Identification of aestivation-dependent longevity and its regulation

• Project/Area Number: 20K20664
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Studies on the Super-Aging Society
• Research Institution: Kagawa University
• Principal Investigator: Nishiyama Akira 香川大学, 医学部, 教授 (10325334)
• Co-Investigator(Kenkyū-buntansha): 杉浦 悠毅 慶應義塾大学, 医学部(信濃町), 特任講師 (30590202) ; 鈴木 美和 日本大学, 生物資源科学部, 教授 (70409069) ; 植田 啓一 一般財団法人沖縄美ら島財団(総合研究センター), 総合研究センター 動物研究室, 上席研究員 (70721728) ; 大崎 博之 神戸大学, 保健学研究科, 准教授 (80438291)
• 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: 夏眠 / 夏眠様反応 / 生体防御反応 / 体液 / 老化 / 健康長寿 / 生活習慣病 / 個体老化 / 腎臓病 / 血圧 / サルコペニア / 体液変化 / イルカ / 宇宙空間

Outline of Research at the Start

健康長寿を目指したこれまでの研究は、個体の「機能低下を生じる要因」に着目し、その要因を阻害あるいは補填して解決を図ろうとするものばかりであり、根本的な解決には至っていない。

そこで視点を180度変え、最近申請者が世界に先駆けて発見した陸上高等動物が持つ目に見えない個体の適応能力である「夏眠(aestivation)反応」に着目し、それを制御することで老化防止や生活習慣病の未病に挑戦する。

先行研究で証明しているげっ歯類の「夏眠」モデルを使用した「夏眠反応」の制御メカニズムの解析や海生哺乳類・イルカでの検討により、新しい学術分野を切り開き、究極の健康長寿獲得への突破口とする。

Outline of Final Research Achievements

Previous research aimed at achieving healthy longevity has focused only on the "factors that cause functional decline" in individuals, and has not yet reached a fundamental solution. Therefore, we made a 180-degree turn and focused on the control of potential defense mechanisms.
As a result, it was proven that a similar biological response called "aestivation," which was acquired by organisms to retain body fluid when they landed during evolution, is preserved in mammals, and it was experimentally demonstrated that aestivation-like response regulates body fluid in the pathogenesis of hypertension, kidney disease, and liver failure in rats. Furthermore, dramatic changes in body fluid in mice bred in space have also been demonstrated and are being studied in collaboration with JAXA.

Academic Significance and Societal Importance of the Research Achievements

健康長寿を目指した研究のすべては、個体の機能低下を生じる「要因」を阻害する、あるいは補足して解決を図るものばかりであり、生体が備え持つ適応能力に着目したものは皆無であった。これに対し本研究は、これまでの申請者の発見に基づき、生体が持つ目に見えない生体防御機構である「夏眠様反応」を制御することで老化防止や生活習慣病の未病を試みる世界初の挑戦であり、新しい学術分野を切り開き、健康長寿獲得への突破口とするものである。

Research Products

• [Int'l Joint Research] DUKE-NUS(シンガポール)
• [Int'l Joint Research] DUKE-NUS(シンガポール)
• [Int'l Joint Research] DUKE-NUS(シンガポール)
• [Journal Article] Possible renoprotective mechanisms of SGLT2 inhibitors. (2023)
  • Author(s): Akira Nishiyama, Kento Kitada
  • Journal Title: Frontiers in Medicine Volume: 10 Pages: 1115413-1115413
  • DOI: 10.3389/fmed.2023.1115413
  • Peer Reviewed / Open Access
• [Journal Article] Possible contribution of phosphate to the pathogenesis of chronic kidney disease in dolphins. (2023)
  • Author(s): Nourin Jahan, Hiroyuki Ohsaki, Kiyoko Kaneko, Asadur Rahman, Takeshi Nishiyama, Makoto Koizumi, Shuichiro Yamanaka, Kento Kitada, Yuki Sugiura, Kenji Matsui, Takashi Yokoo, Takayuki Hamano, Makoto Kuro-O, Takuya Itou, Miwa Suzuki, Keiichi Ueda, Akira Nishiyama
  • Journal Title: Scientific Reports Volume: 13 Issue: 1 Pages: 5161-5161
  • DOI: 10.1038/s41598-023-32399-6
  • Peer Reviewed / Open Access
• [Journal Article] Potential Impact of Non-Steroidal Mineralocorticoid Receptor Antagonists in Cardiovascular Disease (2023)
  • Author(s): Rahman Asadur、Jahan Nourin、Rahman Md Tanvir、Nishiyama Akira
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Issue: 3 Pages: 1922-1922
  • DOI: 10.3390/ijms24031922
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Contributions of renal water loss and skin water conservation to blood pressure elevation in spontaneously hypertensive rats (2022)
  • Author(s): Ogura Takahiro、Kitada Kento、Morisawa Norihiko、Fujisawa Yoshihide、Kidoguchi Satoshi、Nakano Daisuke、Kobara Hideki、Masaki Tsutomu、Titze Jens、Nishiyama Akira
  • Journal Title: Hypertension Research Volume: 46 Issue: 1 Pages: 32-39
  • DOI: 10.1038/s41440-022-01044-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Blood pressure adaptation in vertebrates: comparative biology (2022)
  • Author(s): Nishiyama Akira、Kitada Kento、Suzuki Miwa
  • Journal Title: Kidney International Volume: 102 Issue: 2 Pages: 242-247
  • DOI: 10.1016/j.kint.2022.03.032
  • Peer Reviewed
• [Journal Article] Tolvaptan induces body fluid loss and subsequent water conservation in normal rats (2022)
  • Author(s): Kidoguchi Satoshi、Kitada Kento、Fujisawa Yoshihide、Nakano Daisuke、Yokoo Takashi、Titze Jens、Nishiyama Akira
  • Journal Title: Journal of Pharmacological Sciences Volume: 149 Issue: 3 Pages: 115-123
  • DOI: 10.1016/j.jphs.2022.04.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatocellular carcinoma induces body mass loss in parallel with osmolyte and water retention in rats (2022)
  • Author(s): Kidoguchi Satoshi、Kitada Kento、Nakajima Kazuki、Nakano Daisuke、Ohsaki Hiroyuki、Kittikulsuth Wararat、Kobara Hideki、Masaki Tsutomu、Yokoo Takashi、Takahashi Kazuo、Titze Jens、Nishiyama Akira
  • Journal Title: Life Sciences Volume: 289 Pages: 120192-120192
  • DOI: 10.1016/j.lfs.2021.120192
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Sodium/glucose cotransporter 2 and renoprotection: From the perspective of energy regulation and water conservation. (2021)
  • Author(s): Kento Kitada, Satoshi Kidoguchi, Daisuke Nakano, Akira Nishiyama.
  • Journal Title: Journal of Pharmacological Sciences Volume: 147 Issue: 3 Pages: 245-250
  • DOI: 10.1016/j.jphs.2021.07.006
  • Peer Reviewed / Open Access
• [Journal Article] Renal NG2-expressing cells have a macrophage-like phenotype and facilitate renal recovery after ischemic injury (2021)
  • Author(s): Kittikulsuth Wararat、Nakano Daisuke、Kitada Kento、Suzuki Norio、Yamamoto Masayuki、Nishiyama Akira
  • Journal Title: American Journal of Physiology-Renal Physiology Volume: 321 Issue: 2 Pages: F170-F178
  • DOI: 10.1152/ajprenal.00011.2021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, on sodium dynamics in hypertensive subtotally nephrectomized rats (2021)
  • Author(s): Zhang Anqi、Nakano Daisuke、Morisawa Norihiko、Kitada Kento、Kittikulsuth Wararat、Rahman Asadur、Morikawa Takashi、Konishi Yoshio、Nishiyama Akira
  • Journal Title: Journal of Pharmacological Sciences Volume: 146 Issue: 2 Pages: 98-104
  • DOI: 10.1016/j.jphs.2021.03.007
  • Peer Reviewed / Open Access
• [Journal Article] Adaptive physiological water conservation explains hypertension and muscle catabolism in experimental chronic renal failure (2021)
  • Author(s): Kovarik Johannes J.、Morisawa Norihiko、Wild Johannes、Marton Adriana、Takase‐Minegishi Kaoru、Minegishi Shintaro、Daub Steffen、Sands Jeff M.、Klein Janet D.、Bailey James L.、Kovalik Jean‐Paul、Rauh Manfred、Karbach Susanne、Hilgers Karl F.、Luft Friedrich、Nishiyama Akira、Nakano Daisuke、Kitada Kento、Titze Jens
  • Journal Title: Acta Physiologica Volume: 00 Issue: 1
  • DOI: 10.1111/apha.13629
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cardioprotective Effects of a Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, in Dahl Salt-Sensitive Hypertensive Rats (2021)
  • Author(s): Rahman Asadur、Sawano Tatsuya、Sen Anupoma、Hossain Akram、Jahan Nourin、Kobara Hideki、Masaki Tsutomu、Kosaka Shinji、Kitada Kento、Nakano Daisuke、Imamura Takeshi、Ohsaki Hiroyuki、Nishiyama Akira
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 4 Pages: 2069-2069
  • DOI: 10.3390/ijms22042069
  • Peer Reviewed / Open Access
• [Journal Article] Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation (2020)
  • Author(s): Marton Adriana、Kaneko Tatsuroh、Kovalik Jean-Paul、Yasui Atsutaka、Nishiyama Akira、Kitada Kento、Titze Jens
  • Journal Title: Nature Reviews Nephrology Volume: 17 Issue: 1 Pages: 65-77
  • DOI: 10.1038/s41581-020-00350-x
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 高食塩接種が各骨のナトリウム・カリウム含量に与える影響 (2023)
  • Author(s): 北田 研人，宗定 優紘，中野 大介，西山 成
  • Organizer: 第52回日本心脈管作動物質学会
• [Presentation] シン・ナトリウム調節 (2022)
  • Author(s): 西山 成
  • Organizer: 第52回日本腎臓学会西部学術大会
  • Invited
• [Presentation] New salt concept and significance of MR inhibition. (2022)
  • Author(s): Akira Nishiyama
  • Organizer: The 29th Scientific Meeting of the International Society of Hypertension.
  • Int'l Joint Research / Invited
• [Presentation] Effects of an SGLT2 inhibitor on salt sensitivity of blood pressure and sympathetic nerve activity in a non-diabetic rat model of chronic kidney disease. (2021)
  • Author(s): Wan N, Rahman A, Nishiyama A.
  • Organizer: International Society of Hypertension.
  • Int'l Joint Research
• [Presentation] Pathophysiological mechanism of mineralocorticoid receptor-dependent chronic kidney disease. (2021)
  • Author(s): Nishiyama A.
  • Organizer: The 19th International Symposium on Atherosclerosis.
  • Int'l Joint Research / Invited
• [Presentation] New concept of salt and water balance (2020)
  • Author(s): Akira Nishiyama
  • Organizer: CVMW2020心血管代謝週間（第28回日本血管生物医学会学術集会, 第24回日本心血管内分泌代謝学会学術総会, 第37回国際心臓研究学会日本部会, International Society for Applied Cardiovascular Biology (ISACB）
  • Int'l Joint Research / Invited
• [Presentation] 皮膚におけるナトリウム貯留と電解質調節 (2020)
  • Author(s): 西山 成
  • Organizer: 第63回日本腎臓学会学術総会
  • Invited
• [Presentation] 塩と病態生理・MR阻害薬, (2020)
  • Author(s): 西山 成，北田研人
  • Organizer: 第63回日本糖尿病学会
  • Invited
• [Book] エース薬理学 (2020)
  • Author(s): 金井好克、安西尚彦、安藤 仁、浅井 聰・編
  • Total Pages: 303
  • Publisher: 南山堂
  • ISBN: 9784525140717
• [Remarks] 香川大学医学部薬理学ホームページ
  • URL: http://www.kms.ac.jp/%7Eyakuri/
• [Remarks] 香川大学医学部薬理学ホームページ
  • URL: http://www.kms.ac.jp/%7Eyakuri/4-1_paper.html