Dietary and Gut Microbiota Polyamines in Obesity- and Age-Related Diseases

Bruno Ramos-Molina, Maria Isabel Queipo-Ortuño, Ana Lambertos, Francisco J Tinahones, Rafael Peñafiel, Bruno Ramos-Molina, Maria Isabel Queipo-Ortuño, Ana Lambertos, Francisco J Tinahones, Rafael Peñafiel

Abstract

The polyamines putrescine, spermidine, and spermine are widely distributed polycationic compounds essential for cellular functions. Intracellular polyamine pools are tightly regulated by a complex regulatory mechanism involving de novo biosynthesis, catabolism, and transport across the plasma membrane. In mammals, both the production of polyamines and their uptake from the extracellular space are controlled by a set of proteins named antizymes and antizyme inhibitors. Dysregulation of polyamine levels has been implicated in a variety of human pathologies, especially cancer. Additionally, decreases in the intracellular and circulating polyamine levels during aging have been reported. The differences in the polyamine content existing among tissues are mainly due to the endogenous polyamine metabolism. In addition, a part of the tissue polyamines has its origin in the diet or their production by the intestinal microbiome. Emerging evidence has suggested that exogenous polyamines (either orally administrated or synthetized by the gut microbiota) are able to induce longevity in mice, and that spermidine supplementation exerts cardioprotective effects in animal models. Furthermore, the administration of either spermidine or spermine has been shown to be effective for improving glucose homeostasis and insulin sensitivity and reducing adiposity and hepatic fat accumulation in diet-induced obesity mouse models. The exogenous addition of agmatine, a cationic molecule produced through arginine decarboxylation by bacteria and plants, also exerts significant effects on glucose metabolism in obese models, as well as cardioprotective effects. In this review, we will discuss some aspects of polyamine metabolism and transport, how diet can affect circulating and local polyamine levels, and how the modulation of either polyamine intake or polyamine production by gut microbiota can be used for potential therapeutic purposes.

Keywords: aging; diet; gut microbiota; metabolism; obesity; polyamines.

Figures

Figure 1
Figure 1
Chemical structure of the major biogenic polyamines.
Figure 2
Figure 2
Polyamine metabolism and transport. Biosynthetic (yellow) and degradative (green) pathways of polyamines in mammalian cells, and bacteria (blue). PAs, polyamines; Ac-PAs, acetylated polyamines; C-Spd, carboxyspermidine; PSVs, polyamine sequestering vesicles; PMPP, plasma membrane polyamine permease; VPAT, vesicular polyamine transporter; ODC, Odc, ornithine decarboxylase; Adc, arginine decarboxylase; Ldc, lysine decarboxylase; AMD1, S-adenosylmethionine decarboxylase; SPDSY, Spdsy, spermidine synthase; SPMSY, spermine synthase; SSAT, spermidine/spermine acetyl transferase; PAOX, acetylpolyamine oxidase (microsomal); SMOX, spermine oxidase; AZ, antizyme; AZIN, antizyme inhibitor; Casdh, carboxyspermidine dehydrogenase; Casdc, carboxyspermidine decarboxylase; AdoMet, S-adenosylmethionine; dcAdoMet, decarboxylated S-adenosylmethionine; MTA, methylthioadenosine; Ac-CoA, acetyl-coenzyme A.
Figure 3
Figure 3
Impact of diet and gut microbiota on polyamine-mediated effects in peripheral organs. Gut microbiota composition and microbial polyamine production are affected by several conditions such as the intake of balanced/unbalanced diets, the consumption of prebiotics/probiotics, and antibiotics. Intestinal polyamines levels depends on their uptake from the gut microbiota or from different dietary conditions, which in turn it can be transported into the circulation where they can target various peripheral organs including adipose tissue, brain, liver, heart, or endocrine pancreas.

References

    1. Tabor CW, Tabor H. Polyamines. Annu Rev Biochem. (1984) 53:749–90. 10.1146/annurev.bi.53.070184.003533
    1. Cohen S. A Guide to the Polyamines. Oxford: Oxford University Press; (1997).
    1. Tabor CW, Tabor H. Polyamines in microorganisms. Microbiol Rev. (1985) 49:81–99.
    1. Takahashi T, Kakehi J. Polyamines: ubiquitous polycations with unique roles in growth and stress responses. Ann Bot. (2010) 105:1–6. 10.1093/aob/mcp259
    1. Michael AJ. Biosynthesis of polyamines and polyamine-containing molecules. Biochem J. (2016) 473:2315–29. 10.1042/BCJ20160185
    1. Oshima T. Enigmas of biosyntheses of unusual polyamines in an extreme thermophile, Thermus thermophilus. Plant Physiol Biochem. (2010) 48:521–6. 10.1016/j.plaphy.2010.03.011
    1. Pegg AE, McGill S. Decarboxylation of ornithine and lysine in rat tissues. Biochim Biophys Acta. (1979) 568:416–27. 10.1016/0005-2744(79)90310-3
    1. Raasch W, Regunathan S, Li G, Reis DJ. Agmatine, the bacterial amine, is widely distributed in mammalian tissues. Life Sci. (1995) 56:2319–30. 10.1016/0024-3205(95)00226-V
    1. Pegg AE. Recent advances in the biochemistry of polyamines in eukaryotes. Biochem J. (1986) 234:249–62. 10.1042/bj2340249
    1. Pegg AE. Mammalian polyamine metabolism and function. IUBMB Life. (2009) 61:880–94. 10.1002/iub.230
    1. Bae DH, Lane DJR, Jansson PJ, Richardson DR. The old and new biochemistry of polyamines. Biochim Biophys Acta Gen Subj. (2018) 1862:2053–68. 10.1016/j.bbagen.2018.06.004
    1. Igarashi K, Kashiwagi K. Polyamines: mysterious modulators of cellular functions. Biochem Biophys Res Commun. (2000) 271:559–64. 10.1006/bbrc.2000.2601
    1. Schuster I, Bernhardt R. Interactions of natural polyamines with mammalian proteins. Biomol Concepts. (2011) 2:79–94. 10.1515/bmc.2011.007
    1. Bachrach U, Wang YC, Tabib A. Polyamines: new cues in cellular signal transduction. News Physiol Sci. (2001) 16:106–9. 10.1152/physiologyonline.2001.16.3.106
    1. Janne J, Alhonen L, Pietila M, Keinanen TA. Genetic approaches to the cellular functions of polyamines in mammals. Eur J Biochem. (2004) 271:877–94. 10.1111/j.1432-1033.2004.04009.x
    1. Landau G, Bercovich Z, Park MH, Kahana C. The role of polyamines in supporting growth of mammalian cells is mediated through their requirement for translation initiation and elongation. J Biol Chem. (2010) 285:12474–81. 10.1074/jbc.M110.106419
    1. Landau G, Ran A, Bercovich Z, Feldmesser E, Horn-Saban S, Korkotian E, et al. . Expression profiling and biochemical analysis suggest stress response as a potential mechanism inhibiting proliferation of polyamine-depleted cells. J Biol Chem. (2012) 287:35825–37. 10.1074/jbc.M112.381335
    1. Brenner S, Bercovich Z, Feiler Y, Keshet R, Kahana C. Dual regulatory role of polyamines in adipogenesis. J Biol Chem. (2015) 290:27384–92. 10.1074/jbc.M115.686980
    1. Zwighaft Z, Aviram R, Shalev M, Rousso-Noori L, Kraut-Cohen J, Golik M, et al. . Circadian clock control by polyamine levels through a mechanism that declines with age. Cell Metab. (2015) 22:874–85. 10.1016/j.cmet.2015.09.011
    1. Miller-Fleming L, Olin-Sandoval V, Campbell K, Ralser M. Remaining mysteries of molecular biology: the role of polyamines in the cell. J Mol Biol. (2015) 427:3389–406. 10.1016/j.jmb.2015.06.020
    1. Cason AL, Ikeguchi Y, Skinner C, Wood TC, Holden KR, Lubs HA, et al. . X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome. Eur J Hum Genet. (2003) 11:937–44. 10.1038/sj.ejhg.5201072
    1. Bupp CP, Schultz CR, Uhl KL, Rajasekaran S, Bachmann AS. Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features. Am J Med Genet. (2018) 176, 2548–53. 10.1002/ajmg.a.40523
    1. Russell D, Snyder SH. Amine synthesis in rapidly growing tissues: ornithine decarboxylase activity in regenerating rat liver, chick embryo, and various tumors. Proc Natl Acad Sci USA. (1968) 60:1420–7. 10.1073/pnas.60.4.1420
    1. Pegg AE. Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res. (1988) 48:759–74.
    1. Morrison LD, Kish SJ. Brain polyamine levels are altered in Alzheimer's disease. Neurosci Lett. (1995) 197:5–8. 10.1016/0304-3940(95)11881-V
    1. Lewandowski NM, Ju S, Verbitsky M, Ross B, Geddie ML, Rockenstein E, et al. . Polyamine pathway contributes to the pathogenesis of Parkinson disease. Proc Natl Acad Sci USA. (2010) 107:16970–5. 10.1073/pnas.1011751107
    1. Limon A, Mamdani F, Hjelm BE, Vawter MP, Sequeira A. Targets of polyamine dysregulation in major depression and suicide: activity-dependent feedback, excitability, and neurotransmission. Neurosci Biobehav Rev. (2016) 66:80–91. 10.1016/j.neubiorev.2016.04.010
    1. Gerner EW, Meyskens FL, Jr. Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer. (2004) 4:781–92. 10.1038/nrc1454
    1. Casero RA, Jr, Murray Stewart T, Pegg AE. Polyamine metabolism and cancer: treatments, challenges and opportunities. Nat Rev Cancer. (2018) 18:681–95. 10.1038/s41568-018-0050-3
    1. Tersey SA, Colvin SC, Maier B, Mirmira RG. Protective effects of polyamine depletion in mouse models of type 1 diabetes: implications for therapy. Amino Acids. (2014) 46:633–42. 10.1007/s00726-013-1560-7
    1. LoGiudice N, Le L, Abuan I, Leizorek Y, Roberts SC. Alpha-difluoromethylornithine, an irreversible inhibitor of polyamine biosynthesis, as a therapeutic strategy against hyperproliferative and infectious diseases. Med Sci. (2018) 6:12. 10.3390/medsci6010012
    1. Minois N, Carmona-Gutierrez D, Madeo F. Polyamines in aging and disease. Aging. (2011) 3:716–32. 10.18632/aging.100361
    1. Minois N. Molecular basis of the 'anti-aging' effect of spermidine and other natural polyamines - a mini-review. Gerontology. (2014) 60:319–26. 10.1159/000356748
    1. Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. (2018) 359:eaan2788. 10.1126/science.aan2788
    1. Pendeville H, Carpino N, Marine JC, Takahashi Y, Muller M, Martial JA, et al. . The ornithine decarboxylase gene is essential for cell survival during early murine development. Mol Cell Biol. (2001) 21:6549–58. 10.1128/MCB.21.19.6549-6558.2001
    1. Nishimura K, Nakatsu F, Kashiwagi K, Ohno H, Saito T, Igarashi K. Essential role of S-adenosylmethionine decarboxylase in mouse embryonic development. Genes Cells. (2002) 7:41–7. 10.1046/j.1356-9597.2001.00494.x
    1. Igarashi K, Kashiwagi K. Modulation of cellular function by polyamines. Int J Biochem Cell Biol. (2010) 42:39–51. 10.1016/j.biocel.2009.07.009
    1. Pasini A, Caldarera CM, Giordano E. Chromatin remodeling by polyamines and polyamine analogs. Amino Acids. (2014) 46:595–603. 10.1007/s00726-013-1550-9
    1. Wang Y, Casero RA, Jr. Mammalian polyamine catabolism: a therapeutic target, a pathological problem, or both? J Biochem. (2006) 139:17–25. 10.1093/jb/mvj021
    1. Pegg AE. Toxicity of polyamines and their metabolic products. Chem Res Toxicol. (2013) 26:1782–800. 10.1021/tx400316s
    1. Khan AU, Mei YH, Wilson T. A proposed function for spermine and spermidine: protection of replicating DNA against damage by singlet oxygen. Proc Natl Acad Sci USA. (1992) 89:11426–7. 10.1073/pnas.89.23.11426
    1. Ha HC, Sirisoma NS, Kuppusamy P, Zweier JL, Woster PM, Casero RA, Jr. The natural polyamine spermine functions directly as a free radical scavenger. Proc Natl Acad Sci USA. (1998) 95:11140–5. 10.1073/pnas.95.19.11140
    1. Rider JE, Hacker A, Mackintosh CA, Pegg AE, Woster PM, Casero RA, Jr. Spermine and spermidine mediate protection against oxidative damage caused by hydrogen peroxide. Amino Acids. (2007) 33:231–40. 10.1007/s00726-007-0513-4
    1. Pedreno E, Lopez-Contreras AJ, Cremades A, Penafiel R. Protecting or promoting effects of spermine on DNA strand breakage induced by iron or copper ions as a function of metal concentration. J Inorg Biochem. (2005) 99:2074–80. 10.1016/j.jinorgbio.2005.07.005
    1. Wang L, Liu Y, Qi C, Shen L, Wang J, Liu X, et al. . Oxidative degradation of polyamines by serum supplement causes cytotoxicity on cultured cells. Sci Rep. (2018) 8:10384. 10.1038/s41598-018-28648-8
    1. Jaenne J, Raina A, Siimes M. Spermidine and spermine in rat tissues at different ages. Acta Physiol Scand. (1964) 62:352–8. 10.1111/j.1748-1716.1964.tb10433.x
    1. Wang X, Ikeguchi Y, McCloskey DE, Nelson P, Pegg AE. Spermine synthesis is required for normal viability, growth, and fertility in the mouse. J Biol Chem. (2004) 279:51370–5. 10.1074/jbc.M410471200
    1. Scalabrino G, Ferioli ME. Polyamines in mammalian ageing: an oncological problem, too? A review. Mech Ageing Dev. (1984) 26:149–64. 10.1016/0047-6374(84)90090-3
    1. Nishimura K, Shiina R, Kashiwagi K, Igarashi K. Decrease in polyamines with aging and their ingestion from food and drink. J Biochem. (2006) 139:81–90. 10.1093/jb/mvj003
    1. Watanabe S, Kusama-Eguchi K, Kobayashi H, Igarashi K. Estimation of polyamine binding to macromolecules and ATP in bovine lymphocytes and rat liver. J Biol Chem. (1991) 266:20803–9.
    1. Hoshino K, Momiyama E, Yoshida K, Nishimura K, Sakai S, Toida T, et al. . Polyamine transport by mammalian cells and mitochondria: role of antizyme and glycosaminoglycans. J Biol Chem. (2005) 280:42801–8. 10.1074/jbc.M505445200
    1. Hougaard DM, Nielsen JH, Larsson LI. Localization and biosynthesis of polyamines in insulin-producing cells. Biochem J. (1986) 238:43–7. 10.1042/bj2380043
    1. Garcia-Faroldi G, Rodriguez CE, Urdiales JL, Perez-Pomares JM, Davila JC, Pejler G, et al. . Polyamines are present in mast cell secretory granules and are important for granule homeostasis. PLoS ONE. (2010) 5:e15071. 10.1371/journal.pone.0015071
    1. Takeuchi T, Harada Y, Moriyama S, Furuta K, Tanaka S, Miyaji T, et al. . Vesicular polyamine transporter mediates vesicular storage and release of polyamine from mast cells. J Biol Chem. (2017) 292:3909–18. 10.1074/jbc.M116.756197
    1. Casti A, Orlandini G, Reali N, Bacciottini F, Vanelli M, Bernasconi S. Pattern of blood polyamines in healthy subjects from infancy to the adult age. J Endocrinol Invest. (1982) 5:263–6. 10.1007/BF03348334
    1. Soda K, Kano Y, Sakuragi M, Takao K, Lefor A, Konishi F. Long-term oral polyamine intake increases blood polyamine concentrations. J Nutr Sci Vitaminol. (2009) 55:361–6. 10.3177/jnsv.55.361
    1. Pegg AE. Regulation of ornithine decarboxylase. J Biol Chem. (2006) 281:14529–32. 10.1074/jbc.R500031200
    1. Wu H, Min J, Ikeguchi Y, Zeng H, Dong A, Loppnau P, et al. . Structure and mechanism of spermidine synthases. Biochemistry. (2007) 46:8331–9. 10.1021/bi602498k
    1. Pegg AE, Michael AJ. Spermine synthase. Cell Mol Life Sci. (2010) 67:113–21. 10.1007/s00018-009-0165-5
    1. Pegg AE. S-Adenosylmethionine decarboxylase. Essays Biochem. (2009) 46:25–45. 10.1042/bse0460003
    1. Casero RA, Jr, Pegg AE. Spermidine/spermine N1-acetyltransferase–the turning point in polyamine metabolism. FASEB J. (1993) 7:653–61. 10.1096/fasebj.7.8.8500690
    1. Pegg AE. Spermidine/spermine-N(1)-acetyltransferase: a key metabolic regulator. Am J Physiol Endocrinol Metab. (2008) 294:E995–1010. 10.1152/ajpendo.90217.2008
    1. Vujcic S, Liang P, Diegelman P, Kramer DL, Porter CW. Genomic identification and biochemical characterization of the mammalian polyamine oxidase involved in polyamine back-conversion. Biochem J. (2003) 370:19–28. 10.1042/bj20021779
    1. Vujcic S, Diegelman P, Bacchi CJ, Kramer DL, Porter CW. Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. Biochem J. (2002) 367:665–75. 10.1042/bj20020720
    1. Wang Y, Murray-Stewart T, Devereux W, Hacker A, Frydman B, Woster PM, et al. . Properties of purified recombinant human polyamine oxidase, PAOh1/SMO. Biochem Biophys Res Commun. (2003) 304:605–11. 10.1016/S0006-291X(03)00636-3
    1. Murray-Stewart T, Wang Y, Goodwin A, Hacker A, Meeker A, Casero RA, Jr. Nuclear localization of human spermine oxidase isoforms - possible implications in drug response and disease etiology. FEBS J. (2008) 275:2795–806. 10.1111/j.1742-4658.2008.06419.x
    1. Zhu MY, Iyo A, Piletz JE, Regunathan S. Expression of human arginine decarboxylase, the biosynthetic enzyme for agmatine. Biochim Biophys Acta. (2004) 1670:156–64. 10.1016/j.bbagen.2003.11.006
    1. Lopez-Contreras AJ, Lopez-Garcia C, Jimenez-Cervantes C, Cremades A, Penafiel R. Mouse ornithine decarboxylase-like gene encodes an antizyme inhibitor devoid of ornithine and arginine decarboxylating activity. J Biol Chem. (2006) 281:30896–906. 10.1074/jbc.M602840200
    1. Kanerva K, Makitie LT, Pelander A, Heiskala M, Andersson LC. Human ornithine decarboxylase paralogue (ODCp) is an antizyme inhibitor but not an arginine decarboxylase. Biochem J. (2008) 409:187–92. 10.1042/BJ20071004
    1. Piletz JE, Aricioglu F, Cheng JT, Fairbanks CA, Gilad VH, Haenisch B, et al. . Agmatine: clinical applications after 100 years in translation. Drug Discov Today. (2013) 18:880–93. 10.1016/j.drudis.2013.05.017
    1. Laube G, Bernstein HG. Agmatine: multifunctional arginine metabolite and magic bullet in clinical neuroscience? Biochem J. (2017) 474:2619–40. 10.1042/BCJ20170007
    1. Igarashi K, Kashiwagi K. Characteristics of cellular polyamine transport in prokaryotes and eukaryotes. Plant Physiol Biochem. (2010) 48:506–12. 10.1016/j.plaphy.2010.01.017
    1. Abdulhussein AA, Wallace HM. Polyamines and membrane transporters. Amino Acids. (2014) 46:655–60. 10.1007/s00726-013-1553-6
    1. Seiler N, Delcros JG, Moulinoux JP. Polyamine transport in mammalian cells. An update. Int J Biochem Cell Biol. (1996) 28:843–61. 10.1016/1357-2725(96)00021-0
    1. Grundemann D, Hahne C, Berkels R, Schomig E. Agmatine is efficiently transported by non-neuronal monoamine transporters extraneuronal monoamine transporter (EMT) and organic cation transporter 2 (OCT2). J Pharmacol Exp Ther. (2003) 304:810–7. 10.1124/jpet.102.044404
    1. Heinen A, Bruss M, Bonisch H, Gothert M, Molderings GJ. Pharmacological characteristics of the specific transporter for the endogenous cell growth inhibitor agmatine in six tumor cell lines. Int J Colorectal Dis. (2003) 18:314–9. 10.1007/s00384-002-0466-8
    1. Winter TN, Elmquist WF, Fairbanks CA. OCT2 and MATE1 provide bidirectional agmatine transport. Mol Pharm. (2011) 8:133–42. 10.1021/mp100180a
    1. Sala-Rabanal M, Li DC, Dake GR, Kurata HT, Inyushin M, Skatchkov SN, et al. . Polyamine transport by the polyspecific organic cation transporters OCT1, OCT2, and OCT3. Mol Pharm. (2013) 10:1450–8. 10.1021/mp400024d
    1. Uemura T, Yerushalmi HF, Tsaprailis G, Stringer DE, Pastorian KE, Hawel L, III, et al. . Identification and characterization of a diamine exporter in colon epithelial cells. J Biol Chem. (2008) 283:26428–35. 10.1074/jbc.M804714200
    1. Belting M, Mani K, Jonsson M, Cheng F, Sandgren S, Jonsson S, et al. . Glypican-1 is a vehicle for polyamine uptake in mammalian cells: a pivital role for nitrosothiol-derived nitric oxide. J Biol Chem. (2003) 278:47181–9. 10.1074/jbc.M308325200
    1. Uemura T, Stringer DE, Blohm-Mangone KA, Gerner EW. Polyamine transport is mediated by both endocytic and solute carrier transport mechanisms in the gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol. (2010) 299:G517–522. 10.1152/ajpgi.00169.2010
    1. Murakami Y, Matsufuji S, Kameji T, Hayashi S, Igarashi K, Tamura T, et al. . Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature. (1992) 360:597–9. 10.1038/360597a0
    1. Mitchell JL, Judd GG, Bareyal-Leyser A, Ling SY. Feedback repression of polyamine transport is mediated by antizyme in mammalian tissue-culture cells. Biochem J. (1994) 299:19–22. 10.1042/bj2990019
    1. Kahana C. Antizyme and antizyme inhibitor, a regulatory tango. Cell Mol Life Sci. (2009) 66:2479–88. 10.1007/s00018-009-0033-3
    1. Ramos-Molina B, Lambertos A, Penafiel R. Antizyme inhibitors in polyamine metabolism and beyond: physiopathological implications. Med Sci. (2018) 6:E89. 10.3390/medsci6040089
    1. Lopez-Contreras AJ, Ramos-Molina B, Cremades A, Penafiel R. Antizyme inhibitor 2 (AZIN2/ODCp) stimulates polyamine uptake in mammalian cells. J Biol Chem. (2008) 283:20761–9. 10.1074/jbc.M801024200
    1. Ramos-Molina B, Lopez-Contreras AJ, Lambertos A, Dardonville C, Cremades A, Penafiel R. Influence of ornithine decarboxylase antizymes and antizyme inhibitors on agmatine uptake by mammalian cells. Amino Acids. (2015) 47:1025–34. 10.1007/s00726-015-1931-3
    1. Bardócz S, Grant G, Brown DS, Ralph A, Pusztai A. Polyamines in food—implications for growth and health. J Nutr Biochem. (1993) 4:66–71. 10.1016/0955-2863(93)90001-D
    1. White A, Bardocz S. Estimation of the polyamine body pool: contribution by de novo biosynthesis, diet and luminal bacteria. In: Bardocz S, White A, editors. Polyamines in Health and Nutrition. Aberdeen: Kluwer Academic Publishers; The Rowett Reseach Institute; Greenburn Road Bucksburn; (1999). p. 117–27.
    1. Kalac P, Krausova P. A review of dietary polyamines: formation, implications for growth and health and occurrence in foods. Food Chem. (2005) 90:219–30. 10.1016/j.foodchem.2004.03.044
    1. Kalac P. Biologically active polyamines in beef, pork and meat products: a review. Meat Sci. (2006) 73:1–11. 10.1016/j.meatsci.2005.11.001
    1. Cipolla BG, Havouis R, Moulinoux JP. Polyamine contents in current foods: a basis for polyamine reduced diet and a study of its long term observance and tolerance in prostate carcinoma patients. Amino Acids. (2007) 33:203–12. 10.1007/s00726-007-0524-1
    1. Nishibori N, Fujihara S, Akatuki T. Amounts of polyamines in foods in Japan and intake by Japanese. Food Chem. (2007) 100:491–7. 10.1016/j.foodchem.2005.09.070
    1. Atiya Ali M, Poortvliet E, Stromberg R, Yngve A. Polyamines in foods: development of a food database. Food Nutr Res. (2011) 55:5572. 10.3402/fnr.v55i0.5572
    1. Kalac P. Health effects and occurrence of dietary polyamines: a review for the period 2005–mid 2013. Food Chem. (2014) 161:27–39. 10.1016/j.foodchem.2014.03.102
    1. Milovic V. Polyamines in the gut lumen: bioavailability and biodistribution. Eur J Gastroenterol Hepatol. (2001) 13:1021–5. 10.1097/00042737-200109000-00004
    1. Milovic V, Stein J, Piiper A, Gerhard R, Zeuzem S, Caspary WF. Characterization of putrescine transport across the intestinal epithelium: study using isolated brush border and basolateral membrane vesicles of the enterocyte. Eur J Clin Invest. (1995) 25:97–105. 10.1111/j.1365-2362.1995.tb01533.x
    1. Bardocz S. Polyamines in food and their consequences for food quality and human health. Trends Food Sci Technol. (1995) 6:341–6. 10.1016/S0924-2244(00)89169-4
    1. Bardocz S, Grant G, Brown DS, Pusztai A. Putrescine as a source of instant energy in the small intestine of the rat. Gut. (1998) 42:24–8. 10.1136/gut.42.1.24
    1. Uda K, Tsujikawa T, Fujiyama Y, Bamba T. Rapid absorption of luminal polyamines in a rat small intestine ex vivo model. J Gastroenterol Hepatol. (2003) 18:554–9. 10.1046/j.1440-1746.2003.03020.x
    1. Eisenberg T, Knauer H, Schauer A, Buttner S, Ruckenstuhl C, Carmona-Gutierrez D, et al. . Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. (2009) 11:1305–14. 10.1038/ncb1975
    1. LaRocca TJ, Gioscia-Ryan RA, Hearon CM, Jr, Seals DR. The autophagy enhancer spermidine reverses arterial aging. Mech Ageing Dev. (2013) 134:314–20. 10.1016/j.mad.2013.04.004
    1. Gao M, Zhao W, Li C, Xie X, Li M, Bi Y, et al. . Spermidine ameliorates non-alcoholic fatty liver disease through regulating lipid metabolism via AMPK. Biochem Biophys Res Commun. (2018) 505:93–8. 10.1016/j.bbrc.2018.09.078
    1. Yadav M, Parle M, Jindal DK, Sharma N. Potential effect of spermidine on GABA, dopamine, acetylcholinesterase, oxidative stress and proinflammatory cytokines to diminish ketamine-induced psychotic symptoms in rats. Biomed Pharmacother. (2018) 98:207–13. 10.1016/j.biopha.2017.12.016
    1. Soda K, Kano Y, Chiba F, Koizumi K, Miyaki Y. Increased polyamine intake inhibits age-associated alteration in global DNA methylation and 1,2-dimethylhydrazine-induced tumorigenesis. PLoS ONE. (2013) 8:e64357. 10.1371/journal.pone.0064357
    1. Schwarz C, Stekovic S, Wirth M, Benson G, Royer P, Sigrist SJ, et al. . Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline. Aging. (2018) 10:19–33. 10.18632/aging.101354
    1. Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, et al. . Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. (2016) 22:1428–38. 10.1038/nm.4222
    1. Deloyer P, Peulen O, Dandrifosse G. Dietary polyamines and non-neoplastic growth and disease. Eur J Gastroenterol Hepatol. (2001) 13:1027–32. 10.1097/00042737-200109000-00005
    1. Liu L, Guo X, Rao JN, Zou T, Xiao L, Yu T, et al. . Polyamines regulate E-cadherin transcription through c-Myc modulating intestinal epithelial barrier function. Am J Physiol Cell Physiol. (2009) 296:C801–810. 10.1152/ajpcell.00620.2008
    1. Loser C, Eisel A, Harms D, Folsch UR. Dietary polyamines are essential luminal growth factors for small intestinal and colonic mucosal growth and development. Gut. (1999) 44:12–6. 10.1136/gut.44.1.12
    1. Kaouass M, Deloyer P, Dandrifosse G. Intestinal development in suckling rats: direct or indirect spermine action? Digestion. (1994) 55:160–7.
    1. Larque E, Sabater-Molina M, Zamora S. Biological significance of dietary polyamines. Nutrition. (2007) 23:87–95. 10.1016/j.nut.2006.09.006
    1. Ramos-Molina B, Lopez-Contreras AJ, Cremades A, Penafiel R. Differential expression of ornithine decarboxylase antizyme inhibitors and antizymes in rodent tissues and human cell lines. Amino Acids. (2012) 42:539–47. 10.1007/s00726-011-1031-y
    1. Yuan Q, Ray RM, Viar MJ, Johnson LR. Polyamine regulation of ornithine decarboxylase and its antizyme in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. (2001) 280:G130–138. 10.1152/ajpgi.2001.280.1.G130
    1. Ray RM, Viar MJ, Johnson LR. Amino acids regulate expression of antizyme-1 to modulate ornithine decarboxylase activity. J Biol Chem. (2012) 287:3674–90. 10.1074/jbc.M111.232561
    1. Chabanon H, Persson L, Wallace HM, Ferrara M, Brachet P. Increased translation efficiency and antizyme-dependent stabilization of ornithine decarboxylase in amino acid-supplemented human colon adenocarcinoma cells, Caco-2. Biochem J. (2000) 348 (Pt 2):401–8. 10.1042/bj3480401
    1. Aubel C, Chabanon H, Persson L, Thiman L, Ferrara M, Brachet P. Antizyme-dependent and -independent mechanisms are responsible for increased spermidine transport in amino acid-restricted human cancer cells. Biochem Biophys Res Commun. (1999) 256:646–51. 10.1006/bbrc.1999.0397
    1. Gill J, Kirby L, Seidel ER. Antizyme mRNA distribution along the crypt/villus axis and modulation of expression in response to polyamines. Gastroenterology. (1998) 114:A880 10.1016/S0016-5085(98)83583-X
    1. Qiu S, Liu J, Xing F. Antizyme inhibitor 1: a potential carcinogenic molecule. Cancer Sci. (2017) 108:163–9. 10.1111/cas.13122
    1. Shigeyasu K, Okugawa Y, Toden S, Miyoshi J, Toiyama Y, Nagasaka T, et al. . AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer. JCI Insight. (2018) 3:99976. 10.1172/jci.insight.99976
    1. Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol. (2016) 16:341–52. 10.1038/nri.2016.42
    1. Matsumoto M, Kibe R, Ooga T, Aiba Y, Kurihara S, Sawaki E, et al. . Impact of intestinal microbiota on intestinal luminal metabolome. Sci Rep. (2012) 2:233. 10.1038/srep00233
    1. Bhat MI, Kapila R. Dietary metabolites derived from gut microbiota: critical modulators of epigenetic changes in mammals. Nutr Rev. (2017) 75:374–89. 10.1093/nutrit/nux001
    1. Sugiyama Y, Nara M, Sakanaka M, Gotoh A, Kitakata A, Okuda S, et al. . Comprehensive analysis of polyamine transport and biosynthesis in the dominant human gut bacteria: potential presence of novel polyamine metabolism and transport genes. Int J Biochem Cell Biol. (2017) 93:52–61. 10.1016/j.biocel.2017.10.015
    1. Postler TS, Ghosh S. Understanding the holobiont: how microbial metabolites affect human health and shape the immune system. Cell Metab. (2017) 26:110–30. 10.1016/j.cmet.2017.05.008
    1. Noack J, Kleessen B, Proll J, Dongowski G, Blaut M. Dietary guar gum and pectin stimulate intestinal microbial polyamine synthesis in rats. J Nutr. (1998) 128:1385–91. 10.1093/jn/128.8.1385
    1. Delzenne NM, Kok N, Deloyer P, Dandrifosse G. Dietary fructans modulate polyamine concentration in the cecum of rats. J Nutr. (2000) 130:2456–60. 10.1093/jn/130.10.2456
    1. Noack J, Dongowski G, Hartmann L, Blaut M. The human gut bacteria Bacteroides thetaiotaomicron and Fusobacterium. varium produce putrescine and spermidine in cecum of pectin-fed gnotobiotic rats. J Nutr. (2000) 130:1225–31. 10.1093/jn/130.5.1225
    1. Osborne DL, Seidel ER. Gastrointestinal luminal polyamines: cellular accumulation and enterohepatic circulation. Am J Physiol. (1990) 258(4 Pt 1), G576–584. 10.1152/ajpgi.1990.258.4.G576
    1. Matsumoto M, Benno Y. The relationship between microbiota and polyamine concentration in the human intestine: a pilot study. Microbiol Immunol. (2007) 51:25–35. 10.1111/j.1348-0421.2007.tb03887.x
    1. Hanfrey CC, Pearson BM, Hazeldine S, Lee J, Gaskin DJ, Woster PM, et al. . Alternative spermidine biosynthetic route is critical for growth of Campylobacter jejuni and is the dominant polyamine pathway in human gut microbiota. J Biol Chem. (2011) 286:43301–12. 10.1074/jbc.M111.307835
    1. Burrell M, Hanfrey CC, Murray EJ, Stanley-Wall NR, Michael AJ. Evolution and multiplicity of arginine decarboxylases in polyamine biosynthesis and essential role in Bacillus subtilis biofilm formation. J Biol Chem. (2010) 285:39224–38. 10.1074/jbc.M110.163154
    1. Kibe R, Kurihara S, Sakai Y, Suzuki H, Ooga T, Sawaki E, et al. . Upregulation of colonic luminal polyamines produced by intestinal microbiota delays senescence in mice. Sci Rep. (2014) 4:4548. 10.1038/srep04548
    1. Nakamura A, Ooga T, Matsumoto M. Intestinal luminal putrescine is produced by collective biosynthetic pathways of the commensal microbiome. Gut Microbes. (2018) 5:1–13. 10.1080/19490976.2018.1494466
    1. O'Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. (2016) 16:553–65. 10.1038/nri.2016.70
    1. Mardinoglu A, Shoaie S, Bergentall M, Ghaffari P, Zhang C, Larsson E, et al. . The gut microbiota modulates host amino acid and glutathione metabolism in mice. Mol Syst Biol. (2015) 11:834. 10.15252/msb.20156487
    1. Levy M, Thaiss CA, Zeevi D, Dohnalova L, Zilberman-Schapira G, Mahdi JA, et al. . Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell. (2015) 163:1428–43. 10.1016/j.cell.2015.10.048
    1. Levy M, Thaiss CA, Elinav E. Metabolites: messengers between the microbiota and the immune system. Genes Dev. (2016) 30:1589–97. 10.1101/gad.284091.116
    1. Matsumoto M, Kurihara S, Kibe R, Ashida H, Benno Y. Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production. PLoS ONE. (2011) 6:e23652. 10.1371/journal.pone.0023652
    1. Dejea CM, Wick EC, Hechenbleikner EM, White JR, Mark Welch JL, Rossetti BJ, et al. . Microbiota organization is a distinct feature of proximal colorectal cancers. Proc Natl Acad Sci USA. (2014) 111:18321–6. 10.1073/pnas.1406199111
    1. Johnson CH, Dejea CM, Edler D, Hoang LT, Santidrian AF, Felding BH, et al. . Metabolism links bacterial biofilms and colon carcinogenesis. Cell Metab. (2015) 21:891–7. 10.1016/j.cmet.2015.04.011
    1. Hessels J, Kingma AW, Ferwerda H, Keij J, van den Berg GA, Muskiet FA. Microbial flora in the gastrointestinal tract abolishes cytostatic effects of alpha-difluoromethylornithine in vivo. Int J Cancer. (1989) 43:1155–64. 10.1002/ijc.2910430632
    1. Quemener V, Blanchard Y, Chamaillard L, Havouis R, Cipolla B, Moulinoux JP. Polyamine deprivation: a new tool in cancer treatment. Anticancer Res. (1994) 14:443–8.
    1. Niiranen K, Keinanen TA, Pirinen E, Heikkinen S, Tusa M, Fatrai S, et al. . Mice with targeted disruption of spermidine/spermine N1-acetyltransferase gene maintain nearly normal tissue polyamine homeostasis but show signs of insulin resistance upon aging. J Cell Mol Med. (2006) 10:933–45. 10.1111/j.1582-4934.2006.tb00536.x
    1. Pirinen E, Kuulasmaa T, Pietila M, Heikkinen S, Tusa M, Itkonen P, et al. . Enhanced polyamine catabolism alters homeostatic control of white adipose tissue mass, energy expenditure, and glucose metabolism. Mol Cell Biol. (2007) 27:4953–67. 10.1128/MCB.02034-06
    1. Cerrada-Gimenez M, Tusa M, Casellas A, Pirinen E, Moya M, Bosch F, et al. . Altered glucose-stimulated insulin secretion in a mouse line with activated polyamine catabolism. Transgenic Res. (2012) 21:843–53. 10.1007/s11248-011-9579-6
    1. Kraus D, Yang Q, Kong D, Banks AS, Zhang L, Rodgers JT, et al. . Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature. (2014) 508:258–62. 10.1038/nature13198
    1. Bonhoure N, Byrnes A, Moir RD, Hodroj W, Preitner F, Praz V, et al. . Loss of the RNA polymerase III repressor MAF1 confers obesity resistance. Genes Dev. (2015) 29:934–47. 10.1101/gad.258350.115
    1. Yuan F, Zhang L, Cao Y, Gao W, Zhao C, Fang Y, et al. . Spermidine/spermine N1-acetyltransferase-mediated polyamine catabolism regulates beige adipocyte biogenesis. Metabolism. (2018) 85:298–304. 10.1016/j.metabol.2018.04.007
    1. Jamdar SC, Cao WF, Samaniego E. Relationship between adipose polyamine concentrations and triacylglycerol synthetic enzymes in lean and obese Zucker rats. Enzyme Protein. (1996) 49:222–30. 10.1159/000468632
    1. Yun KU, Ryu CS, Lee JY, Noh JR, Lee CH, Lee HS, et al. . Hepatic metabolism of sulfur amino acids in db/db mice. Food Chem Toxicol. (2013) 53:180–6. 10.1016/j.fct.2012.11.046
    1. Kwak HC, Kim YM, Oh SJ, Kim SK. Sulfur amino acid metabolism in Zucker diabetic fatty rats. Biochem Pharmacol. (2015) 96:256–66. 10.1016/j.bcp.2015.05.014
    1. Sjoholm A, Arkhammar P, Berggren PO, Andersson A. Polyamines in pancreatic islets of obese-hyperglycemic (ob/ob) mice of different ages. Am J Physiol Cell Physiol. (2001) 280:C317–323. 10.1152/ajpcell.2001.280.2.C317
    1. Pelantova H, Bartova S, Anyz J, Holubova M, Zelezna B, Maletinska L, et al. . Metabolomic profiling of urinary changes in mice with monosodium glutamate-induced obesity. Anal Bioanal Chem. (2016) 408:567–78. 10.1007/s00216-015-9133-0
    1. Codoner-Franch P, Tavarez-Alonso S, Murria-Estal R, Herrera-Martin G, Alonso-Iglesias E. Polyamines are increased in obese children and are related to markers of oxidative/nitrosative stress and angiogenesis. J Clin Endocrinol Metab. (2011) 96:2821–5. 10.1210/jc.2011-0531
    1. Erwin BG, Bethell DR, Pegg AE. Role of polyamines in differentiation of 3T3-L1 fibroblasts into adipocytes. Am J Physiol. (1984) 246(3 Pt 1):C293–300. 10.1152/ajpcell.1984.246.3.C293
    1. Vuohelainen S, Pirinen E, Cerrada-Gimenez M, Keinanen TA, Uimari A, Pietila M, et al. . Spermidine is indispensable in differentiation of 3T3-L1 fibroblasts to adipocytes. J Cell Mol Med. (2010) 14:1683–92. 10.1111/j.1582-4934.2009.00808.x
    1. Ishii I, Ikeguchi Y, Mano H, Wada M, Pegg AE, Shirahata A. Polyamine metabolism is involved in adipogenesis of 3T3-L1 cells. Amino Acids. (2012) 42:619–26. 10.1007/s00726-011-1037-5
    1. Hyvonen MT, Koponen T, Weisell J, Pietila M, Khomutov AR, Vepsalainen J, et al. . Spermidine promotes adipogenesis of 3T3-L1 cells by preventing interaction of ANP32 with HuR and PP2A. Biochem J. (2013) 453:467–74. 10.1042/BJ20130263
    1. Sadasivan SK, Vasamsetti B, Singh J, Marikunte VV, Oommen AM, Jagannath MR, et al. . Exogenous administration of spermine improves glucose utilization and decreases bodyweight in mice. Eur J Pharmacol. (2014) 729:94–9. 10.1016/j.ejphar.2014.01.073
    1. Fernandez AF, Barcena C, Martinez-Garcia GG, Tamargo-Gomez I, Suarez MF, Pietrocola F, et al. . Autophagy couteracts weight gain, lipotoxicity and pancreatic beta-cell death upon hypercaloric pro-diabetic regimens. Cell Death Dis. (2017) 8:e2970. 10.1038/cddis.2017.373
    1. Lockwood DH, East LE. Studies of the insulin-like actions of polyamines on lipid and glucose metabolism in adipose tissue cells. J Biol Chem. (1974) 249:7717–22.
    1. Pedersen SB, Hougaard DM, Richelsen B. Polyamines in rat adipocytes: their localization and their effects on the insulin receptor binding. Mol Cell Endocrinol. (1989) 62:161–6. 10.1016/0303-7207(89)90002-6
    1. Michiels CF, Kurdi A, Timmermans JP, De Meyer GRY, Martinet W. Spermidine reduces lipid accumulation and necrotic core formation in atherosclerotic plaques via induction of autophagy. Atherosclerosis. (2016) 251:319–27. 10.1016/j.atherosclerosis.2016.07.899
    1. Sjoholm A. Role of polyamines in the regulation of proliferation and hormone production by insulin-secreting cells. Am J Physiol. (1993) 264(3 Pt 1):C501–18. 10.1152/ajpcell.1993.264.3.C501
    1. Fernandez-Garcia JC, Delpino-Rius A, Samarra I, Castellano-Castillo D, Munoz-Garach A, Bernal-Lopez MR, et al. Type 2 diabetes is associated with a different pattern of serum polyamines: a case(-)control study from the PREDIMED-plus trial. J Clin Med. (2019) 8:71 10.3390/jcm8010071
    1. Deng A, Munger KA, Valdivielso JM, Satriano J, Lortie M, Blantz RC, et al. . Increased expression of ornithine decarboxylase in distal tubules of early diabetic rat kidneys: are polyamines paracrine hypertrophic factors? Diabetes. (2003) 52:1235–9. 10.2337/diabetes.52.5.1235
    1. Mendez JD, Balderas FL. Inhibition by L-arginine and spermidine of hemoglobin glycation and lipid peroxidation in rats with induced diabetes. Biomed Pharmacother. (2006) 60:26–31. 10.1016/j.biopha.2005.08.004
    1. Mendez JD, Hernandez Rde H. L-arginine and polyamine administration protect beta-cells against alloxan diabetogenic effect in Sprague-Dawley rats. Biomed Pharmacother. (2005) 59:283–9. 10.1016/j.biopha.2005.05.006
    1. Jafarnejad A, Bathaie SZ, Nakhjavani M, Hassan MZ. Effect of spermine on lipid profile and HDL functionality in the streptozotocin-induced diabetic rat model. Life Sci. (2008) 82:301–7. 10.1016/j.lfs.2007.11.015
    1. Fetterman JL, Holbrook M, Flint N, Feng B, Breton-Romero R, Linder EA, et al. . Restoration of autophagy in endothelial cells from patients with diabetes mellitus improves nitric oxide signaling. Atherosclerosis. (2016) 247:207–17. 10.1016/j.atherosclerosis.2016.01.043
    1. Nissim I, Horyn O, Daikhin Y, Chen P, Li C, Wehrli SL, et al. . The molecular and metabolic influence of long term agmatine consumption. J Biol Chem. (2014) 289:9710–29. 10.1074/jbc.M113.544726
    1. Wisniewska A, Olszanecki R, Toton-Zuranska J, Kus K, Stachowicz A, Suski M, et al. . Anti-atherosclerotic action of agmatine in ApoE-knockout mice. Int J Mol Sci. (2017) 18:E1706. 10.3390/ijms18081706
    1. Babbar N, Murray-Stewart T, Casero RA, Jr. Inflammation and polyamine catabolism: the good, the bad and the ugly. Biochem Soc Trans. (2007) 35:300–4. 10.1042/BST0350300
    1. Moreno-Indias I, Cardona F, Tinahones FJ, Queipo-Ortuno MI. Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus. Front Microbiol. (2014) 5:190. 10.3389/fmicb.2014.00190
    1. Morselli E, Galluzzi L, Kepp O, Criollo A, Maiuri MC, Tavernarakis N, et al. . Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging. (2009) 1:961–70. 10.18632/aging.100110
    1. Das R, Kanungo MS. Activity and modulation of ornithine decarboxylase and concentrations of polyamines in various tissues of rats as a function of age. Exp Gerontol. (1982) 17:95–103. 10.1016/0531-5565(82)90042-0
    1. Soda K, Dobashi Y, Kano Y, Tsujinaka S, Konishi F. Polyamine-rich food decreases age-associated pathology and mortality in aged mice. Exp Gerontol. (2009) 44:727–32. 10.1016/j.exger.2009.08.013
    1. Yue F, Li W, Zou J, Jiang X, Xu G, Huang H, et al. . Spermidine prolongs lifespan and prevents liver fibrosis and hepatocellular carcinoma by activating MAP1S-mediated autophagy. Cancer Res. (2017) 77:2938–51. 10.1158/0008-5472.CAN-16-3462
    1. Gupta VK, Scheunemann L, Eisenberg T, Mertel S, Bhukel A, Koemans TS, et al. . Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat Neurosci. (2013) 16:1453–60. 10.1038/nn.3512
    1. Fruhauf PK, Ineu RP, Tomazi L, Duarte T, Mello CF, Rubin MA. Spermine reverses lipopolysaccharide-induced memory deficit in mice. J Neuroinflamm. (2015) 12:3. 10.1186/s12974-014-0220-5
    1. Zhang H, Wang J, Li L, Chai N, Chen Y, Wu F, et al. . Spermine and spermidine reversed age-related cardiac deterioration in rats. Oncotarget. (2017) 8:64793–808. 10.18632/oncotarget.18334
    1. Jing YH, Yan JL, Wang QJ, Chen HC, Ma XZ, Yin J, et al. . Spermidine ameliorates the neuronal aging by improving the mitochondrial function in vitro. Exp Gerontol. (2018) 108:77–86. 10.1016/j.exger.2018.04.005
    1. Zhu WW, Xiao F, Tang YY, Zou W, Li X, Zhang P, et al. . Spermidine prevents high glucose-induced senescence in HT-22 cells by upregulation of CB1 receptor. Clin Exp Pharmacol Physiol. (2018) 45:832–40. 10.1111/1440-1681.12955
    1. Morselli E, Marino G, Bennetzen MV, Eisenberg T, Megalou E, Schroeder S, et al. . Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J Cell Biol. (2011) 192:615–29. 10.1083/jcb.201008167
    1. Pietrocola F, Lachkar S, Enot DP, Niso-Santano M, Bravo-San Pedro JM, Sica V, et al. . Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. (2015) 22:509–16. 10.1038/cdd.2014.215
    1. Sacitharan PK, Lwin S, Gharios GB, Edwards JR. Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300. Exp Mol Med. (2018) 50:123. 10.1038/s12276-018-0149-3
    1. Kiechl S, Pechlaner R, Willeit P, Notdurfter M, Paulweber B, Willeit K, et al. . Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am J Clin Nutr. (2018) 108:371–80. 10.1093/ajcn/nqy102
    1. Crous-Bou M, Fung TT, Prescott J, Julin B, Du M, Sun Q, et al. . Mediterranean diet and telomere length in Nurses' Health Study: population based cohort study. BMJ. (2014) 349:g6674. 10.1136/bmj.g6674
    1. Soda K, Phan Nguyen Thanh B, Masanobu K. Mediterranean diet and polyamine intake: possible contribution of increased polyamine intake to inhibition of age-associated disease. Nutr Diet Suppl. (2010) 2011:1–7. 10.2147/NDS.S15349
    1. Jung M, Pfeifer GP. Aging and DNA methylation. BMC Biol. (2015) 13:7. 10.1186/s12915-015-0118-4
    1. Ciccarone F, Tagliatesta S, Caiafa P, Zampieri M. DNA methylation dynamics in aging: how far are we from understanding the mechanisms? Mech Ageing Dev. (2018) 174:3–17. 10.1016/j.mad.2017.12.002
    1. Soda K. Polyamine metabolism and gene methylation in conjunction with one-carbon metabolism. Int J Mol Sci. (2018) 19:3106. 10.3390/ijms19103106
    1. Tsuji T, Usui S, Aida T, Tachikawa T, Hu GF, Sasaki A, et al. . Induction of epithelial differentiation and DNA demethylation in hamster malignant oral keratinocyte by ornithine decarboxylase antizyme. Oncogene. (2001) 20:24–33. 10.1038/sj.onc.1204051
    1. Yamamoto D, Shima K, Matsuo K, Nishioka T, Chen CY, Hu GF, et al. . Ornithine decarboxylase antizyme induces hypomethylation of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2) in human oral cancer cell line. PLoS ONE. (2010) 5:e12554. 10.1371/journal.pone.0012554
    1. Barres R, Zierath JR. DNA methylation in metabolic disorders. Am J Clin Nutr. (2011) 93:897S−900. 10.3945/ajcn.110.001933
    1. Bergman Y, Cedar H. DNA methylation dynamics in health and disease. Nat Struct Mol Biol. (2013) 20:274–81. 10.1038/nsmb.2518
    1. Arpon A, Milagro FI, Razquin C, Corella D, Estruch R, Fito M, et al. . Impact of consuming extra-virgin olive oil or nuts within a mediterranean diet on DNA methylation in peripheral white blood cells within the PREDIMED-navarra randomized controlled trial: a role for dietary lipids. Nutrients. (2017) 10:E15. 10.3390/nu10010015
    1. Chamberlain JA, Dugue PA, Bassett JK, Hodge AM, Brinkman MT, Joo JE, et al. . Dietary intake of one-carbon metabolism nutrients and DNA methylation in peripheral blood. Am J Clin Nutr. (2018) 108:611–21. 10.1093/ajcn/nqy119
    1. Soda K. The mechanisms by which polyamines accelerate tumor spread. J Exp Clin Cancer Res. (2011) 30:95. 10.1186/1756-9966-30-95
    1. Raj KP, Zell JA, Rock CL, McLaren CE, Zoumas-Morse C, Gerner EW, et al. . Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas. Br J Cancer. (2013) 108:512–8. 10.1038/bjc.2013.15
    1. Vargas AJ, Ashbeck EL, Wertheim BC, Wallace RB, Neuhouser ML, Thomson CA, et al. . Dietary polyamine intake and colorectal cancer risk in postmenopausal women. Am J Clin Nutr. (2015) 102:411–9. 10.3945/ajcn.114.103895
    1. Wada M, Funada-Wada U, Mano H, Higashiguchi M, Haba R, Watanabe S, et al. Effects of dietary polyamines on the promotion of mammary tumor in rats. J Health Sci. (2002) 48:376–80. 10.1248/jhs.48.376
    1. Ochocki JD, Khare S, Hess M, Ackerman D, Qiu B, Daisak JI, et al. . Arginase 2 suppresses renal carcinoma progression via biosynthetic cofactor pyridoxal phosphate depletion and increased polyamine toxicity. Cell Metab. (2018) 27:1263–80 e1266. 10.1016/j.cmet.2018.04.009

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever