Regulation of cellular senescence and metabolic health by dietary protein

膳食蛋白质调节细胞衰老和代谢健康

• 批准号: 10678729
• 负责人: Mariah Calubag
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-03 至 2026-04-02
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678729
• 关键词: Adipose tissue; Affect; Age; Aging; Apoptotic; Automobile Driving; Biology of Aging; Branched-Chain Amino Acids; Cardiovascular Diseases; Cell Aging; Cell Culture Techniques; Cell Cycle Arrest; Cells; Complex; Consumption; Cultured Cells; DNA Damage; Dasatinib; Development; Diabetes Mellitus; Diet; Dietary Intervention; Dietary Proteins; Disease; Eating; FRAP1 gene; Faculty; Fellowship; Female; Fibroblasts; Gene Expression; Genetic; Goals; Health; Healthcare Systems; Homeostasis; Hormone Responsive; Human; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Intervention; Isoleucine; Leucine; Life; Liver; Longevity; Macronutrients Nutrition; Malignant Neoplasms; Mediating; Mentorship; Metabolic; Metabolic dysfunction; Metabolism; Methods; Mitochondria; Molecular; Mus; Muscle; Nature; Obese Mice; Pathology; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Process; Protein Kinase; Proteins; Public Health; Quality of life; Quercetin; Regimen; Research Personnel; Resistance; Risk Factors; Rodent; Role; Signal Transduction; Sirolimus; Stimulus; Stress; Supplementation; Testing; Tissues; Training; United States; Valine; age related; aged; cell growth regulation; diet-induced obesity; dietary; dietary manipulation; experimental study; family burden; fibroblast growth factor 21; frailty; healthspan; healthy aging; human old age (65+); improved; in vivo; insight; mTOR Inhibitor; male; member; middle age; mortality; pharmacologic; premature; prevent; protein intake; response; senescence; skills; stressor; tenure track; transcriptome

PROJECT SUMMARY The number of people over age 65 has more than tripled over the past century, placing great burdens on families and the healthcare system. Extending healthspan, the portion of the life that is relatively free from major deficits that impair quality of life, may be the most efficacious way to prevent or delay aging and age- related diseases to reduce such burdens. However, without fully understanding the mechanisms driving aging, identifying and developing effective and translatable interventions to improve health and longevity in humans will likely remain limited. A hallmark of aging, cellular senescence (CS), is an apoptotic-resistant, cell-cycle arrested state induced by various stressors. Senescent cells release pro-inflammatory soluble factors collectively called the senescence- associated secretory phenotype (SASP), which can induce premature CS in healthy cells and promote age-related pathologies. CS can be cleared by genetic or pharmacological (i.e., senolytic drugs) methods, which leads to improvements in metabolic health and reductions age-related diseases. Protein restriction (PR) improves many aspects of metabolic health in both humans and mice, and extends mouse lifespan, specifically through the reduced consumption of the branched-chain amino acids (i.e. leucine, isoleucine and valine; BCAAs). In preliminary studies, I have found that a diet low in BCAAs (BCAA-R) reduces CS in aged and diet-induced obese mice as well as cell culture. The mechanisms by which protein promotes CS, and conversely the mechanisms by which PR and BCAA-R promote healthy aging and reduce CS, are unknown. One mechanism by which BCAA-R may function to reduce CS is the protein kinase mTORC1, which is stimulated by protein and BCAAs. mTORC1 activity promotes the SASP, while the mTOR inhibitor rapamycin inhibits the SASP. BCAA-R has been shown to reduce mTORC1 signaling in the liver and muscle of male mice. Another factor required for PR is fibroblast growth factor 21 (FGF21), which is also induced by BCAA-R. In vitro, FGF21 has been shown to protect against CS burden. In this proposal, I will test if diet affects CS clearance by assessing if senolytics will have the greatest effect on metabolic health and frailty in aged mice eating a high protein diet. I also will test if BCAAs drive high-protein-induced CS and metabolic dysfunction through activation of mTORC1 in vivo and in vitro. Finally, I will test if the action of BCAA-R on FGF21 in the whole body or in specific tissues mediates the effects of a BCAA-R on metabolic health and CS in diet-induced obese mice. Together, these aims will examine multiple mechanisms by which dietary protein and the BCAAs modulate to impact CS burden. I will be completing this fellowship under the mentorship of my sponsor, Dr. Dudley Lamming, an expert in aging biology and metabolism, and my co-sponsor, Dr. Paul Robbins, a world-leading expert in CS. Completing these aims and the accompanying individualized training plan will help me develop the skills necessary to become a successful tenure track faculty member focused on the biology of aging and cellular senescence.

项目摘要 65 岁以上的人口数量在过去一个世纪中增加了两倍多， 给家庭和医疗保健系统带来沉重负担。延长健康寿命，即生命中相对重要的部分 避免影响生活质量的重大缺陷，可能是预防或延缓衰老和衰老的最有效方法 相关疾病，以减轻此类负担。然而，在没有充分了解导致衰老的机制的情况下， 确定和制定有效且可转化的干预措施以改善人类健康和寿命将 可能仍然有限。 细胞衰老 (CS) 是衰老的一个标志，是一种抗凋亡、细胞周期停滞状态，由以下因素引起： 各种压力源。衰老细胞释放促炎可溶性因子，统称为衰老细胞 相关分泌表型（SASP），可诱导健康细胞过早发生 CS 并促进年龄相关 病理学。 CS 可以通过遗传或药理学（即抗衰老药物）方法清除，这会导致 改善代谢健康并减少与年龄相关的疾病。 蛋白质限制（PR）可改善人类和小鼠代谢健康的许多方面，并延长 小鼠寿命，特别是通过减少支链氨基酸（即亮氨酸、 异亮氨酸和缬氨酸；支链氨基酸）。在初步研究中，我发现低支链氨基酸 (BCAA-R) 饮食可减少 CS 在衰老和饮食诱导的肥胖小鼠以及细胞培养物中。蛋白质促进 CS 的机制，以及 相反，PR 和 BCAA-R 促进健康衰老和减少 CS 的机制尚不清楚。 BCAA-R 可能发挥减少 CS 作用的机制之一是蛋白激酶 mTORC1，它是 受到蛋白质和支链氨基酸的刺激。 mTORC1 活性促进 SASP，而 mTOR 抑制剂雷帕霉素则抑制 SASP。 BCAA-R 已被证明可以减少雄性小鼠肝脏和肌肉中的 mTORC1 信号传导。其他 PR 所需的因子是成纤维细胞生长因子 21 (FGF21)，它也是由 BCAA-R 诱导的。在体外，FGF21 已被证明可以防止 CS 负担。在本提案中，我将通过评估饮食是否影响 CS 清除来测试饮食是否会影响 CS 清除 senolytics 对高蛋白饮食的老年小鼠的代谢健康和虚弱影响最大。我也 将测试 BCAA 是否通过体内 mTORC1 激活来驱动高蛋白诱导的 CS 和代谢功能障碍， 体外。最后，我将测试 BCAA-R 对全身或特定组织中 FGF21 的作用是否介导 BCAA-R 对饮食诱导的肥胖小鼠代谢健康和 CS 的影响。 这些目标将共同研究膳食蛋白质和支链氨基酸调节的多种机制 影响CS负担。我将在我的赞助商 Dudley Lamming 博士（Dudley Lamming 博士）的指导下完成这项研究金。 衰老生物学和新陈代谢方面的专家，以及我的共同发起人保罗·罗宾斯博士（Dr. Paul Robbins），他是世界领先的计算机科学专家。 完成这些目标和随附的个性化培训计划将帮助我发展必要的技能 成为一名成功的终身教授，专注于衰老和细胞衰老生物学。