Muscle, Fat and NK Lymphocytes in Aging

衰老过程中的肌肉、脂肪和 NK 淋巴细胞

• 批准号: 8384461
• 负责人: Charles T. Lutz
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384461
• 关键词: Abbreviations; Address; Adipocytes; Adipose tissue; Affect; Age; Aging; Area; Biological Assay; Biology; Biometry; Body Composition; Body mass index; Cell Count; Cell physiology; Cessation of life; Clinical Research; Coin; Communicable Diseases; Communication; Complex; DNA Nucleotidylexotransferase; Development; Dose-Limiting; Dual-Energy X-Ray Absorptiometry; Elderly; Elderly woman; Enzyme-Linked Immunosorbent Assay; Fatty acid glycerol esters; Goals; Human; Immune system; Immunity; Immunoglobulins; In Situ Nick-End Labeling; Individual; Infection; Inflammatory; Interferons; Interleukin-15; Interleukin-6; Investigation; Kentucky; Killer Cells; Label; Lead; Link; Lymphocyte; Lymphocyte Count; Lymphocyte Function; Malignant Neoplasms; Measurement; Measures; Medical; Membrane; Monoclonal Antibodies; Morbidity - disease rate; Muscle; Muscle Fibers; Natural Killer Cells; Obesity; Peripheral; Peripheral Blood Mononuclear Cell; Plasma; Process; Research Personnel; Role; Skeletal Muscle; Surface; Techniques; Testing; Thick; Time; Tumor Necrosis Factor-alpha; Universities; Visceral; Woman; Work; X-Ray Computed Tomography; age related; base; college; cytokine; fighting; healthy aging; human subject; immune function; immunosenescence; improved; innovation; interleukin-15 receptor; loss of function; monocyte; mortality; muscle form; muscle strength; neuronal cell body; novel; operation; receptor; receptor expression; research and development; sarcopenia; wasting; young adult

DESCRIPTION (provided by applicant): We propose that both sarcopenia (loss of muscle mass) and obesity contribute to age-related immunosenescence by negatively regulating natural killer (NK) lymphocyte number and function. Preliminary studies showed an inverse correlation between body mass index and NK cell number in elderly women, but not in young adult women. Therefore, the interplay between skeletal muscle and adipose tissue may contribute to control of human NK cell development, survival, and function in the elderly. Skeletal muscle and fat are known to regulate each other via cytokines, including adipose-derived tumor necrosis factor (TNF) and IL-6, which negatively impact NK cells. Muscle produces lower levels of these cytokines, but produces abundant IL-15, which controls fat and is both absolutely required and rate-limiting for NK cell development and survival. Based on our observations we propose two hypotheses: Muscle promotes NK development and survival and fat negatively regulates NK cells. Muscle supports NK cells via IL-15 and fat inhibits NK cells via TNF and IL-6. Our novel hypotheses lead to two predictions that will be tested in the elderly. 1) NK cell number and function will correlate directly with skeletal muscle strength and mass and correlate inversely with visceral fat mass. 2) Plasma IL-15 will correlate directly with muscle strength and mass and NK cell number and function, but correlate inversely with visceral fat. Our interdisciplinary team has expertise in muscle biology, NK immunity, body composition measurement, and biostatistics. Our highly innovative work will address for the first time whether skeletal muscle affects NK cells and whether IL-15 has a role in this process. Our work will have a highly significant impact because it will open completely new areas of investigation and may suggest novel ways to treat both sarcopenia and declining immunity in aging. PUBLIC HEALTH RELEVANCE: We will investigate a new idea that muscle is good for the immune system and fat is bad for the immune system in elderly people. Specifically, we will test the effects of muscle and fat on natural killer (NK) lymphocytes that are important in fighting infections and cancer. If this idea is correct, it could open up new ways to treat fat accumulation muscle loss, and immune system weakness in old age.

描述（由申请人提供）：我们提出，肌肉减少症（肌肉质量损失）和肥胖都通过负调节自然杀伤（NK）淋巴细胞数量和功能而导致年龄相关的免疫衰老。初步研究表明，老年女性的体重指数和NK细胞数量呈负相关，但在年轻成年女性中则不然。因此，骨骼肌和脂肪组织之间的相互作用可能有助于控制老年人NK细胞的发育、存活和功能。已知骨骼肌和脂肪通过细胞因子相互调节，包括脂肪源性肿瘤坏死因子（TNF）和IL-6，其对NK细胞产生负面影响。肌肉产生较低水平的这些细胞因子，但产生丰富的IL-15，它控制脂肪，是NK细胞发育和存活的绝对必需和限速。根据我们的观察，我们提出了两个假设：肌肉促进NK细胞的发育和存活，脂肪负调节NK细胞。 肌肉通过IL-15支持NK细胞，脂肪通过TNF和IL-6抑制NK细胞。 我们的新假设导致两个预测，将在老年人中进行测试。1)NK细胞数量和功能与骨骼肌强度和质量直接相关，与内脏脂肪质量负相关。2)血浆IL-15与肌肉力量和质量以及NK细胞数量和功能直接相关，但与内脏脂肪负相关。 我们的跨学科团队 在肌肉生物学、NK免疫、身体成分测量和生物统计学方面具有专长。我们高度创新的工作将首次解决骨骼肌是否影响NK细胞以及IL-15是否在此过程中发挥作用。我们的工作将产生非常重要的影响，因为它将开辟全新的研究领域，并可能提出治疗肌肉减少症和衰老免疫力下降的新方法。 公共卫生关系：我们将研究一个新的想法，即肌肉对免疫系统有益，脂肪对老年人的免疫系统有害。具体来说，我们将测试肌肉和脂肪对自然杀伤（NK）淋巴细胞的影响，这些淋巴细胞在对抗感染和癌症方面很重要。如果这个想法是正确的，它可以开辟新的方法来治疗脂肪积累肌肉损失，以及老年免疫系统虚弱。