Part I: 二苯碘鎓透過AMPK/MFF/DRP1主導粒線體分裂以抗老化; Part II: 探究miR-137在生理功能上所扮演的角色: 專注於成長遲緩

Abstract

在第一部分，老化相關的健康問題隨人口逐漸老化而日漸重要，因此開發抗老化藥物是目前重要的課題，過去粒線體已經被證明參與細胞老化的過程，但針對此特徵的抗老藥物卻鮮少被探索，因此在本研究，我們證明二苯碘鎓 (Diphenyleneiodonium, DPI)可以顯著促進粒線體分裂與抑制其呼吸，在不同的細胞老化模型的評估下，二苯碘鎓減少了各項老化的標誌，同時抑制了老化造成的高呼吸率，此外，利用老化老鼠來測試二苯碘鎓抗老化的能力，發現其不僅可以減少老化標誌，也可以減緩老化相關的肝臟纖維化及免疫細胞浸潤，最後，二苯碘鎓也可以改善老化所造成的生理功能退化。總而言之，二苯碘鎓是一個具有抗老化能力藥物，未來可以單獨或合併其他抗老藥物來改善老化相關的疾病或狀態。第二部分， 微小核糖核酸 (MicroRNA) 可以透過影響訊息核糖核酸來調控基因表達，進而參與在許多細胞及生理功能，其中microRNA-137 (miR-137)不僅在不同物種中具有保守性且在神經系統中高度表達，並且調控神經發育與功能，另外也參與在各種癌症的病程，然而miR-137是否參與其他生理功能及癌症生成的角色尚未闡明，因此本研究主要透過在小鼠上剔除Mir137來探索其在活體之功能。有趣的是，Mir137 剔除鼠出現許多表現型包括成長遲緩、出生後死亡、骨質疏鬆、脂肪萎縮、低血糖、低體溫。進一步探索Mir137缺失導致成長遲緩的原因，我們發現Growth hormone (GH)/Insulin-like growth factor 1 (IGF1) 軸被破壞，血清的IGF1降低並伴隨GH的上升，透過體外及體內的實驗發現，Mir137缺失會導致非細胞自主性的GH阻抗，最後利用Cre/LoxP 系統確認了小鼠腦部Mir137的缺失會導致此現象。總結來說，腦部miR-137可以透過影響GH/IGF1途徑來調控身體成長。

In the part I: As the population ages, health issues with aging are becoming increasingly important, making the development of anti-aging drugs a current topic of interest. Previous research has shown that mitochondria play a role in the aging process, but the use of anti-aging drugs targeting this feature has been rare. In this study, we found that Diphenyleneiodonium (DPI) significantly increased mitochondrial fission and suppressed its respiration. When evaluated DPI effect on various models of cell senescence, DPI reduced various senescence markers and decreased the senescence-induced hyper oxygen consumption rate. Additionally, when tested on aging mice, DPI was found to not only reduce senescence markers, but also slow down aging-related liver fibrosis and infiltration of immune cells. It also improved the deterioration of physiological functions caused by aging. Overall, DPI is an effective anti-aging drug that can be used alone or in combination with other anti-aging drugs to improve aging-related diseases or conditions in the future. In the part II: MicroRNA can regulate gene expression by affecting messenger RNA and is involved in many cellular and physiological functions. Mir137 is high conservation in various species and highly expressed in neuron system. It plays a role in neurodevelopment and function, as well as various cancers. However, the role of miR-137 in physiological functions and cancer development is not yet fully clarification. In this study, we explored the function of miR-137 in mice by eliminating it. Interestingly, Mir137 knockout mice displayed several phenotypes including growth retardation, postnatal death, osteoporosis, lipoatrophy, hypoglycemia, and hypothermia. To further understand the cause of the growth retardation caused by the loss of Mir137, we found that Growth hormone (GH)/Insulin-like growth factor (IGF1) axis was disrupted and serum IGF1 decreased with an increase in GH. Through in vitro and in vivo experiments, we discovered that the loss of Mir137 led to non-cell-autonomous GH resistance. Finally, using the Cre/LoxP system, we confirmed that the loss of Mir137 in the mouse brain led to this phenomenon. In summary, brain miR-137 can regulate body growth by affecting the GH/IGF1 pathway.