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

项目摘要/摘要：老年妇女比男性更有可能患有疾病或残疾， 独立生活活动，威胁生活质量。广泛损害健康和 老年妇女的健康状况还没有完全了解，但中年妇女进入更年期的过渡， 随之而来的循环雌激素的减少，是女性寿命中特别突出的里程碑。许多 研究证明了绝经期卵巢激素的丢失与其分泌的激素的丢失之间的联系。 在认知、体能和免疫健康领域的保护作用。雌激素通常作用于这些 系统来优化线粒体氧化磷酸化支持的细胞代谢。雌激素丢失 在中年时，与氧化应激增加和炎症反应增强有关。激素 替代疗法是规定，以减轻迹象和症状的更年期，但其广泛的行动进行 不受欢迎的，有时甚至危及生命的风险。确定补充战略， 绝经期和绝经后妇女代谢和免疫活动的平衡可以减缓年龄相关的 认知，身体和免疫健康下降，而不会引发其他年龄相关疾病的风险。的 生酮饮食可以满足这些标准，因为食用这种高脂肪/低碳水化合物饮食从根本上改变了 代谢谱，从葡萄糖转向脂肪衍生的酮体，同时还 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。这个项目的目标是阐明 生酮饮食减缓多个功能领域年龄相关性衰退的机制 女性寿命本项目将使用正常衰老的大鼠1）确定生酮饮食对大鼠的性别特异性影响， 与年龄相关的脑、肌肉和免疫功能下降; 2）确定生酮饮食的保护作用 对认知、身体功能和免疫功能的影响。这些 在控制良好的衰老和绝经动物模型中进行营养性酮症的研究将是重要的， 他们可以提供必要的机械见解，以指导翻译和发展适当的 饮食干预，医生可以推荐作为主要或辅助治疗老年妇女 过渡到更年期和年龄相关疾病的风险。更广泛地说，确定性别特异性和 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，减少对激素替代的依赖。 治疗作为一线治疗，以打击更年期症状。这些目标是在科学范围内 南卡罗来纳州的COBRE膳食补充剂的范围，并将完成严格的 对衰老的潜在分子和细胞机制进行科学研究， 疾病（阿尔茨海默病，肌肉减少症）在绝经前和绝经后的妇女。

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.