Study for the establishment of new treatment methods using lipoquality for age-related diseases.

• Project/Area Number: 20K21761
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
• Research Institution: The University of Tokushima
• Principal Investigator: MASUDA Masashi 徳島大学, 大学院医歯薬学研究部(医学域), 講師 (50754488)
• Co-Investigator(Kenkyū-buntansha): 大西 康太 京都府立大学, 生命環境科学研究科, 講師 (80723816) ; 大南 博和 徳島大学, 大学院医歯薬学研究部(医学域), 助教 (90803057)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 老化 / SASP因子 / Lipoquality

Outline of Research at the Start

加齢と共に増える老化細胞から分泌されるsenescence-associated secretory phenotype (SASP) 因子が、加齢性疾患の発症に関わっている。老化細胞の除去は生体にとって有益であるが、ヒトに応用するには遺伝子改変に頼らない食事からの治療・予防法の開発が必要である。細胞内外のストレス刺激に応答して形成される異常タンパク質の凝集体 (アグリソーム) は、様々な疾患発症に関わる。本研究は、老化細胞から分泌されるSASP因子やアグリソームを脂肪酸の質の違いにより削除する戦略を構築するために、老化細胞や老化モデル動物を用いて検討する。

Outline of Final Research Achievements

This study aims to establish a strategy to delete senescence-associated secretory phenotype (SASP) factors secreted by senescent cells involved in the pathogenesis of age-related diseases and to elucidate their molecular mechanisms. We investigated the effect of phosphate on cellular senescence by inducing cellular senescence in NIH3T3 cells, a mouse fibroblast cell line, through a series of passages, and found that the effect of P40 on changes in gene expression of SASP factors in cells by the addition of phosphate to the culture medium was smaller than that of P9. These results suggest that an increase in extracellular phosphorus concentration in cells that have not yet undergone cellular senescence may promote cellular senescence.

Academic Significance and Societal Importance of the Research Achievements

加齢と共に増える老化細胞から分泌されるSASP因子は、個体の老化を更に加速させて様々な加齢性疾患を発症させる。また、脂質の多様性が様々な生理機能や病因の中心的な役割を担うことが明らかになり、脂質の量ではなく質 (lipoquality) が注目されている。加齢性疾患の慢性腎臓病で上昇する血中のリンはlipoqualityを変化させることでオートファジー不全や小胞体ストレスを誘発する結果、血管石灰化を引き起こすことが分かっている。本研究の成果は、血中リン濃度の上昇を抑えることでオートファジー不全や小胞体ストレスだけでなく細胞老化の進行も抑制できる可能性を示した。

Research Products

• [Int'l Joint Research] University of Colorado(米国)
• [Int'l Joint Research] University of Colorado(米国)
• [Int'l Joint Research] University of Colorado(米国)
• [Journal Article] Sulforaphane induces lipophagy through the activation of AMPK-mTOR-ULK1 pathway signaling in adipocytes. (2022)
  • Author(s): Masuda M, Yoshida-Shimizu R, Mori Y, Ohnishi K, Adachi Y, Sakai M, Kabutoya S, Ohminami H, Yamanaka-Okumura H, Yamamoto H, Miyazaki M, Taketani Y.
  • Journal Title: Journal of Nutritional Biochemistry Volume: 106 Pages: 109017-109017
  • DOI: 10.1016/j.jnutbio.2022.109017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] All-trans retinoic acid changes muscle fiber type via increasing GADD34 dependent on MAPK signal (2022)
  • Author(s): Adachi Yuichiro、Masuda Masashi、Sakakibara Iori、Uchida Takayuki、Niida Yuki、Mori Yuki、Kamei Yuki、Okumura Yosuke、Ohminami Hirokazu、Ohnishi Kohta、Yamanaka-Okumura Hisami、Nikawa Takeshi、Taketani Yutaka
  • Journal Title: Life Science Alliance Volume: 5 Issue: 7 Pages: e202101345-e202101345
  • DOI: 10.26508/lsa.202101345
  • Peer Reviewed / Open Access
• [Journal Article] Free Deoxycholic Acid Exacerbates Vascular Calcification in CKD through ER Stress-Mediated ATF4 Activation (2021)
  • Author(s): Miyazaki-Anzai Shinobu、Masuda Masashi、Shiozaki Yuji、Keenan Audrey L.、Chonchol Michel、Kremoser Claus、Miyazaki Makoto
  • Journal Title: Kidney360 Volume: 2 Issue: 5 Pages: 857-868
  • DOI: 10.34067/kid.0007502020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of Dietary Phytochemicals Capable of Enhancing the Autophagy Flux in HeLa and Caco-2 Human Cell Lines (2020)
  • Author(s): Ohnishi Kohta、Yano Satoshi、Fujimoto Moe、Sakai Maiko、Harumoto Erika、Furuichi Airi、Masuda Masashi、Ohminami Hirokazu、Yamanaka-Okumura Hisami、Hara Taichi、Taketani Yutaka
  • Journal Title: Antioxidants Volume: 9 Issue: 12 Pages: 1193-1193
  • DOI: 10.3390/antiox9121193
  • NAID: 120007042435
  • Peer Reviewed / Open Access
• [Journal Article] Reduction of stearoyl-CoA desaturase (SCD) contributes muscle atrophy through the excess endoplasmic reticulum stress in chronic kidney disease. (2020)
  • Author(s): Niida Y, Masuda M, Adachi Y, Yoshizawa A, Ohminami H, Mori Y, Ohnishi K, Yamanaka-Okumura H, Uchida T, Nikawa T, Yamamoto H, Miyazaki M, Taketani Y.
  • Journal Title: J Clin Biochem Nutr. Volume: 67(2) Issue: 2 Pages: 179-187
  • DOI: 10.3164/jcbn.20-24
  • NAID: 130007894915
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 食餌性リン負荷が高齢期の脳に及ぼす影響の検討 (2022)
  • Author(s): 木村玲奈、増田真志、山本菜摘、野邊悠太郎、大南博和、奥村仙示、竹谷豊
  • Organizer: 第24・25回日本病態栄養学会年次学術集会
• [Presentation] All-trans retinoic acidは腸管II型ナトリウム依存性リン酸輸送担体（Npt2b）遺伝子発現を低下させる (2020)
  • Author(s): 増田 真志、山本 浩範、竹谷 豊
  • Organizer: 第38回 日本骨代謝学会学術集会