Dietary Supplements and Inflammation Phase-2 (Metabolic Mechanisms and Interventions for Healthy Aging in Females)

项目摘要/摘要：老年女性比男性更有可能患有损害健康的疾病或残疾 独立生活的活动并威胁生活质量。广泛损害健康和健康的机制 老年女性的福祉尚不完全清楚，但中年进入更年期的过渡以及 随后循环雌激素减少，是女性寿命中一个特别显着的里程碑。众多 研究证明，绝经期卵巢激素的丧失与卵巢激素的丧失之间存在关联。 对认知、身体能力和免疫健康领域的保护作用。雌激素通常作用于这些 系统优化由线粒体氧化磷酸化支持的细胞代谢。雌激素流失 中年时期与氧化应激增加和炎症反应增强有关。荷尔蒙 替代疗法的目的是缓解更年期的体征和症状，但其广泛的作用 不良风险，有时甚至危及生命。确定恢复适当的补充策略 围绝经期和绝经后妇女的代谢和免疫活动的平衡可以减缓与年龄相关的 认知、身体和免疫健康下降，但不会带来其他与年龄相关的疾病的风险。的 生酮饮食可能满足这些标准，因为食用这种高脂肪/低碳水化合物饮食从根本上改变了 代谢特征，将依赖从葡萄糖转向脂肪衍生的酮体，同时也 减轻炎症。与这一观点一致，我们的初步数据表明生酮饮食 改善老年雌性大鼠的认知和线粒体功能。该项目的目标是阐明 生酮饮食减缓多种功能域与年龄相关的衰退的机制 女性寿命。该项目将使用正常衰老的大鼠来 1) 确定生酮饮食对性别的特定影响 与年龄相关的大脑、肌肉和免疫功能下降，2) 确定生酮饮食的保护作用 对手术后雌激素缺乏的中年女性的认知、身体功能和免疫状况的影响。这些 在控制良好的衰老和更年期动物模型中进行营养酮症研究将具有重要意义，因为 他们可以提供必要的机制见解来指导适当的翻译和开发 医生可以推荐作为老年女性主要或辅助疗法的饮食干预措施 进入更年期并面临与年龄相关的疾病的风险。更广泛地说，识别特定性别和 适合年龄的饮食指南，以减缓驱动生理和细胞的基本机制 老龄化将广泛改善老年妇女的健康状况并减少对激素替代疗法的依赖 疗法作为对抗更年期症状的一线治疗。这些目标在科学范围内 南卡罗来纳大学 COBRE 关于膳食补充剂的范围，并将完成严格的任务 对导致衰老风险增加的潜在分子和细胞机制的科学研究 绝经前和绝经后妇女的疾病（阿尔茨海默病、肌肉减少症）。

Project Summary/Abstract: Older women are more likely than men to live with disease or disability that impairs activities for independent living and threatens quality of life. The mechanisms that broadly diminish health and well-being among aging women are not fully understood, but the transition into menopause at mid-life, and the ensuing decrease in circulating estrogens, is a particularly salient milestone in the female lifespan. Numerous studies document an association between the loss of ovarian hormones at menopause and the loss of their protective effects in domains of cognition, physical ability, and immune health. Estrogens typically act upon these systems to optimize cellular metabolism supported by mitochondrial oxidative phosphorylation. Loss of estrogens at middle-age is associated with increased oxidative stress and enhanced inflammatory responses. Hormone replacement therapy is prescribed to relieve signs and symptoms of menopause, but its broad actions carry undesirable and sometimes life-threatening risks. Identifying complementary strategies that restore the proper balance of metabolic and immune activities in peri- and post-menopausal women could decelerate age-related declines in cognitive, physical, and immune health without incurring risk for other age-associated diseases. The ketogenic diet may fulfill these criteria as consuming this high fat/low carbohydrate diet fundamentally alters metabolic profiles, shifting dependence away from glucose in favor of fat-derived ketone bodies, while also attenuating inflammation. Consistent with this view our preliminary data demonstrate that a ketogenic diet improved cognitive and mitochondrial function in aging female rats. The goal of this project is to elucidate the mechanisms by which the ketogenic diet decelerates age-related decline in multiple functional domains over the female lifespan. This project will use normally aging rats to 1) determine sex-specific effects of ketogenic diet on age-related decline of brain, muscle, and immune function and 2) determine protective effects of ketogenic diet on cognition, physical function, and immune profiles in surgically estrogen-deficient, middle-aged females. These studies of nutritional ketosis in well-controlled animal models of aging and menopause will be significant because they can provide the necessary mechanistic insights to guide the translation and development of appropriate dietary interventions that physicians can recommend as primary or adjuvant therapies to older women transitioning into menopause and at risk for age-related disorders. More broadly, identifying sex-specific and age-appropriate dietary guidelines to decelerate fundamental mechanisms that drive physiological and cellular aging will broadly improve health outcomes for older women and reduce reliance on hormone replacement therapy as a first-line treatment to combat symptoms of menopause. These objectives are within the scientific scope of the University of South Carolina’s COBRE on Dietary Supplements and will accomplish rigorous scientific research on the underlying molecular and cellular mechanisms of aging leading to increased risk of disease (Alzheimer's disease, sarcopenia) in pre- and post-menopausal women.