Regulation of cellular senescence and metabolic health by dietary protein

项目摘要65岁以上的人口在过去的一个世纪里增加了两倍多，排名 给家庭和医疗系统带来了巨大的负担。延长健康寿命，生命中相对 没有影响生活质量的重大赤字，可能是预防或延缓衰老和衰老的最有效方法- 与之相关的疾病，以减轻这种负担。然而，在没有充分了解衰老驱动机制的情况下， 确定和开发有效和可翻译的干预措施以改善人类的健康和长寿将 可能仍然是有限的。 衰老的一个标志是细胞衰老(CS)，它是一种抗凋亡的细胞周期停滞状态，由 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)，可在健康细胞中诱导早熟CS并促进年龄相关 病理学。CS可通过遗传或药理学方法(即感觉性药物)清除，从而导致 改善代谢健康，减少与年龄相关的疾病。 蛋白质限制(PR)改善了人类和小鼠代谢健康的许多方面，并扩大了 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饮食(BCAA-R)可以减少CS 在衰老和饮食诱导的肥胖小鼠中以及细胞培养。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降低CS的一个机制是蛋白激酶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mTORC1信号。另一个 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具有 已被证明可防止CS负担。在这项建议中，我将通过评估饮食是否影响CS的清除来测试 对于进食高蛋白饮食的老年小鼠，感觉剂对新陈代谢的健康和虚弱的影响最大。我也是 将在体内测试支链氨基酸是否通过激活mTORC1来驱动高蛋白诱导的CS和代谢功能障碍 在试管中。最后，我将测试BCAA-R在全身或特定组织中对FGF21的作用是否介导了 BCAA-R对饮食诱导肥胖小鼠代谢健康和CS的影响 这些目标将共同检验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奖学金，他是 衰老生物学和新陈代谢方面的专家，以及我的共同赞助人保罗·罗宾斯博士，他是CS领域的世界领先专家。 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 为了成为一名成功的终身教职跟踪教员，他们专注于衰老和细胞衰老的生物学。

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.