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The journal of nutrition, health & aging

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13-04-2023 | Epigenetics | Review

The Aryl Hydrocarbon Receptor, Epigenetics and the Aging Process

Authors: Sara Abudahab, E. T. Price, M. G. Dozmorov, L. S. Deshpande, J. L. McClay

Published in: The journal of nutrition, health & aging | Issue 4/2023

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor, classically associated with the regulation of xenobiotic metabolism in response to environmental toxins. In recent years, transgenic rodent models have implicated AhR in aging and longevity. Moreover, several AhR ligands, such as resveratrol and quercetin, are compounds proven to extend the lifespan of model organisms. In this paper, we first review AhR biology with a focus on aging and highlight several AhR ligands with potential anti-aging properties. We outline how AhR-driven expression of xenobiotic metabolism genes into old age may be a key mechanism through which moderate induction of AhR elicits positive benefits on longevity and healthspan. Furthermore, via integration of publicly available datasets, we show that liver-specific AhR target genes are enriched among genes subject to epigenetic aging. Changes to epigenetic states can profoundly affect transcription factor binding and are a hallmark of the aging process. We suggest that the interplay between AhR and epigenetic aging should be the subject of future research and outline several key gaps in the current literature. Finally, we recommend that a broad range of non-toxic AhR ligands should be investigated for their potential to promote healthspan and longevity.

Brinkmann, V., Ale-Agha, N., Haendeler, J. & Ventura, N. The Aryl Hydrocarbon Receptor (AhR) in the Aging Process: Another Puzzling Role for This Highly Conserved Transcription Factor. Front Physiol. 2020;10. doi:https://doi.org/10.3389/fphys.2019.01561.

Mayne, B., Berry, O., Davies, C., Farley, J. & Jarman, S. A genomic predictor of lifespan in vertebrates. Scientific Reports. 2019;9:17866. doi:https://doi.org/10.1038/s41598-019-54447-w.PubMedPubMedCentralCrossRef

Ros, M. & Carrascosa, J. M. Current nutritional and pharmacological anti-aging interventions. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165612. doi:https://doi.org/10.1016/j.bbadis.2019.165612.PubMedCrossRef

Miura, T., Onodera, R., Terashima, J., Ozawa, S. & Habano, W. β-naphthoflavone-induced upregulation of CYP1B1 expression is mediated by the preferential binding of aryl hydrocarbon receptor to unmethylated xenobiotic responsive elements. Exp Ther Med. 2021;22:1410. doi:https://doi.org/10.3892/etm.2021.10846.PubMedPubMedCentralCrossRef

Jiang, J. et al. Role of DNA methylation-related chromatin remodeling in aryl hydrocarbon receptor-dependent regulation of T-2 toxin highly inducible Cytochrome P450 1A4 gene. FASEB J. 2021;35:e21469. doi:https://doi.org/10.1096/fj.202002570RR.PubMedCrossRef

López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The Hallmarks of Aging. Cell. 2013;153:1194–1217. doi:https://doi.org/10.1016/j.cell.2013.05.039.PubMedPubMedCentralCrossRef

Nebert, D. W., Robinson, J. R., Niwa, A., Kumaki, K. & Poland, A. P. Genetic expression of aryl hydrocarbon hydroxylase activity in the mouse. J Cell Physiol. 1975;85:393–414. doi:https://doi.org/10.1002/jcp.1040850407.PubMedCrossRef

Poland, A. & Kende, A. 2,3,7,8-Tetrachlorodibenzo-p-dioxin: environmental contaminant and molecular probe. Fed Proc. 1976;35:2404–2411.PubMed

Bersten, D. C., Sullivan, A. E., Peet, D. J. & Whitelaw, M. L. bHLH-PAS proteins in cancer. Nature Reviews Cancer. 2013;13:827–841. doi:https://doi.org/10.1038/nrc3621.PubMedCrossRef

10.

Kudo, I. et al. The regulation mechanisms of AhR by molecular chaperone complex. The Journal of Biochemistry. 2018;163:223–232. doi:https://doi.org/10.1093/jb/mvx074.PubMedCrossRef

11.

Guyot, E., Chevallier, A., Barouki, R. & Coumoul, X. The AhR twist: ligand-dependent AhR signaling and pharmaco-toxicological implications. Drug Discov Today. 2013;18:479–486. doi:https://doi.org/10.1016/j.drudis.2012.11.014.PubMedCrossRef

12.

McIntosh, B. E., Hogenesch, J. B. & Bradfield, C. A. Mammalian Per-Arnt-Sim proteins in environmental adaptation. Annu Rev Physiol. 2010;72:625–645. doi:https://doi.org/10.1146/annurev-physiol-021909-135922.PubMedCrossRef

13.

Neavin, D. R., Liu, D., Ray, B. & Weinshilboum, R. M. The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases. Int J Mol Sci. 2018;19. doi:https://doi.org/10.3390/ijms19123851.

14.

Gasiewicz, T. A., Singh, K. P. & Bennett, J. A. The Ah receptor in stem cell cycling, regulation, and quiescence. Ann N Y Acad Sci. 2014;1310:44–50. doi:https://doi.org/10.1111/nyas.12361.PubMedPubMedCentralCrossRef

15.

Hernández-Ochoa, I., Karman, B. N. & Flaws, J. A. The Role of the Aryl Hydrocarbon Receptor in the Female Reproductive System. Biochem Pharmacol. 2009;77:547–559. doi:https://doi.org/10.1016/j.bcp.2008.09.037.PubMedCrossRef

16.

Kaeberlein, M. How healthy is the healthspan concept? GeroScience. 2018;40:361–364. doi:https://doi.org/10.1007/s11357-018-0036-9.PubMedPubMedCentralCrossRef

17.

Hirabayashi, Y. & Inoue, T. Aryl hydrocarbon receptor biology and xenobiotic responses in hematopoietic progenitor cells. Biochem Pharmacol. 2009;77:521–535. doi:https://doi.org/10.1016/j.bcp.2008.09.030.PubMedCrossRef

18.

Fernandez-Salguero, P. et al. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science. 1995;268:722–726. doi:https://doi.org/10.1126/science.7732381.PubMedCrossRef

19.

Bravo-Ferrer, I. et al. Lack of the aryl hydrocarbon receptor accelerates aging in mice. The FASEB Journal. 2019;33:12644–12654. doi:https://doi.org/10.1096/fj.201901333R.PubMedCrossRef

20.

Singh, K. P., Casado, F. L., Opanashuk, L. A. & Gasiewicz, T. A. The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations. Biochem Pharmacol. 2009;77:577–587. doi:https://doi.org/10.1016/j.bcp.2008.10.001.PubMedCrossRef

21.

Singh, K. P. et al. Loss of Aryl Hydrocarbon Receptor Promotes Gene Changes Associated with Premature Hematopoietic Stem Cell Exhaustion and Development of a Myeloproliferative Disorder in Aging Mice. Stem Cells and Development. 2013;23:95–106. doi:https://doi.org/10.1089/scd.2013.0346.PubMedPubMedCentralCrossRef

22.

Papadopoli, D. et al. mTOR as a central regulator of lifespan and aging. F1000Res. 2019;8. doi:https://doi.org/10.12688/f1000research.17196.1.

23.

Biljes, D. et al. Impaired glucose and lipid metabolism in ageing aryl hydrocarbon receptor deficient mice. EXCLI J. 2015;14:1153–1163. doi:https://doi.org/10.17179/excli2015-638.PubMedPubMedCentral

24.

Butler, R. et al. Uric acid stones in the urinary bladder of aryl hydrocarbon receptor (AhR) knockout mice. Proc Natl Acad Sci U S A. 2012;109:1122–1126. doi:https://doi.org/10.1073/pnas.1120581109.PubMedPubMedCentralCrossRef

25.

Makhloufi, C. et al. Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease. Int J Mol Sci. 2020;21:E2483. doi:https://doi.org/10.3390/ijms21072483.CrossRef

26.

Eckers, A. et al. The aryl hydrocarbon receptor promotes aging phenotypes across species. Scientific Reports. 2016;6:19618. doi:https://doi.org/10.1038/srep19618.PubMedPubMedCentralCrossRef

27.

Chamoli, M., Singh, A., Malik, Y. & Mukhopadhyay, A. A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans. Aging Cell. 2014;13:641–655. doi:https://doi.org/10.1111/acel.12218.PubMedPubMedCentralCrossRef

28.

Green, C. L., Lamming, D. W. & Fontana, L. Molecular mechanisms of dietary restriction promoting health and longevity. Nat Rev Mol Cell Biol. 2022;23:56–73. doi:https://doi.org/10.1038/s41580-021-00411-4.PubMedCrossRef

29.

Brinkmann, V., Schiavi, A., Shaik, A., Puchta, D. R. & Ventura, N. Dietary and environmental factors have opposite AhR-dependent effects on C. elegans healthspan. Aging (Albany NY). 2020;13:104–133. doi:https://doi.org/10.18632/aging.202316.PubMedCrossRef

30.

Aarnio, V. et al. Fatty acid composition and gene expression profiles are altered in aryl hydrocarbon receptor-1 mutant Caenorhabditis elegans. Comp Biochem Physiol C Toxicol Pharmacol. 2010;151:318–324. doi:https://doi.org/10.1016/j.cbpc.2009.12.006.PubMedCrossRef

31.

Serna, E., Cespedes, C. & Vina, J. Anti-Aging Physiological Roles of Aryl Hydrocarbon Receptor and Its Dietary Regulators. Int J Mol Sci. 2020;22. doi:https://doi.org/10.3390/ijms22010374.

32.

Kaiser, H. et al. Kynurenine, a Tryptophan Metabolite That Increases with Age, Induces Muscle Atrophy and Lipid Peroxidation. Oxid Med Cell Longev. 2019;2019:9894238. doi:https://doi.org/10.1155/2019/9894238.PubMedPubMedCentralCrossRef

33.

Rebelo-Marques, A. et al. Aging Hallmarks: The Benefits of Physical Exercise. Front Endocrinol (Lausanne). 2018;9:258. doi:https://doi.org/10.3389/fendo.2018.00258.PubMedCrossRef

34.

Schenk, A. et al. Acute exercise impacts AhR and PD-1 levels of CD8+ T-cells-Exploratory results from a randomized cross-over trial comparing endurance versus resistance exercise. Eur J Appl Physiol. 2021;121:637–644. doi:https://doi.org/10.1007/s00421-020-04552-w.PubMedCrossRef

35.

Joisten, N. et al. Exercise and the Kynurenine pathway: Current state of knowledge and results from a randomized cross-over study comparing acute effects of endurance and resistance training. Exerc Immunol Rev. 2020;26:24–42.PubMed

36.

Hwang, H. J. et al. Mitochondrial-targeted aryl hydrocarbon receptor and the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin on cellular respiration and the mitochondrial proteome. Toxicology and Applied Pharmacology. 2016;304:121–132. doi:https://doi.org/10.1016/j.taap.2016.04.005.PubMedPubMedCentralCrossRef

37.

Ishikawa, T., Takahashi, S., Morita, K., Okinaga, H. & Teramoto, T. Induction of AhR-mediated gene transcription by coffee. PLoS One. 2014;9:e102152. doi:https://doi.org/10.1371/journal.pone.0102152.PubMedPubMedCentralCrossRef

38.

Zhang, Q. et al. Genotype effects contribute to variation in longitudinal methylome patterns in older people. Genome Medicine. 2018;10:75. doi:https://doi.org/10.1186/s13073-018-0585-7.PubMedPubMedCentralCrossRef

39.

Field, A. E. et al. DNA Methylation Clocks in Aging: Categories, Causes, and Consequences. Molecular Cell. 2018;71:882–895. doi:https://doi.org/10.1016/j.molcel.2018.08.008.PubMedPubMedCentralCrossRef

40.

Pansoy, A., Ahmed, S., Valen, E., Sandelin, A. & Matthews, J. 3-methylcholanthrene induces differential recruitment of aryl hydrocarbon receptor to human promoters. Toxicol Sci. 2010;117:90–100. doi:https://doi.org/10.1093/toxsci/kfq096.PubMedCrossRef

41.

Shimizu, Y. et al. Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proceedings of the National Academy of Sciences. 2000;97:779–782. doi:https://doi.org/10.1073/pnas.97.2.779.CrossRef

42.

Kaiser, H., Parker, E. & Hamrick, M. W. Kynurenine signaling through the aryl hydrocarbon receptor: Implications for aging and healthspan. Exp Gerontol. 2020;130:110797. doi:https://doi.org/10.1016/j.exger.2019.110797.PubMedCrossRef

43.

Takaoka, M. Resveratrol, a new phenolic compound, from Veratrum grandiflorum. Nippon Kagaku Kaishi. 1939;60:1090–1100.CrossRef

44.

Burns, J., Yokota, T., Ashihara, H., Lean, M. E. J. & Crozier, A. Plant foods and herbal sources of resveratrol. J Agric Food Chem. 2002;50:3337–3340. doi:https://doi.org/10.1021/jf0112973.PubMedCrossRef

45.

Revel, A. et al. Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects lung from DNA damage and apoptosis caused by benzo[a]pyrene. J Appl Toxicol. 2003;23:255–261. doi:https://doi.org/10.1002/jat.916.PubMedCrossRef

46.

Pyo, I. S., Yun, S., Yoon, Y. E., Choi, J.-W. & Lee, S.-J. Mechanisms of Aging and the Preventive Effects of Resveratrol on Age-Related Diseases. Molecules. 2020;25. doi:https://doi.org/10.3390/molecules25204649.

47.

Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425:191–196. doi:https://doi.org/10.1038/nature01960.PubMedCrossRef

48.

Tissenbaum, H. A. & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 2001;410:227–230. doi:https://doi.org/10.1038/35065638.PubMedCrossRef

49.

Fischer, N. et al. The resveratrol derivatives trans-3,5-dimethoxy-4-fluoro-4′-hydroxystilbene and trans-2,4′,5-trihydroxystilbene decrease oxidative stress and prolong lifespan in Caenorhabditis elegans. J Pharm Pharmacol. 2017;69:73–81. doi:https://doi.org/10.1111/jphp.12657.PubMedCrossRef

50.

Wood, J. G. et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004;430:686–689. doi:https://doi.org/10.1038/nature02789.PubMedCrossRef

51.

Rogina, B. & Helfand, S. L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proceedings of the National Academy of Sciences. 2004;101:15998–16003. doi:https://doi.org/10.1073/pnas.0404184101.CrossRef

52.

Canedo-Santos, J. C. et al. Resveratrol shortens the chronological lifespan of Saccharomyces cerevisiae by a pro-oxidant mechanism. Yeast. 2022;39:193–207. doi:https://doi.org/10.1002/yea.3677.PubMedCrossRef

53.

Ramos-Gomez, M. et al. Resveratrol induces mitochondrial dysfunction and decreases chronological life span of Saccharomyces cerevisiae in a glucose-dependent manner. J Bioenerg Biomembr. 2017;49:241–251. doi:https://doi.org/10.1007/s10863-017-9709-9.PubMedCrossRef

54.

Hector, K. L., Lagisz, M. & Nakagawa, S. The effect of resveratrol on longevity across species: a meta-analysis. Biol Lett. 2012;8:790–793. doi:https://doi.org/10.1098/rsbl.2012.0316.PubMedPubMedCentralCrossRef

55.

Bhullar, K. S. & Hubbard, B. P. Lifespan and healthspan extension by resveratrol. Biochim Biophys Acta. 2015;1852:1209–1218. doi:https://doi.org/10.1016/j.bbadis.2015.01.012.PubMedCrossRef

56.

Harper, S. A. et al. Resveratrol and exercise combined to treat functional limitations in late life: A pilot randomized controlled trial. Exp Gerontol. 2021;143:111111. doi:https://doi.org/10.1016/j.exger.2020.111111.PubMedCrossRef

57.

Wong RH, Thaung Zaw JJ, Xian CJ, Howe PR. Regular Supplementation with Resveratrol Improves Bone Mineral Density in Postmenopausal Women: A Randomized, Placebo-Controlled Trial. J Bone Miner Res. 2020;35(11):2121–2131. doi:https://doi.org/10.1002/jbmr.4115PubMedCrossRef

58.

Huhn, S. et al. Effects of resveratrol on memory performance, hippocampus connectivity and microstructure in older adults — A randomized controlled trial. Neuroimage. 2018;174:177–190. doi:https://doi.org/10.1016/j.neuroimage.2018.03.023.PubMedCrossRef

59.

Thaung Zaw, J. J., Howe, P. R. & Wong, R. H. Long-term effects of resveratrol on cognition, cerebrovascular function and cardio-metabolic markers in postmenopausal women: A 24-month randomised, double-blind, placebo-controlled, crossover study. Clin Nutr. 2021;40:820–829. doi:https://doi.org/10.1016/j.clnu.2020.08.025.PubMedCrossRef

60.

Anand David, A. V., Arulmoli, R. & Parasuraman, S. Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid. Pharmacogn Rev. 2016;10:84–89. doi:https://doi.org/10.4103/0973-7847.194044.PubMedPubMedCentralCrossRef

61.

Nguyen, L. P. & Bradfield, C. A. The Search for Endogenous Activators of the Aryl Hydrocarbon Receptor. Chem. Res. Toxicol. 2008;21:102–116. doi:https://doi.org/10.1021/tx7001965.PubMedCrossRef

62.

Mohammadi-Bardbori, A., Bengtsson, J., Rannug, U., Rannug, A. & Wincent, E. Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AHR). Chem Res Toxicol. 2012;25:1878–1884. doi:https://doi.org/10.1021/tx300169e.PubMedCrossRef

63.

Wyld, L. et al. Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies. Cancers (Basel). 2020;12. doi:https://doi.org/10.3390/cancers12082134.

64.

Pietsch, K., Saul, N., Menzel, R., Stürzenbaum, S. R. & Steinberg, C. E. W. Quercetin mediated lifespan extension in Caenorhabditis elegans is modulated by age-1, daf-2, sek-1 and unc-43. Biogerontology. 2009;10:565–578. doi:https://doi.org/10.1007/s10522-008-9199-6.PubMedCrossRef

65.

Kampkötter, A. et al. Increase of stress resistance and lifespan of Caenorhabditis elegans by quercetin. Comp Biochem Physiol B Biochem Mol Biol. 2008;149:314–323. doi:https://doi.org/10.1016/j.cbpb.2007.10.004.PubMedCrossRef

66.

Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24:1246–1256. doi:https://doi.org/10.1038/s41591-018-0092-9.PubMedPubMedCentralCrossRef

67.

Saul, N., Pietsch, K., Menzel, R. & Steinberg, C. E. W. Quercetin-mediated longevity in Caenorhabditis elegans: is DAF-16 involved? Mech Ageing Dev. 2008;129:611–613. doi:https://doi.org/10.1016/j.mad.2008.07.001.PubMedCrossRef

68.

Proshkina, E. et al. Geroprotective and Radioprotective Activity of Quercetin, (-)-Epicatechin, and Ibuprofen in Drosophila melanogaster. Front Pharmacol. 2016;7:505. doi:https://doi.org/10.3389/fphar.2016.00505.PubMedPubMedCentralCrossRef

69.

Rinaldi, A. L. et al. Curcumin Activates the Aryl Hydrocarbon Receptor yet Significantly Inhibits (-)-Benzo(a)pyrene-7R-trans-7,8-dihydrodiol Bioactivation in Oral Squamous Cell Carcinoma Cells and Oral Mucosa. Cancer Res. 2002;62:5451–5456.PubMed

70.

Liao, V. H.-C. et al. Curcumin-mediated lifespan extension in Caenorhabditis elegans. Mech Ageing Dev. 2011;132:480–487. doi:https://doi.org/10.1016/j.mad.2011.07.008.PubMedCrossRef

71.

Lee, K.-S. et al. Curcumin extends life span, improves health span, and modulates the expression of age-associated aging genes in Drosophila melanogaster. Rejuvenation Res. 2010;13:561–570. doi:https://doi.org/10.1089/rej.2010.1031.PubMedCrossRef

72.

Kitani, K., Osawa, T. & Yokozawa, T. The effects of tetrahydrocurcumin and green tea polyphenol on the survival of male C57BL/6 mice. Biogerontology. 2007;8:567–573. doi:https://doi.org/10.1007/s10522-007-9100-z.PubMedCrossRef

73.

Basnet, P. & Skalko-Basnet, N. Curcumin: an anti-inflammatory molecule from a curry spice on the path to cancer treatment. Molecules. 2011;16:4567–4598. doi:https://doi.org/10.3390/molecules16064567.PubMedPubMedCentralCrossRef

74.

McCubrey, J. A. et al. Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs. Aging (Albany NY). 2017;9:1477–1536. doi:https://doi.org/10.18632/aging.101250.PubMedCrossRef

75.

Funk, J. L. et al. Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis. Arthritis Rheum. 2006;54:3452–3464. doi:https://doi.org/10.1002/art.22180.PubMedCrossRef

76.

Chandran, B. & Goel, A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res. 2012;26:1719–1725. doi:https://doi.org/10.1002/ptr.4639.PubMedCrossRef

77.

Jagtap, S. et al. Chemoprotective mechanism of the natural compounds, epigallocatechin-3-O-gallate, quercetin and curcumin against cancer and cardiovascular diseases. Curr Med Chem. 2009;16:1451–1462. doi:https://doi.org/10.2174/092986709787909578.PubMedCrossRef

78.

El-Agamy, D. S. Comparative effects of curcumin and resveratrol on aflatoxin B(1)-induced liver injury in rats. Arch Toxicol. 2010;84:389–396. doi:https://doi.org/10.1007/s00204-010-0511-2.PubMedCrossRef

79.

Lim, G. P. et al. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci. 2001;21:8370–8377. doi:https://doi.org/10.1523/JNEUROSCI.21-21-08370.2001.PubMedPubMedCentralCrossRef

80.

Monroy, A., Lithgow, G. J. & Alavez, S. Curcumin and neurodegenerative diseases. Biofactors. 2013;39:122–132. doi:https://doi.org/10.1002/biof.1063.PubMedPubMedCentralCrossRef

81.

Rainey-Smith, S. R. et al. Curcumin and cognition: a randomised, placebo-controlled, double-blind study of community-dwelling older adults. Br J Nutr. 2016;115:2106–2113. doi:https://doi.org/10.1017/S0007114516001203.PubMedCrossRef

82.

Rojas, L. B. A. & Gomes, M. B. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5:6. doi:https://doi.org/10.1186/1758-5996-5-6.PubMedPubMedCentralCrossRef

83.

Anisimov, V. N. et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008;7:2769–2773. doi:https://doi.org/10.4161/cc.7.17.6625.PubMedCrossRef

84.

Martin-Montalvo, A. et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192. doi:https://doi.org/10.1038/ncomms3192.PubMedCrossRef

85.

TAME — Targeting Aging with Metformin. American Federation for Aging Research https://www.afar.org/tame-trial.

86.

Wang, H.-C. & Huang, S.-K. Metformin inhibits IgE- and aryl hydrocarbon receptor-mediated mast cell activation in vitro and in vivo. European Journal of Immunology. 2018;48:1989–1996. doi:https://doi.org/10.1002/eji.201847706.PubMedCrossRef

87.

Do, M. T. et al. Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression. Toxicol Appl Pharmacol. 2014;280:138–148. doi:https://doi.org/10.1016/j.taap.2014.07.021.PubMedCrossRef

88.

Swindell, W. R. Gene expression profiling of long-lived dwarf mice: longevity-associated genes and relationships with diet, gender and aging. BMC Genomics. 2007;8:353. doi:https://doi.org/10.1186/1471-2164-8-353.PubMedPubMedCentralCrossRef

89.

Steinbaugh, M. J., Sun, L. Y., Bartke, A. & Miller, R. A. Activation of genes involved in xenobiotic metabolism is a shared signature of mouse models with extended lifespan. Am. J. Physiol. Endocrinol. Metab. 2012;303:E488–495. doi:https://doi.org/10.1152/ajpendo.00110.2012.PubMedPubMedCentralCrossRef

90.

Miller, R. A. et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13:468–477. doi:https://doi.org/10.1111/acel.12194.PubMedPubMedCentralCrossRef

91.

Toba, G. & Aigaki, T. Disruption of the microsomal glutathione S-transferase-like gene reduces life span of Drosophila melanogaster. Gene. 2000;253:179–187. doi:https://doi.org/10.1016/s0378-1119(00)00246-8.PubMedCrossRef

92.

McElwee, J. J., Schuster, E., Blanc, E., Thomas, J. H. & Gems, D. Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. J Biol Chem. 2004;279:44533–44543. doi:https://doi.org/10.1074/jbc.M406207200.PubMedCrossRef

93.

Zhai, G. et al. Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms. PLoS Genet. 2011;7:e1002025. doi:https://doi.org/10.1371/journal.pgen.1002025.PubMedPubMedCentralCrossRef

94.

Zeng, Y. et al. Novel loci and pathways significantly associated with longevity. Sci Rep. 2016;6:21243. doi:https://doi.org/10.1038/srep21243.PubMedPubMedCentralCrossRef

95.

Shore, D. E. & Ruvkun, G. A cytoprotective perspective on longevity regulation. Trends Cell Biol. 2013;23:409–420. doi:https://doi.org/10.1016/j.tcb.2013.04.007.PubMedPubMedCentralCrossRef

96.

Herholz, M. et al. KLF-1 orchestrates a xenobiotic detoxification program essential for longevity of mitochondrial mutants. Nat Commun. 2019;10:3323. doi:https://doi.org/10.1038/s41467-019-11275-w.PubMedPubMedCentralCrossRef

97.

Kim, I.-W., Han, N., Burckart, G. J. & Oh, J. M. Epigenetic changes in gene expression for drug-metabolizing enzymes and transporters. Pharmacotherapy. 2014;34:140–150. doi:https://doi.org/10.1002/phar.1362.PubMedCrossRef

98.

Fisel, P., Schaeffeler, E. & Schwab, M. DNA Methylation of ADME Genes. Clin. Pharmacol. Ther. 2016;99:512–527. doi:https://doi.org/10.1002/cpt.343.PubMedCrossRef

99.

Kronfol, M. M. et al. DNA methylation and histone acetylation changes to cytochrome P450 2E1 regulation in normal aging and impact on rates of drug metabolism in the liver. Geroscience. 2020;42:819–832. doi:https://doi.org/10.1007/s11357-020-00181-5.PubMedPubMedCentralCrossRef

100.

Fader, K. A. et al. Convergence of Hepcidin Deficiency, Systemic Iron Overloading, Heme Accumulation, and REV-ERBa/β Activation in Aryl Hydrocarbon Receptor-Elicited Hepatotoxicity. Toxicol Appl Pharmacol. 2017;321:1–17. doi:https://doi.org/10.1016/j.taap.2017.02.006.PubMedPubMedCentralCrossRef

101.

Sandoval-Sierra, J. V. et al. Body weight and high-fat diet are associated with epigenetic aging in female members of the BXD murine family. Aging Cell. 2020;19:e13207. doi:https://doi.org/10.1111/acel.13207.PubMedPubMedCentralCrossRef

102.

McLean, C. Y. et al. GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 2010;28:495–501. doi:https://doi.org/10.1038/nbt.1630.PubMedPubMedCentralCrossRef

103.

Thomas, P. D. et al. PANTHER: Making genome-scale phylogenetics accessible to all. Protein Science. 2022;31:8–22. doi:https://doi.org/10.1002/pro.4218.PubMedCrossRef

104.

Sherman, B. T. et al. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. 2022;194. doi:https://doi.org/10.1093/nar/gkac194.

105.

Kudo, K., Takeuchi, T., Murakami, Y., Ebina, M. & Kikuchi, H. Characterization of the region of the aryl hydrocarbon receptor required for ligand dependency of transactivation using chimeric receptor between Drosophila and Mus musculus. Biochim Biophys Acta. 2009;1789:477–486. doi:https://doi.org/10.1016/j.bbagrm.2009.06.003.PubMedCrossRef

106.

Gouédard, C., Barouki, R. & Morel, Y. Induction of the paraoxonase-1 gene expression by resveratrol. Arterioscler Thromb Vasc Biol. 2004;24:2378–2383. doi:https://doi.org/10.1161/01.ATV.0000146530.24736.ce.PubMedCrossRef

107.

Rytel, M. R. et al. DNA methylation in the adipose tissue and whole blood of Agent Orange-exposed Operation Ranch Hand veterans: a pilot study. Environ Health. 2021;20:43. doi:https://doi.org/10.1186/s12940-021-00717-y.PubMedPubMedCentralCrossRef

108.

Kelsey, K. T. et al. Serum dioxin and DNA methylation in the sperm of operation ranch hand veterans exposed to Agent Orange. Environ Health. 2019;18:91. doi:https://doi.org/10.1186/s12940-019-0533-z.PubMedPubMedCentralCrossRef

109.

Amenya, H. Z., Tohyama, C. & Ohsako, S. Dioxin induces Ahr-dependent robust DNA demethylation of the Cyp1a1 promoter via Tdg in the mouse liver. Sci Rep. 2016;6:34989. doi:https://doi.org/10.1038/srep34989.PubMedPubMedCentralCrossRef

110.

Selmin, O. I., Donovan, M. G., Stillwater, B. J., Neumayer, L. & Romagnolo, D. F. Epigenetic Regulation and Dietary Control of Triple Negative Breast Cancer. Front Nutr. 2020;7:159. doi:https://doi.org/10.3389/fnut.2020.00159.PubMedPubMedCentralCrossRef

111.

Zhu, W. et al. Trans-resveratrol alters mammary promoter hypermethylation in women at increased risk for breast cancer. Nutr Cancer. 2012;64:393–400. doi:https://doi.org/10.1080/01635581.2012.654926.PubMedPubMedCentralCrossRef

112.

Farhan, M. et al. Differential Methylation and Acetylation as the Epigenetic Basis of Resveratrol’s Anticancer Activity. Medicines (Basel). 2019;6:24. doi:https://doi.org/10.3390/medicines6010024.PubMedCrossRef

113.

Liggett, W. H. & Sidransky, D. Role of the p16 tumor suppressor gene in cancer. J Clin Oncol. 1998;16:1197–1206. doi:https://doi.org/10.1200/JCO.1998.16.3.1197.PubMedCrossRef

114.

Busch, C. et al. Epigenetic activities of flavonoids in the prevention and treatment of cancer. Clin Epigenetics. 2015;7:64. doi:https://doi.org/10.1186/s13148-015-0095-z.PubMedPubMedCentralCrossRef

115.

Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336(20):1401–1408. doi:https://doi.org/10.1056/NEJM199705153362001PubMedCrossRef

116.

Al-Yousef, N., Shinwari, Z., Al-Shahrani, B., Al-Showimi, M. & Al-Moghrabi, N. Curcumin induces re-expression of BRCA1 and suppression of y synuclein by modulating DNA promoter methylation in breast cancer cell lines. Oncol Rep. 2020;43:827–838. doi:https://doi.org/10.3892/or.2020.7473.PubMedPubMedCentral

117.

Sonowal, R. et al. Indoles from commensal bacteria extend healthspan. Proc Natl Acad Sci U S A. 2017;114:E7506–E7515. doi:https://doi.org/10.1073/pnas.1706464114.PubMedPubMedCentralCrossRef

118.

Bjeldanes, L. F., Kim, J. Y., Grose, K. R., Bartholomew, J. C. & Bradfield, C. A. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc Natl Acad Sci U S A. 1991;88:9543–9547. doi:https://doi.org/10.1073/pnas.88.21.9543.PubMedPubMedCentralCrossRef

119.

Rosser, E. C. et al. Microbiota-Derived Metabolites Suppress Arthritis by Amplifying Aryl-Hydrocarbon Receptor Activation in Regulatory B Cells. Cell Metab. 2020;31:837–851.e10. doi:https://doi.org/10.1016/j.cmet.2020.03.003.PubMedPubMedCentralCrossRef

120.

Jin, U.-H. et al. Microbiome-Derived Tryptophan Metabolites and Their Aryl Hydrocarbon Receptor-Dependent Agonist and Antagonist Activities. Mol Pharmacol. 2014;85:777–788. doi:https://doi.org/10.1124/mol.113.091165.PubMedPubMedCentralCrossRef

Title: The Aryl Hydrocarbon Receptor, Epigenetics and the Aging Process
Authors: Sara Abudahab
E. T. Price
M. G. Dozmorov
L. S. Deshpande
J. L. McClay
Publication date: 13-04-2023
Publisher: Springer Paris
Keyword: Epigenetics
Published in: The journal of nutrition, health & aging / Issue 4/2023
Print ISSN: 1279-7707
Electronic ISSN: 1760-4788
DOI: https://doi.org/10.1007/s12603-023-1908-1

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