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. Longevity is a complex trait that is influenced by the interaction of the environment with multiple genes. The heritable phenotype that predicts longevity is largely undefined. Individuals who harbor longevity assurance genes may be "protected" from vascular disease. We propose identifying aging related vascular phenotypes that are associated with longevity, as part of an ongoing study of longevity in the Old Order Amish. The parent study will recruit Amish probands who lived past the age of 95 years and their offspring. The spouses of the offspring will serve as controls. Identification of a longevity phenotype will later be used to identify genes associated with protection against aging related disease. The Old Order Amish is a founder population that is relatively homogeneous, genetically and environmentally; therefore, this population is desirable for identifying phenotypic and genetic predictors of longevity. The specific aims of this study are to 1) perform electron-beam CT scanning to measure coronary calcification as a measure of subclinical atherosclerosis in 200 subjects included in an ongoing NIH funded study of longevity in the Amish. Subjects will include 100 offspring of probands who lived past the age of 95 years, and 100 spouses of these offspring; 2) to determine if offspring of long-lived probands (cases) will have less atherosclerotic plaque burden, as measured by electron beam CT coronary artery calcium scanning, than their spouses (normal controls); 3) to determine if longevity assurance genes that protect against vascular aging can be identified through association studies of single nucleotide polymorphisms (SNP) with coronary calcification. This third specific aim will be the topic of future studies whithin this cohort. Potential candidate genes include Apo E, Werner locus, and Klotho. Characterization of a longevity phenotype and later identification of genes associated with longevity may provide important mechanistic information about successful vascular aging that may help to identify future therapeutic intervention to prevent disease.
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. The evaluation, treatment, and rehabilitation of frail older adults is a cornerstone of geriatric medicine. Most studies and our preliminary data support the concept that frail individuals are the most vulnerable subset of older adults, with significantly higher rates of morbidity, mortality, and functional decline as compared to age-matched individuals who are not frail. As increasing numbers of Americans live into their 80's and 90's, it will be of critical importance for investigators and clinicians to understand the physiologic basis of frailty and the evolution of disability in order to identify individuals at risk and to facilitate improved prevention and treatment. In the past several years, a number of papers have identified immunologic and endocrine factors that suggest a role in frailty and disability. The purpose and significance of this study is to identify the biologic correlates that may predict frailty in the WHAS II longitudinal study. Through longitudinal data collection and analyses, we may be able to identify causal pathways in these processes as well. In order to accomplish this, we will measure pro and anti- inflammatory cytokines, including IL-6, IFN-gamma, IL-10, and TNF-alpha in addition to any other cytokine deemed important in the evolution of these processes. In addition, hormones such as DHEA-S, IGF-1, salivary cortisol, estradiole, and testosterone will be measured and correlated with the adverse health outcomes of frailty, disability, and mortality.
