Social Determinants of Health as Transducers of Cellular Aging: A New Multi-level Paradigm to Reduce Survivorship Disparities at the Intersection of Cancer and Aging

到2030年，美国2200万癌症幸存者中有四分之三将是65岁及以上， 西班牙裔和黑人幸存者的增长速度将是白人的三倍。这些人口结构的变化 由于缺乏指导老年幸存者护理的证据， 种族/族裔幸存者的数据几乎缺乏。填补这些空白需要了解 在健康差距、老龄化和癌症的交叉点上存在着几种复杂的多方向关系。 与年龄较大的白色幸存者相比，年龄较大的种族/少数民族幸存者一生中暴露于 健康的不利社会决定因素。这些暴露加速老化过程。衰老会增加风险 通过累积的损伤和突变发展成癌症。癌症和它的治疗方法，反过来， 老化的驱动因素。这些相互交织的力量加在一起，可能会加剧当前的种族/民族癌症。 老年幸存者在健康和生活质量方面的差距。这个杰出研究者奖的愿景 是从根本上改变我们处理癌症差异的方式， 细胞衰老在健康和生存结果的社会决定因素之间的关系中的作用。我会 使用一个概念模型，将多层次差异框架与肿瘤学和老年科学相结合 使用转录组学和其他组学分析，表观遗传学，机器学习， 中介模型、综合集成和人口模拟方法。我的跨学科的广泛目标 研究计划是：1）发现细胞衰老过程中的大型队列的老年黑人，西班牙裔和 解释健康决定因素和生活质量之间关系的白色幸存者（例如，通孔应力 通过炎症基因表达对细胞衰老的信号传导和下游作用），2）定义 队列结果建议的途径，并测试针对这些途径的干预措施的影响， 癌症存活率的临床前模型和3）将结果转化为实践和政策。在我不断 在NIH资助的研究生涯中，我做出了变革性的贡献，支持了我提出的研究 程序.很少有人口科学家具有独特的背景和良好的记录， 进行这项深入的研究计划，涵盖从临床前到队列的完整转化连续体 研究、实践和政策。与学科以外的科学家合作将支持我的成功 and generate生成novel新insights见解.新成立的乔治城隆巴迪癌症和衰老研究所， 领导和出色体制承诺和基础设施提供了一个出色的环境。这 杰出研究者奖将为我提供所需的稳定性，以加速知识在一个 具有高度公共卫生意义和临床相关性的未充分研究研究领域。鉴别和检测 基于衰老机制的干预措施将支持为迅速增长的老年人量身定制临床护理的努力 少数族裔幸存者人口，并可以改变我们如何在老龄化的背景下处理癌症的差异。

By 2030, three-quarters of the 22 million US cancer survivors will be 65 and older and the number of older Hispanic and Black survivors will have grown three times faster than Whites. These shifting demographics are driving a crisis in cancer care due to a paucity of evidence to guide care for older survivors, especially older racial/ethnic survivors for whom data is virtually lacking. Filling these gaps will require an understanding of several complex multidirectional relationships at the intersection of health disparities, aging and cancer. Compared to older White survivors, older racial/ethnic minority survivors have had more lifetime exposures to adverse social determinants of health. These exposures accelerate aging processes. Aging increases the risk of developing cancer through accumulated damage and mutations. Cancer and its therapies, in turn, are disease drivers of aging. Together, these intersecting forces are likely to exacerbate current racial/ethnic cancer disparities in the health and quality of life of older survivors. The vision for this Outstanding Investigator Award is to fundamentally shift how we approach cancer disparities by providing a mechanistic understanding of the role of cellular aging in the relationships between social determinants of health and survivorship outcomes. I will use a conceptual model that integrates a multi-level disparities framework with oncology and geroscience perspectives to conduct research using transcriptomic and other -omics analyses, epigenetics, machine learning, mediation models, meta-synthesis and population simulation methods. The broad goals of my transdisciplinary research program are to: 1) discover cellular aging processes in large cohorts of older Black, Hispanic and White survivors that explain relationships between health determinants and quality of life (e.g., via stress signaling and downstream effects on cellular aging via inflammatory gene expression), 2) define mechanistic pathways suggested by cohort results and test the impact of interventions targeting those pathways in a preclinical model of cancer survivorship and 3) translate results to practice and policy. During my continuously NIH-funded research career, I have made transformative contributions that support my proposed research program. There are few population scientists with the unique background and proven track record to successfully conduct this in-depth research program spanning the full translational continuum from preclinical to cohort studies and practice and policy. Collaboration with scientists from outside my discipline will support my success and generate novel insights. The newly established Georgetown Lombardi Institute on Cancer and Aging that I lead and exceptional institutional commitment and infrastructure provide an exceptional environment. This Outstanding Investigator Award will provide me with the stability needed to accelerate knowledge in an understudied research area with high public health significance and clinical relevance. Identification and testing of aging mechanistically-based interventions will support efforts to tailor clinical care for the burgeoning older minority survivor population and could to transform how we approach cancer disparities in the context of aging.