Age-dependent SKN-1/NRF cytoprotection at the cost of metabolic homeostasis

年龄依赖性 SKN-1/NRF 细胞保护以代谢稳态为代价

• 批准号: 10611507
• 负责人: Sean P CURRAN
• 金额: $ 33.83万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611507
• 关键词: Acute; Adult; Age; Aging; Alleles; Animals; Automobile Driving; Biochemical; Caenorhabditis elegans; Cells; Chemoresistance; Complement; Cytoprotection; Data; Defect; Diet; Dietary Intervention; Disease; Dose; Ensure; Exposure to; Free Radicals; Genes; Genetic; Genetic Transcription; Health; Health Promotion; Homeostasis; Human; Incidence; Infection; Innate Immune Response; Life; Life Expectancy; Link; Lipid Mobilization; Lipids; Longevity; Masks; Measures; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Molecular; Molecular Genetics; Mus; Natural Immunity; Nutraceutical; Organism; Outcome; Oxidative Stress; Pathology; Pathway interactions; Phenotype; Physiological; Play; Pseudomonas aeruginosa; Publishing; Reactive Oxygen Species; Regulation; Reporter; Reproduction; Research; Resistance; Role; Source; Stress; System; Testing; Thinking; Tissues; Toxic Environmental Substances; Work; Xenobiotics; age related; cost; cytotoxic; free radical oxygen; gene therapy; healthspan; immune activation; in vivo; lipid metabolism; mutant; novel therapeutic intervention; pathogen; prevent; response; stress tolerance; stressor; theories; transcription factor; transcriptome sequencing; tumor

Abstract SKN-1/NRF2 is a conserved cytoprotective transcription factor that plays established dose dependent roles in response to diverse cytotoxic stressors. As such, the degree of SKN-1/NRF2 activity can impact survival and physiological responses to environmental toxins. Although it makes sense that increased SKN-1/NRF2 activity could be protective, it remains possible that the NRF2 response itself contributes to disease pathology. As such, a major question is whether SKN-1/NRF2 activation is universally helpful or if it can also drive pleiotropic consequences over the lifespan. We have uncovered the existence of a conserved signature, defined by metabolic dysregulation, in worms and mice with activated SKN-1/NRF2. These metabolic defects mask the potentially positive cytoprotective effects of SKN-1/NRF2 activation later in life. The central hypothesis driving our proposal is that animals with activated SKN-1/NRF2, have enhanced resistance to stress, but also increased incidence of metabolic disorders that compromise health later in life; this ultimately diminishes life expectancy. To test our hypotheses, we propose two interconnected specific aims. In Aim 1, we will biochemically define the age-related depletion of somatic lipids when SKN-1/NRF2 is activated, which ultimately leads to reduced health later in life. We will also examine the lifespan and healthspan of animals that where the somatic lipid depletion phenotype is suppressed, by genetic or nutritional interventions, while SKN-1/NRF2 activation is maintained. This will functionally uncouple the positive and negative effects of SKN-1/NRF2 activation on healthspan and lifespan. In Aim 2, we will define the mechanisms underlying the metabolic and stress resistance phenotypes resulting from activated SKN-1/NRF2 by elucidating the molecular, and spatial determinants of these responses, whose capacity is governed by age. Finally, in Aim 3, we will define a new mechanistic link between lipid metabolism and immune activation that is governed by activated SKN-1/NRF. The successful completion of the proposed research will inform strategies to capitalize on the health promoting benefits of molecules like SKN-1 and NRF2 while avoiding pleiotropic outcomes over the lifespan.

摘要 SKN-1/NRF 2是一种保守的细胞保护性转录因子，在细胞凋亡中起着剂量依赖性作用。 对不同细胞毒性应激源的反应。因此，SKN-1/NRF 2活性的程度可以影响存活率， 对环境毒素的生理反应尽管SKN-1/NRF 2活性的增加是有道理的， 尽管NRF 2应答可能具有保护性，但NRF 2应答本身仍可能导致疾病病理学。作为 因此，一个主要问题是SKN-1/NRF 2激活是否普遍有益，或者它是否也可以驱动多效性 在生命周期中的后果。我们已经发现了一个保守的签名的存在，定义为代谢 在具有活化的SKN-1/NRF 2的蠕虫和小鼠中，这些代谢缺陷掩盖了 SKN-1/NRF 2激活在生命后期的细胞保护作用。推动我们提议的核心假设是， SKN-1/NRF 2的激活，增强了对应激的抵抗力，但也增加了代谢紊乱的发生率 这会影响以后的健康，最终会缩短预期寿命。为了验证我们的假设，我们提出两个 相互关联的具体目标。在目标1中，我们将从生物化学上定义与年龄相关的体细胞脂质消耗， SKN-1/NRF 2被激活，最终导致晚年健康状况下降。我们还将研究寿命， 通过遗传或营养抑制体细胞脂质耗竭表型的动物的健康寿命 干预，而SKN-1/NRF 2激活维持。这将在功能上分离积极和消极 SKN-1/NRF 2激活对健康寿命和寿命的影响。在目标2中，我们将定义 通过阐明SKN-1/NRF 2的分子结构， 以及这些反应的空间决定因素，其能力取决于年龄。最后，在目标3中，我们将定义一个 脂质代谢和免疫激活之间的新机制联系，由激活的SKN-1/NRF控制。的 成功完成拟议的研究将为战略提供信息，以利用 SKN-1和NRF 2等分子，同时避免在整个生命周期中出现多效性结果。

项目成果

Nociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects.

• DOI: 10.1007/s11357-021-00487-y
• 发表时间: 2022-03
• 期刊: GeroScience
• 影响因子: 5.6
• 作者: Raffaele M;Kovacovicova K;Biagini T;Lo Re O;Frohlich J;Giallongo S;Nhan JD;Giannone AG;Cabibi D;Ivanov M;Tonchev AB;Mistrik M;Lacey M;Dzubak P;Gurska S;Hajduch M;Bartek J;Mazza T;Micale V;Curran SP;Vinciguerra M
• 通讯作者: Vinciguerra M

WDR23 mediates NRF2 proteostasis and cytoprotective capacity in the hippocampus.

WDR23 介导海马体中 NRF2 的蛋白质稳态和细胞保护能力。

• DOI: 10.1016/j.mad.2024.111914
• 发表时间: 2024
• 期刊: Mechanisms of ageing and development
• 影响因子: 5.3
• 作者: Liu,Jiahui;Duangjan,Chatrawee;Irwin,RonaldW;Curran,SeanP
• 通讯作者: Curran,SeanP