Discovery of a novel anti-aging target by researching chronic infectious disease

• Project/Area Number: 19K21582
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Studies on the Super-Aging Society
• Research Institution: Gifu University
• Principal Investigator: MAEKAWA YOICHI 岐阜大学, 大学院医学系研究科, 教授 (10294670)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 慢性炎症 / 免疫回避 / 抗炎症 / 慢性感染 / 旋毛虫由来因子 / 炎症抑制 / 病原体由来抗炎症分子 / SASP / 寄生虫感染 / 慢性感染症 / 旋毛虫

Outline of Research at the Start

健康寿命延伸のためには老化を緩徐にする必要がある。老化には炎症が密接に関連している。炎症による老化スパイラルを断ち切ることが老化を防止し健康寿命の延伸につながる。私たちは慢性感染症研究から、病原体由来分子が炎症反応を抑制することを見出し、この作用を媒介する宿主受容体候補も同定している。本研究では、病原体由来分子による炎症抑制の分子基盤解明を通して抗老化に向けた創薬シーズの探索を行う。慢性感染症は老化を促進する因子の一つであるが、私たちはここから炎症抑制作用だけを切り分け老化を防ぐ新たな機構を見出したい。本研究では感染症と老化という背反する事項から抗老化に資する新たな概念の創出に挑戦する。

Outline of Final Research Achievements

Inhibition of excessive inflammation is effective in slowing down the aging process. In this study, we aimed to create a new concept of anti-aging prevention and search for drug seeds by applying the suppression of inflammation by pathogen-derived molecules that we discovered in our research on chronic infectious diseases. The pathogen-derived factor Tpp53 inhibits IL-6 production from macrophages. Based on this finding, we comprehensively analyzed the genes whose expression is altered by Tpp53 and found Slamf9 as a candidate for Tpp53 receptor. Based on these results, we generated Slamf9 gene-deficient mice and analyzing the relationship between Tpp53 and aging.

Academic Significance and Societal Importance of the Research Achievements

慢性炎症は老化を促進するとともに種々の疾病と関係している。炎症の抑制を目的とした研究やその成果からその制御方法が確立されようとしている。本研究はこれまでの研究とは異なる視点から炎症を抑制する方法を開発することを目指し、その基盤となる物質を見出している。炎症は複雑は生命現象であるため単一の方法での制御は困難であり、我々の研究を基にした炎症の制御方法や考え方が炎症の多重的制御に貢献できる可能性があると考えている。

Research Products

• [Journal Article] TRAF6 signaling pathway in T cells regulates anti-tumor immunity through the activation of tumor specific Th9 cells and CTLs (2022)
  • Author(s): Dewayani Astri、Kamiyama Naganori、Sachi Nozomi、Ozaka Sotaro、Saechue Benjawan、Ariki Shimpei、Goto Mizuki、Chalalai Thanyakorn、Soga Yasuhiro、Fukuda Chiaki、Kagoshima Yomei、Maekawa Yoichi、Kobayashi Takashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 613 Pages: 26-33
  • DOI: 10.1016/j.bbrc.2022.04.125
  • Peer Reviewed
• [Journal Article] Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment. (2020)
  • Author(s): Miyai M, Kanayama T, Hyodo F, Kinoshita T, Ishihara T, Okada H, Suzuki H, Takashima S, Wu Z, Hatano Y, Egashira Y, Enomoto Y, Nakayama N, Soeda A, Yano H, Hirata A, Niwa M, Sugie S, Mori T, Maekawa Y, Iwama T, Matsuo M, Hara A, Tomita H
  • Journal Title: Neurooncol Adv. Volume: 30 Issue: 1 Pages: 06198-06198
  • DOI: 10.1093/noajnl/vdaa150
  • Peer Reviewed / Open Access
• [Journal Article] How does spaceflight affect acquired immune system? (2020)
  • Author(s): T. Akiyama, K. Horie, E. Hinoi, M. Hiraiwa, A. Kato, Y. Maekawa, A. Takahashi, S. Furukawa
  • Journal Title: NPJ Microgravity. Volume: 0 Issue: 1 Pages: 1-7
  • DOI: 10.1038/s41526-020-0104-1
  • Peer Reviewed / Open Access
• [Journal Article] Neutrophil Elastase Inhibition Ameliorates Endotoxin-Induced Myocardial Injury Accompanying Degradation of Cardiac Capillary Glycocalyx (2019)
  • Author(s): Fukuta T, Okada H, Takemura G, Suzuki K, Takada C, Tomita H, Suzuki A, Oda K, Uchida A, Matsuo S, Fukuda H, Yano H, Muraki I, Zaikokuji R, Kuroda A, Nishio A, Sampei S, Miyazaki N, Hotta Y, Yamada N, Watanabe T, Morishita K, Doi T, Yoshida T, Ushikoshi H, Yoshida S, Maekawa Y, Ogura S
  • Journal Title: Shock Volume: 2019 Nov 19. Issue: 3 Pages: 1-1
  • DOI: 10.1097/shk.0000000000001482
  • Peer Reviewed / Open Access
• [Journal Article] Controlling the Phenotype of Tumor-Infiltrating Macrophages via the PHD-HIF Axis Inhibits Tumor Growth in a Mouse Model (2019)
  • Author(s): Nishide Shunji、Matsunaga Shinji、Shiota Masayuki、Yamaguchi Takehiro、Kitajima Shojiro、Maekawa Yoichi、Takeda Norihiko、Tomura Michio、Uchida Junji、Miura Katsuyuki、Nakatani Tatsuya、Tomita Shuhei
  • Journal Title: iScience Volume: 21 Pages: 205-205
  • DOI: 10.1016/j.isci.2019.10.031
  • Peer Reviewed / Open Access
• [Journal Article] Th2 signals are not essential for the anti‐arthritic effects of Trichinella spiralis in mice (2019)
  • Author(s): Osada Yoshio、Morita Kentaro、Tahara Sayaka、Ishihara Tsubasa、Wu Zhiliang、Nagano Isao、Maekawa Yoichi、Nakae Susumu、Sudo Katsuko、Kanazawa Tamotsu
  • Journal Title: Parasite Immunology Volume: 42 Issue: 1
  • DOI: 10.1111/pim.12677
  • Peer Reviewed
• [Presentation] Modulation of host immune response by extracellular vesicles from parasitic nematode, Trichinella spiralis (2022)
  • Author(s): Sukhonthip Khueangchiangkhwang, Zhiliang Wu, Yoichi Maekawa
  • Organizer: 第14回 寄生虫感染免疫研究会
• [Presentation] Role of extracellular vesicles from parasitic nematode, Trichinella spiralis (2021)
  • Author(s): Sukhonthip Khueangchiangkhwang, Zhiliang Wu, Yoichi Maekawa
  • Organizer: 第76回日本寄生虫学会西日本支部大会
• [Presentation] 免疫環境の変化に対する繊毛虫の対応 (2021)
  • Author(s): 呉志良、Sukhonthip Khueangchiangkhwang、前川洋一
  • Organizer: 第76回日本寄生虫学会西日本支部大会
• [Presentation] AFF3 regulates class switch recombination by enhancing mutagenesis of switch region (2021)
  • Author(s): Shin-ichi Tsukumo, Yoichi Maekawa, Keishi Fujio, Koji Yasutomo
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] T-lineage specific Arf-deficient mice are susceptible to Leishmania major infection (2021)
  • Author(s): Mami Sumiyoshi, Yui Kotani, Yoichi Maekawa, Satoshi Matsuda
  • Organizer: 第50回日本免疫学会学術集会
• [Book] Trichinella and Trichinelllosis (2021)
  • Author(s): Wu Zhiliang, Nagano Isaoa, Khueangchiangkhwang Sukhonthipa, Maekawa Yoichi
  • Publisher: Elsevier