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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000729-21
Application #
8931576
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
Zip Code
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
Soerensen, Mette; Dato, Serena; Tan, Qihua et al. (2012) Human longevity and variation in GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidant pathway genes: cross sectional and longitudinal studies. Exp Gerontol 47:379-87
Soerensen, Mette; Thinggaard, Mikael; Nygaard, Marianne et al. (2012) Genetic variation in TERT and TERC and human leukocyte telomere length and longevity: a cross-sectional and longitudinal analysis. Aging Cell 11:223-7
Andersen, Sofie Dabros; Keijzers, Guido; Rampakakis, Emmanouil et al. (2012) 14-3-3 checkpoint regulatory proteins interact specifically with DNA repair protein human exonuclease 1 (hEXO1) via a semi-conserved motif. DNA Repair (Amst) 11:267-77
Rasmussen, Lene Juel; Sander, Miriam; Wewer, Ulla M et al. (2011) Aging, longevity and health. Mech Ageing Dev 132:522-32
Minor, Robin K; Baur, Joseph A; Gomes, Ana P et al. (2011) SRT1720 improves survival and healthspan of obese mice. Sci Rep 1:70