The age-related resistance to thyroid hormones (THs) explains the paucity of symptoms and signs of hyperthyroidism in older adults and may partly explain the myriad of symptoms and signs of hypothyroidism in biochemically euthyroid older people. This review considers the available data on the mechanisms underlying TH resistance with aging and compares these physiologic changes with the changes observed in congenital TH resistance syndromes. Aging is associated with alterations in TH economy along with a host of changes in the responsiveness of various tissues to THs. The age-related resistance to THs can be attributed to decreased TH transport to tissues, decreased nuclear receptor occupancy, decreased activation of thyroxine to triiodothyronine, and alterations in TH responsive gene expression. Although an increase in serum TH levels is expected in syndromes of TH resistance, unchanged serum TH levels in the euthyroid elderly is the result of increased sensitivity to TH negative feedback with increased suppression of thyroid-stimulating hormone, decreased thyroidal sensitivity to thyroid-stimulating hormone, and decreased TH production and secretion. The current clinical evidence suggests that the age-related TH resistance is mostly an adaptive response of the aging organism. It is tempting to speculate that similar changes can occur prematurely in a group of younger people who present with signs and symptoms of hypothyroidism despite normal serum thyroid function tests.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Nowak FV, Mooradian AD. Endocrine function and dysfunction. In: Birren JE, editor. Encyclopedia of gerontology: age, aging, and the aged, vol. 1. 2nd ed. San Diego (CA): Elsevier Inc.; 2007. p. 480–93.
Mooradian AD. Biology of aging. In: Felsenthal G, Garrison SJ, Steinberg FU, editors. Rehabilitation of the aging and elderly patient. Baltimore (MD): Williams and Wilkins; 1994. p. 3–10.
Oiknine RF, Mooradian AD. Thyroid disorders. In: John Pathy MS, Sinclair AJ, Morley JE, editors. Principles and practice of geriatric medicine, vol. 2. 4th ed. Hoboken: Wiley; 2006. p. 1405–14.
Mooradian AD, Wong NCW. Age-related changes in thyroid hormone action. Eur J Endocrinol. 1994;131:451–61.
Mooradian AD. Asymptomatic hyperthyroidism in older adults: is it a distinct clinical and laboratory entity? Drugs Aging. 2008;25:371–80.
Concolino P, Costella A, Paragliola RM. Mutational landscape of resistance to thyroid hormone beta (RTHβ). Mol Diagn Ther. 2019;23:353–68.
Mooradian AD. Normal age-related changes in thyroid hormone economy. Clin Geriatr Med. 1995;11:159–69.
Pekary AE, Mirell CJ, Turner LF Jr, Walfish PG, Hershman JM. Hypothalamic secretion of thyrotropin releasing hormone declines in aging rats. J Endocrinol. 1987;114:271–7.
Lewis GF, Alessi CA, Imperial JG, Refetoff S. Low serum free thyroxine index in ambulating elderly is due to a resetting of the threshold of thyrotropin feedback suppression. J Clin Endocrinol Metab. 1991;73:843–9.
Friedman D, Reed RL, Mooradian AD. The prevalence of overmedication with levothyroxine in ambulatory elderly patients. Age. 1992;15:9–13.
Suzuki S, Nishio S, Takeda T, Komatsu M. Gender-specific regulation of response to thyroid hormone in aging. Thyroid Res. 2012;5:1.
Tognini S, Polini A, Pasqualetti G, Ursino S, Caraccio N, Ferdeghini M, et al. Age and gender substantially influence the relationship between thyroid status and the lipoprotein profile: results from a large cross-sectional study. Thyroid. 2012;22:1096–103.
Ordene KW, Pan C, Barzel US, Surks MI. Variable thyrotropin response to thyrotropin-releasing hormone after small decreases in plasma thyroid hormone concentrations in patients of advanced age. Metabolism. 1983;32:881–8.
Donda A, Lemarchand-Beraud T. Aging alters the activity of 5′-deiodinase in the adenohypophysis, thyroid gland, and liver of the male rat. Endocrinology. 1989;124:1305–9.
Donda A, Reymond MJ, Zurich MG, et al. Influence of sex and age on T3 receptors and T3 concentration in the pituitary gland of the rat: consequences on TSH secretion. Mol Cell Endocrinol. 1987;54:29–34.
Luongo C, Martin C, Vella K, et al. The selective loss of the type 2 iodothyronine deiodinase in mouse thyrotrophs increases basal TSH but blunts the thyrotropin response to hypothyroidism. Endocrinology. 2015;156:745–54.
van Coevorden A, Mockel J, Laurent E, Kerkhofs M, L’Hermite-Balériaux M, Decoster C, et al. Neuroendocrine rhythms and sleep in aging men. Am J Physiol. 1991;260:E651–61.
Barreca T, Franceschini R, Messina V, Bottaro L, Rolandi E. 24-Hour thyroid stimulating hormone secretory pattern in elderly men. Gerontology. 1985;31:119–23.
Monzani F, Del Guerra P, Caraccio N, Del Corso L, Casolaro A, Mariotti S, et al. Age-related modifications in the regulation of the hypothalamic-pituitary-thyroid axis. Horm Res. 1996;46:107–12.
Greeley GH Jr, Lipton MA, Kizer JS. Serum thyroxine, triiodothyronine, and TSH levels and TSH release after TRH in aging male and female rats. Endocr Res Commun. 1982–1983;9:169–77.
Gregerman RI, Gaffney GW, Shock NW, Crowder SE. Thyroxine turnover in euthyroid man with special reference to changes with age. J Clin Invest. 1962;41:2065–74.
Bano A, Chaker L, Schoufour J, et al. High circulating free thyroxine levels may increase the risk of frailty: the Rotterdam Study. J Clin Endocrinol Metab. 2018;103:328–35.
van den Beld AW, Visser TJ, Feelders RA, Grobbee DE, Lamberts SWJ. Thyroid hormone concentration, disease, physical function and mortality in elderly men. J Clin Endocrinol Metab. 2005;90:6403–9.
van Coevorden A, Laurent E, Decoster C, Kerkhofs M, Neve P, van Cauter E, et al. Decreased basal and stimulated thyrotropin secretion in healthy elderly men. J Clin Endocrinol Metab. 1989;69:177–85.
Mariotti S, Barbesino G, Caturegli P, Bartalena L, Sansoni P, Fagnoni F, et al. Complex alteration of thyroid function in healthy centenarians. J Clin Endocrinol Metab. 1993;77:1130–4.
Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007;92:4575–82.
Surks MI, Boucai L. Age- and race-based serum thyrotropin reference limits. J Clin Endocrinol Metab. 2010;95:496–502.
Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab. 2009;94:1251–4.
Mooradian AD. Subclinical hypothyroidism in the elderly: to treat or not to treat? Am J Ther. 2011;18:477–86.
Peeters RP, Visser TJ. Metabolism of thyroid hormone. Endotext [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK285545/. Accessed 1 Sep 2019.
Pasqualetti G, Calsolaro V, Bernardini S, Linsalata G, Bigazzi R, Caraccio N, et al. Degree of peripheral thyroxin deiodination, frailty, and long-term survival in hospitalized older patients. J Clin Endocrinol Metab. 2018;103:1867–76.
Mooradian AD, Lieberman J. Age-related decrease in serum angiotensin converting enzyme activity: the role of thyroidal status and food intake. J Gerontol Biol Sci. 1990;45:B24–7.
Gambert SR. Effect of age on basal and 3,5,3′ triiodothyronine (T3) stimulated human mononuclear cell sodium-potassium adenosine-triphosphatase (Na+–K+ ATP’ase) activity. Horm Metab Res. 1986;18:649–50.
Davis PJ, Davis FB, Blas SD, Schoenl M, Edwards L. Donor age-dependent decline in response of human red cell Ca2+-ATPase activity to thyroid hormone in vitro. J Clin Endocrinol Metab. 1987;64:921–5.
Davis FB, Deziel MR, Van Liew JB, et al. Effects of caloric restriction and aging on erythrocyte membrane Ca2+-ATPase activity in specific pathogen free Fischer 344 rats. Metabolism. 1991;40:819–24.
Segal J, Troen BR. Effect of age on the 3,5,3′-tri-iodothyronine-induced increase in sugar uptake in rat thymocytes. J Endocrinol. 1986;110:511–5.
Gambert SR, Ingbar SH, Hagen EC. Interaction of age and thyroid hormone status on Na+–K+–ATPase in rat renal cortex and liver. Endocrinology. 1981;108:27–30.
Chehade J, Kim J, Pinnas JL, Mooradian AD. Age-related changes in the thyroid hormone effects on malondialdehyde modified proteins in the rat heart. Proc Soc Exp Biol Med. 1999;222:59–64.
Mooradian AD, Deebaj L, Wong NCW. Age-related alterations in the response of hepatic lipogenic enzymes to altered thyroid states in the rat. J Endocrinol. 1991;128:79–84.
Mooradian AD, Albert SG. The age-related changes in lipogenic enzymes: the role of dietary factors and thyroid hormone responsiveness. Mech Age Develop. 1999;108:139–49.
Mooradian AD, Wong NCW, Shah GN. Age-related changes in the responsiveness of apolipoprotein A1 to thyroid hormone. Am J Physiol. 1996;271:R1602–7.
Mooradian AD, Fox-Robichaud A, Meijer ME, Wong NCW. Relationship between transcription factors and S14 gene expression in response to thyroid hormone and age. Proc Soc Exp Biol Med. 1994;207:97–101.
Maciel LM, Polikar R, Rohrer D, Popovich BK, Dillmann WH. Age-induced decreases in the messenger RNA coding for the sarcoplasmic reticulum Ca2(+)-ATPase of the rat heart. Circ Res. 1990;67:230–4.
Effron MB, Bhatnager GM, Spurgeon HA, Ruano-Arroyo G, Lakatta EG. Changes in myosin isoenzymes, ATPase activity and contraction duration in rat cardiac muscle with aging can be modulated by thyroxine. Circ Res. 1987;60:238–45.
O’Neil L, Holbrook N, Lakatta EG. Progressive changes from young adult age to senescence in mRNA for rat cardiac myosin heavy chain. Cardioscience. 1992;2:1–5.
Mooradian AD, Chehade J, Kim J. Age-related changes in thyroid hormone effects on glucose transporter isoforms of rat heart. Life Sci. 1999;65:981–9.
Mooradian AD, Scarpace PJ. The response of isoproterenol-stimulated adenylate cyclase activity after administration of l-triiodothyronine is reduced in aged rats. Horm Metab Res. 1989;21:638–9.
Scarpace PJ, Abrass IB. Thyroid hormone regulation of beta-adrenergic receptor number in aging rats. Endocrinology. 1981;108:1276–8.
Gresik EW, Wenk-Salamone K, Onetti-Muda A, Gubits RM, Shaw PA. Effect of advanced age on the induction by androgen or thyroid hormone of epidermal growth factor and epidermal growth factor mRNA in the submandibular glands of C57BL/6 male mice. Mech Ageing Dev. 1986;34:175–89.
Gresik EW, Maruyama S. Inductive effects of triiodothyronine or dihydrotestosterone on EGF in the submandibular glands of young, middle-aged, and old C57BL/6NNia female mice. J Gerontol. 1987;42:491–6.
Haas MJ, Mreyoud A, Fishman M, Mooradian AD. Microarray analysis of thyroid hormone-induced changes in mRNA expression in the adult rat brain. Neurosci Lett. 2004;365:14–8.
Mooradian AD, Scarpace PJ. β-Adrenergic receptor activity of cerebral microvessels is reduced in aged rats. Neurochem Res. 1991;16:447–51.
Mooradian AD, Scarpace PJ. 3,5,3′-l-triiodothyronine regulation of B-adrenergic receptor density and adenylyl cyclase activity in synaptosomal membranes of aged rats. Neurosci Lett. 1993;161:101–4.
Mooradian AD, Girgis WE, Shah GN. Thyroid hormone-induced GLUT-1 expression in rat cerebral tissue: effect of age. Brain Res. 1997;747:144–6.
Shah GN, Li J, Mooradian AD. Novel translational repressor (NAT-1) expression is modified by thyroid state and age in brain and liver. Eur J Endocrinol. 1999;139:649–53.
Mooradian AD, Li J, Shah GN. Age-related changes in thyroid hormone responsiveness protein (THRP) expression in cerebral tissue of rats. Brain Res. 1998;793:302–4.
Mooradian AD, Habib MP, Dickerson F, Yetskievych T. The effect of age on l-3,5,3′, triiodothyronine induced ethane exhalation. J Appl Physiol. 1994;77:160–4.
Mooradian AD. Age-related differences in body weight loss in response to altered thyroidal status. Exp Gerontol. 1990;25:29–35.
Mooradian AD. The hepatic transcellular transport of 3,5,3′-triiodothyronine is reduced in aged rats. Biochim Biophys Acta. 1990;1054:1–7.
Mooradian AD. Blood–brain transport of triiodothyronine is reduced in aged rats. Mech Ageing Dev. 1990;52:141–7.
Kvetny J. Nuclear thyroxine and triiodothronine binding in mononuclear cells in dependence of age. Horm Metab Res. 1985;17:35–8.
Jang M, DiStefano JJ 3rd. Some quantitative changes in iodothyronine distribution and metabolism in mild obesity and aging. Endocrinology. 1985;116:457–68.
Visser WE, Bombardieri CR, Zevenbergen C, et al. Tissue-specific suppression of thyroid hormone signaling in various mouse models of aging. PLoS One. 2016;11(3):e0149941.
Onigata K, Szinnai G. Resistance to thyroid hormone. Endocr Dev. 2014;26:118–29.
Ochs N, Auer R, Bauer DC, et al. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med. 2008;148:832–45.
Forti P, Olivelli V, Rietti E, Maltoni B, Pirazzoli G, Gatti R, et al. Serum thyroid-stimulating hormone as a predictor of cognitive impairment in an elderly cohort. Gerontology. 2012;58:41–9.
Winkler A, Weimar C, Jöckel KH, Erbel R, Dragano N, Broecker-Preuss M, et al. Thyroid-stimulating hormone and mild cognitive impairment: results of the Heinz Nixdorf recall study. J Alzheimers Dis. 2016;49:797–807.
Chaker L, Baumgartner C, den Elzen WP, et al. Subclinical hypothyroidism and the risk of stroke events and fatal stroke: an individual participant data analysis. J Clin Endocrinol Metab. 2015;100:2181–91.
Razvi S, Shakoor A, Vanderpump M, et al. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a metaanalysis. J Clin Endocrinol Metab. 2008;93:2998–3007.
Pasqualetti G, Pagano G, Rengo G, Ferrara N, Monzani F. Subclinical hypothyroidism and cognitive impairment: systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100:4240–8.
Ojala AK, Schalin-Jäntti C, Pitkälä KH, Tilvis RS, Strandberg TE. Serum thyroid-stimulating hormone and cognition in older people. Age Ageing. 2016;45:155–7.
Gussekloo J, van Exel E, de Craen AJ, et al. Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004;292:2591–9.
Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006;295:1033–41.
Chueire VB, Romaldini JH, Ward LS. Subclinical hypothyroidism increases the risk for depression in the elderly. Arch Gerontol Geriatr. 2007;44:21–8.
Mariotti S. Thyroid function and aging: do serum 3,5,3′-triiodothyronine and thyroid-stimulating hormone concentrations give the Janus response? J Clin Endocrinol Metab. 2005;90:6735–7.
Mobbs CV, Bray GA, Atkinson RL, et al. Neuroendocrine and pharmacological manipulations to assess how caloric restriction increases life span. J Gerontol. 2001;56A:34–44.
Blanc S, Schoeller D, Kemnitz J, et al. Energy expenditure of rhesus monkeys subjected to 11 years of dietary restriction. J Clin Endocrinol Metab. 2003;88:16–23.
Ooka H, Shinkai T. Effects of chronic hyperthyroidism on the lifespan of the rat. Mech Ageing Dev. 1986;33:275–82.
Speakman JR, Selman C, McLaren JS, et al. Living fast, dying when? The link between aging and energetics. J Nutr. 2002;132(Suppl. 2):S1538–97.
Rieben C, Segna D, da Costa BR, et al. Subclinical thyroid dysfunction and the risk of cognitive decline: a meta-analysis of prospective cohort studies. J Clin Endocrinol Metab. 2016;101:4945–54.
Aubert CE, Bauer DC, da Costa BR, et al. The association between subclinical thyroid dysfunction and dementia: the Health, Aging and Body Composition (Health ABC) Study. Clin Endocrinol (Oxf). 2017;87:617–26.
Gan EH, Pearce SH. Clinical review: the thyroid in mind: cognitive function and low thyrotropin in older people. J Clin Endocrinol Metab. 2012;97:3438–49.
Annerbo S, Lökk J. A clinical review of the association of thyroid stimulating hormone and cognitive impairment. ISRN Endocrinol. 2013;2013:856017.
Moon JH, Park YJ, Kim TH, et al. Lower-but-normal serum TSH level is associated with the development or progression of cognitive impairment in elderly: Korean Longitudinal Study on Health and Aging (KLoSHA). J Clin Endocrinol Metab. 2014;99:424–32.
Delitala AP. Subclinical hyperthyroidism and the cardiovascular disease. Horm Metab Res. 2017;49:723–31.
Williams GR, Bassett JHD. Thyroid diseases and bone health. J Endocrinol Invest. 2018;41:99–109.
Ostan R, Monti D, Mari D, et al. Heterogeneity of thyroid function and impact of peripheral thyroxine deiodination in centenarians and semi-supercentenarians: association with functional status and mortality. J Gerontol A Biol Sci Med Sci. 2019;16(74):802–10.
Stott DJ, Rodondi N, Kearney PM, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376:2534–44.
Franceschi C, Ostan R, Mariotti S, Monti D, Vitale G. The aging thyroid: a reappraisal within the geroscience integrated perspective. Endocr Rev. 2019;40:1250–70.
Piehl S, Hoefig CS, Scanlan TS, Köhrle J. Thyronamines: past, present, and future. Endocr Rev. 2011;32:64–80.
Groeneweg S, Peeters RP, Visser TJ, Visser WE. Therapeutic applications of thyroid hormone analogues in resistance to thyroid hormone (RTH) syndromes. Mol Cell Endocrinol. 2017;458:82–90.
No funding was received for the preparation of this article.
Conflict of interest
Arshag D. Mooradian has no conflicts of interest that are directly relevant to the content of this article.
About this article
Cite this article
Mooradian, A.D. Age-Related Resistance to Thyroid Hormone Action. Drugs Aging 36, 1007–1014 (2019). https://doi.org/10.1007/s40266-019-00711-7