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

项目摘要 肥胖相关的癌症、2型糖尿病和心血管疾病的特征是慢性的， 代谢功能的崩溃，影响生活质量，身体机能和寿命。虽然 肥胖在至少13种癌症的病因学中起着关键作用， 肥胖，身体质量指数（BMI），是不完美的，可能无法确定三分之一的人在这些风险 由于代谢功能障碍而导致的癌症。当细胞损伤和恢复力逐渐消失时 机制是自然衰老过程、损伤累积和体内平衡失调的一部分 可能由代谢功能障碍驱动的机制，可能导致加速生物衰老， 与癌症风险和存活率有关。更好地理解代谢与 健康，无论体重指数，加速老化和癌症，需要告知谁是预防的目标 努力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学特性。 衰老和癌症风险，在所有肥胖水平，以告知干预措施，防止或延迟这些致命的 疾病核心假设是代谢功能障碍，独立于肥胖，与肥胖相关。 加速生物老化和肥胖相关的癌症。目标1（F99阶段）将利用来自犹他州的数据 肥胖研究，以衡量代谢功能障碍（代谢综合征和糖尿病）之间的关联 跨BMI类别（即，“代谢健康表型”）和患肥胖相关癌症的风险 （食管、胃、结直肠、肝、胆囊、胰腺、子宫、卵巢、甲状腺、脑膜瘤、肾和 乳腺癌和多发性骨髓瘤）。在妇女健康倡议（WHI）中， 诊断将根据癌症特异性和总存活率进行测量。这项研究将在 目标2（K00阶段），将研究与加速生物老化相关的代谢健康表型 和肥胖相关的癌症风险。在目标2a中，来自前瞻性WHI、杰克逊心脏研究、健康和 退休研究、心脏病研究和其他研究将被用来衡量 加速的生物学年龄解释了代谢健康表型与肥胖相关癌症的关联 风险在目标2b中，使用来自癌症基因组图谱（TCGA）队列的数据，将加速生物老化 评估与肥胖相关癌症诊断后的生存率的关系。博士生转博士后 候选人将扩大她在生物统计学，流行病学，老龄化和 犹他州大学、亨茨曼癌症研究所和耶鲁医学院的表观遗传学研究。 将获得人体代谢、生物统计学、流行病学、衰老和表观遗传学方面的实践培训 research.拟议的项目将有助于更好地识别那些有患肥胖相关癌症风险的人， 临床癌症管理的变化，以支持糖尿病和加速衰老的预防。

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.