Last Update: February 12, 2026
Silent Information Regulator 2 Homologue 1 (SIRT1) (also called Sirtuin 1)
- OVERALL: Fluoride - T3 antagonism:
T3 increases SIRT1, fluoride decreases SIRT1 (depending on cell types and organ systems)
SIRT1 & Fluoride
Chhabra V, Swamy RS, Reddy ART, Bhushan R, Shenoy S, Maiti S, Abubakar, Meenakshi S, Murti K, Kumar N - "Naringin alleviates fluoride-induced neurodevelopmental disorders by modulation of SIRT1, autophagy, mitochondrial fission, and ROS generation" Naunyn Schmiedebergs Arch Pharmacol. (2025) doi: 10.1007/s00210-025-04398-z.
https://link.springer.com/article/10.10 ... 25-04398-z
NaF-: 10 ppm in drinking water
Chen D, Liu X, Zeng X, Ge Q, Xie C, Dong Y, Deng J, Guan Z - "Expression of silent information regulator in brains of rats with chronic fluorosis and its correlation with the ability of learning and memory" Chinese Journal of Endemiology (12):265-270 (2018) PFPC Library
https://pesquisa.bvsalud.org/portal/res ... wpr-701312
"After 3 and 6 months of fluoride treatment, the expression of SIRT1 protein and mRNA expression in the hippocampus and cortex of rats in the high-fluoride group were significantly lower than those in the control group... After 3 and 6 months of fluoride exposure, SIRT1 protein expression in the hippocampus and cortex of rats was negatively correlated with escape latency and positively correlated with the number of times rats crossed platforms. Conclusion: The reduced learning and memory abilities in rats with chronic fluoride poisoning may be related to the decreased SIRT1 protein expression level in rat brain tissue caused by chronic fluoride poisoning."
Dong S, Yang Y, He B, Xu Z, Zhou Z, Wang J, Chen C, Chen Q - "Effect of Sodium Fluoride on Reproductive Function Through Regulating Reproductive Hormone Level and Circulating SIRT1 in Female Rats" Biol Trace Elem Res 201(4):1825-1836 (2023) doi: 10.1007/s12011-022-03283-7
https://link.springer.com/article/10.10 ... 22-03283-7
Fathima A, Bagang N, Kumar N, Dastidar SG, Shenoy S - "Role of SIRT1 in Potentially Toxic Trace Elements (Lead, Fluoride, Aluminum and Cadmium) Associated Neurodevelopmental Toxicity" Biol Trace Elem Res 202(12):5395-5412 (2024) doi: 10.1007/s12011-024-04116-5
https://pmc.ncbi.nlm.nih.gov/articles/PMC11502598/
Gu X, Wang Z, Gao J, Han D, Zhang L, Chen P, Luo G, Han B - "SIRT1 suppresses p53-dependent apoptosis by modulation of p21 in osteoblast-like MC3T3-E1 cells exposed to fluoride" Toxicol In Vitro 57:28-38 (2019). doi: 10.1016/j.tiv.2019.02.006
https://www.sciencedirect.com/science/a ... 3318307136
Gu Y, Shi Y, Wei B, Zhao Y, Huo M, Zeng L, Zhao Z, Song Y, Yu X, Chen Y, Sun M - "Gestational fluoride exposure compromises ovarian function via SIRT1-ATF4 axis in female offspring" Ecotoxicol Environ Saf 311:119872 (2026)
https://doi.org/10.1016/j.ecoenv.2026.119872
Guo L, Yang B, Chen F, Yuan X, Cheng J, Chen X, Zhou Y, Yang X, Li Y, Liu Y, Tang D, Wang F - "Disruption of the SIRT1/PI3K/AKT Signaling Axis Mediates Fluoride-Induced Cardiotoxicity: Evidence from in Vitro and Zebrafish Models" Biol Trace Elem Res (2025) doi: 10.1007/s12011-025-04828-2.
https://pubmed.ncbi.nlm.nih.gov/40963040/
"F induces cardiotoxicity by disrupting the SIRT1/PI3K/AKT signaling pathway, leading to increased oxidative stress, inflammation, and apoptosis."
Liu Y, Li Y, Wang N, Liu Z, Li H, Liu Y, Wang F - "Expression of Sirtuin1 gene in brain tissues of fluorotoxic rats" Chinese Journal of Endemiology (12):30-34 (2018)
"The levels of SIRT1 mRNA and protein were gradually decreased with increase of fluoride dose in the low, middle and high fluoride groups."
Liu B, Pang S, Zhu S, Wei D, Xie F, Zhang Q, Yang L, Fu G, Tian R, Lei J, Li X, Gao Y, Wei W - "Tregs are key mediators of renal dysfunction induced by low-dose fluoride exposure" J Nutr Biochem 110298 (2026)
https://doi.org/10.1016/j.jnutbio.2026.110298
"Low fluoride exposure inhibited SIRT1 in human peripheral Tregs and decreased SIRT1 and P300 levels in rat peripheral and renal Tregs."
Peng W, Xu S, Zhang J, Zhang Y - "Vitamin C Attenuates Sodium Fluoride-Induced Mitochondrial Oxidative Stress and Apoptosis via Sirt1-SOD2 Pathway in F9 Cells" Biol Trace Elem Res 191(1):189-198 (2019) doi: 10.1007/s12011-018-1599-0
https://link.springer.com/article/10.10 ... 018-1599-0
Ram Mohan SD, Shashidhar KN, Anjanappa R, Chandrappa M - "Estimation of Fluoride and Sirtuin1 in Patients with Diabetic Nephropathy in Kolar District of Karnataka, India" J Lab Physicians 14(1):57-64 (2021). doi: 10.1055/s-0041-1732817
https://www.thieme-connect.com/products ... 41-1732817
"The alterations in serum sirtuin1 levels indicate the severity of damage due to stress during hyperglycemia and toxicity in fluorosis, hence sirtuin1 can be considered a biomarker of aging. Subsequently, the correlation of CML, eGFR, and fluoride with sirtuin1 indicates that increasing sirtuin1 may defend the forthcoming damage, hence could be considered in therapeutics."
Suzuki M, Ikeda A, Bartlett JD - "Sirt1 overexpression suppresses fluoride-induced p53 acetylation to alleviate fluoride toxicity in ameloblasts responsible for enamel formation" Arch Toxicol 92(3):1283-1293 (2018)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667832/
"Our results suggest that SIRT1 deacetylates Ac-p53 to mitigate fluoride-induced cell growth inhibition, mitochondrial damage, DNA damage and apoptosis. This is the first report implicating Ac-p53 in fluoride toxicity."
Suzuki M, Bandoski C, Bartlett JD - "Fluoride induces oxidative damage and SIRT1/autophagy through ROS-mediated JNK signaling" Free Radic Biol Med 89:369-78 (2015). doi: 10.1016/j.freeradbiomed.2015.08.015
https://linkinghub.elsevier.com/retriev ... 15)00567-5
Tu W, Zhang Q, Liu Y, Han L, Wang Q, Chen P, Zhang S, Wang A, Zhou X - "Fluoride induces apoptosis via inhibiting SIRT1 activity to activate mitochondrial p53 pathway in human neuroblastoma SH-SY5Y cells" Toxicol Appl Pharmacol 347:60-69 (2018) doi: 10.1016/j.taap.2018.03.030
https://www.sciencedirect.com/science/a ... 8X18301224
Wang F, Li Y, Tang D, Yang B, Tian T, Tian M, Meng N, Xie W, Zhang C, He Z, Zhu X, Ming D, Liu Y - "Exploration of the SIRT1-mediated BDNF-TrkB signaling pathway in the mechanism of brain damage and learning and memory effects of fluorosis" Front Public Health 11:1247294 (2023) doi: 10.3389/fpubh.2023.1247294
https://www.frontiersin.org/articles/10 ... 47294/full
"The fluoride-exposed rat brain tissue had abnormal AchE and ChAT activity, sparsely arranged hippocampal neurons, blurred cell boundaries, significantly fewer astrocytes, and swollen cells. Furthermore, the nucleoli were absent from the fluoride-exposed rat brain tissue, which also contained folded neuron membranes, deformed mitochondria, absent cristae, vacuole formation, and pyknotic and hyperchromatic chromatin. The fluoride exposure groups had lower SIRT1, BDNF, and TrkB protein levels and higher apoptotic protein levels than the control group, which were closely related to the fluoride dose. The findings demonstrated that excessive fluoride caused brain damage and affected learning and memory abilities."
Wang F, Liu Y, Li Y, Yang X, Zhao J, Yang B, Tang D, Zhang C, He Z, Ming D, Zhu X - "Combining Network Pharmacology and Experimental Verification to Ascertain the Mechanism of Action of Asparagus officinalis Against the Brain Damage Caused by Fluorosis" Environ Toxicol (2024)10.1002/tox.24382.
https://onlinelibrary.wiley.com/doi/10.1002/tox.24382
"Enrichment analyses showed that 'mitogen-activated protein kinase' (MAPK), 'phosphoinositide 3-kinase/protein kinase B' (PI3K-Akt), 'nuclear factor-kappa B' (NF-κB), and the 'neurotrophin signaling pathway' were the most enriched biological processes and signaling pathways...Upon ASP treatment, expression of silent information regulator (SIRT)1, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), MAPK, NF-κB, PI3K, Akt, and B-cell lymphoma-2 in rat brain tissue increased gradually, whereas that of Bax, caspase-3, and p53 decreased gradually. We demonstrated that ASP could regulate the brain damage caused by fluorosis through the SIRT1/BDNF/TrkB signaling pathway, and reported the possible part played by ASP in preventing and treating fluorosis."
Wang D, Yin K, Zhang Y, Lu H, Hou L, Zhao H, Xing M - "Novel pathways of fluoride-induced hepatotoxicity: P53-dependent ferroptosis induced by the SIRT1/FOXOs pathway and Nrf2/HO-1 pathway" Comp Biochem Physiol C Toxicol Pharmacol 264:109526 (2023) doi: 10.1016/j.cbpc.2022.109526.
https://linkinghub.elsevier.com/retriev ... 22)00261-7
"SIRT1/FOXOs pathway can cause the activation of the Nrf2/HO-1 pathway under the condition of fluorosis, and can activate the P53-dependent ferroptosis pathway"
Yang B, Wang F, Yang X, Yuan X, Yang Y, Chen X, Tian T, Chen F, Tang D, He Z, Liu Y, Li Y - "The Role of SIRT1-BDNF Signaling Pathway in Fluoride-Induced Toxicity for Glial BV-2 Cells" Biol Trace Elem Res (2025) doi: 10.1007/s12011-024-04503-y
https://link.springer.com/article/10.10 ... 24-04503-y
"The fluoride-exposed groups had reduced SIRT1, BDNF, TrkB, PI3K, AKT, and MAPK protein expression levels, and increased FOXO1A protein expression. SRT1720 mitigated the harmful effects of NaF, stimulated cell proliferation and cell cycle progression, decreased apoptosis, reduced oxidative stress and inflammatory factors, elevated SIRT1, BDNF, TrkB, PI3K, AKT, and MAPK protein levels, and suppressed FOXO1A protein expression. The results indicate that NaF potentially harms glial cells by suppressing SIRT1 activation, and SIRT1 significantly mitigated the damage."
Xu Z, Dong S, Zhao Y, Yang Z, Chen Q - "Effects of SIRT1 on the reproductive function damaged by fluorosis" Foreign Medicine (Medical Geography Section) (3):296-298 (2017). PFPC Library
Zhao Q, Zhou GY, Niu Q, Chen JW, Li P, Tian ZY, Li DJ, Xia T, Zhang S, Wang AG- " SIRT1, a target of miR-708-3p, alleviates fluoride-induced neuronal damage via remodeling mitochondrial network dynamics" J Adv Res 65:197-210 (2024) doi: 10.1016/j.jare.2023.11.032
https://www.sciencedirect.com/science/a ... 3223003715
PFAS
Duan X, Sun W, Sun H, Zhang - "Perfluorooctane sulfonate continual exposure impairs glucose-stimulated insulin secretion via SIRT1-induced upregulation of UCP2 expression" Environ Pollut 278:116840 (2021) doi: 10.1016/j.envpol.2021.116840
https://linkinghub.elsevier.com/retriev ... 21)00420-6
"Results suggested that PFOS continual exposure could inhibit SIRT1 activity, and the SIRT1-UCP2 pathway mediated, at least partially, the PFOS induced GSIS impairment."
Sonkar R, Kay MK, Choudhury M - "PFOS Modulates Interactive Epigenetic Regulation in First-Trimester Human Trophoblast Cell Line HTR-8/SVneo" Chem Res Toxicol 32(10):2016-2027 (2019) doi: 10.1021/acs.chemrestox.9b00198
https://pubs.acs.org/doi/abs/10.1021/ac ... ox.9b00198
PFOS clearly decreased the gene and protein expression of DNA methyltransferases (DNMTs; DNMT1, 3A, and 3B) and histone deacetylase sirtuins (SIRTs; SIRT1 and 3) in placental cells.
Wang L, Zhou Y, Ma X, Sun W, Liu H - "Perfluorooctanoic acid-induced lipid metabolism disorder in SD rat liver and its effect on the expression of fatty acid metabolism-related proteins" Journal of Central South University (Medical Sciences) 47(1):18-25 (2022) doi: 10.11817/j.issn.1672-7347.2022.210320
https://pmc.ncbi.nlm.nih.gov/articles/PMC10930491/
"PFOA exposure can cause lipid metabolism disorder and glycogen reduction in SD rat livers, which may be related to the activation of Sirt1 and inhibition of Ppar γ expression, leading to affecting the normal metabolism of fatty acids and promoting glycolysis."
Zheng J, Wang Q, Xu K, Ma M, Wang Z, Sun Z, Yang S, Wang X, Yan N, Duan X - "Fluoride induces immune-inflammatory disorder in the kidneys via histone lysine crotonylation in vivo" Ecotoxicol Environ Saf 288:117385 (2024)
https://doi.org/10.1016/j.ecoenv.2024.117385
NOTE: "NaF increased the protein expression of histone decrotonylation enzyme sirtuin1 (sirt1) and histone deacetylase 3 (HDAC3) and upregulated HDAC2 protein."
Thyroid Hormone
Cordeiro A, de Souza LL, Oliveira LS, Faustino LC, Santiago LA, Bloise FF, Ortiga-Carvalho TM, Almeida NA, Pazos-Moura CC - "Thyroid hormone regulation of Sirtuin 1 expression and implications to integrated responses in fasted mice" J Endocrinol 216(2):181-93 (2013). doi: 10.1530/JOE-12-0420
https://pubmed.ncbi.nlm.nih.gov/23151359/
El Agaty SM - "Triiodothyronine improves age-induced glucose intolerance and increases the expression of sirtuin-1 and glucose transporter-4 in skeletal muscle of aged rats" Gen Physiol Biophys 37(6):677-686 (2018) doi: 10.4149/gpb_2018026
https://pubmed.ncbi.nlm.nih.gov/30431435/
Gencarelli M, Lodovici M, Bellusci L, Raimondi L, Laurino A - "Redox Properties of 3-Iodothyronamine (T1AM) and 3-Iodothyroacetic Acid (TA1)" Int J Mol Sci 23(5):2718 (2022). doi: 10.3390/ijms23052718
https://pubmed.ncbi.nlm.nih.gov/35269859/
Gothié JD, Sébillot A, Luongo C, Legendre M, Nguyen Van C, Le Blay K, Perret-Jeanneret M, Remaud S, Demeneix BA - "Adult neural stem cell fate is determined by thyroid hormone activation of mitochondrial metabolism" Mol Metab 6(11):1551-1561 (2017) doi: 10.1016/j.molmet.2017.08.003
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681236/
Hasegawa K, Kawahara T, Fujiwara K, Shimpuku M, Sasaki T, Kitamura T, Yoshikawa K - "Necdin controls Foxo1 acetylation in hypothalamic arcuate neurons to modulate the thyroid axis" J Neurosci 32(16):5562-72 (2012) doi: 10.1523/JNEUROSCI.0142-12.2012
https://www.jneurosci.org/content/32/16/5562.long
Hepp M, Werion A, De Greef A, de Ville de Goyet C, de Bournonville M, Behets C, Lengelé B, Daumerie C, Mourad M, Ludgate M, Many MC, Joris V, Craps J - "Oxidative Stress-Induced Sirtuin1 Downregulation Correlates to HIF-1α, GLUT-1, and VEGF-A Upregulation in Th1 Autoimmune Hashimoto's Thyroiditis" Int J Mol Sci. 22(8):3806 (2021). doi: 10.3390/ijms22083806
"Th1 cytokines also induced a significant decrease of SIRT1 protein expression associated with an upregulation of HIF-1α, GLUT-1, and VEGF-A proteins. With the exception of PRDX1 and SOD1, similar results were obtained in HT [Hashimoto's] thyroids."
NOTE: Gq/11 is required for VEGF upregulation.
López-Mateo I, Rodríguez-Muñoz D, de La Rosa JV, Castrillo A, Alemany S, Aranda A - "Regulation of metabolic and transcriptional responses by the thyroid hormone in cellular models of murine macrophages" Front Immunol 13:923727 (2022) doi: 10.3389/fimmu.2022.923727
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353060/
"We show here that the thyroid hormone T3 is an absolute requirement for the growth of immortal macrophages...The hormone regulates the activity of the main signaling pathways required for proliferation and anabolic processes, including the phosphorylation of ERK and p38 MAPKs, AKT, ribosomal S6 protein, AMPK and Sirtuin-1."
Roehlen N, Doering C, Hansmann ML, Gruenwald F, Vorlaender C, Bechstein WO, Holzer K, Badenhoop K, Penna-Martinez M - "Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer" Front Endocrinol (Lausanne) 9:527 (2018). doi: 10.3389/fendo.2018.00527.
"FOXO3a rs9400239T and rs4945816C may constitute risk factors for HT, independent of the vitamin D status.This indicates the implication of FOXO3a in pathogenesis of autoimmune thyroid diseases. The dependency of anti-proliferative vitamin D effects on SIRT1 activity further suggests a key role of vitamin D-SIRT1-FOXO3a axis for protective vitamin D effects."
Sacripanti G, Lorenzini L, Bandini L, Frascarelli S, Zucchi R, Ghelardoni S - "3-Iodothyronamine and 3,5,3'-triiodo-L-thyronine reduce SIRT1 protein expression in the HepG2 cell line" Horm Mol Biol Clin Investig (2020) 41(1):/j/hmbci.2020.41.issue-1/hmbci-2019-0045/hmbci-2019-0045.xml. doi: 10.1515/hmbci-2019-0045
https://www.degruyter.com/document/doi/ ... -0045/html
Sarumaru M, Watanabe M, Inoue N, Hisamoto Y, Morita E, Arakawa Y, Hidaka Y, Iwatani Y - "Association between functional SIRT1 polymorphisms and the clinical characteristics of patients with autoimmune thyroid disease" Autoimmunity 49(5):329-37 (2016). doi: 10.3109/08916934.2015.1134506.
https://www.tandfonline.com/doi/10.3109 ... 15.1134506
"Polymorphisms in the SIRT1 gene were associated with a greater production of thyroid autoantibodies."
Vidali S, Chéret J, Giesen M, Haeger S, Alam M, Watson REB, Langton AK, Klinger M, Knuever J, Funk W, Kofler B, Paus R - "Thyroid Hormones Enhance Mitochondrial Function in Human Epidermis" J Invest Dermatol 136(10):2003-2012 (2016) doi: 10.1016/j.jid.2016.05.118
"Triiodothyronine increased sirtuin-1, fibrillin-1, proliferator-activated receptor-gamma 1-alpha (PGC1α), collagen I and III transcription, and thyroxine decreased cyclin-dependent kinase inhibitor 2A (p16(ink4)) expression in organ-cultured human skin."
Wang X, Mao J, Zhou X, Li Q, Gao L, Zhao J - "Thyroid Stimulating Hormone Triggers Hepatic Mitochondrial Stress through Cyclophilin D Acetylation" Oxid Med Cell Longev 2020:1249630 (2020). doi: 10.1155/2020/1249630
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970002/
"TSH stimulates hepatic CypD acetylation through the lncRNA-AK044604/SIRT1/SIRT3 signaling pathway, indicating an essential role for TSH in mitochondrial stress in the liver."
Wei X, Tan J, Gao H - "Role of sirtuin 1 in the brain development in congenital hypothyroidism rats via the regulation of p53 signaling pathway" Bioengineered 13(4):9455-9466 (2022) doi: 10.1080/21655979.2022.2060626
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9161855/
Wu W, Cao X, Wang Y - "The role of miRNA-624-5p in congenital hypothyroidism and its molecular mechanism by targeting SIRT1" Genes Genomics. 44(9):1137-1147 (2022). doi: 10.1007/s13258-021-01171-3
https://link.springer.com/article/10.10 ... 21-01171-3
"SIRT1 was a direct target of miR-624-5p. MiR-624-5p inhibitor signally enhanced fT4 levels and reduced TSH levels in the plasma of CH rats, and improved CH rat depressive behaviors by targeting SIRT1."
Zhao X, Cao Y, Jin H, Wang X, Zhang L, Zhang Y, Yu Y, Huang Y, Gao Y, Zhang J - "Hydrogen Sulfide Promotes Thyroid Hormone Synthesis and Secretion by Upregulating Sirtuin-1" Front Pharmacol 13:838248 (2022) doi: 10.3389/fphar.2022.838248
https://www.frontiersin.org/journals/ph ... 38248/full
"Serum H2S levels are decreased with hypothyroidism. H2S promotes the synthesis and secretion of thyroid hormones and the expression of related molecules by upregulating SIRT1."
- See also MAPK, PI3K, BDNF, p53, p21 -> posts on the forum.
PI3K: viewtopic.php?f=7&t=6440
p53: viewtopic.php?f=7&t=6009
Members:
BDNF: viewtopic.php?f=30&t=3917