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

代谢健康表型、加速衰老和肥胖相关的癌症风险和死亡率

• 批准号: 10646063
• 负责人: Prasoona Karra
• 金额: $ 0.15万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10646063
• 关键词: Aging; Health; Metabolic; Obesity associated cancer; Phenotype; cancer risk; mortality

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.

摘要 项目摘要与肥胖有关的癌症、2型糖尿病和心血管疾病的特点是代谢功能的慢性崩溃，影响生活质量、身体功能和寿命。尽管肥胖在至少13种癌症的病因中起着关键作用，但衡量肥胖的传统指标--身体质量指数(BMI)--并不完美，可能由于代谢障碍而无法识别出三分之一的人有患这些癌症的风险。虽然累积的细胞损伤和丧失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，可能导致生物衰老加速，最近已被认为与癌症风险和生存有关。需要更好地了解代谢健康与加速衰老和癌症之间的关系，以便为预防工作提供目标。这项应用的长期目标是了解代谢障碍如何影响所有水平的肥胖的生物衰老和癌症风险，从而为预防或推迟这些致命疾病的干预提供信息。中心假设是代谢功能障碍与肥胖无关，与加速的生物衰老和肥胖相关的癌症有关。目标1(F99阶段)将利用犹他州肥胖研究的数据来衡量BMI类别(即“代谢健康表型”)之间的代谢障碍(代谢综合征和糖尿病)与患肥胖相关癌症(食道、胃、结直肠、肝、胆、胰腺、子宫、卵巢、甲状腺、脑膜瘤、肾癌、乳腺癌和多发性骨髓瘤)风险之间的关系。在妇女健康倡议(WHI)中，将根据癌症特异性和总体存活率来衡量糖尿病在癌症诊断中的状况。这项研究将扩展到目标2(K00阶段)，在该阶段将研究代谢健康表型与加速的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、健康和退休研究、弗雷明翰心脏研究和其他研究的数据将被用来衡量加速的生物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AIM 2b中，使用癌症基因组图谱(TCGA)队列的数据，将评估加速的生物衰老与肥胖相关癌症诊断后的存活率的关系。这位博士后候选人将扩展她在犹他大学、亨茨曼癌症研究所和耶鲁医学院接受的生物统计学、流行病学、老龄化和表观遗传学研究方面的授课和经验培训。将在人类新陈代谢、生物统计学、流行病学、老龄化和表观遗传学研究方面获得实践培训。拟议的项目将有助于更好地识别肥胖相关癌症的风险，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。