| Abstract: | 能量限制可以藉由增加細胞內NAD+濃度，進而活化SIRT1 而能延長壽命和降低老 化相關疾病的發生率。能量限制模仿劑指化學分子或天然分子具有和能量限制相同的作 用，但不需要透過飲食限制的方式。維生素B3 為NAD+的前趨物質，理論上可以作為能 量限制模仿劑，值得深入研究。廣義的維生素B3 分子包括：菸鹼酸、菸鹼醯胺、菸鹼 醯胺核苷及六菸鹼酸肌醇等, 本實驗室先前的研究證實許多維生素B3 分子具有延長人 類Hs68 細胞壽命的能力。本計畫擬進一步以動物試驗模式探討補充維生素B3 延長齧 齒類動物體壽命的能力及機制，並與能量限制作比較。但由於低劑量的補充菸鹼酸(約 >30mg/day)常會產生潮紅等不適的副作用; 菸鹼醯胺核苷則因未商品化，價錢昂貴; 過 量補充菸鹼醯胺則有產生肝毒性的風險，因此，六菸鹼酸肌醇成為最有潛力作為能量限 制模仿劑的維生素B3 分子，但在未產生肝毒性的劑量下，菸鹼醯胺是否具有能量限制 模仿劑的作用亦值得研究。是故本三年計畫選擇菸鹼醯胺及六菸鹼酸肌醇作為維生素 B3 代表分子來進行動物試驗，第一年將以C57BL/6 小鼠進行菸鹼醯胺及六菸鹼酸肌醇 的生存試驗,第二及第三年則以F344/NNarl 大鼠分別進行NAM 及IHN 生理功效、肝毒 性及機制的探討。本研究將有助於了解維生素B3 抗老化的作用和機制，並且提供2~3 位學生學習動物試驗、分子生物及儀器分析的技術。
Calorie restriction (CR) extends lifespan and decreases the occurrence of age-related diseases through the increase in intracellular NAD+ levels followed by activation of SIRT1 protein. A calorie restriction mimetic (CRM) refers to any intervention that can evoke similar effects on aging, health and lifespan to those of CR but without actually restricting caloric intake. Because vitamin B3 is the precursor of NAD+, it theoretically can be a CRM. In fact, with a wider definition, vitamin B3 includes several molecules like nicotinic acid (NA), nicotinamide (NAM), nicotinamide riboside (NR) and intositol hexanicotinate (IHN), etc. In a previous study, we used human Hs68 cell model and had demonstrated that several vitamin B3 molecules can extend the lifespan of Hs68 cells. Thus, this project intends to use animal models to further investigate the ability and mechanisms of how vitamin B3 extends lifespan in rodents, and all of the investigated effects will be compared to CR. However, among these four vitamin B3 molecules, the supplement of a low-dose (>30mg/day) NA usually induces a side effect of flush. NR is still not commercialized to date with a relatively high price. In addition, the supplement of an over dose of NAM can increase the risk of hepatotoxicity. Therefore, IHN seems to become the best candidate to be a CRM. It is still interesting to know whether the NAM can be a CRM under doses without hepatotoxicity. Thus, this three-year project will be designed to take NAM and IHN as representative molecules to study the ability and mechanisms of vitamin B3 to be CRM. During the fist year, we plan to use C57BL/6 mice to study the lifespan-extended effects of NAM and IHN. In the 2nd and 3th years, we will use F344/NNarl rats to study the physiological functions, liver toxicity and the mechanisms of longevity of NAM and IHN, respectively. The study will be contributive to our understanding on the mechanisms and effects of vitamin B3 for anti-aging, and will provide 2~3 students to learn the techniques for animal experiments, molecule biology and instrumental analysis. |
