Muscle, Fat and NK Lymphocytes in Aging

描述(由申请者提供)：我们认为肌肉量减少和肥胖都是通过负向调节自然杀伤(NK)淋巴细胞的数量和功能而导致与年龄相关的免疫衰老。初步研究表明，在老年女性中，体重指数与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人类NK细胞的发育、存活和老年人的功能。众所周知，骨骼肌和脂肪通过细胞因子相互调节，包括脂肪衍生的肿瘤坏死因子(TNF)和IL-6，它们对NK细胞产生负面影响。肌肉产生的这些细胞因子水平较低，但产生大量的IL-15，IL-15控制脂肪，对NK细胞的发育和生存是绝对必要的，也是限速的。基于我们的观察，我们提出了两个假说：肌肉促进NK细胞的发育和存活，脂肪负向调节NK细胞。肌肉通过IL-15支持NK细胞，脂肪通过肿瘤坏死因子和IL-6抑制NK细胞。我们的新假设引出了两个预测，这两个预测将在老年人身上得到验证。1)NK细胞数量和功能与骨骼肌肌力和肌力呈正相关，与内脏脂肪呈负相关。2)血浆IL-15水平与肌力、体重、NK细胞数量和功能呈正相关，与内脏脂肪呈负相关。我们的跨学科团队 拥有肌肉生物学、NK免疫、身体成分测量和生物统计学方面的专业知识。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是否在这一过程中发挥作用。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，并可能提出治疗石棺减少和衰老中免疫力下降的新方法。

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.