Thyroid Hormones and Aging: Modulators of Mitochondrial Health, Metabolic Flexibility, and Longevity Pathways

Abstract

Thyroid hormones, primarily triiodothyronine (T3) and thyroxine (T4), are critical regulators of metabolic rate, mitochondrial function, and cellular repair mechanisms. Emerging evidence suggests that thyroid status may significantly influence aging trajectories and longevity through modulation of key cellular pathways. This review explores the role of thyroid hormones in aging biology, with a focus on their interaction with longevity-associated signaling pathways and the hallmarks of aging. Both physiological and subclinical thyroid states in the context of healthspan, cognitive preservation, metabolic resilience, and mitochondrial integrity are explored. A narrative synthesis of human and animal studies was conducted, including mechanistic, epidemiologic, and clinical data, to evaluate how thyroid hormone levels affect aging pathways such as mechanistic target of rapamycin, AMP-activated protein kinase, IGF-1, sirtuins, FOXO transcription factors, and mitochondrial biogenesis. Thyroid hormones modulate several hallmarks of aging, including mitochondrial dysfunction, genomic instability, epigenetic drift, and deregulated nutrient sensing. T3 enhances mitochondrial respiration and autophagy while interacting with mechanistic target of rapamycin and AMP-activated protein kinase to regulate energy balance. Altered thyroid function—particularly subclinical hypothyroidism—has been paradoxically associated with increased longevity in some centenarian cohorts, possibly due to reduced oxidative metabolism. However, overt thyroid dysfunction is linked to increased metabolic risk in aging populations. Thyroid hormones serve as metabolic gatekeepers that influence both cellular aging and organismal longevity. A deeper understanding of their role in aging pathways may inform novel strategies for promoting healthy aging, including thyroid hormone modulation and personalized endocrine optimization.

Keywords

thyroid hormone - aging - longevity pathways - integrative endocrinology - mitochondrial function

Publication History

Received: 11 August 2025

Accepted after revision: 08 September 2025

Accepted Manuscript online:
08 September 2025

Article published online:
20 October 2025

• References

• 1 United Nations Department of Economic and Social Affairs. World population ageing 2023: highlights. United Nations; 2023 https://www.un.org/development/desa/pd/content/launch-World-Population-Ageing-2023
• 2 Partridge L, Deelen J, Slagboom PE.. Facing up to the global challenges of ageing. Nature 2018; 561 (7721) 45-56
• 3 Mullur R, Liu YY, Brent GA.. Thyroid hormone regulation of metabolism. Physiol Rev 2014; 94: 355-382
• 4 Davis PJ, Goglia F, Leonard JL.. Nongenomic actions of thyroid hormone. Nat Rev Endocrinol 2016; 12: 111-121
• 5 Taylor PN, Lansdown A, Witczak J. et al. Age-related variation in thyroid function - a narrative review highlighting important implications for research and clinical practice. Thyroid Res 2023; 16: 7
• 6 Patel J, Landers K, Li H. et al. Thyroid hormones and fetal neurological development. J Endocrinol 2011; 209: 1-8
• 7 López-Otín C, Blasco MA, Partridge L. et al. The hallmarks of aging. Cell 2013; 153: 1194-1217
• 8 Brent GA.. Mechanisms of thyroid hormone action. J Clin Invest 2012; 122: 3035-3043
• 9 Bianco AC, Anderson G, Forrest D. et al. American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid 2014; 24: 88-168
• 10 Gereben B, Zavacki AM, Ribich S. et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 2008; 29: 898-938
• 11 Galton VA.. The roles of the iodothyronine deiodinases in mammalian development. Thyroid 2005; 15: 823-834
• 12 Weitzel JM, Iwen KA.. Coordination of mitochondrial biogenesis by thyroid hormone. Mol Cell Endocrinol 2011; 342: 1-7
• 13 Klein I, Danzi S.. Thyroid disease and the heart. Circulation 2007; 116: 1725-1735
• 14 Ortiga-Carvalho TM, Sidhaye AR, Wondisford FE.. Thyroid hormone receptors and resistance to thyroid hormone disorders. Nat Rev Endocrinol 2014; 10: 582-591
• 15 Biondi B, Cooper DS.. The clinical significance of subclinical thyroid dysfunction. Endocr Rev 2008; 29: 76-131
• 16 Yen PM.. Physiological and molecular basis of thyroid hormone action. Physiol Rev 2001; 81: 1097-1142
• 17 Villanueva I, Alva-Sánchez C, Pacheco-Rosado J.. The role of thyroid hormones as inductors of oxidative stress and neurodegeneration. Oxid Med Cell Longev 2013; 2013: 218145
• 18 Hernandez A, Martinez ME, Chaves C. et al. Epigenetic developmental programming and intergenerational effects of thyroid hormones. Vitam Horm 2023; 122: 23-49
• 19 Zhou J, Sinha RA, Yen PM.. The roles of autophagy and thyroid hormone in the pathogenesis and treatment of NAFLD. Hepatoma Res 2021; 7: 72
• 20 Young ARJ, Cassidy LD, Narita M.. Autophagy and senescence, converging roles in pathophysiology as seen through mouse models. Adv Cancer Res 2021; 150: 113-145
• 21 Gauthier BR, Sola-García A, Cáliz-Molina MÁ. et al. Thyroid hormones in diabetes, cancer, and aging. Aging Cell 2020; 19: e13260
• 22 Moeller LC, Führer D.. Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective. Endocr Relat Cancer 2013; 20: R19-R29
• 23 López M, Varela L, Vázquez MJ. et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 2010; 16: 1001-1008
• 24 Krassas GE, Poppe K, Glinoer D.. Thyroid function and human reproductive health. Endocr Rev 2010; 31: 702-755
• 25 Fliers E, Klieverik LP, Kalsbeek A.. Novel neural pathways for metabolic effects of thyroid hormone. Trends Endocrinol Metab 2010; 21: 230-206
• 26 Suh JH, Sieglaff DH, Zhang A. et al. SIRT1 is a direct coactivator of thyroid hormone receptor β1 with gene-specific actions. PLoS One 2013; 8: e70097
• 27 Thakran S, Sharma P, Attia RR. et al. Role of sirtuin 1 in the regulation of hepatic gene expression by thyroid hormone. J Biol Chem 2013; 288: 807-818
• 28 Cantó C, Menzies KJ, Auwerx J.. NAD(+) Metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab 2015; 22: 31-53
• 29 López M, Alvarez CV, Nogueiras R. et al. Energy balance regulation by thyroid hormones at central level. Trends Mol Med 2013; 19: 418-427
• 30 Cordeiro A, de Souza LL, Oliveira LS. et al. Thyroid hormone regulation of Sirtuin 1 expression and implications to integrated responses in fasted mice. J Endocrinol 2013; 216: 181-193
• 31 Yau WW, Singh BK, Lesmana R. et al. Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and mTOR-mediated mitophagy. Autophagy 2013; 9: 1128-1144
• 32 López-Lluch G, Navas P.. Calorie restriction as an intervention in ageing. J Physiol 2016; 594: 2043-2060
• 33 Klieverik LP, Coomans CP, Endert E. et al. Thyroid hormone effects on whole-body energy homeostasis and tissue-specific fatty acid uptake in vivo. Endocrinology 2009; 150: 5639-5648
• 34 Martínez-Iglesias O, García-Silva S, Regadera J. et al. Hypothyroidism enhances tumor invasiveness and metastasis development. PLoS One 2009; 4: e6428
• 35 Georg B, Fahrenkrug J, Jørgensen HL. et al. The circadian clock is sustained in the thyroid gland of VIP receptor 2 deficient mice. Front Endocrinol (Lausanne) 2021; 12: 737581
• 36 Ikegami K, Refetoff S, Van Cauter E. et al. Interconnection between circadian clocks and thyroid function. Nat Rev Endocrinol 2019; 15: 590-600
• 37 Atzmon G, Barzilai N, Hollowell JG. et al. Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab 2009; 94: 1251-1254
• 38 Huang SA, Bianco AC.. Reawakened interest in type 3 iodothyronine deiodinase in critical illness and injury. Nat Clin Pract Endocrinol Metab 2008; 4: 148-155
• 39 Rodondi N, den Elzen WPJ, Bauer DC. et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010; 304: 1365-1374
• 40 Biondi B, Cappola AR, Cooper DS.. Subclinical hypothyroidism: a review. JAMA 2019; 322: 153-160
• 41 Waring AC, Arnold AM, Newman AB. et al. Longitudinal changes in thyroid function in the oldest old and survival: the Cardiovascular Health Study All-Stars Study. J Clin Endocrinol Metab 2012; 97: 3944-3950
• 42 Saponaro F, Sestito S, Runfola M. et al. Selective thyroid hormone receptor-beta (TRβ) agonists: new perspectives for the treatment of metabolic and neurodegenerative disorders. Front Med (Lausanne) 2020; 7: 331
• 43 Rayman MP.. Selenium and human health. Lancet 2012; 379 (9822) 1256-1268
• 44 Garasto S, Montesanto A, Corsonello A. et al. Thyroid hormones in extreme longevity. Mech Ageing Dev 2017; 165 Pt B 98-106
• 45 Levine ME, Lu AT, Quach A. et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 2018; 10: 573-591
• 46 Horvath S, Raj K.. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 2018; 19: 371-384
• 47 Taub R, Chiang E, Chabot-Blanchet M. et al. Lipid-lowering and liver safety of the thyroid hormone receptor-β agonist eprotirome in patients with familial hypercholesterolemia. J Clin Endocrinol Metab 2013; 98: 962-970
• 48 Cho SW.. Selective agonists of thyroid hormone receptor beta: promising tools for the treatment of nonalcoholic fatty liver disease. Endocrinol Metab (Seoul) 2024; 39: 285-287
• 49 Peeters RP, van Toor H, Klootwijk W. et al. Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels. Thyroid 2003; 13: 759-768
• 50 van den Beld AW, Kaufman JM, Zillikens MC. et al. The physiology of endocrine systems with ageing. Lancet Diabetes Endocrinol 2018; 6: 647-658
• 51 Rieder R, Wisniewski PJ, Alderman BL. et al. Microbes and mental health: a review. Brain Behav Immun 2017; 66: 9-17