Acceleration of Circulatory and Neurological Aging due to Wildfire Exposures

摘要：野火暴露导致的循环和神经老化加速 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。 States.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，对脑血管和神经系统衰老的病因学分子途径 阿尔茨海默病（AD）和痴呆。然而，平行的分子变化是由衰老和吸入引起的。 血液中的有毒物质，提高其负面相互作用的可能性。其中包括增加 金属蛋白酶，丝氨酸蛋白酶抑制剂和炎症因子，可以直接促进年龄相关的神经 病理学此外，我们的研究记录了吸入的污染物如何引起血液成分的变化， 特别是作为蛋白酶诱导的肽，其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）渗透、神经胶质细胞活化和神经胶质细胞增殖。 促炎分泌和募集，以及AD标志物如淀粉样蛋白β的升高。吸入 毒性和年龄相关的血脑屏障缺陷和相关后遗症显示血管细胞 粘附分子-1（VCAM-1），其在脑血管内皮细胞上直接增加， 暴露于WFS。因此，我们假设WFS会加剧衰老的病理性衰老结果- 相关的分泌蛋白在循环环境中促进BBB妥协，神经炎症， AD的主要发病机制主要通过脑血管VCAM-1的表达/活性。为了验证这一 假设，我们的团队提出了以下目标：1。评估WFS安全性诱导和 衰老相关的循环变化是BBB损伤、神经炎症和 淀粉样蛋白和tau蛋白病。老化x WFS暴露引起的血清成分变化将 在蛋白质、肽和代谢物水平上进行全面评估，并与体内组织病理学配对 以及神经和心血管老化的主要标志的功能性离体表型。2.划定 脑血管内皮受体，即CD 36，作为WFS诱导的脑血管内皮细胞凋亡的中间体， 神经炎症CD 36明显参与血脑屏障对吸入毒物的急性反应， VCAM-1的上调，其最近被认为是衰老相关神经系统的介导者。 后遗症3.使用sirtuin-1激活剂在药理学上减弱WFS暴露引起的加速老化 （白藜芦醇）与NAD+加强剂（NMN）和/或衰老清除鸡尾酒组合以减少衰老相关的循环 因素这些排列将针对目标人群中WFS暴露引起的循环变化的关键结局。 细胞（血管，神经），以减少早期促AD致病性BBB损害，神经炎症和 蛋白质病相关的结果。总之，研究结果将详细说明WFS在推进年龄相关的 通过在循环中产生血管损害和神经胶质刺激因子的AD发病机制，以及 评估在不可避免的WFS暴露后使用的抵消治疗剂。

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.