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Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy

Tezil, Tugsan, Chamoli, Manish, Ng, Che-Ping, Simon, Roman P., Butler, Victoria J., Jung, Manfred, Andersen, Julie, Kao, Aimee W., Verdin, Eric·2019·npj Aging and Mechanisms of Disease
DOI 10.1038/s41514-019-0037-7PMC PMC6775102

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Abstract

Aging is characterized by the progressive loss of physiological function in all organisms. Remarkably, the aging process can be modulated by environmental modifications, including diet and small molecules. The natural compound nordihydroguaiaretic acid (NDGA) robustly increases lifespan in flies and mice, but its mechanism of action remains unclear. Here, we report that NDGA is an inhibitor of the epigenetic regulator p300. We find that NDGA inhibits p300 acetyltransferase activity in vitro and suppresses acetylation of a key p300 target in histones (i.e., H3K27) in cells. We use the cellular thermal shift assay to uniquely demonstrate NDGA binding to p300 in cells. Finally, in agreement with recent findings indicating that p300 is a potent blocker of autophagy, we show that NDGA treatment induces autophagy. These findings identify p300 as a target of NDGA and provide mechanistic insight into its role in longevity.

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  • EP300 is the target of the longevity-enhancing drugs nordihydroguairaretic acid and salicylate.

    “Among these factors, EP300 is the target of the longevity-enhancing drugs nordihydroguairaretic acid 118 and salicylate 119 .”

    From Hallmarks of aging: An expanding universe (2023) · cites this paper as [118]

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Research works printed but not linked: 57

  1. Harrison, D. E. et al. Acarbose, 17-alpha-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell 13, 273–282 (2014). · DOI · Paper page
  2. Economos, A. C., Ballard, R. C., Miquel, J., Binnard, R. & Philpott, D. E. Accelerated aging of fasted Drosophila. Preservation of physiological function and cellular fine structure by thiazolidine carboxylic acid (TCA). Exp. Gerontol. 17, 105–114 (1982). · DOI
  3. Richie, J. P., Jr. Mills, B. J. & Lang, C. A. Dietary nordihydroguaiaretic acid increases the life span of the mosquito. Proc. Soc. Exp. Biol. Med 183, 81–85 (1986). · DOI
  4. Siddique, Y. H., Ara, G., Jyoti, S. & Afzal, M. The dietary supplementation of nordihydroguaiaretic acid (NDGA) delayed the loss of climbing ability in Drosophila model of Parkinson’s disease. J. Diet. Suppl. 9, 1–8 (2012). · DOI
  5. West, M. et al. The arachidonic acid 5-lipoxygenase inhibitor nordihydroguaiaretic acid inhibits tumor necrosis factor alpha activation of microglia and extends survival of G93A-SOD1 transgenic mice. J. Neurochem. 91, 133–143 (2004). · DOI
  6. Lee, J. et al. Modulation of lipid peroxidation and mitochondrial function improves neuropathology in Huntington’s disease mice. Acta Neuropathol. 121, 487–498 (2011). · DOI
  7. Hamaguchi, T., Ono, K., Murase, A. & Yamada, M. Phenolic compounds prevent Alzheimer’s pathology through different effects on the amyloid-beta aggregation pathway. Am. J. Pathol. 175, 2557–2565 (2009). · DOI
  8. Goodman, Y., Steiner, M. R., Steiner, S. M. & Mattson, M. P. Nordihydroguaiaretic acid protects hippocampal neurons against amyloid beta-peptide toxicity, and attenuates free radical and calcium accumulation. Brain Res. 654, 171–176 (1994). · DOI
  9. Floriano-Sanchez, E. et al. Nordihydroguaiaretic acid is a potent in vitro scavenger of peroxynitrite, singlet oxygen, hydroxyl radical, superoxide anion and hypochlorous acid and prevents in vivo ozone-induced tyrosine nitration in lungs. Free Radic. Res. 40, 523–533 (2006). · DOI
  10. Arteaga, S., Andrade-Cetto, A. & Cardenas, R. Larrea tridentata (Creosote bush), an abundant plant of Mexican and US-American deserts and its metabolite nordihydroguaiaretic acid. J. Ethnopharmacol. 98, 231–239 (2005). · DOI
  11. Rojo, A. I. et al. Signaling pathways activated by the phytochemical nordihydroguaiaretic acid contribute to a Keap1-independent regulation of Nrf2 stability: role of glycogen synthase kinase-3. Free Radic. Biol. Med. 52, 473–487 (2012). · DOI
  12. Gelino, S. & Hansen, M. Autophagy—an emerging anti-aging mechanism. J. Clin. Exp. Pathol. Suppl 4, pii: 006 (2012).
  13. Eisenberg, T. et al. Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan. Cell Metab. 19, 431–444 (2014). · DOI · Paper page
  14. Pietrocola, F., Galluzzi, L., Bravo-San Pedro, J. M., Madeo, F. & Kroemer, G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805–821 (2015). · DOI · Paper page
  15. Simon, R. P., Robaa, D., Alhalabi, Z., Sippl, W. & Jung, M. KATching-up on small molecule modulators of lysine acetyltransferases. J. Med. Chem. 59, 1249–1270 (2016). · DOI
  16. Sebti, S. et al. BAT3 modulates p300-dependent acetylation of p53 and autophagy-related protein 7 (ATG7) during autophagy. Proc. Natl Acad. Sci. USA 111, 4115–4120 (2014). · DOI
  17. Lee, I. H. & Finkel, T. Regulation of autophagy by the p300 acetyltransferase. J. Biol. Chem. 284, 6322–6328 (2009). · DOI
  18. Salari, H., Braquet, P. & Borgeat, P. Comparative effects of indomethacin, acetylenic acids, 15-HETE, nordihydroguaiaretic acid and BW755C on the metabolism of arachidonic acid in human leukocytes and platelets. Prostaglandins Leukot. Med. 13, 53–60 (1984). · DOI
  19. Hurst, J. S. & Bazan, H. E. The sensitivity of bovine corneal epithelial lyso-PAF acetyltransferase to cyclooxygenase and lipoxygenase inhibitors is independent of arachidonate metabolites. J. Ocul. Pharm. Ther. 13, 415–426 (1997). · DOI
  20. White, H. L. & Faison, L. D. Inhibition of lyso-PAF: acetyl-CoA acetyltransferase by salicylates and other compounds. Prostaglandins 35, 939–944 (1988). · DOI
  21. Shirakawa, K. et al. Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. Elife 5, https://doi.org/10.7554/eLife.11156 (2016). · DOI
  22. Dancy, B. M. & Cole, P. A. Protein lysine acetylation by p300/CBP. Chem. Rev. 115, 2419–2452 (2015). · DOI
  23. Thompson, P. R. et al. Regulation of the p300 HAT domain via a novel activation loop. Nat. Struct. Mol. Biol. 11, 308–315 (2004). · DOI · Paper page
  24. Balasubramanyam, K., Swaminathan, V., Ranganathan, A. & Kundu, T. K. Small molecule modulators of histone acetyltransferase p300. J. Biol. Chem. 278, 19134–19140 (2003). · DOI
  25. Ogryzko, V. V., Schiltz, R. L., Russanova, V., Howard, B. H. & Nakatani, Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87, 953–959 (1996). · DOI · Paper page
  26. Jin, Q. et al. Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. EMBO J. 30, 249–262 (2011). · DOI · Paper page
  27. McCord, R. P. et al. Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome. Genome Res. 23, 260–269 (2013). · DOI
  28. Buffenstein, R. The naked mole-rat: a new long-living model for human aging research. J. Gerontol. A Biol. Sci. Med. Sci. 60, 1369–1377 (2005). · DOI
  29. Tan, L. et al. Naked mole rat cells have a stable epigenome that resists iPSC reprogramming. Stem Cell Rep. 9, 1721–1734 (2017). · DOI · Paper page
  30. Crump, N. T. et al. Dynamic acetylation of all lysine-4 trimethylated histone H3 is evolutionarily conserved and mediated by p300/CBP. Proc. Natl Acad. Sci. USA 108, 7814–7819 (2011). · DOI
  31. Suzuki, T., Kimura, A., Nagai, R. & Horikoshi, M. Regulation of interaction of the acetyltransferase region of p300 and the DNA-binding domain of Sp1 on and through DNA binding. Genes Cells 5, 29–41 (2000). · DOI
  32. Martinez Molina, D. et al. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science 341, 84–87 (2013). · DOI · Paper page
  33. Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008). · DOI · Paper page
  34. Hansen, M., Rubinsztein, D. C. & Walker, D. W. Autophagy as a promoter of longevity: insights from model organisms. Nat. Rev. Mol. Cell Biol. 19, 579–593 (2018). · DOI · Paper page
  35. Rubinsztein, D. C., Shpilka, T. & Elazar, Z. Mechanisms of autophagosome biogenesis. Curr. Biol. 22, R29–R34 (2012). · DOI
  36. Yoshimori, T., Yamamoto, A., Moriyama, Y., Futai, M. & Tashiro, Y. Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J. Biol. Chem. 266, 17707–17712 (1991). · DOI
  37. Seglen, P. O., Grinde, B. & Solheim, A. E. Inhibition of the lysosomal pathway of protein degradation in isolated rat hepatocytes by ammonia, methylamine, chloroquine and leupeptin. Eur. J. Biochem. 95, 215–225 (1979). · DOI
  38. Victor, M. et al. HAT activity is essential for CBP-1-dependent transcription and differentiation in Caenorhabditis elegans. EMBO Rep. 3, 50–55 (2002). · DOI
  39. Chang, J. T., Kumsta, C., Hellman, A. B., Adams, L. M. & Hansen, M. Spatiotemporal regulation of autophagy during Caenorhabditis elegans aging. Elife 6, https://doi.org/10.7554/eLife.18459 (2017). · DOI
  40. Akimaru, H. et al. Drosophila CBP is a co-activator of cubitus interruptus in hedgehog signalling. Nature 386, 735–738 (1997). · DOI
  41. Yao, T. P. et al. Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell 93, 361–372 (1998). · DOI
  42. Farria, A., Li, W. & Dent, S. Y. KATs in cancer: functions and therapies. Oncogene 34, 4901–4913 (2015). · DOI
  43. Valor, L. M., Viosca, J., Lopez-Atalaya, J. P. & Barco, A. Lysine acetyltransferases CBP and p300 as therapeutic targets in cognitive and neurodegenerative disorders. Curr. Pharm. Des. 19, 5051–5064 (2013). · DOI
  44. Brown, J. A., Bourke, E., Eriksson, L. A. & Kerin, M. J. Targeting cancer using KAT inhibitors to mimic lethal knockouts. Biochem. Soc. Trans. 44, 979–986 (2016). · DOI
  45. Gaddis, M., Gerrard, D., Frietze, S. & Farnham, P. J. Altering cancer transcriptomes using epigenomic inhibitors. Epigenetics Chromatin 8, 9 (2015). · DOI
  46. Lasko, L. M. et al. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature 550, 128–132 (2017). · DOI · Paper page
  47. Lafuente-Lafuente, C. et al. Amiodarone concentrations in plasma and fat tissue during chronic treatment and related toxicity. Br. J. Clin. Pharm. 67, 511–519 (2009). · DOI
  48. Damle, B., Stogniew, M. & Dowell, J. Pharmacokinetics and tissue distribution of anidulafungin in rats. Antimicrob. Agents Chemother. 52, 2673–2676 (2008). · DOI
  49. Jenny, N. S. Inflammation in aging: cause, effect, or both? Disco. Med. 13, 451–460 (2012).
  50. Congdon, E. E. Sex differences in autophagy contribute to female vulnerability in Alzheimer’s disease. Front. Neurosci. 12, 372 (2018). · DOI
  51. Rubinsztein, D. C., Marino, G. & Kroemer, G. Autophagy and aging. Cell 146, 682–695 (2011). · DOI · Paper page
  52. Mercken, E. M. et al. SIRT1 but not its increased expression is essential for lifespan extension in caloric-restricted mice. Aging Cell 13, 193–196 (2014). · DOI
  53. Pietrocola, F. et al. Aspirin recapitulates features of caloric restriction. Cell Rep. 22, 2395–2407 (2018). · DOI
  54. Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010). · DOI · Paper page
  55. Castoldi, F., Pietrocola, F., Maiuri, M. C. & Kroemer, G. Aspirin induces autophagy via inhibition of the acetyltransferase EP300. Oncotarget 9, 24574–24575 (2018). · DOI
  56. Wan, W. et al. mTORC1 phosphorylates acetyltransferase p300 to regulate autophagy and lipogenesis. Mol. Cell 68, 323–335 e326 (2017). · DOI
  57. Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974). · DOI

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Metadata

Authors
Tezil, T., Chamoli, M., Ng, C.-P., Simon, R. P., Butler, V. J., Jung, M., Andersen, J., Kao, A. W., & Verdin, E.
ORCID
Venue
npj Aging and Mechanisms of Disease
Publisher
Springer Science and Business Media LLC
Published
2019-10-02
Volume
5
Issue
1
ISSN
2056-3973
DOI
10.1038/s41514-019-0037-7
PMC
PMC6775102
Cited by
40
References
12
Language
en
Licence
Funders
  • Glenn Foundation for Medical Research
  • Larry L. Hillblom Foundation
  • Deutsche Forschungsgemeinschaft (DFG, RTG1976)

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