This project seeks to speed both the understanding of aging and aging-related diseases, and the development of precision medicine interventions to increase the duration of healthy adult life, by developing novel low-cost, high-throughput assays for several sequence features of telomeric DNA. Telomeres, the DNA and protein complexes at the ends of linear chromosomes, prevent the chromosome ends from being recognized by the cell as double-strand breaks in the DNA, which would otherwise trigger a DNA damage response. The DNA sequence at the telomere consists of hundreds to thousands of tandem repeats of a six-base sequence, TTAGGG (AATCCC on the other DNA strand), ending with a single-stranded overhang of the G-rich strand that is up to a few hundred bases long. The telomeric DNA sequence shortens during aging in all of the body's tissues in which cells regularly divide, with the exception of the egg and sperm-forming tissues (the germline). Eventually, telomere shortening causes tissues to lose healthy cells, either to programmed cell death, or by cells entering a dysfunctional state called cellular senescence, or by cells becoming cancerous. Telomere shortening is now believed to contribute to the development of a wide variety of aging-related diseases. Importantly, there is significant variation between age-matched people in both telomere length and the rate of telomere shortening, and this variation contributes significantly to differences in how long people live.
Aim 1 is to improve the existing quantitative polymerase chain reaction (QPCR) assays for average telomere length;
Aim 2 is to develop completely novel QPCR assays for the shortest, and the longest, telomeres;
and Aim 3 is to develop novel QPCR assays for the average lengths of telomeric single-stranded 3' or 5' overhangs. All of these telomeric measures of genomic stability will then be quantified in DNA samples from a well-studied set of 47 three-generation Utah families, and tested for associations with overall survival, cause-specific mortality, and several quantitative biomarkers of aging. Future studies seeking the underlying causes (genetic and non-genetic) of inter-individual variation in these telomeric quantitative traits will also be enabled by these assays. Improved, low-cost, high-throughput assays of telomere sequence features may allow early detection of the people at greatest risk of developing telomere-related diseases. Also, these assays should be useful in testing the effectiveness of new telomere-directed therapeutics as they are being developed. Once safe and effective telomere-directed therapeutics are available, since patients' responses to treatment are likely to vary, these assays may also help in monitoring responses, so that treatment dosages and schedules may be tailored on an individual basis, a goal of precision medicine.
Telomeres, specialized structures found at the ends of chromosomes, contain a tandemly repeated DNA sequence that is progressively lost with age in many tissues, eventually causing tissue dysfunction and the onset of multiple aging-related diseases. This project will develop novel low-cost, high-throughput quantitative assays for several features of telomeric DNA, and test their association with overall survival, cause-specific mortality, and several biomarkers of aging. These assays may eventually prove useful in assessing an individual's risk for aging- related diseases, and tailoring interventions to reduce that risk.
