Using DNA Repair and Damage as a Tool in Personalizing Aging and Aging Related Diseases

This project aims to use DNA repair and damage as a tool to personalize aging and aging-related diseases, with a particular focus on US veterans who are at increased risk for lung diseases such as COPD and lung cancer. The global population, including our veterans, is aging rapidly, with the percentage of people aged 60 and over projected to equal that of those younger than 15 by 2050. Aging is characterized by a range of characteristic DNA alterations, including decreasing telomere length, epigenetic alterations, and genomic instability, which are considered hallmarks of aging. Decreased expression of DNA repair genes through epigenetic regulation is implicated in the development of lung, breast, and other cancers of advancing age, providing a plausible mechanism by which accumulated DNA damage leads to genomic instability. Additionally, decreased DNA repair has been linked to accelerated COPD in an early aging pattern. Through our previous work, we have optimized a host cell reactivation-coupled flow-cytometry assay to measure titratable levels of DNA repair capacity (DRC) for two repair pathways, Nucleotide Excision Repair (NER) and Non-Homologous End Joining (NHEJ), in human cryopreserved peripheral blood mononuclear cells (PBMCs). The research hypothesis is that individual DRC measured in human PBMCs is decreased with age and further decreased in those with aging diseases including lung cancer and COPD and can be modified by lifestyle modifications. The study will measure NER and NHEJ DRC in cryopreserved PBMCs as well as DNA damage collected from young subjects, as well as those with and without age-related lung diseases, to determine if DRC can serve as a personalizing biomarker of premature biological aging. The study will also investigate whether specific lifestyle interventions, particularly in a high-risk population, can help improve DNA repair and decrease DNA damage as a step towards modifying aging processes and its related diseases. The project's outcomes are expected to identify the interaction between DRC and biologic vs. physiologic aging, as well as interrogate the mechanistic impact. The project will also determine the impact of specific DNA repair/damage processes on the risk of developing lung cancer and COPD, as well as how individual PBMC DRC is affected by modifiable lifestyle factors. The results of this study will have a strong impact on understanding the aging process and aging-related diseases. Additionally, it can help identify those at increased risk for such diseases, allowing for personalized, targeted interventions, including lifestyle modification or early, disease-specific screening Project Number: 1IK2BX006464-01A2 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Nawar Al Nasrallah | Institution: RLR VA MEDICAL CENTER, INDIANAPOLIS, IN | Activity Code: IK2 | Study Section: Special Emphasis Panel[ZRD1 PULM-T (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11053367