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

摘要 我们使用老年科学框架来推动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，并确定睡眠在其中的作用 两性关系。我们在老年女性中使用衰老和乳腺癌的接口来达到这一目的，因为他们 独特的双向关系。生物衰老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了衰老。癌症治疗可以 进一步加快老龄化进程。尽管癌症和ADRD之间可能存在反向关系，但乳房 癌症治疗与短期认知功能下降有关，这可能是由于加速的 潜在的早期ADRD的生物老化或与ADRD相关的类似系统的损害。随着年龄的增长，睡觉吧 是修复损害以维持系统调节和动态平衡的基础，包括清除废物 阿尔茨海默氏症(AD)中的产品。睡眠不佳在癌症幸存者中很常见，而睡眠一直以来 与生物衰老和/或身体衰退、认知问题和ADRD风险增加有关 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，告知关于认知老化和早期ADRD的研究。我们的跨学科团队 在老龄化和癌症、生物衰老、睡眠、神经科学、阿尔茨海默病等领域的国家公认领导者 而老年医学在填补这一空白方面处于独特的地位。这项拟议的研究利用现有的队列来有效地 对生物衰老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) 乳腺癌幸存者在全身治疗前的生物衰老是否比同时发生的频率更多- 匹配的非癌症对照？2)全身治疗是否会进一步导致生物衰老和认知能力下降 随着时间的推移，幸存者的身体功能是否超出了非癌症对照组的水平？3)睡眠不好会导致 衰老程度更高，机能更差？为了解决这些问题，我们从乳腺癌幸存者(N=368)开始。 60岁以上的同时评估的非癌症对照组(N=354)与以下患者的幸存者频率匹配 年龄、种族、教育程度和招聘地点。这些妇女有丰富的治疗前/入学情况 获得并储存神经认知、身体和睡眠数据以及血液，以专门测试衰老标记物。我们 将进行为期48个月的随访，并对生物老化的几个特征进行分析(表观遗传学 年龄、DNA损伤、细胞衰老、SASP和白细胞端粒长度)。虽然加速的生物 衰老被认为可以解释癌症患者和非癌症患者的认知和功能衰退， 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 提出的问题很重要，随着人口老龄化，这些问题只会变得更加重要。这 临床翻译项目解决了NIA的关键优先领域，并将提供重要数据供未来参考 ADRD研究和干预措施，以改善我们老龄化人口的健康和复原力。

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.