{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:43:53Z","timestamp":1792017833379,"version":"4.4.0"},"reference-count":58,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2007,10,10]],"date-time":"2007-10-10T00:00:00Z","timestamp":1191974400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2008,3]]},"abstract":"<jats:p>\n                    Methylene blue (MB) has been used clinically for about a century to treat numerous ailments. We show that MB and other diaminophenothia\u2010zines extend the life span of human IMR90 fibroblasts in tissue culture by &gt;20 population doubling (PDLs). MB delays senescence at nM levels in IMR90 by enhancing mitochondrial function. MB increases mitochon\u2010drial complex IV by 30%, enhances cellular oxygen consumption by 37\u201370%, increases heme synthesis, and reverses premature senescence caused by H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    or cadmium. MB also induces phase\u20102 antioxidant enzymes in hepG2 cells. Flavin\u2010dependent enzymes are known to use NAD(P)H to reduce MB to leucomethyl\u2010ene blue (MBH\n                    <jats:sub>2<\/jats:sub>\n                    ), whereas cytochrome\n                    <jats:italic>c<\/jats:italic>\n                    reoxidizes MBH\n                    <jats:sub>2<\/jats:sub>\n                    to MB. Experiments on lysates from rat liver mitochondria suggest the ratio MB\/cytochrome\n                    <jats:italic>c<\/jats:italic>\n                    is important for the protective actions of MB. We propose that the cellular senescence delay caused by MB is due to cycling between MB and MBH\n                    <jats:sub>2<\/jats:sub>\n                    in mitochondria, which may partly explain the increase in specific mito\u2010chondrial activities. Cycling of MB between oxidized and reduced forms may block oxidant production by mitochondria. Mitochondrial dysfunction and oxidative stress are thought to be key aberrations that lead to cellular senescence and aging. MB may be useful to delay mitochondrial dysfunction with aging and the decrease in complex IV in Alzheimer disease.\u2014At\u2010amna H., Nguyen, A., Schultz, C., Boyle, K., Newberry, J., Kato, H., Ames B. N. Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 22, 703\u2013712 (2008)\n                  <\/jats:p>","DOI":"10.1096\/fj.07-9610com","type":"journal-article","created":{"date-parts":[[2007,10,10]],"date-time":"2007-10-10T20:39:59Z","timestamp":1192048799000},"page":"703-712","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":226,"title":["Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways"],"prefix":"10.1096","volume":"22","author":[{"given":"Hani","family":"Atamna","sequence":"first","affiliation":[{"name":"Nutrition and Metabolism Center Children\u2032s Hospital Oakland Research Institute Oakland California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Nutrition and Metabolism Center Children\u2032s Hospital Oakland Research Institute Oakland California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Schultz","sequence":"additional","affiliation":[{"name":"Nutrition and Metabolism Center Children\u2032s Hospital Oakland Research Institute Oakland California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Boyle","sequence":"additional","affiliation":[{"name":"Nutrition and Metabolism Center Children\u2032s Hospital Oakland Research Institute Oakland California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Newberry","sequence":"additional","affiliation":[{"name":"Nutrition and Metabolism Center Children\u2032s Hospital Oakland Research Institute Oakland California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Kato","sequence":"additional","affiliation":[{"name":"Nutrition and Metabolism Center Children\u2032s Hospital Oakland Research Institute Oakland California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce N.","family":"Ames","sequence":"additional","affiliation":[{"name":"Nutrition and Metabolism Center Children\u2032s Hospital Oakland Research Institute Oakland California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,10,10]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1994.1132"},{"key":"e_1_2_6_3_1","doi-asserted-by":"crossref","first-page":"B276","DOI":"10.1093\/gerona\/54.7.B276","article-title":"Aminoguanidine supplementation delays the onset of senescence in vitro in dermal fibroblast\u2010like cells from senescence\u2010accelerated mice","volume":"54","author":"Fujisawa H.","year":"1999","journal-title":"J. Gerontol. A. Biol. Sci. Med. Sci."},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.01-0134com"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.10.6741"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0047-6374(00)00231-1"},{"key":"e_1_2_6_7_1","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.2174\/1389450110607011531","article-title":"Towards a life\u2010prolonging pill? Small molecules with anti\u2010ageing properties","volume":"7","author":"Wagner G.","year":"2006","journal-title":"Curr. Drug Targets"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/bc034139l"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(95)02258-9"},{"key":"e_1_2_6_10_1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0022-3565(25)32778-3","article-title":"Relationship between cyclic guanosine 3\u2032:5\u2032\u2010monophosphate formation and relaxation of coronary arterial smooth muscle by glyceryl trinitrate, nitroprusside, nitrite and nitric oxide: effects of methylene blue and methemoglobin","volume":"219","author":"Gruetter C. A.","year":"1981","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0093-691X(00)00346-0"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-1097.2004.tb00389.x"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.2307\/3577503"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(88)90393-1"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M004223200"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-4165(78)90204-0"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1472-6483(10)61884-6"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgh139"},{"key":"e_1_2_6_19_1","doi-asserted-by":"crossref","first-page":"395","DOI":"10.3109\/10715769109093428","article-title":"Spin trapping by use of N\u2010tert\u2010butylhydroxylamine. Involvement of Fenton reactions","volume":"14","author":"Lagercrantz C.","year":"1991","journal-title":"Free Radic. Res. Commun."},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1G114"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.1999.0917"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1177\/0885066606290671"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/00045391-200307000-00009"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jamcollsurg.2006.12.030"},{"key":"e_1_2_6_25_1","volume-title":"Toxicology and Carcinogenesis Studies of Methylene Blue Trihydrate in F344 Rats and B6C3F1 Mice","author":"Bristol D. W.","year":"2006"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1159\/000091525"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1024142400835"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1159\/000046094"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(85)91218-8"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1080\/07435809909066138"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(91)90311-R"},{"key":"e_1_2_6_32_1","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/S0022-3565(24)38206-0","article-title":"Inhibition and stimulation of long\u2010chain fatty acid oxidation by chloroacetaldehyde and methylene blue in rats","volume":"289","author":"Visarius T. M.","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0100-879X1999001200012"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.3758\/BF03326744"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2003.10.007"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2006.07.012"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(02)00827-3"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpedi.1994.02170030076017"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1537-2995.1995.35595259151.x"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/j100286a029"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)63246-6"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-1097.1998.tb05208.x"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1562\/0031-8655(2002)0750392IVPAOA2.0.CO2"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/0531-5565(92)90066-9"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0600134103"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/133.9.2721"},{"key":"e_1_2_6_47_1","doi-asserted-by":"crossref","first-page":"S319","DOI":"10.1042\/bst026s319","article-title":"Effect of increasing methylation on the ability of methylene blue to cause diaphorase\u2010catalysed oxidation of NADH","volume":"26","author":"Rice L.","year":"1998","journal-title":"Biochem. Soc. Trans."},{"key":"e_1_2_6_48_1","first-page":"337","article-title":"The influence of NO synthase inhibitor and free oxygen radicals scavenger\u2013 methylene blue\u2013on streptozotocin\u2010induced diabetes in rats","volume":"47","author":"Haluzik M.","year":"1998","journal-title":"Physiol. Res."},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1997.0408"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(93)90072-5"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0162-0134(03)00314-3"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.6943"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211898200"},{"key":"e_1_2_6_54_1","doi-asserted-by":"crossref","first-page":"15168","DOI":"10.1016\/S0021-9258(18)95717-0","article-title":"Methylene blue directly oxidizes glutathione without the intermediate formation of hydrogen peroxide","volume":"260","author":"Kelner M. J.","year":"1985","journal-title":"J. Biol. Chem."},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar0200807"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2006.03.013"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209681200"},{"key":"e_1_2_6_58_1","first-page":"L78","article-title":"Reduction of thiazine dyes by bovine pulmonary arterial endothelial cells in culture","volume":"269","author":"Bongard R. D.","year":"1995","journal-title":"Am. J. Physiol."},{"key":"e_1_2_6_59_1","first-page":"L673","article-title":"Pulmonary endothelial thiazine uptake: separation of cell surface reduction from intracellular reoxidation","volume":"272","author":"Merker M. P.","year":"1997","journal-title":"Am. J. Physiol."}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.07-9610com","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.07-9610com","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.07-9610com","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T22:18:04Z","timestamp":1761689884000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.07-9610com"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,10,10]]},"references-count":58,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2008,3]]}},"alternative-id":["10.1096\/fj.07-9610com"],"URL":"https:\/\/doi.org\/10.1096\/fj.07-9610com","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,10,10]]},"assertion":[{"value":"2007-08-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2007-10-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}