Acceleration of Circulatory and Neurological Aging due to Wildfire Exposures

摘要：暴露于Wildfire可加速循环和神经衰老 野火对不断增长和老龄化的全球人口构成越来越大的威胁，特别是在美国西部 各州。人们对吸入的环境污染物的影响知之甚少，例如野火烟雾。 (WFS)暴露，在脑血管和神经衰老的病因中的分子通路 阿尔茨海默病(AD)和痴呆。然而，老化和吸入会引起平行的分子变化。 血液中的有毒物质，增加了它们相互作用的可能性。这包括增加 金属蛋白酶、蛇毒和炎症因子可直接促进年龄相关的神经功能 病理学。此外，我们的研究记录了吸入污染物是如何导致血液成分变化的， 特别是作为蛋白酶诱导的多肽，促进血管功能障碍和神经炎症。 吸入毒物诱导的循环因子促进血脑屏障(BBB)的渗透，胶质细胞的激活和 促炎分泌和募集，以及AD标志物如淀粉样β蛋白的升高。吸入 毒物和年龄相关的血脑屏障缺陷和相关后遗症显示血管细胞共同受累 黏附分子-1(VCAM-1)，其在脑血管内皮细胞上直接增加 暴露在WFS中。因此，我们假设WFS增加了衰老的病理性衰老结果- 循环环境中的相关分泌蛋白促进血脑屏障损害、神经炎症和 AD的发病机制主要是通过脑血管VCAM-1的表达/活性来实现的。为了测试这一点 假设，我们的团队提出了以下目标：1.评估WFS暴露诱导的和 与衰老相关的循环变化是血脑屏障损害、神经炎症和早期证据的驱动因素 淀粉样蛋白和tau蛋白病。由老化x WFS暴露引起的血清成分变化将是 对蛋白质、多肽和代谢物水平进行综合评估，并与体内组织病理学配对 神经和心血管衰老的主要特征的功能性体外表型。2.划定 脑血管内皮细胞受体CD36作为中间体在WFS诱导中的作用 神经炎。CD36显然参与了血脑屏障对吸入毒物的急性反应，并可能 血管细胞黏附分子-1上调，最近被认为是衰老相关神经功能的调节因子 后遗症。3.使用sirtuin-1激活剂从药物上减轻WFS暴露引起的加速衰老 (白藜芦醇)与NAD+助推剂(NMN)和/或抗衰老鸡尾酒一起使用，以减少与衰老相关的循环 各种因素。这些排列将针对暴露在靶区的WFS引起的循环变化的关键结果 细胞(血管、神经)可减少早期亲AD致病血脑屏障损害、神经炎症和 与蛋白质病相关的结局。总而言之，研究结果将详细说明WFS在与年龄相关的年龄增长中的影响 通过在循环中产生血管妥协和神经胶质刺激因子而致AD发病，以及 评估在不可避免地暴露于WFS后使用的中和疗法。

SUMMARY: Acceleration of Circulatory and Neurological Aging due to Wildfire Exposures Wildfires pose an increasing threat to a growing and aging global population, notably in the Western United States. Little is known about the influence of inhaled environmental pollutants, such as from wildfire smoke (WFS) exposure, on molecular pathways governing cerebrovascular and neurological aging in the etiology of Alzheimer’s disease (AD) and dementia. Yet, parallel molecular changes are induced by aging and inhaled toxicants within the blood, raising the potential for their negative interaction. This includes increased metalloproteinases, serpins and inflammatory factors that can directly promote age-related neurological pathologies. Moreover, our research documents how inhaled pollutants cause blood compositional changes, particularly as protease-induced peptides, that promote vascular dysfunction and neurological inflammation. Inhaled toxicant induced circulating factors promote blood-brain barrier (BBB) permeation, glial activation and pro-inflammatory secretion and recruitment, and elevation of AD markers such as amyloid beta. Inhaled toxicant and age-related BBB deficits and associated sequelae show common involvement for vascular cell adhesion molecule-1 (VCAM-1), which is directly increased on cerebrovascular endothelial cells following exposure to WFS. Thus, we hypothesize that WFS augments pathological aging outcomes of senescence- associated secretory proteins in the circulating milieu to advance BBB compromise, neuroinflammation, and prime AD pathogenesis principally through expression/activity of cerebrovascular VCAM-1. To test this hypothesis, our team proposes the following aims: 1. Assess interaction between WFS exposure-induced and aging-related circulatory changes as drivers of BBB impairment, neuroinflammation, and early evidence of amyloid and tau proteinopathy. Serum compositional changes caused by aging x WFS exposure will be comprehensively assessed at the protein, peptide and metabolite levels and paired with in vivo histopathology and functional ex vivo phenotyping of major hallmarks of neurological and cardiovascular aging. 2. Delineate the role of cerebrovascular endothelial receptors, namely CD36, as intermediates in WFS-induced neuroinflammation. CD36 is clearly involved in acute responses of the BBB to inhaled toxicants, and likely to upregulation of VCAM-1, which has been recently implicated as a mediator of aging-related neurological sequelae. 3. Pharmacologically attenuate accelerated aging from WFS exposure using a sirtuin-1 activator (resveratrol) with an NAD+ booster (NMN) and/or a senolytic cocktail to reduce aging-related circulating factors. These permutations will target the key outcomes of circulatory changes from WFS exposure in target cells (vascular, neural) to reduce early pro-AD pathogenic BBB compromise, neuroinflammation and proteinopathy related outcomes. Together, findings will detail the influence of WFS in advancing age-related AD pathogenesis by generating vascular-compromising and glial-stimulating factors in the circulation, and evaluate counteracting therapeutics for use following unavoidable WFS exposure.