PHYSIOLOGIC & MOLECULAR BASIS OF THE SYNDROME OF FRAILTY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。老年病学家普遍认为，随着年龄的增长，身体虚弱越来越普遍。体弱多病的老年人被确定为老年人的高风险人群，他们最有可能住院、功能下降、早期发病和死亡。虚弱发展的机制尚不清楚，可能与潜在的疾病过程有关。然而，很可能存在与年龄相关的生理参数变化，这些变化在某些个体中被夸大了，这可能会影响该综合征的发展。具体目的是：1)通过肌肉力量和力量评估，描述标准化定义的虚弱表型与骨骼肌质量和功能之间的关系；2)表征虚弱与皮质醇分泌、性类固醇水平、甲状腺功能、免疫系统功能和细胞因子水平之间的关系；3)确定体弱者生理和分子参数之间的关系。为了帮助确定潜在的生理因素，这些因素可能允许早期干预并阻止虚弱综合征的发展，我们将从约翰霍普金斯大学和周围中心的各种来源中识别虚弱和非虚弱的个体。年龄在70岁至70岁之间的人将被筛查，但不包括那些有可能导致虚弱定义异常的医疗条件的人；如帕金森病、脑血管意外伴残缺偏瘫、症状性类风湿性疾病、症状性心血管疾病、Folstein Mini Mental score异常水平。我们将检查这些病例的医疗图表，然后对那些没有被排除在医疗诊断之外的患者进行以下检查。虚弱被定义为具有3-5个组成部分的综合征，包括握力无力，超过15英尺的定时步行速度缓慢，主观评估疲劳和低体力活动，以及在过去2年内无意中体重减轻5%或更多。使用相同的检查，我们将确定一组年龄匹配的对照，不符合上述标准。体弱多病和非体弱多病的参与者将在GCRC参加研究的第二部分。拟人化测量将在护士检查后进行，包括皮肤褶皱、二头肌、三头肌和大腿内侧的测量，使用口径和卷尺测量。将对GCRC单元进行DEXA扫描，以测量总瘦体重、总脂肪质量和骨密度。将抽取血液样本，并收集尿液，这将是一个24小时的样本，第二天返回到单位进行分析。我们已经确定了免疫和内分泌系统功能在虚弱和非虚弱队列之间的显著差异。我们已经确定，与非体弱个体相比，体弱个体的淋巴细胞增殖率较低，并且现在已经确定了体弱和非体弱参与者单核细胞中的差异基因表达。这些发现可能有助于解释为什么体弱的老年人感染和败血症的风险比非体弱的成年人高得多，并将导致其他涉及免疫系统标志物的转化实验。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Frailty is widely viewed by geriatricians as increasingly prevalent with old age. Elderly individuals who are frail are identified as a high risk subset of older adults who are most at risk for hospitalization, functional decline and early morbidity and mortality. The mechanisms by which frailty develop are unclear and may be related to underlying disease processes. However, it is likely that there are age related variations in physiologic parameters that are exaggerated in some individuals and which may influence the development of this syndrome. The specific aims are: 1) to characterize the association of a standardized defined phenotype of frailty with skeletal muscle mass and function as assessed by muscle power and strength; 2) to characterize the association between frailty and cortisol secretion, sex steroid levels, thyroid function, immune system function, and levels of cytokines; and 3) determine the relationship between physiologic and molecular parameters in the frail. To help identify underlying physiologic factors that may allow earlier interventions and head off the development of the syndrome of frailty, we will identify frail and non-frail individuals from a variety of sources throughout Johns Hopkins and surrounding centers. Ages >70 individuals will be screened excluding those with medical conditions that may cause abnormalities in the definition of frailty; such as Parkinson's disease, cerebral vascular accident with residual hemiparesis, symptomatic rheumatoid disease, symptomatic cardiovascular disease, and level of abnormality in the Folstein Mini Mental score. We will review medical charts for these and then perform the following exam on those who are not excluded secondary to medical diagnosis. Frailty is defined as having 3-5 components of a syndrome consisting of grip strength weakness, slow timed walking speed over 15 feet, subjective assessment of fatigue and low physical activity as well as unintentional weight loss of 5% or greater in the past 2 years. Using the same exam, we will identify a group of age-matched controls that meet none of the above criteria. The frail and non-frail participants will be enrolled in the second portion of the study at the GCRC. Anthropomorphic measurements will be performed after a nurse's exam, involving skin fold, biceps, triceps and inner thigh measurements using caliber and tape measurements. A DEXA scan will be performed on the GCRC unit in order to take meaurements of total lean body mass, total fat mass, and bone mineral density. Blood samples will be drawn on the unit as well as urine collection, which will be a 24-hour sample, returned to the unit the next day for analysis. We have identified significant differences in immune and endocrine system function between frail and non-frail cohorts. We have identified a lower lymphocyte proliferation rate in those frail individuals as compare to non-frail, and have now identified differential gene expression in monocytes from frail and non-frail participants. These findings may help explain why frail older adults are at much higher risk of infection and sepsis than non-frail adults, and will lead to other translational experiements involving immune system markers.