Accelerated Aging during Chronic Oxidative Stress: A Role for PARP-1

Abstract

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.

Demonstration of potential link between Helicobacter pylori related promoter CpG island methylation and telomere shortening in human gastric mucosa

“…In blood cells, biological age predicted by DNA methylation status rather than chronological age is well correlated more with telomere length shortening and acquired aplastic anemia or dyskeratosis congenita - two diseases associated with progressive bone marrow failure [32]. The link between telomere shortening and subtelomeric DNA methylation was also confirmed in vitro using human fibroblasts cultured under conditions of chronic oxidative stress, induced by tert-butyl hydroperoxide [33]. Together with link between H. pylor i related PCGI methylation and telomere shortening in the stomach, it is suggested that alteration of telomere shortening and DNA methylation predict various pathological state and clinical outcomes across the different tissue types.…”

Pregnancy‐associated venous insufficiency course with placental and systemic oxidative stress

“…The complete study was performed with 114 patients, including 62 women with VI during pregnancy and 52 control women without evidence of VI during pregnancy. The mean age is 33 [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] VI and 34 [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] HC. Not exist significant differences in the mean age of patients (P = .06915).…”

“…53,54 Oxidative stress severely impairs cellular metabolism that involves mitochondrial function, and it damages molecules such as DNA. 32,55,56 The critical metabolism regulator iNOS is expressed in conditions of cellular oxidative stress. 19,52 We have observed the selective overexpression of iNOS in syncytiotrophoblast cells from the placentas of women with pregnancy-associated VI.…”

“…55,60 Thus, PARP expression is a biomarker of DNA damage. 32 Indeed, increased PARP expression has been observed in cytotrophoblast cells suffering from oxidative stress. 49 Our findings demonstrate an enhanced PARP expression in the syncytiotrophoblast and decidual cells in the placentas of women with pregnancy-associated VI.…”

“…28,29 Authors have observed how oxidative stress and metabolic changes can create DNA damage that is associated with an increase in poly(ADP-ribose) polymerase PARP (PARP) repair activity. [30][31][32] In this sense, the mitogen-activated protein kinase/ extracellular signal-regulated (MAPK/ERK) pathway has been mentioned as a point of great importance in cellular damage processes. Signalling pathways (MAPK/ERK) play fundamental roles in a wide range of cellular processes and are often deregulated in disease states.…”