A molecular mechanism of aging through epigenome and muscle regeneration

• Project/Area Number: 17K13228
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied health science
• Research Institution: Keio University
• Principal Investigator: Hayano Motoshi 慶應義塾大学, 医学部(信濃町), 特任講師 (30593644)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 老化 / エピゲノム / DNA損傷 / 筋肉 / サルコペニア / FOXO1 / CTCF / ヒストン修飾 / 再生医療

Outline of Final Research Achievements

ICE (Induced changes in epigenome) mice is a novel mouse model in which aging related phenotypes and the changes in epigenome are induced by DNA damage through I-PpoI endonuclease. By induction of DNA damage for three weeks at 4 to 6 months age in mice, muscle mass and muscle functions are declined at 10 months post-treatment. Transcriptome analysis with RNA-seq showed ribosomal genes (RPS28 and RPS 24), OXPHOS genes (ATP5k, Ndufa8, COX8) and myosin-related genes (Myh7, Myh9) are altered at 10 month after induction of aging along with changes in H3K4me1 and H4K20me1 at those genes in ICE mice. Those data indicate that LSD1 and SETD8 invloved in regulation of aging and muscle function during aging.

Academic Significance and Societal Importance of the Research Achievements

老化に伴ってDNA損傷の蓄積やエピゲノム変化が報告されており、DNA損傷による老化や老化関連疾患誘導の分子機序が着目されてきた。その中で、DNA損傷によってゲノム変異を伴わないエピゲノム変化による老化は、生後生じる老化誘導の分子機序をあきらかにするだけでなく、老化の可逆性を証明することが可能となる。本研究によって、DNA損傷は特異的なエピゲノム変化と遺伝子発現を引き起こすことで、老化速度を変化させることをあきらかにした。今後、代謝やタンパク質合成を含めた制御を介してエピゲノムを標的としたサルコペニア創薬の基盤となる。

Research Products

• [Int'l Joint Research] Harvard Medical School/Carnegie Mellon University(米国)
• [Presentation] Evidence for an epigenetic cause of aging in mice (2018)
  • Author(s): Motoshi Hayano, Elias Levy Itshak Salfati, John Apostolides, Jae-Hyun Yang, Michael S. Bonkowski, Luis A. Rajman, Sachin Thakur, Neha Garg, Ana-Maria Balta, Sarah Mitchell, Yasuaki Mohri, Rafael deCabo, Emi Nishimura Andreas R. Pfenning, Philipp Oberdoerffer and David A. Sinclair.
  • Organizer: The International Meeting on RECQ Helicases and Related Diseases 2018
  • Int'l Joint Research
• [Presentation] エピゲノム変動による老化モデル構築及び、 老化関連疾患誘導のメカニズム (2018)
  • Author(s): 早野 元詞
  • Organizer: 第6回AAA (Academy of Aging and CArdiovascular-Diabetes Research)
  • Invited
• [Presentation] エピゲノム変動による老化モデルとその分子機構 (2017)
  • Author(s): 早野 元詞、Elias Salfati、Abhirup Das、John Apostolides、Luis Rajman、Michael Bonkowski、Sachin Thakur、Neha Garg、Sarah Mitchell、Andreas Pfenning、Jae-Hyun Yang、Rafael deCabo、Shelley Berger、Philipp Oberdoerffer、David Sinclair
  • Organizer: Conbio2017
  • Invited
• [Presentation] エピゲノム変動による老化モデル構築及び、 老化関連疾患誘導のメカニズム (2017)
  • Author(s): Motoshi Hayano, Luis A.Rajman ,Michael S. Bonkowski , Sachin Thakur , Neha Garg , John Apostolides , Sarah Mitchell , Andreas Pfenning, Jae-Hyun Yang, Rafael deCabo, Shelley L. Berger, Philipp Oberdoerffer5 and David A. Sinclair.
  • Organizer: 第１０回 Symphony
  • Invited
• [Presentation] Evidence for an epigenetic cause of aging in mice (2017)
  • Author(s): Motoshi Hayano, Luis A.Rajman ,Michael S. Bonkowski , Sachin Thakur , Neha Garg , John Apostolides , Sarah Mitchell , Andreas Pfenning, Jae-Hyun Yang, Rafael deCabo, Shelley L. Berger, Philipp Oberdoerffer5 and David A. Sinclair
  • Organizer: Keystone Symposia, Aging and Mechanisms of Aging-Related Disease
  • Int'l Joint Research