Respiratory Control in Old Age

到2030年，美国将有7000万人超过65岁， >85岁。随着人口老龄化， 与年龄相关的肌肉萎缩和无力（肌肉减少症），这是一个重要的预测因素 慢性病和老年人死亡率的关系。之前我们发现肌肉减少症 影响膈肌（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DIAm相当大 年老时更虚弱。重要的是，我们发现在老年大鼠中， 更少的大膈运动神经元（PMN），包括更多的疲劳运动单位。 这就提出了一个有趣的可能性，即DIAm肌肉减少症是由于失去了更大的 中性粒细胞，导致IIx和/或IIb型肌纤维去神经支配和DIAm无力。 作为支持，我们发现DIAm肌肉减少症与运动能力受损有关。 更高的力气道清除行为（例如，咳嗽，打喷嚏），这可能是 老年人呼吸道感染的风险增加。 结论：与年龄相关的PMN丢失的根本原因尚不清楚。肯定与 呼吸，较小的PMNs更频繁地被招募，因此它们的能量需求 更高。因此，在初步研究中，我们发现， 较小的PMN中的线粒体更加融合并且具有更高的体积密度。在 肌萎缩性侧索硬化症（ALS）、线粒体断裂 似乎先于运动神经元的丧失，这与Mfn 2减少有关 增加Drp 1的表达。事实上，实验性干预支持 线粒体融合或抑制分裂似乎改善了运动神经元功能障碍， ALS模型中的退化。同样重要的是要注意，脑源性神经营养素 通过其高亲和力受体（TrkB.F1）的BDNF信号传导促进运动神经元的运动。 神经元存活和线粒体融合，这表明可能存在联系。为了表示支持， TrkB.Fl共定位于线粒体外膜，并且在初步研究中， 我们发现增强的BDNF/TrkB信号传导促进NSC 34中的线粒体融合， 培养的运动神经元 概念框架：我们假设，年龄相关的损失较大的中性粒细胞是 与线粒体碎片有关，这是由于Mfn 2减少和 增加Drp 1表达，并通过增强的BDNF/TrkB信号转导减轻。 具体目标1：检验以下假设： 中性粒细胞中的线粒体形态随着年龄的增长而恶化， Mfn 2和Drp 1表达的差异。 具体目标2：检验较大PMN的年龄相关损失是 与线粒体碎片有关，这是由于Mfn 2减少和 增加Drp 1的表达。 具体目的3：为了检验增强BDNF/TrkB.Fl信号传导的假设， PMN通过对Mfn 2和Drp 1的影响减轻与年龄相关的PMN损失 表达和线粒体形态。

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.