2019-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/659792摘要：依據內政部統計，2018年台灣正式邁入”高齡化社會”；同份資料亦預測，台灣將於2030年會成為”超高齡化社會”。老化不但造成各式的慢性疾病；衍生的老年健康照護問題，勢必成為未來的公衛負擔。 老化的定義為生物體隨時間增長而造成細胞、組織及生理功能的喪失。這種惡化的狀況在糖尿病、心血管疾病與腎臟病，扮演重要角色。最近的研究發現，年老的囓齒動物，其心臟與腎臟皆有粒線體異常的狀況；而調控粒線體功能，則可作為 治療老化相關心臟與腎臟病的策略。 我們研究團隊先前的數據，支持早期開始的熱量限制，可降低老年小鼠肝臟粒腺體的氧化壓力，增進能量(ATP)的供應。『熱量限制』是指一種以降低總熱能攝取量20-40%的飲食介入方法。熱量限制在健康與長壽的優點已在許多模式動物 ，包括單細胞酵母菌到靈長類中獲得確認，顯示其具有高度的一致性效果。然而，熱量限制試驗的設計，例如動物開始執行的年紀，與熱量限制的時間長短都可能導致對健康優勢效果的差異。 心臟與腎臟是體內兩個高能量消耗的器官；而粒線體與能量代謝在這兩個器官正常功能維持上，扮演重要角色。因此，本篇研究想要探討，早期開始的熱量限制對老化心臟與腎臟的保護功效，以及粒線體恆定可能參與的機轉。為了釐清粒線體 促進老年小鼠健康的可能角色，我們將會分析心臟與腎臟的粒線體生合成，融合與分裂，細胞自噬與能量生合成。 關鍵目標 1.建立老化小鼠模型 2.找出心臟與腎臟老化過程中，造成粒線體異常的關鍵因子 3.確認早期開始的熱量限制減緩老化心臟與腎臟惡化的效應 4.釐清粒線體恆定在熱量限制改善老化心臟與腎臟的角色 5.建立老化的體外細胞模型 6.藉由細胞模型的功能缺失型突變以及/或者功能獲得型突變，探索熱量限制參與 老化誘發病理生理學的分子機轉。 本計劃將建立老化小鼠模型作為生物醫學的應用。試驗的結果，不但對了解老化相關的病理機轉極具價值；亦可藉由飲食介入發展治療的策略。<br> Abstract: According to the statics of Ministry of the Interior, Taiwan officially becomes an aged society in 2018. The same data also shows that Taiwan would become a “Super-aged society” in 2030. Aging not only leads to varieties of chronic diseases, the derivative elder health care problems would become public health loadings in the future. Aging is defined as the time&#8208;dependent progressive loss of cellular, tissue, and physiological functions of living organisms. This deterioration plays a critical role in the pathogenesis for chronic diseases, including diabetes, cardiovascular diseases, and renal diseases. Recent study shows that in aged rodents, mitochondria abnormalities are noticed in the heart and kidney, and strategies aimed at modulating mitochondrial functions hold promise for treating age-related heart and kidney diseases. Previous data from our research team support that early-onset caloric restriction (CR) decreased mitochondrial oxidative stress, and enhanced energy supply (ATP) in the liver of aged mice. “Caloric restriction” refers to a dietary intervention with an overall 20-40% reduction of total caloric intake. The beneficial effect of CR on healthspan and lifespan has been confirmed in model organisms ranging from unicellular yeast to primates, indicating a highly conserved effect. However, the design of CR experiment, such as initiation age of animal, and duration of CR, might cause discrepancies in health benefits. Heart and kidney are the two major high energy-consuming organs, and mitochondria/ energy metabolism plays a critical role to maintain the normal functions of heart and kidney. As a result, this study wants to explore the protective effect of early-onset CR on aging heart and kidney and the potential mechanism regarding the mitochondrial homeostasis. To elucidate the potential role of mitochondria on promoting health of aging mice, we will analyze the mitochondrial biogenesis, fission and fusion, mitophagy, and bioenergetics in the heart and kidney. Our specific aims are 1.Establish an aging mouse model 2.Identify the key factors that responsible for the mitochondrial dysfunction in aging heart and kidney 3.Confirm the effect of early-onset CR on reducing the deteriorations in aging heart and kidney 4.Elucidate the role of mitochondrial homeostasis in the protection of CR on aging heart and kidney 5.Establish an aging cell model 6.Explore the molecular mechanism of CR involved in aging-induced pathophysiology by a loss-of-function and/or gain-of-function cell model This project will establish an aging mouse for biomedical application. The result would be invaluable in understanding the aging-related pathophysiology as well as in developing therapeutic strategies by dietary intervention.熱量限制老化心臟病變腎臟病變粒線體恆定能量代謝caloric restrictionagingcardiomyopathynephropathymitochondrial homeostasisenergy metabolism