DNA damage and repair in old and young and in participants in the BLSA

老年人、年轻人以及 BLSA 参与者的 DNA 损伤和修复

• 批准号: 8552452
• 负责人: Vilhelm A Bohr
• 金额: $ 18.12万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552452
• 关键词: Age; Aging; Aging-Related Process; Animals; Baltimore; Biological Markers; Blood Cells; Cell Aging; Cells; Chemicals; Clinical; DNA; DNA Damage; DNA Repair; Disease; Double Strand Break Repair; Environment; Exposure to; Fluorescent Antibody Technique; Genetic Transcription; Genomic Instability; Histones; Human; Hypertension; Individual; Lesion; Life; Longitudinal Studies; Metabolism; Morbidity - disease rate; Normal Cell; Oxidative Stress; Participant; Phosphorylation; Population; Proteins; Radiation; Recording of previous events; Relative (related person); Role; Surrogate Markers; Testing; Variant; Vitamin D Deficiency; age related; cancer risk; cell age; human morbidity; repaired; research study

Double strand breaks are very dangerous lesions in DNA and must be repaired to allow cells to complete replication and transcription. Cells with deficiencies in double strand break repair are subject to genomic instability and individuals with these deficiencies are often at elevated risk for cancer. The presence of double strand breaks can be determined by examining cells for the phosphorylated form of a histone protein variant known as H2AX. Phosphorylation of the protein occurs rapidly in the vicinity of a double strand break, and persists until the break is repaired. Consequently phospho-H2AX (g-H2AX) serves as a surrogate marker for breaks. This species can be easily detected by immunofluorescence techniques, and thus can be detected in single cells. We sought to test the hypothesis that double strand breaks are present in elevated levels in cells from aged individuals, as compared with younger individuals. Our analysis reveals that g-H2AX foci increase in a linear fashion with regards to age, peaking at 57 years. We found a significant increase in foci in individuals with a known history of vitamin D deficiency as well as in individuals 57 y/o with hypertension. Our results support a role for increased DNA damage in the morbidity of age-related diseases and that g-H2AX may be a biomarker for human morbidity in age-related diseases. We are currently investigating the correlations between -H2AX foci and different clinical diseases which are known to be associated with genome instability and/or oxidative stress.  

双链断裂是DNA中非常危险的损伤，必须进行修复才能让细胞完成复制和转录。双链断裂修复缺陷的细胞容易受到基因组不稳定的影响，并且具有这些缺陷的个体患癌症的风险通常较高。双链断裂的存在可以通过检查细胞中组蛋白变体（H2AX）的磷酸化形式来确定。蛋白质的磷酸化在双链断裂附近迅速发生，并持续到断裂被修复。因此，磷酸-H2AX (g-H2AX) 可作为断裂的替代标记。该物种可以通过免疫荧光技术轻松检测到，因此可以在单细胞中检测到。我们试图检验这样的假设：与年轻个体相比，老年个体的细胞中双链断裂的水平升高。我们的分析表明，g-H2AX 病灶随年龄呈线性增长，在 57 岁时达到峰值。我们发现，已知有维生素 D 缺乏病史的个体以及 57 岁患有高血压的个体中，病灶显着增加。我们的结果支持 DNA 损伤增加在年龄相关疾病发病中的作用，并且 g-H2AX 可能是人类年龄相关疾病发病的生物标志物。我们目前正在研究 -H2AX 病灶与已知与基因组不稳定和/或氧化应激相关的不同临床疾病之间的相关性。