One aspect of aging that leads to the most common forms of morbidity and mortality is the aging of the vascular system. One of the most important processes involves the balance between the oxidative burden seen by the vasculature and the capacity of antioxidants to counteract that burden. Telomere length is also closely related to vascular aging, measuring biological age rather than chronological age. Telomeres determine processes related to cellular and DNA repair, cellular replicative capacity, and apoptosis. Shorter telomeres have been associated with decreased longevity and increased pulse pressure and cardiovascular disease. In addition, oxidant/antioxidant balance appears to play an important role in regulating the length of telomeres. Although the individual effects of each system have been studied in vitro and in small samples of human subjects, their individual and interactive effects have not been studied in large population cohorts to assess their influence on vascular aging and morbidity. One of the aims of this grant is to relate these two systems to comprehensive measures of vascular dysfunction and aging in a 22-year longitudinally followed cohort of 1500 relatives in 98 large Utah pedigrees. These comprehensive measures assess aging in multiple vascular beds and include small and large artery stiffness/compliance, carotid intima-media thickness, coronary and abdominal aortic calcium levels, endothelial function (flow mediated dilation), peripheral artery disease, and pulse pressure. Multiple measures of baseline and 22-year rates of change in total antioxidant capacity, indicators of total oxidant stress, and telomere length will be related to these subclinical aging indicators. Because pedigrees are being studied which already have genome search markers genotyped, some of the underlying genes contributing to the expression of the above phenotypes may be localized by linkage and identified through pedigree-based haplotype association analyses. Evidence of significant linkage for multiple antioxidants and other indicators of aging have been found in these pedigrees, and the underlying genes will be pursued and related to the subclinical vascular measures. This collection of longitudinally followed pedigrees provides a powerful study design to address a wide range of genetic epidemiological analyses of aging.
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