The role of oxidative stress on aging

• Project/Area Number: 18H03173
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: University of Tsukuba
• Principal Investigator: Ishii Yukio 筑波大学, 医学医療系, 教授 (80272194)
• Co-Investigator(Kenkyū-buntansha): 森島 祐子 筑波大学, 医学医療系, 准教授 (10375511) ; 松野 洋輔 筑波大学, 医学医療系, 講師 (30633177)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2021: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
• Keywords: 老化 / 肺 / 転写因子 / 酸化ストレス / アンチエイジング / Nrf2 / 環境因子

Outline of Final Research Achievements

Aging rate is regulated by environmental factors, such as oxidative stress. Because lung is the most important organ exposed to environmental agents, the degree of lung antioxidative activity is thought to be related to aging rate. Nrf2 is a transcription factor regulating the intracellular antioxidant responses. Nrf2 is expressed abundantly in the lung. In the present study, therefore, we investigate the protective effects of Nrf2 on the development of aging-related pulmonary infections. In both pneumococcal pneumonia and non-tuberculous mycobacterial pulmonary disease models in mice, survival rate after the infections was lower in elderly mice than in young mice. The degree of pulmonary inflammation and lung bacterial growth after the infections were higher in elderly mice than in young mice with less pulmonary activation of Nrf2. These results suggest that Nrf2 plays a protective role in the development of aging-related pulmonary infections.

Academic Significance and Societal Importance of the Research Achievements

健康寿命を延伸することは高齢化社会における本質的な対策である。老化を遅らせること、老化関連疾患を予防管理することは健康寿命延伸の最も有効な方法と考えられる。今回の研究において、肺の抗酸化能の差異が老化スピードに影響を及ぼすことが明らかになり、Nrf2の誘導的活性化が健康寿命の延伸や、アンチエイジングに有用である可能性が示された。またNrf2の活性化は、老化関連肺感染症であり最近関心の高まっている肺非結核性抗酸菌症や肺炎球菌性肺炎の発症予防や重症化予防にもつながることが示され、研究成果は老年医学および感染症学の分野で意義のあるものと考える。

Research Products

• [Journal Article] Has2 deficiency enhances OVA-induced airway inflammation and hyperresponsiveness in mice (2021)
  • Author(s): Yoshiya Tsunoda, Mingma Thsering Sherpa, Takumi Kiwamoto, Masashi Matsuyama, Hajime Osawa, Hirofumi Sakurai, Shigen Hayashi, Yosuke Matsuno, Yuko Morishima, Yukio Ishii, Nobuyuki Hizawa
  • Journal Title: Allergy Volume: - Issue: 7 Pages: 2214-2218
  • DOI: 10.1111/all.14715
  • Peer Reviewed
• [Journal Article] The Role of NRF2 in Mycobacterial Infection (2021)
  • Author(s): Matsuyama Masashi、Nonaka Mizu、Nakajima Masayuki、Morishima Yuko、Ishii Yukio、Hizawa Nobuyuki
  • Journal Title: Antioxidants Volume: 10 Issue: 12 Pages: 1861-1861
  • DOI: 10.3390/antiox10121861
  • Peer Reviewed / Open Access
• [Journal Article] Depletion of PD-1 or PD-L1 did not affect the mortality of mice infected with Mycobacterium avium (2021)
  • Author(s): Nakajima Masayuki、Matsuyama Masashi、Kawaguchi Mio、Matsumura Sosuke、Kiwamoto Takumi、Matsuno Yosuke、Morishima Yuko、Yoshida Kazufumi、Sherpa Mingma Thsering、Yazaki Kai、Tanaka Ryota、Okiyama Naoko、Muratani Masafumi、Ishii Yukio、Hizawa Nobuyuki
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 18008-18008
  • DOI: 10.1038/s41598-021-97391-4
  • Peer Reviewed / Open Access
• [Journal Article] ROS-Nrf2 pathway mediates the development of TGF-β1-induced epithelial-mesenchymal transition through the activation of Notch signaling (2021)
  • Author(s): Yazaki Kai、Matsuno Yosuke、Yoshida Kazufumi、Sherpa Mingma、Nakajima Masayuki、Matsuyama Masashi、Kiwamoto Takumi、Morishima Yuko、Ishii Yukio、Hizawa Nobuyuki
  • Journal Title: European Journal of Cell Biology Volume: 100 Issue: 7-8 Pages: 151181-151181
  • DOI: 10.1016/j.ejcb.2021.151181
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptome genetic differences between responders and non-responders before bronchial thermoplasty (2021)
  • Author(s): Ano Satoshi、Kikuchi Norihiro、Matsuyama Masashi、Nakajima Masayuki、Kondo Yuzuru、Masuda Michiko、Osawa Hajime、Ishii Yukio、Hizawa Nobuyuki
  • Journal Title: Journal of Asthma Volume: - Issue: 8 Pages: 1-11
  • DOI: 10.1080/02770903.2021.1945088
  • Peer Reviewed
• [Journal Article] Nrf2 Regulates Granuloma Formation and Macrophage Activation during Mycobacterium avium Infection via Mediating Nramp1 and HO-1 Expressions (2021)
  • Author(s): Nakajima Masayuki、Matsuyama Masashi、Kawaguchi Mio、Kiwamoto Takumi、Matsuno Yosuke、Morishima Yuko、Yoshida Kazufumi、Sherpa Mingma、Yazaki Kai、Osawa Hajime、Muratani Masafumi、Ishii Yukio、Hizawa Nobuyuki
  • Journal Title: mBio Volume: 12 Issue: 1
  • DOI: 10.1128/mbio.01947-20
  • Peer Reviewed / Open Access
• [Journal Article] Transcription Factor T-bet Attenuates the Development of Elastase-induced Emphysema in Mice (2019)
  • Author(s): Hayashi Shigen、Matsuno Yosuke、Tsunoda Yoshiya、Sakurai Hirofumi、Kiwamoto Takumi、Morishima Yuko、Ishii Yukio、Yoh Keigyou、Takahashi Satoru、Hizawa Nobuyuki
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: 61 Issue: 4 Pages: 525-536
  • DOI: 10.1165/rcmb.2018-0109oc
  • Peer Reviewed
• [Journal Article] Sulforaphane ameliorates steroid insensitivity through an Nrf2-dependent pathway in cigarette smoke-exposed asthmatic mice (2018)
  • Author(s): Sakurai Hirofumi、Morishima Yuko、Ishii Yukio、Yoshida Kazufumi、Nakajima Masayuki、Tsunoda Yoshiya、Hayashi Shih-Yuan、Kiwamoto Takumi、Matsuno Yosuke、Kawaguchi Mio、Yamamoto Masayuki、Hizawa Nobuyuki
  • Journal Title: Free Radical Biology and Medicine Volume: 129 Pages: 473-485
  • DOI: 10.1016/j.freeradbiomed.2018.10.400
  • Peer Reviewed
• [Journal Article] Notch signaling regulates cell density-dependent apoptosis of NIH 3T3 through an IL-6/STAT3 dependent mechanism (2018)
  • Author(s): Matsuno Yosuke、Kiwamoto Takumi、Morishima Yuko、Ishii Yukio、Hizawa Nobuyuki、Hogaboam Cory M.
  • Journal Title: European Journal of Cell Biology Volume: 97 Issue: 7 Pages: 512-522
  • DOI: 10.1016/j.ejcb.2018.09.001
  • Peer Reviewed / Open Access
• [Presentation] RNA-seqによる遺伝子発現解析に基づいた，RNA-seqによる遺伝子発現解析に基づいたMycobacterium avium感染後の宿主免疫応答の評価 (2021)
  • Author(s): 松村聡介，中嶋真之，松山政史，酒井千緒，矢崎 海，吉田和史，際本拓未，松野洋輔，森島祐子，石井幸雄，檜澤伸之
  • Organizer: 第61回日本呼吸器学会学術講演会
• [Presentation] Elovl6欠損による肺組織脂肪酸組成変化がもたらす喘息重症化の分子病態の解明 (2021)
  • Author(s): 吉田和史, 森島祐子, 櫻井啓文, 大澤 翔, 矢崎 海, 中嶋真之, 松山政史, 際本拓未, 松野洋輔, 石井幸雄, 檜澤伸之
  • Organizer: 第61回日本呼吸器学会学術講演会
• [Presentation] 老化は如何に呼吸器疾患に関与するか －COPDや感染症における検証－ (2021)
  • Author(s): 石井 幸雄
  • Organizer: 第52回結核・非定型抗酸菌症治療研究会
• [Presentation] Role of Nrf2 in pulmonary MAC infection using mice model. (2020)
  • Author(s): Nakajima M, Matsuyama M, Kawaguchi M, Sherpa M, Osawa H, Yoshida K, Yazaki K, Kiwamoto T, Matsuno Y, Morishima Y, Ishii Y, Hizawa N
  • Organizer: 2020 International Conference of American Thoracic Society
  • Int'l Joint Research
• [Presentation] Hyaluronan synthase 2 attenuates airway inflammation and remodeling in an ovalbumin-induced chronic mouse model of asthma. (2020)
  • Author(s): Sherpa M, Kiwamoto T, Tsunoda Y, Osawa H, Yoshida K, Nakajima M, Matsuyama M, Matsuno Y, Morishima Y, Ishii Y, Hizawa N.
  • Organizer: 2020 International Conference of American Thoracic Society
  • Int'l Joint Research
• [Presentation] マウスを用いた肺MAC感染モデルにおけるNrf2の役割 (2020)
  • Author(s): 中嶋 真之, 松山 政史, 川口未央, Mingma Sherpa, 大澤 翔, 矢崎 海, 吉田 和史, 塩澤利博, 中澤健介, 小川良子, 際本 拓未, 松野 洋輔, 森島 祐子, 石井 幸雄, 坂本 透, 檜澤 伸之
  • Organizer: 第60回日本呼吸器学会学術講演会
• [Presentation] Deletion of Elovl6 alters fatty acid composition in lung tissue and enhances allergic airway inflammation. (2019)
  • Author(s): Yoshida K, Morishima Y, Sakurai H, Sherpa M, Tsunoda Y, Nakajima M, Matsuyama M, Kiwamoto T, Matsuno Y, Ishii Y, Hizawa N.
  • Organizer: 2019 International Conference of American Thoracic Society
  • Int'l Joint Research
• [Presentation] Role of PD-1 pathway in pulmonary MAC infection using mice model. (2019)
  • Author(s): Nakajima M, Matsuyama M, Kawaguchi M, Sherpa M, Yoshida K, Kiwamoto T, Matsuno Y, Morishima Y, Ishii Y, Hizawa N.
  • Organizer: 2019 International Conference of American Thoracic Society
  • Int'l Joint Research
• [Presentation] Hyaluronan synthase 2 (HAS2) mediates airway inflammation and remodeling in chronic ovalbumin model of asthma. (2019)
  • Author(s): Sherpa M, Kiwamoto T, Tsunoda Y, Yoshida K, Osawa H, Nakajima M, Matsuyama M, Matsuno Y, Morishima Y, Ishii Y, Hizawa N.
  • Organizer: 2019 International Conference of American Thoracic Society
  • Int'l Joint Research
• [Presentation] ROS-Nrf2 pathway mediates the development of TGF-b1-induced epithelial-mesenchymal transition through the interaction with notch signaling (2018)
  • Author(s): Matsuno Y, Matsuyama M, Kiwamoto T, Morishima Y, Ishii Y, Hizawa N
  • Organizer: International Conference of American Thoracic Society
  • Int'l Joint Research