Targeting Senescence to Improve Frailty in Older Cancer Survivors

项目摘要/摘要 癌症治疗会加速衰老。对于65岁以上的人来说，加速衰老可能会产生更严重的后果 而不是年轻的成年人。加速老龄化最重要的后果之一就是脆弱。脆弱是相互关联的 失去独立、摔倒和死亡。老年癌症幸存者变得虚弱的频率是前者的2-4倍， 与年龄匹配的对照组相比，年龄更早。人们才刚刚开始了解脆弱的潜在机制。 导致虚弱的一个关键衰老机制是细胞衰老--一种终末生长停滞的状态。衰老 是自然衰老和癌症治疗的结果；放射和化疗都会导致衰老 细胞(SNC)。在先导性生物标记物研究中，我观察到接受化疗的老年幸存者(与不接受化疗的 化疗)增加了T细胞p16INK4a(P16)的表达。P16是一种公认的SNCs标志物。我也是 观察到表达p16的T细胞的百分比与临床脆弱程度有关。我的发现是一致的 已发表的研究将p16与儿童癌症幸存者的脆弱联系起来。这些数据加在一起提供了 测试针对和消除老年幸存者SNC的临床干预措施的前提。最近，毒品已经 已发现选择性地消除SNCS-感受器裂解物。一种这样的感觉剂是非瑟汀，一种天然产品 草莓和其他水果中的类黄酮类化合物。因为鱼腥草素在食物中的含量差异很大，所以它是 在天然饮食中不可能达到消除SNCs的足够水平；然而，菲西汀可以作为一种 膳食补充剂在临床前模型中，非瑟丁可减少SNCs、炎症和虚弱。因此，菲瑟丁现在是 在10个用于缓解虚弱老年人年龄相关性疾病的有效性试验中，到目前为止，该药具有良好的安全性 侧写。到目前为止，还没有试验在虚弱的老年癌症幸存者身上测试非赛汀。在这里，我建议使用一种随机安慰剂- 用多模式生物标志物进行的对照试验，以测试非赛汀的初步疗效、安全性和耐受性 改善虚弱老年癌症幸存者的虚弱和减轻SNC负担。在坚定的机械论理论的指导下， 初步数据，我的总体假设是非瑟丁是有效的(改善脆弱性)，安全，可耐受 在虚弱的老年幸存者身上。为了检验我的假设，我将把65岁的癌症幸存者随机分为步态减少的人 速度(0.8米/S)到60天的菲赛汀与安慰剂疗程。主要终点是步态速度从 第1天至第60天。次要终点包括p16、炎性生物标记物和脆弱指标的变化。 (Fried的标准、脆弱指数、握力)。我还将评估非赛汀的安全性和耐受性，并探索更长时间- 疗效的长期可持续性，通过150天的步态速度来衡量。这项研究的有希望的结果将 为一项大型多中心临床试验(R01)提供初步证据，以确定非瑟丁对老年人的疗效 幸存者。此外，通过完成这项研究，我将填补我之前接受的癌症临床试验培训的空白 老年科学研究方面的培训。这项研究将成为我制定独立研究计划的基础 确保老年癌症幸存者在癌症治疗后过上健康生活的保护性干预措施。

PROJECT SUMMARY/ABSTRACT Cancer treatment accelerates aging. In people over 65, accelerated aging may have far greater consequences than in younger adults. One of the most important consequences of accelerated aging is frailty. Frailty is linked to loss of independence, falls, and death. Older cancer survivors develop frailty 2- to 4-fold more frequently and at an earlier age than age-matched controls. Mechanisms underlying frailty are just starting to be understood. One key aging mechanism driving frailty is cellular senescence – a state of terminal growth arrest. Senescence is the result of both natural aging and cancer treatment; radiation and chemotherapy both generate senescent cells (Sncs). In pilot biomarker studies, I observed that older survivors treated with chemotherapy (vs. no chemotherapy) have increased T-cell expression of P16INK4a (p16). p16 is an established marker of Sncs. I also observed that the percentage of T-cells expressing p16 correlates with clinical frailty. My findings are consistent with published studies linking p16 and frailty in childhood cancer survivors. Together, these data provide the premise for testing clinical interventions to target and eliminate Sncs in older survivors. Recently, drugs have been discovered that selectively eliminate Sncs – senolytics. One such senolytic is fisetin, a natural product flavonoid found in strawberries and other fruits. Because the amount of fisetin varies considerably in food, it is not possible to achieve sufficient levels for eliminating Sncs in a natural diet; however, fisetin is available as a dietary supplement. In preclinical models, fisetin reduces Sncs, inflammation, and frailty. As such, fisetin is now in >10 efficacy trials to alleviate age-related conditions in frail older adults and, so far, has had a favorable safety profile. No trial to date has tested fisetin in frail older cancer survivors. Here, I propose a randomized placebo- controlled trial with multi-modality biomarkers to test the preliminary efficacy, safety, and tolerability of fisetin to improve frailty and reduce Snc burden in frail older cancer survivors. Guided by a firm mechanistic rationale and preliminary data, my overall hypothesis is that fisetin is efficacious (improves frailty), safe, and tolerable in frail older survivors. To test my hypothesis, I will randomize cancer survivors age >65 with diminished gait speed (<0.8 m/s) to a 60-day course of fisetin vs. placebo. The primary endpoint is change in gait speed from day 1 to day 60. Secondary endpoints include changes in p16, inflammatory biomarkers, and frailty measures (Fried’s criteria, frailty index, grip strength). I also will assess safety and tolerability of fisetin and explore longer- term sustainability of efficacy, as measured by gait speed at 150 days. Promising results from this study will provide preliminary evidence for a large multi-center clinical trial (R01) to establish the efficacy of fisetin in older survivors. Additionally, by completing this study, I will fill a gap in my prior training in cancer clinical trials with training in geroscience research. This study will form the basis of my independent research program to develop geroprotective interventions to ensure that older cancer survivors live healthy lives well after cancer treatment.