NAD+ metabolism controls inflammation during senescence

We have recently discovered that nicotinamide adenine dinucleotide metabolism controls the pro-inflammatory senescence-associated secretory phenotype during cellular senescence. This newly discovered epigenetic-metabolic signaling axis, mediated by high mobility group A and nicotinamide phosphoribosyltransferase, drives key metabolic changes and pro-inflammatory responses of senescent cells that fuel cancer progression

Inhibition of mTOR Prevents ROS Production Initiated by Ethidium Bromide-Induced Mitochondrial DNA Depletion

The regulation of mitochondrial mass and DNA content involves a complex interaction between mitochondrial DNA replication machinery, functional components of the electron transport chain, selective clearance of mitochondria, and nuclear gene expression. In order to gain insight into cellular responses to mitochondrial stress, we treated human diploid fibroblasts with ethidium bromide at concentrations which induced loss of mitochondrial DNA over a period of 7 days. The decrease in mitochondrial DNA was accompanied by a reduction in steady state levels of the mitochondrial DNA binding protein, TFAM, a reduction in several ETC protein levels, increased mitochondrial and total cellular ROS, and activation of p38 MAPK. However, there was an increase in mitochondrial mass and VDAC levels. In addition, mTOR activity, as judged by p70S6K targets, was decreased while steady state levels of p62/SQSTM1 and parkin were increased.Treatment of cells with rapamycin created a situation in which cells were better able to adapt to the mitochondrial dysfunction, resulting in decreased ROS and increased cell viability but did not prevent the reduction in mitochondrial DNA. These effects may be due to a more efficient flux through the electron transport chain, increased autophagy, or enhanced AKT signaling, coupled with a reduced growth rate. Together, the results suggest that mTOR activity is affected by mitochondrial stress, which may be part of the retrograde signal system required for normal mitochondrial homeostasis

Epigenetic Basis of Cellular Senescence and Its Implications in Aging

Cellular senescence is a tumor suppressive response that has become recognized as a major contributor of tissue aging. Senescent cells undergo a stable proliferative arrest that protects against neoplastic transformation, but acquire a secretory phenotype that has long-term deleterious effects. Studies are still unraveling the effector mechanisms that underlie these senescence responses with the goal to identify therapeutic interventions. Such effector mechanisms have been linked to the dramatic remodeling in the epigenetic and chromatin landscape that accompany cellular senescence. We discuss these senescence-associated epigenetic changes and their impact on the senescence phenotypes, notably the proliferative arrest and senescence associated secretory phenotype (SASP). We also explore possible epigenetic targets to suppress the deleterious effects of senescent cells that contribute towards aging

ARID1A mutation and genomic stability

We have recently discovered that AT-rich interactive domain-containing protein 1A (ARID1A) protects telomere cohesion through regulation of the cohesin subunit stromal antigen 1 (STAG1). ARID1A inactivation results in mitotic defects and negatively selects gross chromosomal aberrations, resulting in preservation of genomic stability in ARID1A-mutated cancers. These findings explain the long-standing paradox between mitotic defects caused by ARID1A inactivation and the lack of genomic instability in ARID1A-mutated cancers

The effect of oxidative stress on phagocytosis and apoptosis in the earthworm Eisenia hortensis

The effect of exogenous hydrogen peroxide (H202) on phagocytic function and apoptosis in coelomocytes from Eisenia hortensis was investigated. Treating coelomocytes with H202 (0.26 to 8.4 mM) evoked a significant increase in phagocytosis for one or more of the concentrations of H202 employed in 67 % of cases. Using annexin V-FITC we show that H202 induced apoptosis of coelomocytes in vitro. We found that 100 % of viable coelomocyte populations exhibited significant increases in phosphatidylserine translocation for one or more of the concentrations of H202 tested (8.4 to 67.6 mM). Using a fluorescent inhibitor of caspases, we revealed the presence of activated caspases observing increased caspase activity in 67 % of viable coelomocyte populations treated with 33.8mM H202, and in 100 % of cases treated with 67.6 mM H202. Agarose gel electrophoresis and the TUNEL assay showed DNA fragmentation in samples treated with 16.9 and 33.8 mM H202. In addition, endogenous H202 production during phagocytosis by hyaline amoebocytes was detected using a fluorogenic substrate. Thus, free radicals not only appear to facilitate phagocytosis and are produced during phagocytosis, but they also promote an oxidative-stress-induced apoptosis that may play an important function in regulating innate immune responses in E. hortensi