Apoptosis and Life-Long Caloric Restriction

描述（由申请人提供）：细胞凋亡是一种高度调节的细胞死亡形式，其特征在于特定的形态学、生物化学和分子事件。然而，它在衰老过程中的作用，特别是在有丝分裂后的组织，如大脑，心脏和骨骼肌中的作用尚未深入研究。随着年龄的增长，有丝分裂后组织中的细胞凋亡似乎会增加，这可能是观察到的组织功能随年龄增长而丧失的主要因素。随着年龄的增长和可能防止细胞凋亡的适应性变化诱导细胞凋亡的机制仍有待确定。氧化剂和钙启动一系列事件，这些事件在线粒体和内质网介导的细胞死亡途径的激活中起关键作用。我们将内源性地增加线粒体超氧自由基的水平，并外源性地向年轻（6个月）和老年（24个月）大鼠的分离线粒体中添加过氧化氢、过氧亚硝酸盐和/或钙。将在年轻和老年大鼠中通过给予多柔比星（增加线粒体超氧化物）和毒胡萝卜素（刺激钙从内质网释放），引起细胞凋亡增加，在体内研究细胞凋亡介导的途径和内质网介导的途径的激活和适应潜力。此外，我们将确定在正常老化过程中，在6-，12-，18-，24-和26个月大的Fischer 344大鼠的细胞凋亡和改变的细胞凋亡信号转导通路的激活，通过研究调节蛋白急性激活调节细胞凋亡。我们将使用热量限制-一种减少氧化剂产生，改善钙处理，减少细胞损失和延长最大寿命的干预措施-进一步研究抗凋亡适应。此外，我们还将研究骨骼肌和心肌功能随年龄的变化，并将其与细胞凋亡和热量限制引起的细胞凋亡衰减联系起来。这种方法将能够更好地理解在年轻和老年动物，正常衰老和热量限制的急性应激过程中体内细胞凋亡的机制。

DESCRIPTION (provided by applicant): Apoptosis is a highly regulated form of cell death characterized by specific morphological, biochemical, and molecular events. However, its role during aging, particularly in post mitotic tissues such as the brain, heart and skeletal muscle has not been studied in depth. Apoptosis appear to increase in post-mitotic tissues with age and it may be a major contributing factor to the observed loss in tissue function with age. The mechanisms by which apoptosis are induced with advancing age and adaptations that may protect against apoptosis remain to be identified. Oxidants and calcium initiate a sequence of events that play a key role in the activation of the mitochondrial - and the endoplasmic reticulum-mediated pathways of cell death. We will endogenously increase levels of mitochondrial superoxide radical and also exogenously add hydrogen peroxide, peroxynitrite and/or calcium to isolated mitochondria in young (6-month) and old (24-month) rats. The activation and adaptive potential of the mitochondrial-mediated pathway and endoplasmic reticulum -mediated pathway will be investigated in vivo, in young and old rats, through the administration of both doxorubicin (increases mitochondrial superoxide) and thapsigargin (stimulates calcium release from the endoplasmic reticulum), causing an increase in apoptosis. Moreover, we will determine apoptosis and alterations in the activation of the apoptotic signal transduction pathways during normal aging, in 6-, 12-, 18-, 24- and 26-month old Fischer 344 rats, by studying regulatory proteins acutely activated to regulate apoptosis. We will use caloric restriction - an intervention that reduces oxidant production, improves calcium handling, reduces cell loss and extends maximum life span - to further study the anti-apoptotic adaptations. In addition, we will investigate skeletal and heart muscle function with age and relate this to apoptosis and the attenuation of apoptosis by caloric restriction. This approach will enable a greater understanding of the mechanisms of apoptosis in vivo during acute stress in young and old animals, normal aging, and caloric restriction.