Respiratory Control in Old Age

到2030年，美国将有约7000万人65岁，约1000万人 现年85岁。随着我们人口的老龄化，将有更多的发病率 与年龄相关的肌肉萎缩和无力(肌萎缩症)，这是一个重要的预测因素 老年人的慢性病和死亡率。此前，我们发现石棺减少症 影响横隔肌(DIAM)，伴有更易疲劳的IIx和/或IIb型萎缩 肌肉纤维，以及最大比力的减少，使直径相当大 年老时身体虚弱。对拟议的研究很重要，我们发现在老年大鼠中 较少的大的膈运动神经元(PMN)组成更易疲劳的运动单位。 这提出了一种耐人寻味的可能性，即Diam石棺减少是由于较大的 中性粒细胞，导致IIx和/或IIb型肌肉纤维失神经和Diam虚弱。 在Support中，我们发现Diam石棺减少与运动能力受损有关 更强的呼吸道清除行为(例如，咳嗽、打喷嚏)，这可能是 老年人呼吸道感染的风险增加。 前提：与年龄相关的PMN丢失的潜在原因尚不清楚。当然是用 呼吸时，较小的PMN被更频繁地招募，因此它们的能量需求 是更高的。因此，在初步研究中，我们发现 在较小的PMN中，线粒体更融合，具有更高的体密度。在……里面 肌萎缩侧索硬化症(ALS)、线粒体碎裂等疾病 似乎先于运动神经元的丧失，这与Mfn2的减少有关 增加DRp1的表达。事实上，实验干预支持 线粒体融合或抑制分裂似乎可以改善运动神经元功能障碍和 ALS模型中的退行性变。同样重要的是要注意到，脑源性神经营养 脑源性神经营养因子(BDNF)通过其高亲和力受体TrkB.F1促进运动 神经元存活和线粒体融合，这表明两者之间可能存在联系。在支持方面， TrkB.Fl共定位于线粒体外膜，并在初步研究中 我们发现增强的BDNF/TrkB信号促进了NSC34的线粒体融合 培养的运动神经元。 概念框架：我们假设较大的PMN与年龄相关的损失是 与线粒体碎裂有关，这是由于Mfn2和Mfn2减少引起的 增加Drp1的表达，并被增强的BDNF/TrkB信号缓解。 具体目标1：检验以下假设：大小相关的差异 中性粒细胞线粒体形态随增龄而加重，并与 Mfn2和Drp1表达的差异。 具体目标2：检验较大PMN的年龄相关损失是 与线粒体碎裂有关，这是由于Mfn2和Mfn2减少引起的 DRp1表达增加。 具体目标3：验证增强BDNF/TrkB.F1信号在脑内的假设 PMN通过影响Mfn2和Drp1减轻与年龄相关的PMN丢失 线粒体的表达和形态。

By 2030, ~70 million people in the USA will be >65 years of age and ~10 million will be >85 years old. With aging of our population, there will be an increased incidence of age-related muscle wasting and weakness (sarcopenia), which is a significant predictor of chronic disease and mortality in the elderly. Previously, we found that sarcopenia affects the diaphragm muscle (DIAm) with atrophy of more fatigable type IIx and/or IIb muscle fibers, and a reduction in maximum specific force, making the DIAm considerably weaker in old age. Important to the proposed studies, we found that in older rats there are fewer large phrenic motor neurons (PMNs) that comprise more fatigable motor units. This raises the intriguing possibility that DIAm sarcopenia results from the loss of larger PMNs, leading to denervation of type IIx and/or IIb muscle fibers and DIAm weakness. In support, we found that DIAm sarcopenia is associated with impaired performance of higher force airway clearance behaviors (e.g., coughing, sneezing), which may underlie the increased risk of airway infections in older adults. Premise: The underlying cause of age-related PMN loss is unclear. Certainly with breathing, smaller PMNs are recruited more frequently, and thus their energy demands are higher. Accordingly, it is not surprising that in preliminary studies, we found that mitochondria in smaller PMNs are more fused and have a higher volume density. In diseases such as amyotrophic lateral sclerosis (ALS), mitochondrial fragmentation appears to precede the loss of motor neurons, which is associated with decreased Mfn2 and increased Drp1 expression. Indeed, experimental interventions that support mitochondrial fusion or inhibit fission appear to ameliorate motor neuron dysfunction and degeneration in ALS models. It is also important to note that brain-derived neurotropic factor (BDNF) signaling through its high affinity receptor (TrkB.Fl) promotes motor neuron survival, and mitochondrial fusion, suggesting there may be a link. In support, TrkB.Fl is co-localized to the mitochondrial outer membrane, and in preliminary studies we found that enhanced BDNF/TrkB signaling promotes mitochondrial fusion in NSC34 cultured motor neurons. Conceptual Framework: We hypothesize that the age-related loss of larger PMNs is related to mitochondrial fragmentation, which results from decreased Mfn2 and increased Drp1 expression, and is mitigated by enhanced BDNF/TrkB signaling. Specific Aim 1: To test the hypothesis that size-dependent differences in mitochondrial morphology in PMNs are exacerbated with aging and relate to differences in Mfn2 and Drp1 expression. Specific Aim 2: To test the hypothesis that the age-related loss of larger PMNs is related to mitochondrial fragmentation, which results from decreased Mfn2 and increased Drp1 expression. Specific Aim 3: To test the hypothesis that enhanced BDNF/TrkB.Fl signaling in PMNs mitigates age-related PMN loss, through an effect on Mfn2 and Drp1 expression and mitochondrial morphology.