PROJECT SUMMARY Telomere length is considered a good biomarker of organismal and cellular aging. Telomeres get progressively shorter with each cell division and rates of cellular turnover vary from cell type to cell type and tissue to tissue. When telomeres become critically short, cells arrest their proliferation and go into senescence resulting in tissue dysfunction. Telomere length and the rate of telomere shortening shows a great deal of interindividual variability and is dependent on many factors including genetics, age, environment, and lifestyle. Several age- related diseases have been associated with telomere shortening including pulmonary fibrosis, COPD, liver fibrosis, aplastic anemia, myelodysplastic syndrome, Alzheimer’s disease, Parkinson’s disease, myocardial hypertrophy, dilated cardiomyopathy, ischemia-reperfusion injury, chronic kidney disease, kidney fibrosis, osteoporosis, and osteoarthritis. The effect of genetics on telomere length has been estimated to be 35-85% and at least 17 genes have been reported to regulate telomere length and cause telomere biology disorders (TBD) when disrupted (DKC1, TERC, TERT, NOP10, NHP2, TINF2, WRAP53, CTC1, RTEL1, PARN, ACD, POT1, NAF1, STN1, ZCCHC8, RPA1, and DCLRE1B). These genes do not explain all cases of TBD and more telomere length regulators have yet to be characterized. Our proposal is in response to NOT-AG-23-020, which is meant “to encourage the use of existing cohorts and datasets for well-focused secondary analyses” to address critical questions in aging research. We have designed our proposal to harness the unique large data resources at Vanderbilt University Medical Center (VUMC), including idiopathic pulmonary fibrosis (IPF) and BioVU, and the large public data resources (GTEx consortium, All of Us, and the UK Biobank). We will reanalyze these datasets, combining multi-omics modeling and phenome-scale interrogation, to identify new genes and variants responsible for telomere shortening, telomere disease risk, premature aging, and their phenome-wide consequences. By re-analyzing large data sets already at our disposal, we will be able to identify novel genes and variants responsible for the telomere shortening and provide a more complete picture of the role of aberrant telomere length and dysfunctional telomere maintenance in pathophysiological processes. A better understanding of the genetic and biological drivers of telomere shortening may provide insights into disease risk, earlier diagnosis, and new kinds of therapies. Our Aims are to: 1) Determine the genetic basis of telomere shortening in diverse tissues, 2) Determine the phenome-wide consequences of telomere length using large-scale biobanks, 3) Identify disease causing variants (DVs) in novel genes associated with Telomere Biology Disorders (TBD)