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.

抽象的 项目摘要与肥胖相关的癌症，2型糖尿病和心血管疾病的特征是代谢功能的慢性分解，会影响生活质量，身体功能和寿命。尽管肥胖症在至少13种癌症类型的病因中起着关键作用，但测量肥胖，体重指数（BMI）的传统指标并不完美，并且可能无法识别出由于代谢功能障碍而有可能患有这些癌症风险的三分之一的人。虽然丙烯酸损伤和敏捷的弹性机制是自然衰老过程的一部分，但损伤加速和稳态机制的失调可能是由代谢功能障碍驱动的，可能会导致与癌症风险和生存有关的加速生物学衰老。需要更好地了解代谢健康之间的关系，无论BMI如何，都需要加速衰老和癌症，以告知谁针对预防工作。该应用的长期目标是了解代谢功能障碍如何影响生物学衰老和癌症风险，以在各种肥胖水平上影响预防或延迟这些致命疾病的干预措施。中心假设是，与肥胖无关的代谢功能障碍与加速生物衰老和与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”）的代谢功能障碍（代谢综合征和糖尿病）之间的联系脑膜瘤，肾脏和乳腺癌以及多发性骨髓瘤）。在女性健康计划（WHI）中，将根据癌症特异性和总体生存率来衡量癌症诊断的糖尿病状况。这项研究将在AIM 2（k00阶段）中扩展，其中将研究代谢健康表型，以与加速的生物衰老和与肥胖相关的癌症风险有关。在AIM 2A中，来自前瞻性WHI，杰克逊心脏研究，健康和退休研究，弗雷明汉心脏研究等的数据将用于衡量加速生物年龄的程度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，使用来自癌症基因组图集（TCGA）队列的数据，将根据肥胖相关癌症诊断后的生存评估加速的生物老化。博士后至博士后候选人将在犹他大学，亨斯曼癌症研究所和耶鲁大学医学院的生物统计学，流行病学，衰老和表观遗传学研究方面进行教学和实验培训。将在人类代谢，生物统计学，流行病学，衰老和表观遗传学研究中获得实践培训。拟议的项目将有助于更好地识别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预防衰老。