Targeting Senescence to Improve Frailty in Older Cancer Survivors

项目总结/摘要 癌症治疗加速衰老。在65岁以上的人群中，加速老化可能会产生更大的后果 比年轻的成年人。加速老化的最重要后果之一是脆弱。脆弱与 失去独立性，福尔斯，和死亡。年龄较大的癌症幸存者出现虚弱的频率要高出2到4倍， 比同龄对照组更早。人们才刚刚开始了解脆弱的潜在机制。 导致身体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;放射和化疗都会产生衰老， 细胞（Sncs）。在生物标志物的初步研究中，我观察到接受化疗的老年幸存者（与不接受化疗的老年幸存者相比）， 化疗）增加了P16 INK 4a（p16）的T细胞表达。p16是Sncs的一个确定的标记。我也 观察到表达p16的T细胞的百分比与临床虚弱相关。我的发现与 已发表的研究将p16与儿童癌症幸存者的虚弱联系起来。这些数据共同提供了 测试临床干预措施的前提，以靶向和消除老年幸存者的SNCs。最近，毒品 被发现选择性地消除SnCs - senolytics。其中一种抗衰老剂是非瑟酮，一种天然产品 草莓和其他水果中的类黄酮。由于非瑟酮的含量在食物中变化很大， 不可能在天然饮食中达到足够的水平来消除Snc;然而，非瑟酮可作为 膳食补充剂在临床前模型中，非瑟酮减少了Sncs，炎症和虚弱。因此，非瑟酮现在 在>10项有效性试验中，用于缓解体弱老年人的年龄相关疾病，迄今为止， profile.到目前为止，还没有试验在虚弱的老年癌症幸存者中测试非瑟酮。在这里，我提出一个随机安慰剂- 多模态生物标志物的对照试验，以测试非瑟酮的初步疗效、安全性和耐受性， 改善虚弱老年癌症幸存者的虚弱并减少Snc负担。以坚定的机械原理为指导， 根据初步数据，我的总体假设是非瑟酮有效（改善虚弱）、安全且可耐受 年老体弱的幸存者为了验证我的假设，我将随机选择65岁以上步态不稳的癌症幸存者， 速度（<0.8 m/s）对非瑟酮与安慰剂的60天疗程的影响。主要终点是步态速度的变化， 第1天至第60天。次要终点包括p16、炎症生物标志物和虚弱指标的变化 （Fried标准，虚弱指数，握力）。我还将评估非瑟酮的安全性和耐受性，并探索更长的时间- 有效性的长期持续性，如在150天时通过步态速度测量的。这项研究的结果将 为大型多中心临床试验（R 01）提供初步证据，以确定非瑟酮在老年人中的疗效 幸存者此外，通过完成这项研究，我将填补我之前在癌症临床试验方面的培训空白， 老年科学研究培训。这项研究将成为我独立研究计划的基础， 老年保护干预措施，以确保老年癌症幸存者在癌症治疗后过上健康的生活。

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.