理解人类衰老和衰老相关疾病的基本细胞信号链接:在中年hypovascularity缺氧的假设
炒河粉j . Phua- 分子医学,新南威尔士健康病理学,约翰亨特医院、纽卡斯尔、新南威尔士、澳大利亚
体内缺氧、氧化应激和炎症病理生理学与人类与年龄相关的致癌作用和慢性疾病密切相关。然而,缺氧和激素的细胞信号通路之间的关系尚不清楚,但这种人类与年龄相关的共病疾病做配合性荷尔蒙信号下降的中年时期。这个范围审查评估相关的跨学科的证据评估函数的系统生物学,监管、和体内平衡,以识别和解读之间的联系的病因缺氧和荷尔蒙信号在人类与年龄相关的共病的疾病。假设图表的发展越来越多的证据支持一个缺氧的环境和氧化stress-inflammation病理生理学在中年人群,以及淀粉样变的感应,在体内自噬,epithelial-to-mesenchymal过渡变性。综上所述,这种新方法和策略可以提供清晰的概念和模式来确定下降的原因多血管血流动力学(血流)和生理氧化灌注(氧生物利用度)与氧气体内平衡和多血管导致缺氧(hypovascularity缺氧)。的中年hypovascularity缺氧假说可以提供机械接口连接内分泌,一氧化氮,和氧稳态信号,退行性肥大的进步条件密切相关,萎缩、纤维化和肿瘤。深入理解这些内在生物过程发展中中年缺氧可以为时间治疗提供潜在的新策略在维护健寿为健康的生活方式老化,医疗成本节约,卫生系统的可持续性。
介绍
体内缺氧、氧化应激和炎症病理生理学与人类与年龄相关的致癌作用和慢性疾病密切相关(Muz et al ., 2015;Gobel et al ., 2021;Mas-Bargues et al ., 2021;Bouhamida et al ., 2022;Gambini Stromsnes, 2022;Leyane et al ., 2022;魏et al ., 2022)。然而,缺氧和激素的细胞信号通路之间的联系还不清楚(杨et al ., 2018;Tran et al ., 2020;Jehanno et al ., 2022),但这样的人类与年龄相关的共病疾病做配合的中年时期下降性荷尔蒙信号(Horstman et al ., 2012;Diamanti-Kandarakis et al ., 2017;Khadilkar 2019)。之间的中年时期前的第五(40)和第七(60)十年的生活(Phua 2021)。Aged-related共病疾病(Franceschi et al ., 2018;Laconi et al ., 2020)是一个全球性的负担(Kocarnik et al ., 2022对未来的医疗体系的可持续性()和后果Soerjomataram布雷,2021)。在一项研究癌症相关的死亡在美国,90%的癌症确诊年龄群50年以上(西格尔et al ., 2022)。
当前的知识表明,人类的衰老相关疾病是复杂和异构。这个范围审查(穆恩et al ., 2018;Sargeant奥康纳,2019旨在评估相关交叉学科(格林沃尔德和邓恩,2009;冈村,2019;Cherbuin et al ., 2021)的证据,应计评估系统生物学(王et al ., 2018;巴蒂埃et al ., 2022;Zhang et al ., 2022)的功能、调节和体内平衡为了辨别和破译的病因缺氧和激素信号在人类之间的联系与年龄相关的共病的疾病。它需要一个描述性的方法来提供一系列的分段,以证据为基础的跨学科之间的功能交互模块构建hypovascularity缺氧的假说。
总之,这种新方法和策略(布伦南和大卫史密斯,2022年;Diokno 2022;Zhang et al ., 2022)可以提供清晰的概念和模式来确定下降的原因多血管血流动力学(血流)和生理氧化灌注(physoxia)与氧气体内平衡和血管,导致组织缺氧(hypovascularity缺氧)。
前列腺衰老退化假设假设这三睾酮,血管,和inflamm-aging结果的连接和血管内皮功能障碍和差别一氧化氮对这些炎症,导致与年龄相关的淀粉样变功能失调和自噬在进化的肿瘤发生微环境(Phua 2021)。早些时候作者的简短文本发现,发表在《药物MDPI,形式的基础讨论前列腺衰老退化,以及睾酮之间的串扰,血管,inflamm-aging, p53、细胞衰老、淀粉样变和自噬。
这个综合范围审查(穆恩et al ., 2018;Sargeant奥康纳,2020)将评估血管功能的重要性与前列腺的衰老退化假设(Phua 2021在打开生物衰老的秘密(Borras 2021)和non-mutagenic推动者的致癌作用(布伦南和大卫史密斯,2022年)。干扰细胞氧稳态和它们对人体的生理功能的影响(添头et al ., 2021),以及氧气传感,癌症(正在被抢劫Claesson-Welsh 2020),是相关的。
中年hypovascularity缺氧假说模式
基本单元信令链路
的中年hypovascularity缺氧假说可以为我们提供洞察连接各种细胞信号通路在创世纪了解缺氧的病因及其下游细胞病理生理效应。这些都是基于这三个至关重要的细胞信号发现可以解释的发展hypovascularity缺氧(图1):
1。内分泌信号:睾酮或雌激素替代疗法可以有效地扭转睾丸激素不足引起的睾丸切除术与尿道hypovascularity(老鼠的实验Yura呢et al ., 2020;Gerbie et al ., 2021),hypogonadal状态病人被发现有尿道hypovascularity (而莫雷,2018)。
2。一氧化氮信号:内皮功能障碍协会和一氧化氮信号在阿尔茨海默病的发病机制(艾哈迈德et al ., 2022)和雌激素减少,降低一氧化氮的生物利用度,导致淀粉样蛋白沉积,已经观察到(Cheboub et al ., 2019)。
3所示。氧气体内平衡:在研究老化,低氧反应的低氧诱导因子(HIF)在15%的氧气的环境缺氧6周与更高的血管分布和被认为是连续的,non-full-scale低氧诱导因子的激活途径,间接保护神经退化(Ollonen et al ., 2022)。当细胞正常的氧气水平,不断退化的低氧诱导因子(Jaakkola et al ., 2001;Berra et al ., 2003;我们和Sankaran, 2020通过氧感受通路)为了维持体内平衡氧(杨g . et al ., 2020;Claesson-Welsh 2020;廖,2020张;van Vliet et al ., 2021 a)。
图1。中年缺氧的假设。
各种aged-related慢性病,如代谢紊乱、心血管疾病、勃起功能障碍、认知、和癌症,与内分泌有关(Asih et al ., 2017;Diamanti-Kandarakis et al ., 2017;Foresta et al ., 2017;Cai和李,2020年;Cannarella et al ., 2021;大学运动员和刘,2021年;Leisegang et al ., 2021;国et al ., 2022;Mazzilli et al ., 2022;Romejko et al ., 2022)和一氧化氮信号(x射线检验,2018;Carlstrom 2021;利多et al ., 2021;明茨et al ., 2021;Pourbagher-Shahri et al ., 2021)。全身性微血管缺血性内皮功能障碍是一种常见的条件相关疾病的发病机理(Andersson et al ., 2017;Jalnapurkar et al ., 2021;Balistreri 2022)、缺氧(陈et al ., 2008;荣格et al ., 2016;陈et al ., 2022 a)和血管重建(元,Kevil, 2016年;Rajendran p . et al ., 2019;黄et al ., 2022)。失去微脉管系统(hypovascularity)意味着发展中慢性缺氧缺氧环境,提出一个重要的角色作为一个解释的渐进性质fibrosis-the慢性缺氧假说(罚款和诺曼,2008年)。缺氧是血管重建的主要原因之一(黄et al ., 2022),但还没有研究直接联系的发展hypovascularity缺氧(micro-vessel密度下降)(黄和佐丹奴,2008)。
生理氧化灌注
氧稳态及其主监管机构,低氧诱导因子,是组织原则对于理解后生动物的进化,本体,生理学和病理学(西门,2010)。老化是伴随着系统性的发展,逐渐增加hypoxia-related障碍,这是许多人类疾病的特点(圆顶礼帽和Ladomery, 2019;Dzhalilova Makarova, 2022;罗et al ., 2022)。慢性(连续,没有打扰,持续)和环(间歇和瞬态)缺氧,表现为波动的氧含量(巴德et al ., 2020),与人类疾病和癌症的发展(Saxena快活,2019;陈et al ., 2020;刘et al ., 2022)。慢性持续缺氧(CSH)似乎妥协肺循环和颈动脉体刺激维持氧含量,而慢性间歇性缺氧的影响(CIH)似乎更有针对性的体循环(Prieto-Lloret et al ., 2021)。
目前,实验细胞氧生物利用度水平,发现是混乱和缺乏清晰的文献。有许多出版物显示广泛的氧含量和应用:环境缺氧(15%啊2)(Ollonen et al ., 2022),non-physiological氧过多(21%啊2)(舒马赫et al ., 2022),normoxia /缺氧/氧过多的相对性(添头et al ., 2020;添头,2022)、间歇hyperoxia-hypoxia悖论(Hadanny Efrati, 2020),normobaric氧气悖论(Fratantonio et al ., 2021)、氧过多(100% O2)/缺氧(12%啊2)(hom et al ., 2022),normoxia O (> 8.5%2)(刘et al ., 2022)和“氧微量氧工厂”(王w . et al ., 2022)。这表明需要标准化的定义和理解的波动在活的有机体内在细胞生理过程和毒性氧生物利用度水平(Tessema et al ., 2021;阿尔瓦et al ., 2022;刘家Syafaah, 2022)。
因此,由于缺乏标准化的定义,缺氧反应的结果由“环境缺氧”的低氧诱导因子15%氧气6周在衰老小鼠研究模型中,伴随着更高的血管(Ollonen et al ., 2022在7%的氧气)和“生理缺氧”在实验室培养条件表现出增强的微脉管系统形成肾瀑样(舒马赫et al ., 2022),需要仔细的解释为“physoxia氧化灌注。”
本文侧重于实际的生理水平的氧暴露在正常的人体组织在活的有机体内(生物利用度)(阿尔瓦et al ., 2022)。一系列约3% -7.4%的氧气(physoxia)将允许氧生物利用度水平physoxia之间的比较(5%啊2),normoxia (20% O2O)和缺氧(1%2)(部,2014)。此外,的另一个术语physoxia physioxia (Adebayo Nakshatri, 2022;阿尔瓦et al ., 2022),这表明不同的关键信号网络表达自己在实验室癌细胞概括physio-pathological状态中在活的有机体内微环境(Kumar et al ., 2022)。
这是血流动力学(血流)微脉管系统(微血管/内皮)灌注网络(别哭et al ., 2019;施密德et al ., 2019;泰勒和Bordoni, 2022年),而不是血液中氧气的含量,是生理的主要驱动因素在活的有机体内组织氧灌注红细胞(份永久性et al ., 2020)。老化的微脉管系统(Kalaria哈泽,2019;格拉夫et al ., 2021)与hypovascularity灌注,影响血流动力学,氧化和血管重建,是引起人类疾病(Forsberg et al ., 2018;Moeini et al ., 2018;Dalby et al ., 2019;Santamaria et al ., 2020)。组织氧合血液流动的主要保证人(血流动力学)(雅各et al ., 2016),这将影响发展hypovascularity微血管构筑。
氮oxide-cyclic鸟苷酸pathway-vascular函数
的oxide-cyclic氮鸟嘌呤核苷3′,5′一磷酸(NO-cGMP)通路(Garmaroudi et al ., 2016;莫妮卡et al ., 2016;Carlstrom 2021维护和保持血管舒张(的)是中央沼泽和Hannemann, 2020),脉管系统(科斯塔et al ., 2021)和血管功能(Golshiri et al ., 2020),一氧化氮的生物利用度降低会导致内皮功能障碍(Munzel et al ., 2021;Boughaleb et al ., 2022)、血管收缩(银行et al ., 1994;Hannemann沼泽,2022)和缺氧(Reinero et al ., 2021;Gajecki et al ., 2022)。性激素,如睾丸激素,与NO-cGMP通路(Andric et al ., 2010睾酮),指示一个相互依存的关系(雄激素)和一氧化氮水平(Hotta et al ., 2019;Gur et al ., 2020;Zabbarova et al ., 2022),它可以与氧灌注生物利用度的波动(索尼和Padwad, 2017;Nascimento-Filho et al ., 2022)。内皮细胞是一个内分泌器官(斯坦内克et al ., 2018;Kruger-Genge et al ., 2019)在人类血管系统(乔杜里et al ., 2022),形成最大的微脉管系统内皮表面区域网络和充当看门人的血管功能(亨尼希et al ., 2021;硼和菲格罗亚,2022;豪et al ., 2022)微脉管系统移动通信(克莱格和Mac Gabhann, 2015年;reiter和布兰科,2020)。这样的微血管功能障碍(内皮功能障碍)是一种常见的病理生理改变,发生在各种各样的疾病,如2型糖尿病、心力衰竭、痴呆和抑郁症(胡本et al ., 2017;李w . et al ., 2020)。这提供了一个相互之间testosterone-vascular-inflammation-aging三合会(Phua 2021)和一氧化氮信号(x射线检验,2018;Carlstrom 2021;利多et al ., 2021;明茨et al ., 2021;Pourbagher-Shahri et al ., 2021)。
Testosterone-vascular-inflamm-aging三合会
testosterone-vascular-inflamm-aging三位一体(Phua 2021)的特点是睾丸激素水平下降与超过40岁(灰色et al ., 1991;Araujo Wittert, 2011)和睾丸激素调节NO-cGMP通路(Andric et al ., 2010;Hotta et al ., 2019;Gur et al ., 2020;Zabbarova et al ., 2022)。睾丸素不足是导致内皮功能障碍(Hotta et al ., 2019;男人味儿,2019;巴布科克et al ., 2022),减少peri-urethral多血管(hypovascularity) (而et al ., 2017),影响微血管充血(血流)(科里根et al ., 2015),减少一氧化氮产量(巴尔加斯et al ., 2007;熊et al ., 2020)。反过来,血管衰老是由内皮功能障碍(Donato et al ., 2018;Marchio et al ., 2019;Rizzoni et al ., 2019),导致降低外周血管(Crecelius et al ., 2010;海豹和亚历山大,2018;da Silva et al ., 2022),与一氧化氮减少生产(Vanhoutte et al ., 2017;Hotta et al ., 2019)。Inflamm-aging慢性氧化应激和炎症的病理生理学(Phua 2021)是血管老化的一部分(Guzik Touyz, 2017)和睾丸素不足(儿子et al ., 2016;Kataoka et al ., 2017;Rovira-Llopis et al ., 2017;巴布科克et al ., 2022)。
一氧化氮signaling-vasodilation /血管收缩physoxia血液动力学
健康组织功能、调节和体内平衡依赖于多血管血流动力学(微循环)。血管内皮和氮oxide-mediated信号控制血液微循环的规定(特et al ., 2019)。一氧化氮的生物利用度和表达式(Gantner et al ., 2020;Akseh et al ., 2021;Koukoulis et al ., 2022在信号转导)(Lundberg Weitzberg, 2022)通过NO-cGMP通路(Golshiri et al ., 2020)是一种重要的生物方面对一氧化氮信号(x射线检验,2018;Carlstrom 2021;利多et al ., 2021;明茨et al ., 2021;Pourbagher-Shahri et al ., 2021)和内源性一氧化氮gasotransmitter (杨et al ., 2016;Nowaczyk et al ., 2021)在癌症(Salihi et al ., 2022)、纤维化(陈et al ., 2021 b)和炎症(王l . et al ., 2022)。一氧化氮(NO)作为旁分泌血管舒张的中介(在2017年,小贩,重获自由),激活可溶性guanylyl环化酶(国网公司)在血管平滑肌细胞和生产环鸟苷酸(cGMP)。正是这种NO-sGC-cGMP信号通路启动血管平滑肌的松弛(血管扩张)和抑制血小板聚集在系统性和肺发行量(Vanhoutte et al ., 2017;沼泽和Hannemann, 2020)。在体循环,缺氧导致局部血管舒张,这已被证明是稳定带来的低氧factor-1α(HIF1α)和伴随upregulation内皮一氧化氮合酶(沼泽和Hannemann, 2020)。相比之下,生理反应在肺循环血管收缩(缺氧沼泽和Hannemann, 2020)。氮oxide-mediated激活环鸟苷酸(cGMP)信号抑制的低氧诱导肿瘤细胞的恶性表型(金正日et al ., 2020)。一氧化氮缺乏有关氧化应激和炎症的病理生理条件(Shefa et al ., 2017;Abdel-Zaher et al ., 2021;Bayarri et al ., 2021),这是类似于testosterone-vascular-inflamm-aging三合会(Phua 2021)。
基于这些事实,疗法,保持和维持一氧化氮的生物利用度和表达式(Gantner et al ., 2020;Akseh et al ., 2021;Koukoulis et al ., 2022)通过NO-mediated cGMP途径表明一氧化氮调制的氧传感(Berchner-Pfannschmidt et al ., 2007;希科克et al ., 2013)。一氧化氮信号捐赠者/增强剂治疗(安德森,2018;杨et al ., 2021 b;Lundberg Weitzberg, 2022)将提供血管扩张血液动力学和physoxia(生理)氧化药效学。相反,治疗将提供差别导致一氧化氮对这些血管收缩血液动力学和缺氧药效学。这种反对治疗药效治疗显示截然相反的生物效果和副作用。
一氧化氮在氧气传感:一个新的方法和策略
从今以后,调制一氧化氮的氧传感(Berchner-Pfannschmidt et al ., 2007;希科克et al ., 2013)是一种新的方法和策略来理解“physoxia”(生理)氧化(林et al ., 2019;Mas-Bargues et al ., 2019;Merkhan et al ., 2021;reiter et al ., 2022)灌注physoxia-NO-mediated rejuvenation-regeneration (Hachmo et al ., 2020;令Kamat et al ., 2021;金兰和琼斯,2021年通过血液脉管系统()罗德里格斯et al ., 2021)。生理氧浓度对培养是至关重要的干细胞用于组织工程和再生医学(Mas-Bargues et al ., 2019),它可以减少细胞因子分析检查参与组成分泌腺的人类间充质干细胞(Merkhan et al ., 2021)。氮oxide-mediated血管舒张血管的血流动力学(在2017年,小贩,重获自由;沼泽和Hannemann, 2020)将提供必要的physoxia氧化灌注细胞不断降低低氧诱导因子(Jaakkola et al ., 2001;Berra et al ., 2003;我们和Sankaran, 2020通过氧感受通路)为了维持体内平衡氧(杨g . et al ., 2020;Claesson-Welsh 2020;廖,2020张;van Vliet et al ., 2021 b)。因此,oxide-enhanced氧化氮等血流动力学机制(Dewhirst et al ., 2005;蜀et al ., 2015;亚当斯et al ., 2021;科斯塔et al ., 2021)可以被视为physoxia-NO-mediated减少低氧诱导的氧化应激和炎症。没有是宿主防御机制的重要组成部分和炎症部位发挥保护作用(岩田聪et al ., 2020)。
一氧化氮的生物利用度和表达的信号
雄激素可以调节慢性间歇性低氧对大脑的影响(斯奈德et al ., 2018)、与代谢、血管疾病、糖尿病和肥胖的参数(Groti Antoničet al ., 2020)和衰减低氧诱导高血压(江et al ., 2021)。睾丸素已被证明积极调节功能人工阴茎海绵体活动通过抑制磷酸二酯酶5型(PDE5)表达和cGMP的形成和一氧化氮(Gur et al ., 2020)。血清睾酮水平密切相关的内皮一氧化氮水平水平(Akseh et al ., 2021)。它还具有抗氧化剂(曼奇尼et al ., 2008;Popp来说马林et al ., 2010;Mendell说MacLusky, 2019;Koukoulis et al ., 2022)和抗炎(Aminuddin et al ., 2019;Zhang et al ., 2021 b;纳赛尔et al ., 2021;Rastrelli et al ., 2022)药效学性质。睾酮替代疗法用于预防2型糖尿病(海德尔et al ., 2020;Wittert et al ., 2021;易普Wittert, 2022),勃起功能障碍(Canguven et al ., 2016;Podlasek et al ., 2016),阴茎纤维化(Montorsi Oettel, 2005;Iacono et al ., 2012)和治疗下尿路症状(Ko et al ., 2013;亚辛et al ., 2014;冈田克也et al ., 2018)。
睾酮可以抑制PDE5的表达(Gur et al ., 2020)。PDE5 NO-sGC-cGMP-PDE5信号通路的一部分(Bajraktari et al ., 2017;Gur et al ., 2020),它的抑制与其余有关癌症治疗(Muniyan et al ., 2020),抵消糖尿病心脏动力学(Pofi et al ., 2022),改善心衰通过cGMP-dependent蛋白激酶(PKG)激活(朱et al ., 2022),和支持增加血液灌注氧化的脉管系统(朱利亚诺et al ., 2013)。PDE5抑制剂恢复一氧化氮(Kalsi et al ., 2005;李et al ., 2022)和选择性血管舒张药NO-cGMP信号通路(男婴et al ., 2019;艾哈迈德et al ., 2021)。PDE5抑制剂已被证明血管氧化(Morelli et al ., 2011;米歇尔et al ., 2015),防止ischemia-hypoxia (齐藤et al ., 2014;Zarifpour et al ., 2015;藤井裕久et al ., 2019),并减少微血管内皮功能障碍(Cellek et al ., 2014;Olmestig et al ., 2020;Statsenko Urologiia, 2021);他们还减少氧化应激(松尾et al ., 2020),炎症(Vignozzi et al ., 2013;Peixoto和戈麦斯,2015)、淀粉(康et al ., 2022)和前列腺重量(小林et al ., 2022)。
精氨酸/ L-citrulline (Shatanawi et al ., 2020;吴g . et al ., 2021;Bahadoran et al ., 2021;Wijnands et al ., 2021)和姜黄素(Santos-Parker et al ., 2017;Changal et al ., 2020;Alidadi et al ., 2021;李K.-X。et al ., 2022))是补充,增加一氧化氮产量通过各自L-arginine-nitric氧化途径(Fleszar et al ., 2019;Cziraki et al ., 2020;Bahadoran et al ., 2021)。增加一氧化氮的生物利用度改善血管内皮功能,这是对人体健康有益。
抗疗法
雄激素剥夺疗法(ADT)会引起副作用,如体重增加和情感变化,它会增加心血管疾病的风险,糖尿病和骨质疏松症(•麦乐伦et al ., 2023)。欧洲泌尿外科协会的指南建议不提供新辅助ADT前列腺癌患者手术前(•麦乐伦et al ., 2023)。ADT增加氧化应激的标记/炎症和血栓素A2 (TXA2)的血清水平与心血管风险相关(Alvarez-Maestro et al ., 2021)和内皮功能障碍(吉尔伯特et al ., 2013;销量et al ., 2022),类似于在睾丸素不足(Hotta et al ., 2019;男人味儿,2019;巴布科克et al ., 2022)。
抗疗法和差别意味着一氧化氮对这些已知导致减少血液动力学(Angrimani et al ., 2020;Yoon et al ., 2020)、微血管密度(hypovascularity) (Hochberg et al ., 2002;•多诺休et al ., 2005;哈瓦et al ., 2016;太阳et al ., 2018;Khera et al ., 2020)和炎症(塞勒et al ., 2012;Hoogland et al ., 2021;Nazha Bilen, 2021)。Finasteride-related抗治疗与高品位前列腺癌的风险增加(Scailteux et al ., 2019;胡锦涛等人。,2020年),勃起功能障碍(多数时候et al ., 2017),副作用的post-finasteride综合症(古普塔m . a . et al ., 2020;Diviccaro et al ., 2020;Traish 2020;豪厄尔et al ., 2021;Saengmearnuparp et al ., 2021)。此外,finasteride-related阴茎弯曲/纤维性海绵体炎与大多数药物不良反应报告(Schifano et al ., 2022),这种纤维性海绵体炎与低睾酮(民兵et al ., 2019),炎症(帕特尔et al ., 2020;Swislocki艾森伯格,2021)和白膜的纤维化(钟et al ., 2020;Segundo Glina, 2020)。
转化成像技术和视网膜微脉管系统
Hypovascularity (而莫雷,2018;Yura呢et al ., 2020;Gerbie et al ., 2021)是检测micro-vascularity,几何结构作为一个接口中心血液动力学、氧化和灌注交流(Secomb 2016;波洛克et al ., 2022)。目前,转化成像技术在审问的结构和功能状态微循环正在探索人类疾病的临床应用(Guerraty et al ., 2021)。有很多视网膜微血管结构和血流的研究显示血管老化(有一定的联系魏et al ., 2017;奥洛夫et al ., 2019;阿诺德)et al ., 2022;Gomez-Sanchez et al ., 2022)、性激素(Nuzzi et al ., 2018;冯et al ., 2021;身处et al ., 2022),慢性疾病如神经退化/糖尿病性视网膜病变(品牌et al ., 2022)、冠状动脉疾病(钟et al ., 2022)、2型糖尿病(金正日h . et al ., 2022)和高血压(曾庆红等人。,2022年)。视网膜微脉管系统的结构也对氧的可用性(hom et al ., 2022),减少老龄化> 50年(阿拜et al ., 2022),和抗5α-reductase抑制剂(Shin et al ., 2020)。
讨论
中年hypovascularity缺氧假说:循环/慢性缺氧环境
的中年hypovascularity缺氧的后果假说认为,中年伴随性激素下降(男人更年期绝经期)和一氧化氮信号(Phua 2021)导致的持续损失多血管,血流动力学变化,增加循环/慢性低氧环境(罚款和诺曼,2008年)(图1)。
亏损micro-vascularity (而莫雷,2018;Gerbie et al ., 2021)意味着一个重要的角色为循环/慢性低氧环境(罚款和诺曼,2008年使地区化灌注和导致人类老年性退行性疾病的共病的进展。与年龄相关的性激素下降(男人更年期/更年期)是由没有氧气传感(Berchner-Pfannschmidt et al ., 2007;希科克et al ., 2013),造成缺氧应激条件和失调的淀粉样变性的细胞生物学(Cheboub et al ., 2019;艾哈迈德et al ., 2022),由自噬中和(壮族et al ., 2018;小王和勒,2019年;王、张,2019年),连同epithelial-to-mesenchymal过渡(EMT) (伯恩et al ., 2016;金即et al ., 2022;Ribatti 2022;穆罕默德et al ., 2023)。区域性限制氧灌注是一个循环/慢性缺氧环境,可能导致退行性疾病如肥大、萎缩、纤维化和肿瘤由于发展中局部缺氧(图1)。这样的例子可以看到一系列缺氧退行性疾病在急性高海拔缺氧(低比重的缺氧)器官肥大(佩纳et al ., 2022)和组织水肿(Mesentier-Louro et al ., 2021)。其他包括雄激素剥夺疗法促进epithelial-mesenchymal过渡(伯恩et al ., 2016),癌症相关的成纤维细胞(金即et al ., 2022)和前列腺癌进展转移(穆罕默德et al ., 2023)。
氮oxide-mediated hypovascularity: hypoxia-dependent流程
前列腺癌形成的主流叙事进程通常是由一个androgen-dependent过程(Aurilio et al ., 2020)。然而,hypovascularity缺氧假说,积累了以证据为基础的模式,展示了一个“androgen-induced氮oxide-mediated hypovascularity hypoxia-dependent过程。“雄性激素(荷尔蒙)和缺氧信号通路是单独和独立(Tran et al ., 2020)。一氧化氮(降低et al ., 2021通过cGMP) (Friebe et al ., 2020)提供的基本链接各种NO-sGC-cGMP (Vanhoutte et al ., 2017;沼泽和Hannemann, 2020)和NO-sGC-cGMP-PDE5 (Bajraktari et al ., 2017;Gur et al ., 2020)细胞信号通路影响NO-mediated氧传感(Berchner-Pfannschmidt et al ., 2007;希科克et al ., 2013),影响血管、血流动力学和氧合灌注(Amdahl et al ., 2019;Kapil et al ., 2020)(图2)。
图2。与年龄相关的链接。
成人前列腺展示了非凡的再生能力在多个周期的阉割和雄激素管理局,表明存在androgen-independent上皮祖在良性前列腺增生和前列腺癌(约瑟夫et al ., 2021)。雄激素和雌激素受体已被证明与HIF / NF-kB信号在前列腺癌(Russo et al ., 2016)和缺氧增加雄激素受体的活动(公园et al ., 2006low-androgen环境(内)Mitani et al ., 2011)。更高的侵略性前列腺癌与睾丸素不足(Neuzillet et al ., 2019),hormone-naive前列腺癌的进展与低血管血管的数量(Smentoch et al ., 2019)。在一个案例研究中,出色的微血管成像(SMI)确定贫穷内部血流在前列腺间质肉瘤(大桥et al ., 2022)。
血管老化hypovascularity利基市场
氧气在细胞内稳态中发挥着关键作用,各器官和生理氧含量范围在2%和9%之间在活的有机体内肾脏,水平最高的9%和最低的0.5%的部分大脑的(Adebayo Nakshatri, 2022)。Hypovascularity (Yura呢et al ., 2020;Gerbie et al ., 2021),降低微血管密度(Querfeld et al ., 2020),部分保留老化微脉管系统(林et al ., 2019)减少的证据多血管、血流动力学灌注和生理氧化。血管老化,表现为血管壁的结构和功能的改变,是一种老化的标志(肖利et al ., 2014;徐et al ., 2017;Gkaliagkousi et al ., 2022)和血管内皮细胞可以重塑他们的微环境,形成一个“利基”(Lei et al ., 2022)。降低血管内皮细胞密度和子集的老化动力学发生在内分泌系统(J。陈et al ., 2021)。在衰老小鼠模型,研究人员利用超分辨率超声定位显微镜(乌尔姆),发现显著降低血液流速、显著提高血管弯曲度在所有年龄群体大脑区域(Lowerison et al ., 2022)。
这样的亲密血管老化的关系中形成inter-transient临床前(Krishnan et al ., 2018;尤尼斯et al ., 2019;Adebayo Nakshatri, 2022)在physoxia regeneration-hypoxia变性和自适应(Pomatto et al ., 2019 a;Pomatto et al ., 2019 b)病理(Lasne et al ., 2006;Gilmore et al ., 2021体内平衡,时间(明et al ., 2013;伯恩et al ., 2016;Rouverdo et al ., 2023)。的双重动态观察CIH和CSH (沼泽和Hannemann, 2020;Prieto-Lloret et al ., 2021)形式集成(当地)和扩展(地区)这两个操作模式通过后退微脉管系统网络之间的交互区域内循环/慢性缺氧环境组织、腺体和器官利基(南城et al ., 2019;Jambusaria et al ., 2020;Gifre-Renom et al ., 2022;徐et al ., 2022)(图3)。
图3。双重活力CIH-CSH。
受损组织氧输送器官损伤和失败的主要原因是在危重患者中,即使系统参数,包括心输出量和动脉血红蛋白饱和度,接近正常(罗伊和Secomb, 2021)。评估微血管功能的器官系统,因此,至关重要的(Ku et al ., 2021;徐c . et al ., 2022)。中位数在骨骼肌微血管密度降低了29%,24%的心在慢性肾脏疾病的动物模型和人类活检32%,解剖和成像研究(Querfeld et al ., 2020)。这样一个发展循环/慢性缺氧环境提供了慢性病理轨迹在类风湿性关节炎(Fearon et al ., 2016;寂et al ., 2022)、心血管(李et al ., 2020 b;戈蓝et al ., 2021;Cornuault et al ., 2022)、糖尿病(怀特里,郑2021)障碍。
缺氧病理微环境领域
早些时候inter-transient临床期多血管CIH-systemic循环(沼泽和Hannemann, 2020;Prieto-Lloret et al ., 2021)可以充分应对physoxia regeneration-rejuvenation (Hachmo et al ., 2020;令Kamat et al ., 2021;金兰和琼斯,2021年)。然而,局部循环/间歇性缺氧(CIH)在一个区域是一个有效的促炎的刺激在人类疾病(Schaefer et al ., 2017;威尔逊et al ., 2018;Korbecki et al ., 2021)。因此,推进建立晚期功能失调的脉管系统通过血管重建(后退)(Ouarne et al ., 2021;艾哈迈德et al ., 2022;Ollonen et al ., 2022),它将扩展“CSH肺循环妥协”地区(沼泽和Hannemann, 2020;Prieto-Lloret et al ., 2021)到一个集成、开发、本地化CSH自我hypovascularity循环/慢性缺氧病理微环境利基(Carnero Lleonart, 2016;Macharia et al ., 2021;傅强恩et al ., 2022)(图3)。
,与年龄相关的疾病的病理过程与缺氧有关越来越被认可在慢性肝病(Wan et al ., 2022),慢性肾脏疾病(王b . et al ., 2022),低尿路symptoms-diabetes (阿伯勒和Vezina, 2018)、慢性前列腺疾病(Luisetto et al ., 2019)和前列腺癌形成(深,Panigrahia, 2015年;阿什顿和布里斯托,2020年;穆罕默德et al ., 2023)。循环/间歇性缺氧(CIH)诱发复制灾难,导致增加的活动APOBEC3B (巴德et al ., 2021)。缺氧导致基因组不稳定性通过突变频率的增加和增强复制压力,抑制DNA修复(马纳尔哈桑et al ., 2020;卡普兰和格雷泽,2020年;Saitoh Oda, 2021)。肿瘤是体细胞发生和发展进化过程受基因改变的积累(Lahouel et al ., 2020;查希尔et al ., 2020),定时分析表明,驱动突变往往先于诊断(临床)多年,如果不是几十年(Gerstung et al ., 2020)。
窗口的细胞regeneration-rejuvenation:机会和时间的假设
综上所述,关键inter-transient临床前阶段(疾病或癌症)physoxia-NO-mediated血流动力学(林et al ., 2019;Mas-Bargues et al ., 2019;Merkhan et al ., 2021;reiter et al ., 2022)细胞regeneration-rejuvenation窗口(Hachmo et al ., 2020;令Kamat et al ., 2021;金兰和琼斯,2021年)可以与机会和时间相关的假说(图3)。机会之窗和时机假说是激素疗法的关键时机发起对年龄和/或更年期(和男人更年期)过渡,和优化效果明显,早期启动(真希,2013;Speth et al ., 2018)。
当前观测数据表明,绝经期/荷尔蒙替代疗法(MPT /荷尔蒙替代疗法)降低全因死亡率(akt et al ., 2022;布卢姆,2022;hodi和麦克,2022;2022年北美更年期学会),降低老年痴呆症的风险在女性抑郁症患者(金T.-Y。et al ., 2022)),降低患乳腺癌的风险(韩国)(门敏et al ., 2022),减少COVID-19死亡(Sund et al ., 2022)。睾酮替代疗法(TRT)建议迟发性性功能减退的老年男性超过65岁(Nieschlag 2020;Burte et al ., 2021),但这仍然是一个争议的话题(Diokno 2022;面et al ., 2022)。无论睾丸激素水平,大部分迟发性性功能减退症状已被证明不相关(李et al ., 2020 c;石川et al ., 2020;La Vignera et al ., 2020;鹤et al ., 2022)。
发现睾丸激素疗法的随机临床试验显示,它不影响下尿路症状,但它确实改善与良性前列腺增生的前列腺炎对男性的标志(Rastrelli et al ., 2022)。这可以反映CIH之间的双重活力和CSH模式(沼泽和Hannemann, 2020;Prieto-Lloret et al ., 2021),睾丸激素治疗无效的下尿路症状已经建立缺氧病理症状本地化CSH利基。相反,部分保留老化微脉管系统仍将提供pro-vasculogenic CIH系统性作用(林et al ., 2019)的睾丸激素疗法改善与良性前列腺增生的前列腺炎对男性的标志(Rastrelli et al ., 2022)(图3)。
Epithelial-mesenchymal过渡
EMT包含从epithelial-to-mesenchymal表型细胞组织中的动态变化,从而导致功能变化在细胞迁移和入侵,在各种不同的生理和病理条件(杨j . et al ., 2020)。这些变化发生在胚胎发生1型(EMT),伤口愈合,组织再生,纤维化(2型EMT)和癌症,他们具备干细胞有助于细胞(可塑性),耐药性,免疫逃避和转移(类型3 EMT) (Manfioletti费德勒正在,2022)。EMT可以视为一段bet-hedging-evolutionary细胞适应(欢乐的et al ., 2018;Capp和托马斯,2022年;Jain et al ., 2022),分散间质表型(癌症具备干细胞)和增加他们的生存(Mortezaee Majidpoor, 2022)改变低氧诱导病理生理学(李et al ., 2020;Papale et al ., 2020;Nushtaeva et al ., 2023;Zhang et al ., 2023)。
缺氧促进前列腺癌的侵犯上调表达的EMT活化剂Zeb1和SK3通道(贝里et al ., 2020)。HIF-α促进癌症相关的成纤维细胞的迁移和入侵mir - 210 (杨问:et al ., 2021)。EMT监管者扭曲、蛞蝓和蜗牛与前列腺癌预后差(Børretzen et al ., 2021)和转换增长factor-β1 (TGF-β1)与自噬诱导细胞因子在肿瘤微环境(耶拿et al ., 2022)。
转基因小鼠实验模型与浓缩的鲁米那祖细胞前列腺炎症,良性前列腺肥大、前列腺癌和内在阉割的宽容这些细胞在抗雄激素剥夺疗法建议在致癌作用(鲍尔et al ., 2022)。基因组分析良性前列腺增生引起细胞re-landscaping疾病发病机理(米德尔顿et al ., 2019),5股alpha还原酶抑制剂(抗)诱导前列腺腔的俱乐部在人类细胞过渡良性前列腺增生(约瑟夫et al ., 2022)。
Mesenchymal-to-epithelial过渡
EMT mesenchymal-to-epithelial逆转的过渡(了)(杨j . et al ., 2020;Manfioletti费德勒正在,2022),2型EMT可同义,reparative-associated纤维化过程在慢性炎症反应(马可尼et al ., 2021)。首席候选人EMT逆转(再生/复兴)将及时改善缺氧(Lopez-Novoa和分担2009;李et al ., 2020;Papale et al ., 2020;Nushtaeva et al ., 2023;Zhang et al ., 2023)建立dysregulation-degeneration缺氧细胞生物学(Phua 2021;金兰和琼斯,2021年)和细胞衰老(结果和Giaccia, 2011;Barabutis et al ., 2018;Lacroix et al ., 2020;Otero-Albiol Carnero, 2021)。在一篇评论文章中,新方法通过调制减轻缺氧血管状态的肿瘤微环境提供承诺卵巢癌免疫治疗策略(Klemba et al ., 2020)。因此,EMT的逆转也可以联系会见关键inter-transient临床前(疾病或癌症)一段时间(明et al ., 2013;伯恩et al ., 2016;Rouverdo et al ., 2023)physoxia-NO-mediated血液动力学(林et al ., 2019;Mas-Bargues et al ., 2019;Merkhan et al ., 2021;reiter et al ., 2022)细胞regeneration-rejuvenation窗口(Hachmo et al ., 2020;令Kamat et al ., 2021;金兰和琼斯,2021年)和机会之窗和时机假说(真希,2013;Speth et al ., 2018)。
在体外再生医学实验可以提供证据支持的有利的好处physoxia / physioxia氧化(Yttersian Sletta et al ., 2017;丹尼斯et al ., 2020;多尔蒂et al ., 2020;多根et al ., 2022),生长因子(王et al ., 2007;Zhang et al ., 2021 a;Kataoka et al ., 2022),雄性激素(Bui et al ., 2017;尼奎斯特et al ., 2019),减少炎症(谢泼德et al ., 2022)和增强型微脉管系统(舒马赫et al ., 2022)。重组造血血管老化利基阻碍再生,促进纤维化(陈et al ., 2021 c在血管组织重塑wall-associated) (克雷格et al ., 2022),它也扮演了一定的角色在该协会在心肌炎的心脏成纤维细胞和内皮细胞(宣et al ., 2022)。
细胞senescence-autophagy
细胞衰老期间持续老化和促进与年龄相关的疾病通过炎性senescence-associated分泌表型(SASP) (Covarrubias et al ., 2020;van Vliet et al ., 2021 b),它的表达依赖于氧化水平(van Vliet et al ., 2021 b)。与年龄相关的细胞衰老病态的当代方面也可以geroscience透视图中的串扰的一部分的描述SASP“remodeling-associated分泌表型”(宝石和克恩,2022年)、血管老化机制(Ungvari et al ., 2020),内分泌疾病和衰老的作用科斯拉et al ., 2020)。
野生型p53的早期保护作用在抑制炎症和癌症是密切相关的重要的细胞活动的调控衰老的细胞周期和细胞凋亡(Barabutis et al ., 2018;Agupitan et al ., 2020;Lacroix et al ., 2020)。TP53基因的错义突变被发现最常在所有癌症类型和产生突变型p53蛋白失去肿瘤抑制的活动(多亏尤文和et al ., 2019;Sabapathy巷,2019;斯坦et al ., 2019)。
细胞衰老是一种专门的逮捕和增长起着至关重要的作用在肿瘤抑制和衰老,衰老过程中自噬被激活(杨et al ., 2012;Rajendran s . et al ., 2019;Tabibzadeh 2023)。氧浓度可以调节细胞衰老和自噬人滋养层细胞(Seno et al ., 2018)。
自噬在早期肿瘤抑制中发挥作用的细胞调控通路的失调在后期阶段,他们作为肿瘤促进剂(嫁妆et al ., 2018;Alvarez-Meythaler et al ., 2020;李h . et al ., 2020;Lim和没吃,2020)。受损的自噬容易使人衰老相关疾病,而干预刺激通常自噬促进长寿(Leidal et al ., 2018;Condello et al ., 2019;罗和秦,2019年;黄et al ., 2020)。
阴茎康复氧化
事实上,这种“physoxia-mediated”(氧化)血流动力学用于早期前列腺切除术后阴茎的康复治疗效果(Marcu et al ., 2020;Osadchiy et al ., 2020;尼科莱et al ., 2021)。常规的勃起(Montorsi Oettel, 2005)是用于提高氧化和血流动力学(减少缺氧和炎症)(Welliver et al ., 2014;Hadanny et al ., 2018;森et al ., 2020)和保护内皮结构使用PDE5抑制剂(Elkamshoushi et al ., 2021)防止阴茎纤维化(El-Sakka亚辛,2010;Kaminsky et al ., 2011)。长期睾酮疗法改善长期的阴茎动脉血液循环,阴茎的长度和周长、勃起功能,夜间阴茎肿胀和持续时间(Canguven et al ., 2016)。电刺激阴茎勃起在小鼠体内诱导血管生成,细胞生存、增殖和抗纤维化信号通路(Kwon et al ., 2016)。
Hypoxia-related致癌作用和慢性疾病
氧化应激和炎症都是由缺氧(Biddlestone et al ., 2015;McGarry et al ., 2018;Korbecki et al ., 2021;Mesentier-Louro et al ., 2021),这可以解释为什么氧化疗法无法恢复细胞氧化还原内稳态(添头et al ., 2021)。内皮细胞功能和生物学障碍(Charreau 2022)是一种新兴的方法来理解微血管内皮细胞的异质性和炎症(杨et al ., 2021 c;罗西et al ., 2022)。内皮功能受损是导致心血管疾病的风险增加(克雷格亥et al ., 2020)、血管老化与动脉粥样硬化相关的缺血性中风(Koutsaliaris et al ., 2022),氧化stress-inflammation在慢性肾脏疾病(艾伯特et al ., 2021)。老化与慢性低度炎症、癌症发病率和死亡率(Guerville et al ., 2022),一个生理过程由许多生物和遗传途径,这是所有的动力与年龄相关的疾病(李et al ., 2021)。癌症的上下文中经常出现一个改变组织微环境景观(Laconi et al ., 2021)。
缺氧引起的病理生理学的氧化stress-inflammation是应对人类暴露于急性高空缺氧(Malacrida et al ., 2019;Mrakic-Sposta et al ., 2022;范教授et al ., 2022)。大自然的适应性反应,一氧化氮强调一氧化氮的血管舒张作用的重要性在本地居民生活在高海拔缺氧环境(漆et al ., 2021;詹姆斯et al ., 2022)。东非高地人基因相似,阿姆哈拉部落,平衡最低限度血红蛋白升高常环境缺氧,而奥罗莫人部落主要依赖于血红蛋白升高响应(畅et al ., 2017;Getu 2022)。从高地地区新生儿骆驼有一个减少急性缺氧引起肺血管收缩反应增强的途径(雷耶斯et al ., 2018)。有一个17β-estradiol受体和一氧化氮信号之间的联系,增强高海拔适应的攀登者高地人(Pooja et al ., 2021)。死亡率降低心血管疾病、糖尿病和癌症被认为在本地高地居民(Thiersch斯文森,2018;漫步et al ., 2020;Burtscher et al ., 2021)。
缺氧中扮演着一个关键的角色在形成癌症的基因和进化景观(班达里et al ., 2020;张x et al ., 2020),多方面的相互作用激素,生长因子,在肿瘤缺氧微环境环境(Lappano et al ., 2022),包括低氧诱导因子(Satija et al ., 2021;塞巴斯蒂et al ., 2021)和转化生长因子(TGF-β)在缺氧,产生慢性炎性设置(Mortezaee Majidpoor, 2022)。雄激素缺乏/不足引起激烈的内皮功能障碍,导致血流量减少(缺血/ hypovascularity)前列腺(Angrimani et al ., 2020;金曹和巴西,2020年;Yoon et al ., 2020),导致一个ischemia-hypoxia压力组织微环境(瑟蒙德et al ., 2015;伯恩et al ., 2016)。缺氧应激引起的感应amyloidosis-autophagy-EMT细胞信号交互,开始与淀粉样变(Cheboub et al ., 2019;Phua 2021),允许细胞进入休眠/静止期(Audas et al ., 2016;Mizejewski 2017;Pavliukeviciene et al ., 2019)。老年性amyloidoses (鲁贝尔et al ., 2020;Tasaki et al ., 2021)也越来越多的被讨论的主流文学,包括一系列的器官:大脑/阿尔茨海默氏症(谢伊et al ., 2019;Schweighauser et al ., 2022)、肾淀粉样变(古普塔n . et al ., 2020;埃雷拉,2021;和李,2022年),眼睛/阿尔茨海默病视网膜病变(Mirzaei et al ., 2020),2型糖尿病/阿尔茨海默氏症(王Westermark, 2021)和心脏淀粉样变(Garcia-Pavia et al ., 2021;Hanselmann et al ., 2022)。
反过来,淀粉样蛋白聚集的自噬和泛素蛋白酶体系统(壮族et al ., 2018;小王和勒,2019年;王、张,2019年)。的可用性在缺氧诱导因子和炎症病理生理状态主要是调节你通过泛素蛋白酶体系统(自噬)(Gunter et al ., 2017;科恩et al ., 2019)。低氧诱导因子激活细胞适应减少氧生物利用度(艾博年et al ., 2020;副大臣,2020),随机波动的氧气,会选择bet-hedging (Warburg)表型(EMT) (Gravenmier et al ., 2018)。缺氧的条件下,大多数真核细胞可以从氧化磷酸化改变他们的主要代谢策略增加有氧糖酵解,称为Warburg效应(Elzakra和金,2021年;基兰和泰勒,2021年)。
缺氧在慢性肾脏疾病(副检察官et al ., 2021;王b . et al ., 2022)已经被研究和使用来突出了中年(> 50年)(Ryu et al ., 2019)hypovascularity (罚款和诺曼,2008年;埃文斯et al ., 2020;Querfeld et al ., 2020)缺氧(副检察官et al ., 2021;王l . et al ., 2022)病理轨迹连接内分泌系统(赵和教育,2020年;李l . et al ., 2022;Romejko et al ., 2022)、一氧化氮信号和氧稳态病理生理学(Burmakin et al ., 2021;Carlstrom 2021;徐m . et al ., 2022;爱德华兹和Kurtcuoglu, 2022年)。氧化stress-inflammation病理生理学(艾伯特et al ., 2021)、淀粉样变(Ryu et al ., 2019;埃雷拉,2021;和李,2022年),自噬(唐et al ., 2020),EMT (陈et al ., 2022 b)将导致退行性肥大、纤维化萎缩和肿瘤(Ryu et al ., 2019;平托et al ., 2021)并存状况(查尔斯和费里斯,2020年)。此外,PDE5抑制剂可以通过改善血液动力学有有益的肾保护作用,减少氧化应激和炎症(皮质et al ., 2020;Coskuner Ozkan, 2021)。
中年性hormone-endogenous oxide-mediated氮氧体内平衡
维护细胞氧体内平衡和减少血流动力学差别在氧化性hormone-nitric对这些由于hypovascularity是关键的生理挑战在中年(Kumar和崔2015;Gravenmier et al ., 2018;Janaszak-Jasiecka et al ., 2021;国et al ., 2022;徐c . et al ., 2022)。当“physoxia”氧气交付是由微血管hypovascularity中断(ischemia-hypoxia),它触发内在适应性的生物过程促进异构hypoxia-degenerative细胞生存环境(Feil et al ., 2022;威克斯,西门2022;杨et al ., 2022)。这表明一个关键时刻的时间当这个窗口的“细胞regeneration-rejuvenation-timing”可能在含氧量恢复正常“physoxia”条件(多根et al ., 2021,2022年;Merkhan et al ., 2021)。
早期干预的目的是为了防止生理缺氧(缺氧)与衰老相关(罚款和诺曼,2008年;Kumar和崔2015;Claesson-Welsh 2020;魏et al ., 2022)。雄激素可能具有预防与年龄相关的损害ischemia-induced新血管形成(林et al ., 2019;Gerbie et al ., 2021),可以不断提供血流动力学physoxia氧化法在低氧诱导分子降解通过氧感受通路(Jaakkola et al ., 2001;Berra et al ., 2003;Strowitzki et al ., 2019;我们和Sankaran, 2020)。
人类一氧化氮产量随着年龄降低,失去了40岁和85% 50% 65岁(格哈德et al ., 1996;塔代伊et al ., 2001)。这个临床前时期恰逢一氧化氮在所有慢性疾病的科学与受影响的器官血流量减少,导致增加炎症,氧化应激和免疫功能紊乱(布莱恩et al ., 2023)。缺乏一氧化氮的生物利用度在绝经后的妇女是有据可查(Novensa et al ., 2011;弗戴迪et al ., 2018;Somani et al ., 2019),和更年期激素替代疗法(MPT /荷尔蒙替代疗法)可以替代一氧化氮(最好的et al ., 1998;Cicinelli et al ., 1999;Bednarek-Tupikowska et al ., 2008)。雌激素替代疗法已被证明,以减少氧化应激(Bellanti et al ., 2013;unf et al ., 2015;Borras et al ., 2021),减少氧化应激和炎症(Vural et al ., 2006;Georgiadou Sbarouni, 2009;Jee et al ., 2021;Estrada-Cruz et al ., 2022),改善血液动力学(Redberg et al ., 2000;光et al ., 2001;Deschenes et al ., 2010)。类似地,睾酮替代疗法可以减少氧化应激(曼奇尼et al ., 2008;Popp来说马林et al ., 2010;Mendell说MacLusky, 2019;Koukoulis et al ., 2022)和炎症(比安奇,2019;穆罕默德et al ., 2019;Rastrelli et al ., 2019)和改善血液动力学(Efesoy et al ., 2018;康尼锡et al ., 2019;Cipriani et al ., 2021)。这表明性激素可以减少低氧诱导氧化应激和炎症细胞再生的关键窗口期间,复兴,并通过physoxia-NO-mediated血流动力学氧化时间周期。在癌症中,专注于两个专业(两相的)假设一氧化氮已确定,促进一氧化氮水平低是癌症,而高水平的一氧化氮是预防癌症索尼et al ., 2020)。
中年组的并发症(35-59年)缺血性心脏病的那么严重比年龄较大组(60 - 69年)(周et al ., 2022),与第一个慢性病发展50或60年代(朱et al ., 2018)。数据分析显示,减少心血管疾病和年龄为60岁以下的女性乳腺癌在激素替代疗法,在妇女健康倡议试验(兰格,2017;Lobo 2017;El Khoudary et al ., 2020)。女性BRCA1和BRCA2突变携带者,45岁以下接受降低输卵管卵巢切除术和激素替代治疗并不影响他们的乳腺癌发病率(Michaelson-Cohen et al ., 2021)。此外,绝经前女性更好的防止心脏肥大(吴et al ., 2020)。睡眠质量和皮质的积累amyloid-β有关从二氧化钛在绝经后妇女雌激素预防早期研究(Zeydan et al ., 2021)和长期临床前(约。阿尔茨海默病症状出现前10 - 15年)(尤尼斯et al ., 2019;Elman et al ., 2020;Elman-Shina Efrati, 2022)。
前列腺癌发病率是罕见的50岁以下,增加1 52 59岁和超过1 2 65岁或以上(罗萨里奥和罗萨里奥,2022)。更高的睾酮水平与小前列腺大小(夏et al ., 2021),年轻睾酮替代疗法导致前列腺稳定(张问:et al ., 2020)。在前列腺癌患者中,低血清睾酮被发现与雄激素受体表达(Schatzl et al ., 2002;侯赛因et al ., 2016;冯,他,2019年;Hashmi et al ., 2019)。
一氧化氮的生理状况和nitrate-nitrite-nitric氧化途径
一氧化氮是一种强有力的血管扩张性和抗炎信号分子,扮演着不同的角色在维持血管内稳态(Cyr et al ., 2020)、生物功能(Gantner et al ., 2020在致癌作用),(明茨et al ., 2021)。这个新战略,作为physoxia-NO-mediated机制,允许一个因果关系(Kiani et al ., 2022)后被理解性与非规范差别hormone-nitric氧化物对这些通路体内一氧化氮合成,称为nitrate-nitrite-nitric氧化途径(Kapil et al ., 2020;明茨et al ., 2021)。
结果符合观测报告链接饮食一氧化氮的来源与地中海饮食有益健康结果相关(Martinez-Gonzalez et al ., 2015;香农et al ., 2021)、膳食亚精胺(吴et al ., 2022),和长寿(健寿)蓝区人群(Vasto et al ., 2014;Nieddu et al ., 2020)。地中海饮食增加血清一氧化氮(香农et al ., 2018;Mohajeri和西塞罗,2023年),改善内皮功能(香农et al ., 2020;法蒂玛et al ., 2023),抗氧化剂(Gantenbein Kanaka-Gantenbein, 2021;Karbasi et al ., 2023),是抗炎(Tsigalou et al ., 2020;苏打et al ., 2021)。甜菜根汁硝酸作为膳食补充改善外周血流,内皮功能,抗炎在个人地位与雷诺氏现象(牧羊人et al ., 2019)。
结论
这两种学说前列腺衰老变性(Phua 2021)和中年hypovascularity hypoxia-provide赠送的证据的重要性,时间维护血管功能和血管的血流动力学,分别。
在孟德尔随机化分析研究中,表观遗传的证据表明更年期加速老化的血(莱文et al ., 2016)。缺氧是癌症的共同特征之一(廖et al ., 2023),hypovascularity缺氧早期缺氧环境成因的假说提供了证据在中年氮oxide-mediated血管老化。癌症缺氧是癌症的最重要的标志之一;它会影响基因表达、代谢,最终,肿瘤生物学过程(塞巴斯蒂et al ., 2021)。总之,这个范围检查可以提供清晰的概念和模式来确定衰老机制由于氮oxide-mediated hypovascularity缺氧发展影响的下游早期和晚期阶段的系统生物学功能,调节和体内平衡(图4)。
图4。衰老的机制。
一氧化氮是必要的维护和维持生理氧化过程中细胞的关键窗口regeneration-rejuvenation和激素治疗的时机假说。睾酮的生理浓度显著增加一氧化氮生产(Campelo et al ., 2012睾丸激素水平),基线预测身体成分和代谢反应泰爱泰党(迪et al ., 2022)和支持泰爱泰党在新诊断男性的前列腺安全与性腺机能减退(Debruyne et al ., 2017)。
一个数据驱动生成模型显示一种机械的解释为什么选择健身优势(bet-hedging)引入了特定驱动基因在肿瘤发生tissue-dependent时间表(Lahouel et al ., 2020)。Hypovascularity缺氧构成的机械接口自我Hypovascularity循环/慢性缺氧双重活力CIH-CSH模式(沼泽和Hannemann, 2020;Prieto-Lloret et al ., 2021在病理肿瘤发生微环境利基)(希弗et al ., 2018)(图3)。
内源性一氧化氮的生物利用度和表达是关键gasotransmitter NO-cGMP通路(刘et al ., 2017;Krishnan et al ., 2018;Friebe et al ., 2020;Feil et al ., 2022;康et al ., 2022)。一氧化氮参与调节血管舒张,血小板聚集,炎症、缺氧适应和氧化应激(Gajecki et al ., 2022)。因此,这个阴险的早期绝经年龄/男人更年期内源氮oxide-mediated hypovascularity缺氧发展需要进一步调查。新兴的基因来自人口和实验研究的证据指出non-mutagenic促进剂的一个重要的角色在推动癌症发病率和新的方法和研究策略需要打破这种僵局(布伦南和大卫史密斯,2022年)。这个可以提供所需的答案到这个重要的问题关于健寿为健康的生活方式老化,在医疗、节约成本和可持续性的卫生系统。
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关键词:健寿、老化、缺氧、氧化应激、炎症、一氧化氮、低氧诱导因子、氧传感
引用:Phua TJ(2023)理解人类衰老和衰老相关疾病的基本细胞信号链接:在中年hypovascularity缺氧的假设。前面。老化4:1196648。doi: 10.3389 / fragi.2023.1196648
收到:2023年3月30日;接受:2023年5月23日;
发表:2023年6月13日。
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