{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:46:03Z","timestamp":1790189163689,"version":"4.1.0"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T00:00:00Z","timestamp":1608163200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T00:00:00Z","timestamp":1608163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"a grant-in-aid for scientific research (C) of the Japan Society for Promotion of Science","award":["20K09705"],"award-info":[{"award-number":["20K09705"]}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Cell Science Research Foundatio"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Oxidative stress causes tissue damage, affecting age-related pathologies. Protein restriction (PR) provides a powerful intervention strategy for reducing oxidative stress, which may have a positive effect on individual organs. However, it is unknown whether PR intervention influences the olfactory system. Here, we investigated how 10\u00a0months of PR could affect the cell dynamics of the olfactory epithelium (OE) in mice. We found that PR reduced age-related loss of outer hair cells in the cochlea, providing preventive effects against age-related hearing loss. In contrast, PR resulted in reduced mature olfactory sensory neurons (OSNs), increased proliferative basal cells, and increased apoptotic OSNs in zone 1 (the only area containing neurons expressing NQO1 [quinone dehydrogenase 1]) of the OE in comparison with animals given a control diet. Substantial oxidative stress occurred in NQO1-positive cells and induced apoptotic OSNs in zone 1. These results indicate that in contrast to the positive effect on the auditory system, PR induces oxidative stress and structurally and functionally negative effects on OSNs in zone 1, which is probably involved in the bioactivation of NQO1.<\/jats:p>","DOI":"10.1038\/s41598-020-79249-3","type":"journal-article","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T11:07:12Z","timestamp":1608203232000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Zone-specific damage of the olfactory epithelium under protein restriction"],"prefix":"10.1038","volume":"10","author":[{"given":"Ayinuer","family":"Tuerdi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Kikuta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Kinoshita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teru","family":"Kamogashira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Kondo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Yamasoba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,17]]},"reference":[{"key":"79249_CR1","doi-asserted-by":"publisher","first-page":"e19785","DOI":"10.1371\/journal.pone.0019785","volume":"6","author":"HJ Sung","year":"2011","unstructured":"Sung, H. J. et al. Ambient oxygen promotes tumorigenesis. PLoS\u00a0One 6, e19785. https:\/\/doi.org\/10.1371\/journal.pone.0019785 (2011).","journal-title":"PLoS\u00a0One"},{"issue":"Suppl","key":"79249_CR2","doi-asserted-by":"publisher","first-page":"S18","DOI":"10.1038\/nrn1434","volume":"10","author":"JK Andersen","year":"2004","unstructured":"Andersen, J. K. Oxidative stress in neurodegeneration: Cause or consequence?. Nat. Med. 10(Suppl), S18-25. https:\/\/doi.org\/10.1038\/nrn1434 (2004).","journal-title":"Nat. Med."},{"key":"79249_CR3","doi-asserted-by":"publisher","first-page":"2034","DOI":"10.1161\/01.CIR.0000093661.90582.c4","volume":"108","author":"KK Griendling","year":"2003","unstructured":"Griendling, K. K. & FitzGerald, G. A. Oxidative stress and cardiovascular injury: Part II: Animal and human studies. Circulation 108, 2034\u20132040. https:\/\/doi.org\/10.1161\/01.CIR.0000093661.90582.c4 (2003).","journal-title":"Circulation"},{"key":"79249_CR4","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1161\/01.atv.0000122852.22604.78","volume":"24","author":"A Ceriello","year":"2004","unstructured":"Ceriello, A. & Motz, E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler. Thromb. Vasc. Biol. 24, 816\u2013823. https:\/\/doi.org\/10.1161\/01.atv.0000122852.22604.78 (2004).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"79249_CR5","first-page":"123","volume":"8","author":"JD Kim","year":"1996","unstructured":"Kim, J. D., McCarter, R. J. & Yu, B. P. Influence of age, exercise, and dietary restriction on oxidative stress in rats. Aging (Milan, Italy) 8, 123\u2013129 (1996).","journal-title":"Aging (Milan, Italy)"},{"key":"79249_CR6","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1111\/j.1474-9726.2012.00798.x","volume":"11","author":"S Nakagawa","year":"2012","unstructured":"Nakagawa, S., Lagisz, M., Hector, K. L. & Spencer, H. G. Comparative and meta-analytic insights into life extension via dietary restriction. Aging Cell 11, 401\u2013409. https:\/\/doi.org\/10.1111\/j.1474-9726.2012.00798.x (2012).","journal-title":"Aging Cell"},{"key":"79249_CR7","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.freeradbiomed.2013.05.037","volume":"66","author":"ME Walsh","year":"2014","unstructured":"Walsh, M. E., Shi, Y. & Van Remmen, H. The effects of dietary restriction on oxidative stress in rodents. Free Radic. Biol. Med. 66, 88\u201399. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2013.05.037 (2014).","journal-title":"Free Radic. Biol. Med."},{"key":"79249_CR8","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1016\/j.cmet.2014.02.009","volume":"19","author":"SM Solon-Biet","year":"2014","unstructured":"Solon-Biet, S. M. et al. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab. 19, 418\u2013430. https:\/\/doi.org\/10.1016\/j.cmet.2014.02.009 (2014).","journal-title":"Cell Metab."},{"key":"79249_CR9","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1007\/s10863-004-9001-7","volume":"36","author":"A Sanz","year":"2004","unstructured":"Sanz, A., Caro, P. & Barja, G. Protein restriction without strong caloric restriction decreases mitochondrial oxygen radical production and oxidative DNA damage in rat liver. J. Bioenerg. Biomembr. 36, 545\u2013552. https:\/\/doi.org\/10.1007\/s10863-004-9001-7 (2004).","journal-title":"J. Bioenerg. Biomembr."},{"key":"79249_CR10","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1113\/jp275075","volume":"596","author":"NE Cummings","year":"2018","unstructured":"Cummings, N. E. et al. Restoration of metabolic health by decreased consumption of branched-chain amino acids. J. Physiol. 596, 623\u2013645. https:\/\/doi.org\/10.1113\/jp275075 (2018).","journal-title":"J. Physiol."},{"key":"79249_CR11","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1146\/annurev-biochem-060815-014422","volume":"85","author":"GA Soultoukis","year":"2016","unstructured":"Soultoukis, G. A. & Partridge, L. Dietary protein, metabolism, and aging. Annu. Rev. Biochem. 85, 5\u201334. https:\/\/doi.org\/10.1146\/annurev-biochem-060815-014422 (2016).","journal-title":"Annu. Rev. Biochem."},{"key":"79249_CR12","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1016\/j.celrep.2016.05.092","volume":"16","author":"L Fontana","year":"2016","unstructured":"Fontana, L. et al. Decreased consumption of branched-chain amino acids improves metabolic health. Cell Rep. 16, 520\u2013530. https:\/\/doi.org\/10.1016\/j.celrep.2016.05.092 (2016).","journal-title":"Cell Rep."},{"key":"79249_CR13","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1111\/nyas.12973","volume":"1363","author":"BC Lee","year":"2016","unstructured":"Lee, B. C., Kaya, A. & Gladyshev, V. N. Methionine restriction and life-span control. Ann. N. Y. Acad. Sci. 1363, 116\u2013124. https:\/\/doi.org\/10.1111\/nyas.12973 (2016).","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"79249_CR14","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1002\/ar.10047","volume":"269","author":"JE Schwob","year":"2002","unstructured":"Schwob, J. E. Neural regeneration and the peripheral olfactory system. Anat. Rec. 269, 33\u201349 (2002).","journal-title":"Anat. Rec."},{"key":"79249_CR15","doi-asserted-by":"publisher","first-page":"475","DOI":"10.3389\/fimmu.2016.00475","volume":"7","author":"F Imamura","year":"2016","unstructured":"Imamura, F. & Hasegawa-Ishii, S. Environmental toxicants-induced immune responses in the olfactory mucosa. Front. Immunol. 7, 475. https:\/\/doi.org\/10.3389\/fimmu.2016.00475 (2016).","journal-title":"Front. Immunol."},{"key":"79249_CR16","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.1046\/j.1432-1033.2003.03571.x","volume":"270","author":"Y Oka","year":"2003","unstructured":"Oka, Y. et al. O-MACS, a novel member of the medium-chain acyl-CoA synthetase family, specifically expressed in the olfactory epithelium in a zone-specific manner. Eur. J. Biochem. 270, 1995\u20132004 (2003).","journal-title":"Eur. J. Biochem."},{"key":"79249_CR17","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1016\/S0891-5849(02)01367-9","volume":"34","author":"CJ Reed","year":"2003","unstructured":"Reed, C. J., Robinson, D. A. & Lock, E. A. Antioxidant status of the rat nasal cavity. Free Radic. Biol. Med. 34, 607\u2013615 (2003).","journal-title":"Free Radic. Biol. Med."},{"key":"79249_CR18","doi-asserted-by":"publisher","first-page":"2511","DOI":"10.1111\/j.0953-816X.2004.03331.x","volume":"19","author":"F Gussing","year":"2004","unstructured":"Gussing, F. & Bohm, S. NQO1 activity in the main and the accessory olfactory systems correlates with the zonal topography of projection maps. Eur. J. Neurosci. 19, 2511\u20132518. https:\/\/doi.org\/10.1111\/j.0953-816X.2004.03331.x (2004).","journal-title":"Eur. J. Neurosci."},{"key":"79249_CR19","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.cmet.2017.06.015","volume":"26","author":"CE Riera","year":"2017","unstructured":"Riera, C. E. et al. The sense of smell impacts metabolic health and obesity. Cell Metab. 26, 198-211 e195. https:\/\/doi.org\/10.1016\/j.cmet.2017.06.015 (2017).","journal-title":"Cell Metab."},{"key":"79249_CR20","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/S0006-2952(94)00333-5","volume":"49","author":"E Cadenas","year":"1995","unstructured":"Cadenas, E. Antioxidant and prooxidant functions of DT-diaphorase in quinone metabolism. Biochem. Pharmacol. 49, 127\u2013140 (1995).","journal-title":"Biochem. Pharmacol."},{"key":"79249_CR21","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.heares.2013.01.021","volume":"303","author":"T Yamasoba","year":"2013","unstructured":"Yamasoba, T. et al. Current concepts in age-related hearing loss: Epidemiology and mechanistic pathways. Hear. Res. 303, 30\u201338. https:\/\/doi.org\/10.1016\/j.heares.2013.01.021 (2013).","journal-title":"Hear. Res."},{"key":"79249_CR22","doi-asserted-by":"publisher","first-page":"9","DOI":"10.2147\/oaap.s7202","volume":"2","author":"RD Frisina","year":"2010","unstructured":"Frisina, R. D. & Zhu, X. Auditory sensitivity and the outer hair cell system in the CBA mouse model of age-related hearing loss. Open Access Anim. Physiol. 2, 9\u201316. https:\/\/doi.org\/10.2147\/oaap.s7202 (2010).","journal-title":"Open Access Anim. Physiol."},{"key":"79249_CR23","doi-asserted-by":"publisher","first-page":"17300","DOI":"10.1038\/s41598-018-35607-w","volume":"8","author":"A Tuerdi","year":"2018","unstructured":"Tuerdi, A. et al. Dorsal-zone-specific reduction of sensory neuron density in the olfactory epithelium following long-term exercise or caloric restriction. Sci. Rep. 8, 17300. https:\/\/doi.org\/10.1038\/s41598-018-35607-w (2018).","journal-title":"Sci. Rep."},{"key":"79249_CR24","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/0092-8674(93)90145-G","volume":"73","author":"KJ Ressler","year":"1993","unstructured":"Ressler, K. J., Sullivan, S. L. & Buck, L. B. A zonal organization of odorant receptor gene expression in the olfactory epithelium. Cell 73, 597\u2013609 (1993).","journal-title":"Cell"},{"key":"79249_CR25","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/0092-8674(93)90422-M","volume":"74","author":"R Vassar","year":"1993","unstructured":"Vassar, R., Ngai, J. & Axel, R. Spatial segregation of odorant receptor expression in the mammalian olfactory epithelium. Cell 74, 309\u2013318 (1993).","journal-title":"Cell"},{"key":"79249_CR26","doi-asserted-by":"publisher","first-page":"2657","DOI":"10.1523\/jneurosci.2484-14.2015","volume":"35","author":"S Kikuta","year":"2015","unstructured":"Kikuta, S. et al. Sensory deprivation disrupts homeostatic regeneration of newly generated olfactory sensory neurons after injury in adult mice. J. Neurosci. 35, 2657\u20132673. https:\/\/doi.org\/10.1523\/jneurosci.2484-14.2015 (2015).","journal-title":"J. Neurosci."},{"key":"79249_CR27","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1097\/CAD.0b013e328330098d","volume":"20","author":"K Terai","year":"2009","unstructured":"Terai, K. et al. Cisplatin enhances the anticancer effect of beta-lapachone by upregulating NQO1. Anticancer Drugs 20, 901\u2013909. https:\/\/doi.org\/10.1097\/CAD.0b013e328330098d (2009).","journal-title":"Anticancer Drugs"},{"key":"79249_CR28","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1089\/ars.2011.3999","volume":"15","author":"T Fukai","year":"2011","unstructured":"Fukai, T. & Ushio-Fukai, M. Superoxide dismutases: Role in redox signaling, vascular function, and diseases. Antioxid. Redox Signal. 15, 1583\u20131606. https:\/\/doi.org\/10.1089\/ars.2011.3999 (2011).","journal-title":"Antioxid. Redox Signal."},{"key":"79249_CR29","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/j.1749-6632.1994.tb12816.x","volume":"736","author":"JA Sechzer","year":"1994","unstructured":"Sechzer, J. A. et al. Sex and gender bias in animal research and in clinical studies of cancer, cardiovascular disease, and depression. Ann. N Y Acad. Sci. 736, 21\u201348. https:\/\/doi.org\/10.1111\/j.1749-6632.1994.tb12816.x (1994).","journal-title":"Ann. N Y Acad. Sci."},{"key":"79249_CR30","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1097\/mol.0000000000000536","volume":"29","author":"K Chella Krishnan","year":"2018","unstructured":"Chella Krishnan, K., Mehrabian, M. & Lusis, A. J. Sex differences in metabolism and cardiometabolic disorders. Curr. Opin. Lipidol. 29, 404\u2013410. https:\/\/doi.org\/10.1097\/mol.0000000000000536 (2018).","journal-title":"Curr. Opin. Lipidol."},{"key":"79249_CR31","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1101\/gr.5217506","volume":"16","author":"X Yang","year":"2006","unstructured":"Yang, X. et al. Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res. 16, 995\u20131004. https:\/\/doi.org\/10.1101\/gr.5217506 (2006).","journal-title":"Genome Res."},{"key":"79249_CR32","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/0378-5955(94)90112-0","volume":"80","author":"JR Coleman","year":"1994","unstructured":"Coleman, J. R., Campbell, D., Cooper, W. A., Welsh, M. G. & Moyer, J. Auditory brainstem responses after ovariectomy and estrogen replacement in rat. Hear. Res. 80, 209\u2013215. https:\/\/doi.org\/10.1016\/0378-5955(94)90112-0 (1994).","journal-title":"Hear. Res."},{"key":"79249_CR33","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13293-018-0171-0","volume":"9","author":"B Milon","year":"2018","unstructured":"Milon, B. et al. The impact of biological sex on the response to noise and otoprotective therapies against acoustic injury in mice. Biol. Sex Differ. 9, 12. https:\/\/doi.org\/10.1186\/s13293-018-0171-0 (2018).","journal-title":"Biol. Sex Differ."},{"key":"79249_CR34","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1093\/geronj\/30.2.157","volume":"30","author":"I Kunstyr","year":"1975","unstructured":"Kunstyr, I. & Leuenberger, H. G. Gerontological data of C57BL\/6J mice. I. Sex differences in survival curves. J. Geronto.l 30, 157\u2013162. https:\/\/doi.org\/10.1093\/geronj\/30.2.157 (1975).","journal-title":"J. Geronto.l"},{"key":"79249_CR35","doi-asserted-by":"publisher","first-page":"19432","DOI":"10.1073\/pnas.0908786106","volume":"106","author":"S Someya","year":"2009","unstructured":"Someya, S. et al. Age-related hearing loss in C57BL\/6J mice is mediated by Bak-dependent mitochondrial apoptosis. Proc. Natl. Acad. Sci. USA 106, 19432\u201319437. https:\/\/doi.org\/10.1073\/pnas.0908786106 (2009).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"79249_CR36","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/ng1226","volume":"35","author":"K Noben-Trauth","year":"2003","unstructured":"Noben-Trauth, K., Zheng, Q. Y. & Johnson, K. R. Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss. Nat. Genet. 35, 21\u201323. https:\/\/doi.org\/10.1038\/ng1226 (2003).","journal-title":"Nat. Genet."},{"key":"79249_CR37","doi-asserted-by":"publisher","first-page":"44450","DOI":"10.1038\/srep44450","volume":"7","author":"KR Johnson","year":"2017","unstructured":"Johnson, K. R. et al. Effects of Cdh23 single nucleotide substitutions on age-related hearing loss in C57BL\/6 and 129S1\/Sv mice and comparisons with congenic strains. Sci. Rep. 7, 44450. https:\/\/doi.org\/10.1038\/srep44450 (2017).","journal-title":"Sci. Rep."},{"key":"79249_CR38","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.heares.2008.06.001","volume":"243","author":"SH Sha","year":"2008","unstructured":"Sha, S. H. et al. Age-related auditory pathology in the CBA\/J mouse. Hear. Res. 243, 87\u201394. https:\/\/doi.org\/10.1016\/j.heares.2008.06.001 (2008).","journal-title":"Hear. Res."},{"key":"79249_CR39","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/s0378-5955(99)00003-9","volume":"130","author":"QY Zheng","year":"1999","unstructured":"Zheng, Q. Y., Johnson, K. R. & Erway, L. C. Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses. Hear. Res. 130, 94\u2013107. https:\/\/doi.org\/10.1016\/s0378-5955(99)00003-9 (1999).","journal-title":"Hear. Res."},{"key":"79249_CR40","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1016\/s0140-6736(05)67423-5","volume":"366","author":"GA Gates","year":"2005","unstructured":"Gates, G. A. & Mills, J. H. Presbycusis. Lancet (Lond., Engl.) 366, 1111\u20131120. https:\/\/doi.org\/10.1016\/s0140-6736(05)67423-5 (2005).","journal-title":"Lancet (Lond., Engl.)"},{"key":"79249_CR41","doi-asserted-by":"publisher","first-page":"11308","DOI":"10.1523\/jneurosci.2493-16.2016","volume":"36","author":"C Han","year":"2016","unstructured":"Han, C. et al. Effects of long-term exercise on age-related hearing loss in mice. J. Neurosci. 36, 11308\u201311319. https:\/\/doi.org\/10.1523\/jneurosci.2493-16.2016 (2016).","journal-title":"J. Neurosci."},{"key":"79249_CR42","doi-asserted-by":"publisher","first-page":"20","DOI":"10.2174\/1874609811003010020","volume":"3","author":"S Someya","year":"2010","unstructured":"Someya, S., Tanokura, M., Weindruch, R., Prolla, T. A. & Yamasoba, T. Effects of caloric restriction on age-related hearing loss in rodents and rhesus monkeys. Curr. Aging Sci. 3, 20\u201325 (2010).","journal-title":"Curr. Aging Sci."},{"key":"79249_CR43","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1016\/j.cmet.2016.09.001","volume":"24","author":"SM Solon-Biet","year":"2016","unstructured":"Solon-Biet, S. M. et al. Defining the nutritional and metabolic context of FGF21 using the geometric framework. Cell Metab. 24, 555\u2013565. https:\/\/doi.org\/10.1016\/j.cmet.2016.09.001 (2016).","journal-title":"Cell Metab."},{"key":"79249_CR44","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1016\/j.ebiom.2019.04.005","volume":"43","author":"M Kitada","year":"2019","unstructured":"Kitada, M., Ogura, Y., Monno, I. & Koya, D. The impact of dietary protein intake on longevity and metabolic health. EBioMedicine 43, 632\u2013640. https:\/\/doi.org\/10.1016\/j.ebiom.2019.04.005 (2019).","journal-title":"EBioMedicine"},{"key":"79249_CR45","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/0009-2797(91)90080-Q","volume":"79","author":"C Eriksson","year":"1991","unstructured":"Eriksson, C. & Brittebo, E. B. Metabolic activation of the herbicide dichlobenil in the olfactory mucosa of mice and rats. Chem. Biol. Interact. 79, 165\u2013177 (1991).","journal-title":"Chem. Biol. Interact."},{"key":"79249_CR46","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/S0304-4165(97)00131-1","volume":"1380","author":"J Smythies","year":"1998","unstructured":"Smythies, J. & Galzigna, L. The oxidative metabolism of catecholamines in the brain: A review. Biochem. Biophys. Acta. 1380, 159\u2013162 (1998).","journal-title":"Biochem. Biophys. Acta."},{"key":"79249_CR47","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1016\/j.nut.2004.05.009","volume":"20","author":"JP Richie Jr","year":"2004","unstructured":"Richie, J. P. Jr. et al. Tissue glutathione and cysteine levels in methionine-restricted rats. Nutrition 20, 800\u2013805. https:\/\/doi.org\/10.1016\/j.nut.2004.05.009 (2004).","journal-title":"Nutrition"},{"key":"79249_CR48","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1111\/j.1474-9726.2005.00152.x","volume":"4","author":"RA Miller","year":"2005","unstructured":"Miller, R. A. et al. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell 4, 119\u2013125. https:\/\/doi.org\/10.1111\/j.1474-9726.2005.00152.x (2005).","journal-title":"Aging Cell"},{"key":"79249_CR49","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1093\/chemse\/bjs059","volume":"37","author":"B Palouzier-Paulignan","year":"2012","unstructured":"Palouzier-Paulignan, B. et al. Olfaction under metabolic influences. Chem. Senses 37, 769\u2013797. https:\/\/doi.org\/10.1093\/chemse\/bjs059 (2012).","journal-title":"Chem. Senses"},{"key":"79249_CR50","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1210\/endo-112-3-898","volume":"112","author":"DG Baskin","year":"1983","unstructured":"Baskin, D. G., Porte, D. Jr., Guest, K. & Dorsa, D. M. Regional concentrations of insulin in the rat brain. Endocrinology 112, 898\u2013903. https:\/\/doi.org\/10.1210\/endo-112-3-898 (1983).","journal-title":"Endocrinology"},{"key":"79249_CR51","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1016\/0306-4522(86)90082-5","volume":"17","author":"JM Hill","year":"1986","unstructured":"Hill, J. M., Lesniak, M. A., Pert, C. B. & Roth, J. Autoradiographic localization of insulin receptors in rat brain: Prominence in olfactory and limbic areas. Neuroscience 17, 1127\u20131138 (1986).","journal-title":"Neuroscience"},{"key":"79249_CR52","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1002\/(SICI)1096-9861(19980615)395:4<535::AID-CNE9>3.0.CO;2-2","volume":"395","author":"JK Elmquist","year":"1998","unstructured":"Elmquist, J. K., Bjorbaek, C., Ahima, R. S., Flier, J. S. & Saper, C. B. Distributions of leptin receptor mRNA isoforms in the rat brain. J. Comp. Neurol. 395, 535\u2013547 (1998).","journal-title":"J. Comp. Neurol."},{"key":"79249_CR53","doi-asserted-by":"publisher","first-page":"2898","DOI":"10.1152\/jn.91169.2008","volume":"101","author":"A Savigner","year":"2009","unstructured":"Savigner, A. et al. Modulation of spontaneous and odorant-evoked activity of rat olfactory sensory neurons by two anorectic peptides, insulin and leptin. J. Neurophysiol. 101, 2898\u20132906. https:\/\/doi.org\/10.1152\/jn.91169.2008 (2009).","journal-title":"J. Neurophysiol."},{"key":"79249_CR54","doi-asserted-by":"publisher","first-page":"2751","DOI":"10.1113\/jphysiol.2013.269639","volume":"592","author":"N Kuczewski","year":"2014","unstructured":"Kuczewski, N. et al. Insulin modulates network activity in olfactory bulb slices: Impact on odour processing. J. Physiol. 592, 2751\u20132769. https:\/\/doi.org\/10.1113\/jphysiol.2013.269639 (2014).","journal-title":"J. Physiol."},{"key":"79249_CR55","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.regpep.2005.01.003","volume":"129","author":"AF Apelbaum","year":"2005","unstructured":"Apelbaum, A. F., Perrut, A. & Chaput, M. Orexin A effects on the olfactory bulb spontaneous activity and odor responsiveness in freely breathing rats. Regul. Pept. 129, 49\u201361. https:\/\/doi.org\/10.1016\/j.regpep.2005.01.003 (2005).","journal-title":"Regul. Pept."},{"key":"79249_CR56","doi-asserted-by":"publisher","first-page":"2332","DOI":"10.1152\/jn.2000.83.4.2332","volume":"83","author":"DA Fadool","year":"2000","unstructured":"Fadool, D. A., Tucker, K., Phillips, J. J. & Simmen, J. A. Brain insulin receptor causes activity-dependent current suppression in the olfactory bulb through multiple phosphorylation of Kv1.3. J. Neurophysiol. 83, 2332\u20132348 (2000).","journal-title":"J. Neurophysiol."},{"key":"79249_CR57","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1093\/chemse\/25.1.93","volume":"25","author":"JK McEntire","year":"2000","unstructured":"McEntire, J. K. & Pixley, S. K. Olfactory receptor neurons in partially purified epithelial cell cultures: Comparison of techniques for partial purification and identification of insulin as an important survival factor. Chem. Senses 25, 93\u2013101 (2000).","journal-title":"Chem. Senses"},{"key":"79249_CR58","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1016\/j.nut.2009.08.003","volume":"26","author":"RI Henkin","year":"2010","unstructured":"Henkin, R. I. Intranasal insulin: From nose to brain. Nutrition (Burbank, Los Angeles County, Calif.) 26, 624\u2013633. https:\/\/doi.org\/10.1016\/j.nut.2009.08.003 (2010).","journal-title":"Nutrition (Burbank, Los Angeles County, Calif.)"},{"key":"79249_CR59","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1002\/ar.24066","volume":"303","author":"S Goncalves","year":"2020","unstructured":"Goncalves, S. & Goldstein, B. J. Acute N-acetylcysteine administration ameliorates loss of olfactory neurons following experimental injury in vivo. Anat. Rec. (Hoboken) 303, 626\u2013633. https:\/\/doi.org\/10.1002\/ar.24066 (2020).","journal-title":"Anat. Rec. (Hoboken)"},{"key":"79249_CR60","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1038\/nrn3209","volume":"13","author":"AM Fernandez","year":"2012","unstructured":"Fernandez, A. M. & Torres-Aleman, I. The many faces of insulin-like peptide signalling in the brain. Nat. Rev. Neurosci. 13, 225\u2013239. https:\/\/doi.org\/10.1038\/nrn3209 (2012).","journal-title":"Nat. Rev. Neurosci."},{"key":"79249_CR61","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1038\/nn800","volume":"5","author":"X Zhang","year":"2002","unstructured":"Zhang, X. & Firestein, S. The olfactory receptor gene superfamily of the mouse. Nat. Neurosci. 5, 124\u2013133. https:\/\/doi.org\/10.1038\/nn800 (2002).","journal-title":"Nat. Neurosci."},{"key":"79249_CR62","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1146\/annurev-neuro-112210-112917","volume":"34","author":"K Mori","year":"2011","unstructured":"Mori, K. & Sakano, H. How is the olfactory map formed and interpreted in the mammalian brain?. Annu. Rev. Neurosci. 34, 467\u2013499. https:\/\/doi.org\/10.1146\/annurev-neuro-112210-112917 (2011).","journal-title":"Annu. Rev. Neurosci."},{"key":"79249_CR63","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/nature06281","volume":"450","author":"K Kobayakawa","year":"2007","unstructured":"Kobayakawa, K. et al. Innate versus learned odour processing in the mouse olfactory bulb. Nature 450, 503\u2013508. https:\/\/doi.org\/10.1038\/nature06281 (2007).","journal-title":"Nature"},{"key":"79249_CR64","doi-asserted-by":"publisher","first-page":"1939","DOI":"10.1093\/jn\/123.11.1939","volume":"123","author":"PG Reeves","year":"1993","unstructured":"Reeves, P. G., Nielsen, F. H. & Fahey, G. C. Jr. AIN-93 purified diets for laboratory rodents: Final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J. Nutr. 123, 1939\u20131951 (1993).","journal-title":"J. Nutr."},{"key":"79249_CR65","doi-asserted-by":"publisher","first-page":"325702","DOI":"10.1155\/2013\/325702","volume":"2013","author":"M Kinoshita","year":"2013","unstructured":"Kinoshita, M., Sakamoto, T., Kashio, A., Shimizu, T. & Yamasoba, T. Age-related hearing loss in Mn-SOD heterozygous knockout mice. Oxid. Med. Cell Longev. 2013, 325702. https:\/\/doi.org\/10.1155\/2013\/325702 (2013).","journal-title":"Oxid. Med. Cell Longev."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-79249-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-79249-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-79249-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T00:56:44Z","timestamp":1670374604000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-79249-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,17]]},"references-count":65,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["79249"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-79249-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,17]]},"assertion":[{"value":"3 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 December 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 December 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"22175"}}