible causes of altered thyroid status observed in familial longevity.
Fig. 5: Principles and core assumptions of Mendelian randomization studies.

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References

  1. Kirkwood, T. B. Understanding the odd science of aging. Cell 120, 437–447 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Bowers, J. et al. Thyroid hormone signaling and homeostasis during aging. Endocr. Rev. 34, 556–589 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Taylor, P. N. et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat. Rev. Endocrinol. 14, 301–316 (2018).

    Article  PubMed  Google Scholar 

  5. McDermott, M. T. & Ridgway, E. C. Subclinical hypothyroidism is mild thyroid failure and should be treated. J. Clin. Endocrinol. Metab. 86, 4585–4590 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Cooper, D. S. & Biondi, B. Subclinical thyroid disease. Lancet 379, 1142–1154 (2012).

    Article  PubMed  Google Scholar 

  7. Schreiber, G. The evolutionary and integrative roles of transthyretin in thyroid hormone homeostasis. J. Endocrinol. 175, 61–73 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Bianco, A. C. et al. Paradigms of dynamic control of thyroid hormone signaling. Endocr. Rev. 40, 1000–1047 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Szarek, E., Cheah, P. S., Schwartz, J. & Thomas, P. Molecular genetics of the developing neuroendocrine hypothalamus. Mol. Cell Endocrinol. 323, 115–123 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Steinfelder, H. J. et al. Thyrotropin-releasing hormone regulation of human TSHB expression: role of a pituitary-specific transcription factor (Pit-1/GHF-1) and potential interaction with a thyroid hormone-inhibitory element. Proc. Natl Acad. Sci. USA 88, 3130–3134 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Silva, J. E. & Larsen, P. R. Pituitary nuclear 3,5,3′-triiodothyronine and thyrotropin secretion: an explanation for the effect of thyroxine. Science 198, 617–620 (1977).

    Article  CAS  PubMed  Google Scholar 

  12. Fonseca, T. L. et al. Coordination of hypothalamic and pituitary T3 production regulates TSH expression. J. Clin. Invest. 123, 1492–1500 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fliers, E., Kalsbeek, A. & Boelen, A. Beyond the fixed setpoint of the hypothalamus–pituitary–thyroid axis. Eur. J. Endocrinol. 171, R197–R208 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. O’Brian, J. T. et al. Thyroid hormone homeostasis in states of relative caloric deprivation. Metabolism 29, 721–727 (1980).

    Article  PubMed  Google Scholar 

  15. Kopp, P. The TSH receptor and its role in thyroid disease. Cell Mol. Life Sci. 58, 1301–1322 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Bianco, A. C., Salvatore, D., Gereben, B., Berry, M. J. & Larsen, P. R. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr. Rev. 23, 38–89 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Visser, W. E., Friesema, E. C. & Visser, T. J. Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol. Endocrinol. 25, 1–14 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gereben, B. et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr. Rev. 29, 898–938 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sap, J. et al. The c-erb-A protein is a high-affinity receptor for thyroid hormone. Nature 324, 635–640 (1986).

    Article  CAS  PubMed  Google Scholar 

  20. Thompson, C. C., Weinberger, C., Lebo, R. & Evans, R. M. Identification of a novel thyroid hormone receptor expressed in the mammalian central nervous system. Science 237, 1610–1614 (1987).

    Article  CAS  PubMed  Google Scholar 

  21. Flamant, F. et al. Thyroid hormone signaling pathways: time for a more precise nomenclature. Endocrinology 158, 2052–2057 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cao, X., Kambe, F., Moeller, L. C., Refetoff, S. & Seo, H. Thyroid hormone induces rapid activation of Akt/protein kinase B-mammalian target of rapamycin-p70S6K cascade through phosphatidylinositol 3-kinase in human fibroblasts. Mol. Endocrinol. 19, 102–112 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Maia, A. L., Kim, B. W., Huang, S. A., Harney, J. W. & Larsen, P. R. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. J. Clin. Invest. 115, 2524–2533 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pilo, A. et al. Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans by multicompartmental analysis. Am. J. Physiol. 258, E715–E726 (1990).

    CAS  PubMed  Google Scholar 

  25. Gudernatsch, J. F. Feeding experiments on tadpoles. I. The influence of specific organs given as food on growth and differentiation. A contribution to the knowledge of organs with internal secretion. Arch. Entwicklungsmech Org. 35, 457–483 (1912).

    Article  Google Scholar 

  26. Furlow, J. D. & Neff, E. S. A developmental switch induced by thyroid hormone: xenopus laevis metamorphosis. Trends Endocrinol. Metab. 17, 40–47 (2006).

    Article  PubMed  Google Scholar 

  27. Yoshimura, T. et al. Light-induced hormone conversion of T4 to T3 regulates photoperiodic response of gonads in birds. Nature 426, 178–181 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Mai, W. et al. Thyroid hormone receptor α is a molecular switch of cardiac function between fetal and postnatal life. Proc. Natl Acad. Sci. USA 101, 10332–10337 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Williams, F. L. et al. Developmental trends in cord and postpartum serum thyroid hormones in preterm infants. J. Clin. Endocrinol. Metab. 89, 5314–5320 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Furumoto, H. et al. An unliganded thyroid hormone beta receptor activates the cyclin D1/cyclin-dependent kinase/retinoblastoma/E2F pathway and induces pituitary tumorigenesis. Mol. Cell Biol. 25, 124–135 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bianco, A. C. & Kim, B. W. Deiodinases: implications of the local control of thyroid hormone action. J. Clin. Invest. 116, 2571–2579 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: an expanding universe. Cell 186, 243–278 (2023).

    Article  CAS  PubMed  Google Scholar 

  33. Mourouzis, I., Politi, E. & Pantos, C. Thyroid hormone and tissue repair: new tricks for an old hormone? J. Thyroid. Res. 2013, 312104 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Luongo, C., Dentice, M. & Salvatore, D. Deiodinases and their intricate role in thyroid hormone homeostasis. Nat. Rev. Endocrinol. 15, 479–488 (2019).

    Article  PubMed  Google Scholar 

  35. Remaud, S. et al. Transient hypothyroidism favors oligodendrocyte generation providing functional remyelination in the adult mouse brain. eLlife 6, e29996 (2017).

    Article  Google Scholar 

  36. Hollowell, J. G. et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J. Clin. Endocrinol. Metab. 87, 489–499 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Surks, M. I. & Hollowell, J. G. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J. Clin. Endocrinol. Metab. 92, 4575–4582 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Surks, M. I. & Boucai, L. Age- and race-based serum thyrotropin reference limits. J. Clin. Endocrinol. Metab. 95, 496–502 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Andersen, S., Bruun, N. H., Pedersen, K. M. & Laurberg, P. Biologic variation is important for interpretation of thyroid function tests. Thyroid 13, 1069–1078 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Jonklaas, J. & Razvi, S. Reference intervals in the diagnosis of thyroid dysfunction: treating patients not numbers. Lancet Diabetes Endocrinol. 7, 473–483 (2019).

    Article  PubMed  Google Scholar 

  41. van der Spoel, E., Roelfsema, F. & van Heemst, D. Within-person variation in serum thyrotropin concentrations: main sources, potential underlying biological mechanisms, and clinical implications. Front. Endocrinol. 12, 619568 (2021).

    Article  Google Scholar 

  42. Mariotti, S., Franceschi, C., Cossarizza, A. & Pinchera, A. The aging thyroid. Endocr. Rev. 16, 686–715 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. Peeters, R. P., Debaveye, Y., Fliers, E. & Visser, T. J. Changes within the thyroid axis during critical illness. Crit. Care Clin. 22, 41–55 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Chatzitomaris, A. et al. Thyroid allostasis-adaptive responses of thyrotropic feedback control to conditions of strain, stress, and developmental programming. Front. Endocrinol. 8, 163 (2017).

    Article  Google Scholar 

  45. Vadiveloo, T., Donnan, P. T., Murphy, M. J. & Leese, G. P. Age- and gender-specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland: the Thyroid Epidemiology, Audit, and Research Study (TEARS). J. Clin. Endocrinol. Metab. 98, 1147–1153 (2013).

    Article  CAS  PubMed  Google Scholar 

  46. Boucai, L. & Surks, M. I. Reference limits of serum TSH and free T4 are significantly influenced by race and age in an urban outpatient medical practice. Clin. Endocrinol. 70, 788–793 (2009).

    Article  Google Scholar 

  47. Hadlow, N. C. et al. The relationship between TSH and free T(4) in a large population is complex and nonlinear and differs by age and sex. J. Clin. Endocrinol. Metab. 98, 2936–2943 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Bremner, A. P. et al. Age-related changes in thyroid function: a longitudinal study of a community-based cohort. J. Clin. Endocrinol. Metab. 97, 1554–1562 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Waring, A. C. et al. Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study. J. Clin. Endocrinol. Metab. 97, 3944–3950 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mammen, J. S., McGready, J., Ladenson, P. W. & Simonsick, E. M. Unstable thyroid function in older adults is caused by alterations in both thyroid and pituitary physiology and is associated with increased mortality. Thyroid 27, 1370–1377 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Roberts, L. et al. Stability of thyroid function in older adults: the Birmingham Elderly Thyroid Study. Br. J. Gen. Pract. 68, e718–e726 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Chaker, L. et al. Thyroid function characteristics and determinants: the Rotterdam study. Thyroid 26, 1195–1204 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Atzmon, G., Barzilai, N., Hollowell, J. G., Surks, M. I. & Gabriely, I. Extreme longevity is associated with increased serum thyrotropin. J. Clin. Endocrinol. Metab. 94, 1251–1254 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Atzmon, G., Barzilai, N., Surks, M. I. & Gabriely, I. Genetic predisposition to elevated serum thyrotropin is associated with exceptional longevity. J. Clin. Endocrinol. Metab. 94, 4768–4775 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rozing, M. P. et al. Familial longevity is associated with decreased thyroid function. J. Clin. Endocrinol. Metab. 95, 4979–4984 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Rozing, M. P. et al. Low serum free triiodothyronine levels mark familial longevity: the Leiden Longevity Study. J. Gerontol. A 65, 365–368 (2010).

    Article  Google Scholar 

  57. Jansen, S. W. et al. Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism. Sci. Rep. 5, 11525 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yagi, H., Pohlenz, J., Hayashi, Y., Sakurai, A. & Refetoff, S. Resistance to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function that cannot be explained by altered in vitro 3,5,3′-triiodothyroinine binding affinity. J. Clin. Endocrinol. Metab. 82, 1608–1614 (1997).

    CAS  PubMed  Google Scholar 

  59. Zutinic, A. et al. Circulating thyroid hormone profile in response to a triiodothyronine challenge in familial longevity. J. Endocr. Soc. 4, bvaa117 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Szkudlinski, M. W., Fremont, V., Ronin, C. & Weintraub, B. D. Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure–function relationships. Physiol. Rev. 82, 473–502 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Zutinic, A. et al. Familial longevity is associated with an attenuated thyroidal response to recombinant human thyroid stimulating hormone. J. Clin. Endocrinol. Metab. 105, e2572–e2580 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Hoermann, R., Midgley, J. E., Larisch, R. & Dietrich, J. W. Homeostatic control of the thyroid–pituitary axis: perspectives for diagnosis and treatment. Front. Endocrinol. 6, 177 (2015).

    Article  Google Scholar 

  63. Hoermann, R., Midgley, J. E., Larisch, R. & Dietrich, J. W. Integration of peripheral and glandular regulation of triiodothyronine production by thyrotropin in untreated and thyroxine-treated subjects. Horm. Metab. Res. 47, 674–680 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Jansen, S. W. et al. Familial longevity is associated with higher TSH secretion and strong TSH–fT3 relationship. J. Clin. Endocrinol. Metab. 100, 3806–3813 (2015).

    Article  CAS  PubMed  Google Scholar 

  65. Harper, M. E. & Seifert, E. L. Thyroid hormone effects on mitochondrial energetics. Thyroid 18, 145–156 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. van der Spoel, E., van Vliet, N. A. & van Heemst, D. Viewpoint on the role of tissue maintenance in ageing: focus on biomarkers of bone, cartilage, muscle, and brain tissue maintenance. Ageing Res. Rev. 56, 100964 (2019).

    Article  PubMed  Google Scholar 

  67. Luongo, C. et al. Type 2 deiodinase Thr92Ala polymorphism and aging are associated with a decreased pituitary sensitivity to thyroid hormone. Thyroid 33, 294–300 (2023).

    Article  CAS  PubMed  Google Scholar 

  68. Silvestri, E. et al. Age-related changes in renal and hepatic cellular mechanisms associated with variations in rat serum thyroid hormone levels. Am. J. Physiol. Endocrinol. Metab. 294, E1160–E1168 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Visser, W. E. et al. Tissue-specific suppression of thyroid hormone signaling in various mouse models of aging. PLoS One 11, e0149941 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Blum, M. R. et al. Subclinical thyroid dysfunction and fracture risk: a meta-analysis. JAMA 313, 2055–2065 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Aubert, C. E. et al. Thyroid function tests in the reference range and fracture: individual participant analysis of prospective cohorts. J. Clin. Endocrinol. Metab. 102, 2719–2728 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Segna, D. et al. Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts. J. Intern. Med. 283, 56–72 (2018).

    Article  CAS  PubMed  Google Scholar 

  73. Roa Duenas, O. H. et al. Thyroid function and the risk of prediabetes and type 2 diabetes. J. Clin. Endocrinol. Metab. 107, 1789–1798 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Rodondi, N. et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 304, 1365–1374 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Collet, T. H. et al. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch. Intern. Med. 172, 799–809 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Wopereis, D. M. et al. The relation between thyroid function and anemia: a pooled analysis of individual participant data. J. Clin. Endocrinol. Metab. 103, 3658–3667 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Gencer, B. et al. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. Circulation 126, 1040–1049 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Aubert, C. E. et al. The association between subclinical thyroid dysfunction and dementia: the Health, Aging and Body Composition (Health ABC) study. Clin. Endocrinol. 87, 617–626 (2017).

    Article  CAS  Google Scholar 

  79. Rieben, C. et al. Subclinical thyroid dysfunction and the risk of cognitive decline: a meta-analysis of prospective cohort studies. J. Clin. Endocrinol. Metab. 101, 4945–4954 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. van Vliet, N. A. et al. Association of thyroid dysfunction with cognitive function: an individual participant data analysis. JAMA Intern. Med. 181, 1440–1450 (2021).

    Article  PubMed  Google Scholar 

  81. Inoue, K., Tsujimoto, T., Saito, J. & Sugiyama, T. Association between serum thyrotropin levels and mortality among euthyroid adults in the United States. Thyroid 26, 1457–1465 (2016).

    Article  CAS  PubMed  Google Scholar 

  82. van Vliet, N. A. et al. Thyroid status and mortality in nonagenarians from long-lived families and the general population. Aging 9, 2223–2234 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Cappola, A. R. et al. Thyroid function in the euthyroid range and adverse outcomes in older adults. J. Clin. Endocrinol. Metab. 100, 1088–1096 (2015).

    Article  CAS  PubMed  Google Scholar 

  84. Gussekloo, J. et al. Thyroid status, disability and cognitive function, and survival in old age. JAMA 292, 2591–2599 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. van den Beld, A. W., Visser, T. J., Feelders, R. A., Grobbee, D. E. & Lamberts, S. W. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J. Clin. Endocrinol. Metab. 90, 6403–6409 (2005).

    Article  PubMed  Google Scholar 

  86. Cappola, A. R. et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA 295, 1033–1041 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Yeap, B. B. et al. Higher free thyroxine levels are associated with all-cause mortality in euthyroid older men: the Health In Men Study. Eur. J. Endocrinol. 169, 401–408 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Lawlor, D. A., Tilling, K. & Davey Smith, G. Triangulation in aetiological epidemiology. Int. J. Epidemiol. 45, 1866–1886 (2016).

    PubMed  Google Scholar 

  89. Ebrahim, S. & Davey Smith, G. Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology? Hum. Genet. 123, 15–33 (2008).

    Article  PubMed  Google Scholar 

  90. Porcu, E. et al. A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS Genet. 9, e1003266 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Teumer, A. et al. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. Nat. Commun. 9, 4455 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Gudmundsson, J. et al. Discovery of common variants associated with low TSH levels and thyroid cancer risk. Nat. Genet. 44, 319–322 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. van Vliet, N. A. et al. Thyroid stimulating hormone and bone mineral density: evidence from a two-sample Mendelian randomization study and a candidate gene association study. J. Bone Min. Res. 33, 1318–1325 (2018).

    Article  Google Scholar 

  94. van Vliet, N. A. et al. Thyroid function and risk of anemia: a multivariable-adjusted and Mendelian randomization analysis in the UK biobank. J. Clin. Endocrinol. Metab. 107, e643–e652 (2022).

    Article  PubMed  Google Scholar 

  95. Kjaergaard, A. D. et al. Thyroid function, pernicious anemia and erythropoiesis: a two-sample Mendelian randomization study. Hum. Mol. Genet. 31, 2548–2559 (2022).

    Article  CAS  PubMed  Google Scholar 

  96. Ellervik, C. et al. Assessment of the relationship between genetic determinants of thyroid function and atrial fibrillation: a Mendelian randomization study. JAMA Cardiol. 4, 144–152 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Shi, M. et al. Genetic thyrotropin regulation of atrial fibrillation risk is mediated through an effect on height. J. Clin. Endocrinol. Metab. 106, 2124–2132 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Marouli, E. et al. Thyroid function and the risk of Alzheimer’s disease: a Mendelian randomization study. Thyroid 31, 1794–1799 (2021).

    Article  CAS  PubMed  Google Scholar 

  99. Li, G. H., Cheung, C. L., Cheung, E. Y., Chan, W. C. & Tan, K. C. Genetically determined TSH level within reference range is inversely associated with Alzheimer disease. J. Clin. Endocrinol. Metab. 106, e5064–e5074 (2021).

    PubMed  Google Scholar 

  100. Zhao, J. V. & Schooling, C. M. Thyroid function and ischemic heart disease: a mendelian randomization study. Sci. Rep. 7, 8515 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Larsson, S. C., Allara, E., Mason, A. M., Michaelsson, K. & Burgess, S. Thyroid function and dysfunction in relation to 16 cardiovascular diseases. Circ. Genom. Precis. Med. 12, e002468 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. van Vliet, N. A. et al. Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling. BMC Med. 19, 266 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Bos, M. M., Smit, R. A. J., Trompet, S., van Heemst, D. & Noordam, R. Thyroid signaling, insulin resistance, and 2 diabetes mellitus: a Mendelian randomization study. J. Clin. Endocrinol. Metab. 102, 1960–1970 (2017).

    Article  PubMed  Google Scholar 

  104. Kus, A. et al. Variation in normal range thyroid function affects serum cholesterol levels, blood pressure, and type 2 diabetes risk: a Mendelian randomization study. Thyroid 31, 721–731 (2021).

    Article  CAS  PubMed  Google Scholar 

  105. Bos, M. M., van Vliet, N. A., Mooijaart, S. P., Noordam, R. & van Heemst, D. Genetically determined higher TSH is associated with a lower risk of diabetes mellitus in individuals with low BMI. J. Clin. Endocrinol. Metab. 106, e2502–e2511 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Pearce, S. H. et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur. Thyroid. J. 2, 215–228 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Jonklaas, J. & DeSale, S. The ages and TSH values of patients being prescribed levothyroxine. Ther. Adv. Endocrinol. Metab. 11, 2042018820937896 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chaker, L. et al. Subclinical hypothyroidism and the risk of stroke events and fatal stroke: an individual participant data analysis. J. Clin. Endocrinol. Metab. 100, 2181–2191 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Walsh, J. P. Thyroid function across the lifespan: do age-related changes matter? Endocrinol. Metab. 37, 208–219 (2022).

    Article  CAS  Google Scholar 

  110. Stott, D. J. et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N. Engl. J. Med. 376, 2534–2544 (2017).

    Article  CAS  PubMed  Google Scholar 

  111. Mooijaart, S. P. et al. Association between levothyroxine treatment and thyroid-related symptoms among adults aged 80 years and older with subclinical hypothyroidism. JAMA 322, 1977–1986 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Feller, M. et al. Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism: a systematic review and meta-analysis. JAMA 320, 1349–1359 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Wildisen, L. et al. Effect of levothyroxine therapy on the development of depressive symptoms in older adults with subclinical hypothyroidism: an ancillary study of a randomized clinical trial. JAMA Netw. Open. 4, e2036645 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Gonzalez Rodriguez, E. et al. Skeletal effects of levothyroxine for subclinical hypothyroidism in older adults: a TRUST randomized trial nested study. J. Clin. Endocrinol. Metab. 105, dgz058 (2020).

    Article  PubMed  Google Scholar 

  115. Buchi, A. E. et al. Bone geometry in older adults with subclinical hypothyroidism upon levothyroxine therapy: a nested study within a randomized placebo controlled trial. Bone 161, 116404 (2022).

    Article  CAS  PubMed  Google Scholar 

  116. Gencer, B. et al. The impact of levothyroxine on cardiac function in older adults with mild subclinical hypothyroidism: a randomized clinical trial. Am. J. Med. 133, 848–856 (2020).

    Article  CAS  PubMed  Google Scholar 

  117. Lowsky, D. J., Olshansky, S. J., Bhattacharya, J. & Goldman, D. P. Heterogeneity in healthy aging. J. Gerontol. A 69, 640–649 (2014).

    Article  Google Scholar 

  118. Mooijaart, S. P. et al. Evidence-based medicine in older patients: how can we do better? Neth. J. Med. 73, 211–218 (2015).

    CAS  PubMed  Google Scholar 

  119. Cappola, A. R. The thyrotropin reference range should be changed in older patients. JAMA 322, 1961–1962 (2019).

    Article  PubMed  Google Scholar 

  120. Taylor, P. N. et al. Age-related variation in thyroid function—a narrative review highlighting important implications for research and clinical practice. Thyroid. Res. 16, 7 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Bosma, M., Du Puy, R. S. & Ballieux, B. Screening for thyroid dysfunction with free T4 instead of thyroid stimulating hormone (TSH) improves efficiency in older adults in primary care. Age Ageing 51, afac215 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Abbey, E. J., McGready, J., Sokoll, L. J., Simonsick, E. M. & Mammen, J. S. R. Free thyroxine distinguishes subclinical hypothyroidism from other aging-related changes in those with isolated elevated thyrotropin. Front. Endocrinol. 13, 858332 (2022).

    Article  Google Scholar 

  123. Biondi, B., Cappola, A. R. & Cooper, D. S. Subclinical hypothyroidism: a review. JAMA 322, 153–160 (2019).

    Article  CAS  PubMed  Google Scholar 

  124. Somwaru, L. L., Arnold, A. M., Joshi, N., Fried, L. P. & Cappola, A. R. High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over. J. Clin. Endocrinol. Metab. 94, 1342–1345 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Sawin, C. T., Herman, T., Molitch, M. E., London, M. H. & Kramer, S. M. Aging and the thyroid. Decreased requirement for thyroid hormone in older hypothyroid patients. Am. J. Med. 75, 206–209 (1983).

    Article  CAS  PubMed  Google Scholar 

  126. Carle, A. et al. Hypothyroid symptoms fail to predict thyroid insufficiency in old people: a population-based case-control study. Am. J. Med. 129, 1082–1092 (2016).

    Article  PubMed  Google Scholar 

  127. Cappola, A. R. et al. Thyroid and cardiovascular disease: research agenda for enhancing knowledge, prevention, and treatment. Thyroid 29, 760–777 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Wiersinga, W. M. Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism. Nat. Rev. Endocrinol. 10, 164–174 (2014).

    Article  CAS  PubMed  Google Scholar 

  129. Goede, S. L., Leow, M. K., Smit, J. W. & Dietrich, J. W. A novel minimal mathematical model of the hypothalamus–pituitary–thyroid axis validated for individualized clinical applications. Math. Biosci. 249, 1–7 (2014).

    Article  CAS  PubMed  Google Scholar 

  130. Biondi, B. & Cappola, A. R. Subclinical hypothyroidism in older individuals. Lancet Diabetes Endocrinol. 10, 129–141 (2022).

    Article  CAS  PubMed  Google Scholar 

  131. Diez, J. J. & Iglesias, P. Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure. J. Clin. Endocrinol. Metab. 89, 4890–4897 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Peeters, R. P. Subclinical hypothyroidism. N. Engl. J. Med. 376, 2556–2565 (2017).

    Article  PubMed  Google Scholar 

  133. Somwaru, L. L., Rariy, C. M., Arnold, A. M. & Cappola, A. R. The natural history of subclinical hypothyroidism in the elderly: the Cardiovascular Health Study. J. Clin. Endocrinol. Metab. 97, 1962–1969 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Meyerovitch, J. et al. Serum thyrotropin measurements in the community: five-year follow-up in a large network of primary care physicians. Arch. Intern. Med. 167, 1533–1538 (2007).

    Article  CAS  PubMed  Google Scholar 

  135. Kim, T. H. et al. Effect of seasonal changes on the transition between subclinical hypothyroid and euthyroid status. J. Clin. Endocrinol. Metab. 98, 3420–3429 (2013).

    Article  CAS  PubMed  Google Scholar 

  136. Taylor, P. N. et al. Falling threshold for treatment of borderline elevated thyrotropin levels-balancing benefits and risks: evidence from a large community-based study. JAMA Intern. Med. 174, 32–39 (2014).

    Article  CAS  PubMed  Google Scholar 

  137. Ravensberg, A. J. et al. Effects of discontinuation of levothyroxine treatment in older adults: protocol for a self-controlled trial. BMJ Open. 13, e070741 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

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    Diana van Heemst

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van Heemst, D. The ageing thyroid: implications for longevity and patient care. Nat Rev Endocrinol 20, 5–15 (2024). https://doi.org/10.1038/s41574-023-00911-7

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