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.

在过去的世纪，65岁以上的人口数量增加了两倍多， 给家庭和医疗系统带来沉重负担。延长健康寿命，生命中相对 没有损害生活质量的主要缺陷，可能是预防或延缓衰老和衰老的最有效方法- 相关疾病，以减轻这些负担。然而，在没有完全理解导致衰老的机制的情况下， 确定和制定有效和可转化的干预措施，以改善人类的健康和寿命， 可能仍然有限。 衰老的标志，细胞衰老（CS），是一种抗肿瘤的，细胞周期停滞的状态， 各种压力源衰老细胞释放促炎可溶性因子，统称为衰老- 相关分泌表型（SASP），它可以诱导健康细胞中的过早CS，并促进年龄相关的 病理学CS可以通过遗传或药理学（即，senolytic药物）的方法，这导致 改善新陈代谢健康和减少与年龄有关的疾病。 蛋白质限制（PR）改善了人类和小鼠代谢健康的许多方面， 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; BCAA）。在初步研究中，我发现低支链氨基酸（BCAA-R）的饮食可以减少CS 在老年和饮食诱导的肥胖小鼠以及细胞培养中。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可用于减少CS的一种机制是蛋白激酶mTORC 1，其是 受到蛋白质和支链氨基酸的刺激mTORC 1活性促进SASP，而mTOR抑制剂雷帕霉素抑制SASP。 SASP。BCAA-R已被证明可以减少雄性小鼠肝脏和肌肉中的mTORC 1信号。另一 PR所需的因子是成纤维细胞生长因子21（FGF 21），其也由BCAA-R诱导。在体外，FGF 21具有 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清除率来测试， senolytics将对食用高蛋白饮食的老年小鼠的代谢健康和虚弱具有最大的影响。我也 将测试BCAA是否通过体内mTORC 1的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FGF 21的作用是否介导了FGF 21的表达。 BCAA-R对饮食诱导的肥胖小鼠的代谢健康和CS的影响。 总之，这些目标将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。我将在我的赞助人达德利拉明博士的指导下完成这项研究， 这两位是衰老生物学和新陈代谢方面的专家，还有我的共同赞助人，保罗·罗宾斯博士，一位世界领先的CS专家。 完成这些目标和相应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职员工，专注于衰老和细胞衰老的生物学。