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. In an independent study, we are screening for BER single nucleotide polymorphisms within the BLSA sample populations. Any findings from the initial screen will be replicated in an independent cohort.
|Soerensen, Mette; Dato, Serena; Tan, Qihua et al. (2013) Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity. Age (Dordr) 35:487-500|