Accelerated Aging During Chronic Oxidative Stress: A Role For Parp-1?

Oxidative stress plays a major role in the pathophysiology of chronic inflammatory diseases, but 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. Loss of telomeric DNA will result in telomere shortening and eventually cellular senescence. Research has shown that poly(ADP‐ribose)‐polymerase‐1 (PARP‐1) plays a role in telomere length regulation. We hypothesized that PARP‐1 plays a role in accelerated aging in chronic inflammatory diseases. In cultured human fibroblasts, effects of mild and strong inhibition of PARP‐1 under conditions of chronic oxidative stress, induced by tert‐butyl hydroperoxide (t‐BHP), were investigated. Fisetin (Fis), a flavonoid, was used as a mild inhibitor and Minocycline (Mino), an antibiotic, as a strong inhibitor of PARP‐1. Results indicated that t‐BHP and Mino alone induced a delay in cell growth and accelerated telomere shortening. However, when Mino was given in combination with t‐BHP, cells did not show a decrease in telomere length. Additionally, both Fis and Mino lowered the transcription of inflammation‐related genes in cells treated with t‐BHP. We conclude that PARP‐1 inhibition appears to be beneficial in conditions of chronic oxidative stress, but may be detrimental under relatively normal conditions.