Metabolic health phenotype, accelerated aging and obesity-related cancer risk and mortality

摘要 肥胖相关癌症、2型糖尿病和心血管疾病的特征是代谢功能的慢性崩溃，影响生活质量、身体功能和寿命。虽然肥胖在至少13种癌症类型的病因学中起着关键作用，但测量肥胖的传统指标-体重指数（BMI）-并不完美，并且可能无法识别由于代谢功能障碍而处于这些癌症风险中的三分之一。虽然累积的细胞损伤和废除的弹性机制是自然衰老过程的一部分，但损伤累积和稳态机制的失调，可能由代谢功能障碍驱动，可能导致加速生物衰老，最近与癌症风险和生存有关。需要更好地了解代谢健康（无论BMI如何）与加速衰老和癌症之间的关系，以告知预防工作的目标。该应用程序的长期目标是了解代谢功能障碍如何影响生物衰老和癌症风险，在所有肥胖水平上，为预防或延迟这些致命疾病的干预措施提供信息。核心假设是代谢功能障碍，独立于肥胖，与加速的生物衰老和肥胖相关的癌症有关。目标1（F99阶段）将利用来自犹他州肥胖研究的数据来测量不同BMI类别（即，在某些实施方案中，肥胖症患者具有与肥胖相关的癌症（例如，“代谢健康表型”）和发展肥胖相关的癌症（食道癌、胃癌、结肠直肠癌、肝癌、胆囊癌、胰腺癌、子宫癌、卵巢癌、甲状腺癌、脑膜瘤、肾癌和乳腺癌以及多发性骨髓瘤）的风险。在妇女健康倡议（WHI）中，癌症诊断时的糖尿病状态将与癌症特异性和总生存率相关。这项研究将在目标2（K 00阶段）中扩展，其中将研究代谢健康表型与加速生物衰老和肥胖相关癌症风险的关系。在目标2a中，来自前瞻性WHI、杰克逊心脏研究、健康与退休研究、弗雷泽心脏研究和其他研究的数据将用于测量加速生物学年龄在多大程度上解释了代谢健康表型与肥胖相关癌症风险的关联。在目标2b中，使用来自癌症基因组图谱（TCGA）队列的数据，将评估加速生物老化与肥胖相关癌症诊断后生存率的关系。博士前博士后候选人将扩大她在生物统计学，流行病学，衰老和表观遗传学研究的教学和经验培训都在犹他州，亨茨曼癌症研究所和耶鲁大学医学院。将获得人体代谢、生物统计学、流行病学、衰老和表观遗传学研究方面的实践培训。拟议的项目将有助于更好地识别那些有肥胖相关癌症风险的人，并支持临床癌症管理的变化，以支持糖尿病和加速衰老预防。

Abstract PROJECT SUMMARY Obesity-related cancers, type 2 diabetes mellitus and cardiovascular disease, are characterized by a chronic breakdown in metabolic functioning that impacts quality of life, physical functioning and longevity. Though obesity plays a pivotal role in the etiology of at least 13 cancer types, the traditional metric for measuring obesity, body mass index (BMI), is imperfect and may fail to identify a third of individuals at risk of these cancers owing to metabolic dysfunction. While accumulated cellular damage and abrogated resilience mechanisms are part of the natural aging process, damage accumulation and dysregulation of homeostasis mechanisms, potentially driven by metabolic dysfunction, may lead to accelerated biological aging that has recently been linked to cancer risk and survival. A better understanding of the relationship between metabolic health, regardless of BMI, with accelerated aging and cancer is needed to inform who to target for prevention efforts. The long-term goal of this application is to understand how metabolic dysfunction influences biological aging and risk of cancer, at all levels of adiposity, to inform interventions that prevent or delay these deadly diseases. The central hypothesis is that metabolic dysfunction, independent of obesity, is associated with accelerated biological aging and obesity-related cancers. Aim 1 (F99 phase) will leverage data from the Utah Obesity Study to measure the association between metabolic dysfunction (metabolic syndrome and diabetes) across BMI categories (i.e., “metabolic health phenotype”) and risk of developing obesity-related cancer (esophageal, gastric, colorectal, liver, gallbladder, pancreas, uterus, ovary, thyroid, meningioma, kidney, and breast cancers, and multiple myeloma). In the Women’s Health Initiative (WHI), diabetes status at cancer diagnosis will be measured in relation to cancer-specific and overall survival. This research will be extended in Aim 2 (K00 phase) where metabolic health phenotype will be studied in relation to accelerated biological aging and obesity-related cancer risk. In Aim 2a, data from the prospective WHI, Jackson Heart Study, Health and Retirement Study, Framingham Heart Study and others will be used to measure the extent to which accelerated biological age explains the association of metabolic health phenotype with obesity-related cancer risk. In Aim 2b, using data from The Cancer Genomic Atlas (TCGA) cohort, accelerated biological aging will be evaluated in relation to survival after obesity-related cancer diagnosis. The pre-doctoral to post-doctoral candidate will expand upon her didactic and experiential training in biostatistics, epidemiology, aging and epigenetics research both at the University of Utah, Huntsman Cancer Institute, and Yale School of Medicine. Practical training will be obtained in human metabolism, biostatistics, epidemiology, aging and epigenetics research. The proposed project will help to better identify those at risk of obesity-related cancers and support changes in clinical cancer management to support diabetes and accelerated aging prevention.