Patterns of biological, cognitive, and physical aging in cancer survivors and controls and the role of sleep health: Relevance for Alzheimer's Disease and Related Dementias

癌症幸存者和对照者的生物、认知和身体衰老模式以及睡眠健康的作用：与阿尔茨海默氏病和相关痴呆症的相关性

• 批准号: 10670011
• 负责人: Judith E Carroll
• 金额: $ 89.28万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670011
• 关键词: Acceleration; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Area; Behavior Therapy; Biological; Biological Aging; Biological Assay; Biological Specimen Banks; Biological Testing; Blood; Breast Cancer Patient; Breast Cancer survivor; Breast Cancer therapy; Cancer Center; Cancer Control; Cancer Survivor; Cell Aging; Chronology; Cognitive; Cognitive aging; Consent; Control Groups; DNA Damage; Data; Demographic Factors; Disease; Educational Status; Elderly; Enrollment; Epigenetic Process; Frequencies; Future; Geriatrics; Geroscience; Goals; Grant; Hand Strength; Health; Heterogeneity; Homeostasis; Impaired cognition; Indiana; Inflammation; Intervention; Knowledge; Lead; Length; Leukocytes; Long-Term Effects; Longitudinal cohort; Malignant Neoplasms; Measurement; Modeling; Neurocognitive; Neurosciences; Newly Diagnosed; Obesity; Oncology; Parents; Pathway interactions; Patient Self-Report; Pattern; Persons; Physical Function; Physical assessment; Population; Process; Psychosocial Factor; Regulation; Research; Risk; Role; Site; Sleep; Survivors; Syndrome; System; Systemic Therapy; Testing; Thinking; Time; United States National Institutes of Health; Universities; Visit; Waste Products; Woman; Work; actigraphy; age related; aged; aging population; biobank; cancer therapy; clinical translation; cognitive function; cohort; comparison control; follow-up; functional decline; improved; improvement on sleep; malignant breast neoplasm; multiple chronic conditions; neurocognitive test; novel; older women; parent grant; poor sleep; primary outcome; prospective test; racial population; recruit; repaired; resilience; sleep health; telomere; theories; transcriptome sequencing

Abstract We use a geroscience framework to advance Alzheimer’s disease-related dementias (ADRD) research by establishing how biological aging affects cognitive and physical decline and defining the role of sleep in these relationships. We use the interface of aging and breast cancer in older women for this purpose because of their unique bi-directional relationships. Biological aging processes increase the risk of developing cancer, so that newly diagnosed breast cancer patients may have accelerated aging prior to therapy. Cancer treatments can further accelerate aging processes. Despite possible inverse relationships between cancer and ADRD, breast cancer therapy is associated with short-term cognitive decline and this may be due to the effects of accelerated biological aging on underlying early ADRD or damage to similar systems as involved in ADRD. As we age, sleep is fundamental to repairing damage to maintain system regulation and homeostasis, including clearance of waste products seen in Alzheimer’s disease (AD). Poor sleep is common in cancer survivors and sleep has been associated with biological aging and/or physical decline and cognitive problems and increased risk for ADRD in non-cancer settings. However, there is very limited longitudinal research testing these relationships in older survivors with control groups to inform research into cognitive aging and early ADRD. Our transdisciplinary team of nationally recognized leaders in aging and cancer, biological aging, sleep, neuroscience, Alzheimer’s disease and geriatrics are uniquely placed to fill this gap. The proposed study leverages an extant cohort to efficiently conduct a novel new study of the effects of biological aging on health. Our primary research questions are: 1) Do breast cancer survivors have more biological aging before systemic treatment than concurrent frequency- matched non-cancer controls?, 2) Do systemic treatments drive further biological aging and lower cognitive and physical function in survivors beyond that seen in non-cancer controls over time? and 3) Does poor sleep lead to more aging and lower function? To address these questions, we begin with breast cancer survivors (N=368) aged 60+ and contemporaneously evaluated non-cancer controls (N=354) frequency-matched to survivors on age, racial group, education level and recruitment site. These women have rich pre-treatment/enrollment neurocognitive, physical and sleep data and blood obtained and banked to specifically test aging markers. We will conduct follow-up out to 48-months and perform assays of several hallmarks of biological aging (epigenetic age, DNA damage, cellular senescence, SASP, and leukocyte telomere length). While accelerated biological aging has been postulated to explain cognitive and functional decline among people with and without cancer, this rigorous project will be the first to our knowledge to definitively evaluate this theory. The population and questions proposed are significant and will only become more important with the aging of the population. This clinical translational project addresses key NIA priority areas and will provide important data to inform future ADRD studies and interventions to improve health and resilience of our aging population.

摘要 我们使用老年科学框架来推进阿尔茨海默病相关痴呆（ADRD）的研究， 确定生物衰老如何影响认知和身体衰退，并确定睡眠在这些方面的作用。 关系。我们在老年妇女中使用衰老和乳腺癌的界面，因为他们 独特的双向关系。生物老化过程会增加患癌症的风险，因此， 新诊断的乳腺癌患者可能在治疗前加速衰老。癌症治疗可能会 进一步加速老化过程。尽管癌症和ADRD之间可能存在反比关系，但乳腺癌和ADRD之间可能存在负相关关系。 癌症治疗与短期认知能力下降有关，这可能是由于加速的 潜在早期ADRD的生物学老化或ADRD中涉及的类似系统的损伤。随着年龄的增长，睡眠 是修复损伤以维持系统调节和体内平衡的基础，包括清除废物 阿尔茨海默氏病（AD）中常见的产品。睡眠不足在癌症幸存者中很常见，睡眠一直是 与生物老化和/或身体衰退和认知问题相关， 非癌症环境。然而，在老年人中测试这些关系的纵向研究非常有限。 幸存者与对照组，为认知老化和早期ADRD的研究提供信息。我们的跨学科团队 在衰老和癌症、生物衰老、睡眠、神经科学、阿尔茨海默病等领域的国家公认的领导者 而老年病学是填补这一空白的独特之处。拟议的研究利用现有的队列， 对生物老化对健康的影响进行一项新的研究。我们的主要研究问题是：1） 乳腺癌幸存者在系统治疗前的生物老化是否比并发频率更高- 匹配的非癌症对照组2)系统性治疗是否会导致进一步的生物衰老和降低认知能力， 随着时间的推移，幸存者的身体功能是否超过非癌症对照组？（3）睡眠不好会导致 衰老和功能下降的原因吗为了解决这些问题，我们开始与乳腺癌幸存者（N=368） 年龄60岁以上和同期评价的非癌症对照组（N=354）与存活者频率匹配， 年龄、种族、教育程度和招聘地点。这些女性有丰富的治疗前/入组 神经认知、身体和睡眠数据以及血液，并将其储存起来以专门测试衰老标志物。我们 将进行48个月的随访，并对生物衰老的几个标志（表观遗传学）进行分析 年龄、DNA损伤、细胞衰老、SASP和白细胞端粒长度）。虽然加速生物 衰老已经被假定为解释患有和没有癌症的人的认知和功能下降， 据我们所知，这个严谨的项目将是第一个明确评估这一理论的项目。人口和 所提出的问题十分重要，而且随着人口老化，这些问题只会变得更加重要。这 临床转化项目解决了NIA的关键优先领域，并将提供重要数据，为未来的研究提供信息。 ADRD研究和干预措施，以改善我们老龄化人口的健康和恢复力。