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: 10436150
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436150
• 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; Metabolic stress; 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/NRF2是一种保守的细胞保护性转录因子，在 对不同的细胞毒性应激源的反应。因此，SKN-1/NRF2的活性程度可以影响生存和 对环境毒素的生理反应。尽管SKN-1/NRF2活性增加是有道理的 虽然可能是保护性的，但NRF2反应本身仍有可能对疾病病理做出贡献。AS 这样的一个主要问题是，SKN-1/NRF2的激活是否对所有人都有帮助，或者它是否也可以驱动多效性 对寿命的影响。我们已经发现了新陈代谢定义的保守信号的存在 在带有激活的SKN-1/NRF2的蠕虫和小鼠中，存在调节失调。这些代谢缺陷掩盖了潜在的积极因素 生命后期SKN-1/NRF2激活的细胞保护作用我们提议的核心假设是动物 随着SKN-1/NRF2的激活，对应激的抵抗力增强，但代谢紊乱的发生率也增加 这会损害晚年的健康；这最终会缩短预期寿命。为了检验我们的假设，我们提出了两个 相互关联的具体目标。在目标1中，我们将用生化方法定义与年龄相关的体脂消耗，当 SKN-1/NRF2被激活，最终导致晚年健康状况下降。我们还将检查寿命和 体脂耗竭表型受遗传或营养抑制的动物的健康寿命 干预，同时维持SKN-1/NRF2的激活。这将在功能上将积极和消极分开 SKN-1/NRF2激活对健康和寿命的影响在目标2中，我们将定义潜在的机制 通过阐明SKN-1/NRF2激活引起的代谢和抗逆表型， 以及这些反应的空间决定因素，其能力由年龄决定。最后，在目标3中，我们将定义一个 脂代谢和免疫激活之间新的机制联系，这是由激活的SKN-1/NRF控制的。这个 成功完成拟议的研究将有助于制定战略，以利用以下物质促进健康的益处 SKN-1和NRF2这样的分子，同时避免在寿命内产生多效性结果。