Accelerated aging during chronic oxidative stress: a role for PARP-1.

Oxidative stress plays a major role in the pathophysiology of chronic inflammatory disease and it has also been linked to accelerated telomere shortening. Telomeres are specialized structures at the ends of linear chromosomes that protect these ends from degradation and fusion. Telomeres shorten with each cell division eventually leading to cellular senescence. Research has shown that poly(ADP-ribose) polymerase-1 (PARP-1) and subtelomeric methylation play a role in telomere stability. We hypothesized that PARP-1 plays a role in accelerated aging in chronic inflammatory diseases due to its role as coactivator of NF-κb and AP-1. Therefore we evaluated the effect of chronic PARP-1 inhibition (by fisetin and minocycline) in human fibroblasts (HF) cultured under normal conditions and under conditions of chronic oxidative stress, induced by tert-butyl hydroperoxide (t-BHP). Results showed that PARP-1 inhibition under normal culturing conditions accelerated the rate of telomere shortening. However, under conditions of chronic oxidative stress, PARP-1 inhibition did not show accelerated telomere shortening. We also observed a strong correlation between telomere length and subtelomeric methylation status of HF cells. We conclude that chronic PARP-1 inhibition appears to be beneficial in conditions of chronic oxidative stress but may be detrimental under relatively normal conditions.

Mild oxidative damage in the diabetic rat heart is attenuated by glyoxalase-1 overexpression.

Diabetes significantly increases the risk of heart failure. The increase in advanced glycation endproducts (AGEs) and oxidative stress have been associated with diabetic cardiomyopathy. We recently demonstrated that there is a direct link between AGEs and oxidative stress. Therefore, the aim of the current study was to investigate if a reduction of AGEs by overexpression of the glycation precursor detoxifying enzyme glyoxalase-I (GLO-I) can prevent diabetes-induced oxidative damage, inflammation and fibrosis in the heart. Diabetes was induced in wild-type and GLO-I transgenic rats by streptozotocin. After 24-weeks of diabetes, cardiac function was monitored with ultrasound under isoflurane anesthesia. Blood was drawn and heart tissue was collected for further analysis. Analysis with UPLC-MSMS showed that the AGE Nε-(1-carboxymethyl)lysine and its precursor 3-deoxyglucosone were significantly elevated in the diabetic hearts. Markers of oxidative damage, inflammation, and fibrosis were mildly up-regulated in the heart of the diabetic rats and were attenuated by GLO-I overexpression. In this model of diabetes, these processes were not accompanied by significant changes in systolic heart function, i.e., stroke volume, fractional shortening and ejection fraction. This study shows that 24-weeks of diabetes in rats induce early signs of mild cardiac alterations as indicated by an increase of oxidative stress, inflammation and fibrosis which are mediated, at least partially, by glycation.

Telomere length, oxidative stress, and antioxidant status in elderly men in Zutphen and Crete.

The incidence of chronic diseases such as cardiovascular diseases is lower in Mediterranean Southern Europe than Northern Europe. This may be due to a lower level of oxidative stress and a higher antioxidant status in people living around the Mediterranean Sea. Oxidative stress may influence the rate of shortening of telomeres, the nucleoprotein structures at the ends of chromosomes. We compared leukocyte telomere length (LTL) in elderly men from Northern and Southern Europe and investigated the possible relationship between LTL and indicators of oxidative stress and antioxidant status. We examined 143 elderly Dutch men (mean age 83.9 years) and 109 Greek elderly men (mean age 84.6 years) and found that the Greek men had significantly longer telomeres (geometric mean 4.95 kbp, 95% confidence interval (CI): 4.71-5.23 kbp) compared to the men from the Netherlands (4.76 kbp, 95% CI: 4.55-4.98 kbp; P=0.001). Age was inversely associated with LTL (ß=-0.10, P=0.31 in Cretan men and ß=-0.19, P=0.02 in Dutch men). In all men LTL was not related to indicators of oxidative stress and plasma antioxidants. However, the endogenous antioxidants serum albumin (ß=0.18, P=0.007) and uric acid (ß=0.13, P=0.045) were positively associated with LTL. The age-adjusted difference between Crete and Zutphen was reduced by 25% after adjustment for serum albumin and uric acid. We conclude that Greek elderly men have significantly longer LTL compared to Dutch counterparts. The endogenous antioxidants albumin and uric acid were positively associated with longer telomeres.