Our initial work focused on understanding DNA repair parameters on a population basis in the Healthy Aging in Neighborhood across the Life Span (HANDLS). We adapted the Alkaline Comet Assay to examine whether demographic and epidemiologic factors, such as age, sex, race, BMI, hypertension, tobacco or alcohol use, affect the repair capacity of single strand breaks (SSB) in humans. We examined repair of gamma-radiation-induced DNA damage in unstimulated cryopreserved peripheral blood mononuclear cells (PBMCs) from four age- and sex-matched groups of whites and African-Americans between ages 30-64. We found that age, race and sex affect the fast component of DNA repair, while the slow component was unaffected. In addition to assessing DNA repair capacity in the HANDLS cohort, we used our small comet study to correlate single strand break (SSB) level with markers of oxidant stress and inflammation and found that females have higher single strand break (SSB) levels than males and that there was a positive correlation between SSBs in African American males with both two markers of oxidative stress and inflammation, heme-degradation products and high-sensitivity C-reactive protein (hs-CRP). The data from the literature and from our preliminary study suggest a complex relationship between measures of oxidative stress and frequently used clinical parameters believed to reflect inflammation or oxidative stress. Since hs-CRP is linked to chronic inflammation that is a consequence of oxidative stress, it is relevant to examine the importance of hs-CRP as a biomarker of disease states related to oxidative stress. Accumulating evidence indicates that the levels of hsCRP are important for assessment of cardiovascular disease (CVD) risk and for the diagnosis and treatment of CVD. Recent data suggests that hsCRP is not only a marker of inflammation but may also contribute to the pathogenesis of vascular disease. However, whether hsCRP plays a direct role in promoting atherosclerotic processes is still controversial and little is known about how hsCRP may elicit these effects. Nonetheless, important information has been obtained from correlating findings discovered from human populations to in vitro studies. Since our work has shown that women had higher levels of DNA damage and lower levels of DNA repair, and it is known that women have higher levels of hsCRP than men and are particularly vulnerable to CVD we were anxious to examine the association between inflammation and oxidative stress by examining commonly assayed inflammatory markers and the DNA base adduct 8-oxodG, as a marker of oxidative stress in a cohort of middle-aged women with low, mid-range, and high hsCRP values. In the HANDLS cohort of women, matched on age and race in three groups (n=39 per group) who had low (<3 mg/L) hsCRP, mid (>320 mg/L), and high (>20 mg/L) hsCRP, we found a significant relationship between hsCRP level and the oxidative stress marker, 8-oxodG. 8-oxodG was positively correlated with systolic blood pressure, pulse pressure and IL-23. hsCRP was associated with obesity variables, HDL, serum insulin levels, IL-12p70 and ICAM-1. Incubation of primary human endothelial cells with hsCRP generated reactive oxygen species in vitro. Furthermore, hsCRP specifically induced DNA base lesions, but not other forms of DNA damage including single and double strand breaks. Our findings suggest that hsCRP production may enhance inflammatory processes, such as atherosclerosis and thrombosis, in part, by increasing oxidative stress and inducing DNA damage.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000519-09
Application #
8736573
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2013
Total Cost
$574,008
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Noren Hooten, Nicole; Martin-Montalvo, Alejandro; Dluzen, Douglas F et al. (2016) Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell 15:572-81
Plank-Bazinet, Jennifer L; Kornstein, Susan G; Clayton, Janine Austin et al. (2016) A Report of the Women's Health Congress Workshop on The Health of Women of Color: A Critical Intersection at the Corner of Sex/Gender and Race/Ethnicity. J Womens Health (Larchmt) 25:4-10
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Tin, Adrienne; Köttgen, Anna; Folsom, Aaron R et al. (2015) Genetic loci for serum magnesium among African-Americans and gene-environment interaction at MUC1 and TRPM6 in European-Americans: the Atherosclerosis Risk in Communities (ARIC) study. BMC Genet 16:56
Evans, Michele K; Longo, Dan L (2014) PALB2 mutations and breast-cancer risk. N Engl J Med 371:566-8

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