Identification of NAD+-degrading enzymes for the breakdown of NAD+ under the resting conditions

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K11696
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Shimane University
• Principal Investigator: Hara Nobumasa 島根大学, 医学部, 特別協力研究員 (20284028)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: NAD+代謝 / ポリ（ADP-リボース）ポリメラーゼ / CD38 / サーチュイン / 老化

Outline of Final Research Achievements

NAD+ is continuously degraded and synthesized under resting conditions in mammalian cells. We deleted or overexpressed the known NAD+-degrading enzymes including PARP1 and CD38 and found that these modifications do not induce obvious changes in the rate of cellular NAD+ breakdown. No observed changes in the rate are, at least in part, the result of the compensatory regulation of cellular NAD+ breakdown. Thus, the total cellular NAD+-degrading activity may be kept constant against changes in the expression of NAD+-degrading enzymes. Many studies suggest that cellular NAD+ levels fall during aging and in age-related diseases such as metabolic syndrome, neurodegeneration, and cancer, and that raising the NAD+ levels back to normal healthy levels promotes healthy aging and delays the age-related diseases. Further elucidation of the molecular mechanism underlying the compensatory regulation of cellular NAD+ breakdown should provide an important clue toward an NAD+ boosting strategy.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

加齢性疾患がさまざまな臓器のNAD+レベルの低下と関連があり、NAD+レベルを増加させ、長寿に関わるとされるNAD+依存性脱アセチル化酵素サーチュイン（SIRT）を活性化することがこれら疾患の予防および治療に有益であると考えられている。そのため細胞内NAD+濃度([NAD+])調節の制御機序解明は重要である。本研究はNAD+分解酵素による[NAD+]調節機序の一端を明らかにした。このことは[NAD+]を増加させSIRTを活性化すること、すなわち加齢性疾患の予防および治療につながるものと期待される。