Abstract 006: Age And Sex Differentially Regulate Epigenetic Mechanisms In The Heart

Abstract

Understanding epigenetic mechanisms associated with aging might reveal potential biomarkers for aging as well as therapeutic targets for reversing or ameliorating aging pathologies, including cardiovascular disease. There is a sex difference in the age of onset of cardiovascular disease, where females are protected against age related changes, including hypertension and fibrosis, until menopause. We hypothesized that epigenetic mechanisms would be differentially regulated in a sex and age dependent manner, with changes in the older females reflecting the loss of estrogen with aging. To test this hypothesis, we examined heart tissue from 4-month (4M), 12-month (12M), and 24-month (24M)-old male and female C57BL/6JN mice (National Institute of Aging). Surprisingly histone deacetylase (HDAC) activity (ELISA) was significantly higher in all female mice than in age-matched males (4M, female 5.2 ± 0.6 vs male 2.8 vs 0.5; 12M, female 4.2 ± 0.4 vs male 1.3 ± 0.2; 24M, female 8.1 ± 0.6 vs male 2.3 ± 0.4; ng/min/mg protein; p < 0.05). In females age increased HDAC activity (35% increase 24M v 4M; p < 0.05). Western blot analysis revealed that expression levels of profibrotic class I HDACs were significantly higher in 12M and 24M old female mice (HDAC1, 52% and 48%, p < 0.05 and HDAC2, 52% and 79%, p < 0.05), respectively, as compared with age-matched males. However, histone acetyltransferase activity was comparable in all male and female groups as was histone 3 (H3) acetylation at lysine 9 and 27. Levels of circulating histones were determined in the serum. Histones are released in the extracellular space during disease state, act as damage-associated molecular pattern molecules and activate inflammatory pathways. Circulating H3 levels in serum increased significantly with age in both sexes (male 12M, 17.1 ± 1.4; and 24M, 21.4 ± 0.8 vs. 4M, 4.0 ± 0.6; ng/ml, p < 0.05; female 12M, 13.8 ± 2.1 and 24M, 17.4 ± 1.4 vs. 4M, 7.2 ± 1.0 p < 0.05). The data demonstrate the effect of age and sex in heart tissues with aged female mice exhibiting higher levels of profibrotic epigenetic enzymes compared to males. These findings will have important implications in age-related cardiac injury as aging is a primary risk factor for hypertension and related heart disease in men and women.