Brain-wide screen for a neural pacemaker of aging

摘要 衰老是一个渐进的过程，会导致全身细胞功能的丧失， 导致许多慢性疾病，从而增加死亡率。阐明精确度 衰老机制对于减少疾病和延长健康寿命至关重要。 然而，几乎身体的每一个组织都会随着年龄的增长而改变，因此很难 找出衰老的主要控制者。这项提案的目标是确定 大脑是否通过离散的协调活动模式来调节衰老 神经网络。我们将使用寿命最短的脊椎动物之一，非洲 绿松石龙鱼，作为一种快速、高通量的衰老模型，揭示了基因- 定义的神经元调节细胞新陈代谢和寿命。大规模雇佣 在千里鱼的光片成像中，我们将可视化全脑钙活动动力学以 不带偏见地识别对长寿干预有反应的神经元。我们将描述 通过免疫组织化学、 单细胞和磷酸化核糖体捕获方法。以考察是否 这些神经元在大脑和其他组织中起着控制整体细胞功能的因果作用 组织，我们将通过光基因激活这些神经元并测量分子 脑部和外周组织的年轻特征和体内代谢活动。我们 将监测和操纵神经活动在短短的生命周期中使用 纤维光度法来确定这种‘神经起搏器’是否决定了衰老和 年轻的行为。然后，这些方法将扩展到寿命更长的物种- 斑马鱼和老鼠。从这些研究中获得的知识应该转变为 了解调节和同步衰老的基本机制 长寿。因为年龄是许多疾病的主要风险因素，包括神经退行性疾病。 疾病，这项提议应该提供新的，基于电路的方法来治疗这些疾病 疾病。 好了！

Summary Aging is a gradual process that results in the loss of cellular function across the body, leading to numerous chronic diseases that promote mortality. Elucidating the precise mechanisms of aging is critical for reducing illness and extending healthy lifespan. However, almost every tissue in the body is modified by aging, making it difficult to pinpoint the principal controller of aging. The goal of this proposal is to determine whether the brain modulates aging through coordinated activity patterns within discrete neuronal networks. We will use one of the shortest-living vertebrates, the African turquoise killifish, as a rapid, high-throughput model of aging to uncover genetically- defined neurons that regulate cellular metabolism and lifespan. Employing large-scale light-sheet imaging in killifish, we will visualize brain-wide calcium activity dynamics to unbiasedly identify neurons that respond to longevity interventions. We will characterize the genetic profiles of the identified neurons via a combination of immunohistochemical, single cell, and phosphorylated ribosome capture approaches. To examine whether these neurons play a causal role to control overall cellular function in the brain and other tissues, we will optogenetically activate these neurons and measure molecular signatures of youth and in vivo metabolic activity in the brain and peripheral tissues. We will monitor and manipulate neural activity throughout the short lifespan of killifish using fiber photometry to determine if this ‘neural pacemaker’ dictates the tempo of aging and youthful behavior. These approaches will then be extended to longer-lived species – zebrafish and mice. Knowledge resulting from these studies should be transformative to understand the fundamental mechanisms that regulate and synchronize aging and longevity. As age is the prime risk factor for many diseases, including neurodegenerative diseases, this proposal should provide new, circuit-based approaches to treat these diseases. !