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

双链断裂是DNA中非常危险的损伤，必须修复才能使细胞完成复制和转录。双链断裂修复缺陷的细胞易受基因组不稳定性的影响，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测细胞中被称为H2AX的组蛋白变体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）作为断裂的替代标记物。该物种可以很容易地通过免疫荧光技术检测到，因此可以在单细胞中检测到。我们试图验证这样一个假设，即与年轻人相比，老年个体的细胞中双链断裂的水平升高。我们的分析显示，g-H2AX病灶随年龄呈线性增长，在57岁时达到峰值。我们发现，已知维生素D缺乏史的个体以及57岁/岁的高血压患者的病灶显著增加。我们的研究结果支持DNA损伤增加在年龄相关疾病发病率中的作用，并且g-H2AX可能是人类年龄相关疾病发病率的生物标志物。我们目前正在研究-H2AX位点与已知与基因组不稳定性和/或氧化应激相关的不同临床疾病之间的相关性。

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.