Muscle, Fat and NK Lymphocytes in Aging

描述（由申请人提供）：我们认为肌肉减少症（肌肉量减少）和肥胖都通过负性调节自然杀伤（NK）淋巴细胞数量和功能而导致与年龄相关的免疫衰老。初步研究表明，老年妇女的体重指数与NK细胞数量呈负相关，但在年轻成年妇女中没有。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，它们对NK细胞产生负面影响。肌肉产生较低水平的这些细胞因子，但产生大量的IL-15， IL-15控制脂肪，是NK细胞发育和存活的绝对必需和限速的物质。根据我们的观察，我们提出两个假设：肌肉促进NK细胞的发育和存活，脂肪负调控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种预测，将在老年人身上得到验证。1) NK细胞数量和功能与骨骼肌力量和质量呈正相关，与内脏脂肪质量呈负相关。2)血浆IL-15与肌肉力量和质量、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

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.