Long-Term Trajectories of Accelerated Biological Aging and Functional Decline Associated with Breast Cancer and its Treatment

项目摘要/摘要 超过380万生活在美国的女性有浸润性乳腺癌的病史，其中大多数 年龄在65岁以上。由于15年存活率超过80%，老年乳腺癌幸存者是 不断增长的人口，与通常的老龄化模式相比，有不同的健康考虑。癌症幸存者是 年龄相关疾病的风险增加，但对其背后的衰老轨迹知之甚少 这种风险升高，或影响下降严重程度的因素。来自临床前模型的证据表明癌症 治疗有助于与衰老相一致的分子和细胞变化，这可能是后者的基础 出现功能性衰退。虚弱在乳腺癌患者中非常普遍，并与 长期发病率和死亡率的风险更大。表观遗传年龄加速是生物学的一个指标 衰老受癌症及其治疗的影响，也是健康和寿命的有力预测因素。我们 假设癌症及其治疗将有助于功能和表观遗传的加速轨迹 相对于没有癌症病史的女性来说，这些变化将长期持续，并有所不同 按治疗类型和强度分类。为了检验这些假设，我们将结合30年前和后30年的 《妇女健康》中绝经后妇女的诊断、临床、自我报告和生理数据 倡议(WHI)，包括对9000多名乳腺癌幸存者的功能状况进行年度评估 年龄与非癌症对照组相匹配。我们将从采集的血液样本中估计表观遗传年龄 乳腺癌幸存者和“通常衰老”对照组的治疗前和治疗后的多个时间点。 凭借这一独特的数据和相关专家的多学科团队，我们将进行第一次大规模研究 乳腺癌诊断前后表观遗传学和功能老化的长期纵向测量 和治疗，解决以下具体目标：1)表征物理的长期轨迹 乳腺癌存活者的功能(V.对照组中通常的衰老)并测试它们是否被类型改变 和癌症治疗的强度；2)检查乳腺癌及其治疗是否增加了 表观遗传衰老以及这种衰老在治疗后是否继续加速；以及3)检验两者之间的关系 表观遗传衰老和功能衰退的比率以及乳腺癌之间的差异 幸存者和通常的衰老控制组。这项工作是表征衰老预测因素的关键的第一步 癌症幸存者的轨迹，并确定哪些人可以从支持性干预中受益 在这个快速增长的人口中最大限度地提高健康水平。

PROJECT SUMMARY/ABSTRACT More than 3.8 million women living in the United States have a history of invasive breast cancer, a majority of whom are over age 65. With 15-year survival rates exceeding 80%, older breast cancer survivors are a growing population with distinct health considerations relative to patterns of usual aging. Cancer survivors are at an increased risk of age-related conditions, but little is known about the trajectories of aging that underlie this elevated risk, or factors affecting the severity of decline. Evidence from preclinical models suggest cancer treatment contributes to molecular and cellular changes consistent with aging that may underlie the later emergence of functional decline. Frailty is highly prevalent in breast cancer patients and is associated with a greater hazard of long-term morbidity and mortality. Epigenetic age acceleration is an indicator of biologic aging that is influenced by cancer and its treatment, and also a strong predictor of healthspan and lifespan. We hypothesize that cancer and its treatment will contribute to accelerated trajectories of functional and epigenetic aging relative to women without a history of cancer, that these changes will be sustained long-term, and vary by treatment type and intensity. To test these hypotheses, we will combine three decades of pre- and post- diagnosis clinical, self-reported, and physiological data from post-menopausal women in the Women’s Health Initiative (WHI), including annual assessments of functional status in over 9,000 breast cancer survivors matched by age to cancer-free controls. We will estimate epigenetic age from blood samples collected at multiple pre- and post-treatment time points in a subset of breast cancer survivors and ‘usual aging’ controls. With this unique data and multidisciplinary team of relevant experts, we will conduct the first large study with long-term, longitudinal measures of epigenetic and functional aging before and after breast cancer diagnosis and treatment, addressing the following specific aims: 1) Characterize long-term trajectories of physical function in breast cancer survivors (v. usual aging in controls) and test whether they are modified by the type and intensity of cancer treatments; 2) Examine whether breast cancer and its treatment increase the rate of epigenetic aging and whether this aging continues to accelerate after treatment; and 3) Test the relationship between the rate of epigenetic aging and functional decline and how it may differ between breast cancer survivors and usual aging controls. This work is a critical first step to characterize predictors of aging trajectories among cancer survivors and identify those who could benefit from supportive interventions to maximize healthspan in this rapidly growing population.