The Aryl Hydrocarbon Receptor, Epigenetics and the Aging Process.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor, classically associated with the regulation of xenobiotic metabolism in response to environmental toxins. In recent years, transgenic rodent models have implicated AhR in aging and longevity. Moreover, several AhR ligands, such as resveratrol and quercetin, are compounds proven to extend the lifespan of model organisms. In this paper, we first review AhR biology with a focus on aging and highlight several AhR ligands with potential anti-aging properties. We outline how AhR-driven expression of xenobiotic metabolism genes into old age may be a key mechanism through which moderate induction of AhR elicits positive benefits on longevity and healthspan. Furthermore, via integration of publicly available datasets, we show that liver-specific AhR target genes are enriched among genes subject to epigenetic aging. Changes to epigenetic states can profoundly affect transcription factor binding and are a hallmark of the aging process. We suggest that the interplay between AhR and epigenetic aging should be the subject of future research and outline several key gaps in the current literature. Finally, we recommend that a broad range of non-toxic AhR ligands should be investigated for their potential to promote healthspan and longevity.

Reverse Translational Study of Fenofibrate's Observed Effects in Diabetes-Associated Retinopathy.

Clinical trials suggest that fenofibrate reduces the progression of retinopathies in patients with type 2 diabetes. Furthermore, patients with retinopathies have elevated levels of inflammatory chemokines and dysfunctional retinal angiogenesis. Therefore, we investigated the effects of fenofibrate on the production of inflammatory chemokines and genes associated with angiogenesis. Retinal pigment epithelial cells (RPECs) were cultured with IL-1ß and fenofibrate ranging from 1-50 µM. ENA-78, IL-8, and RANTES were measured in cell culture by ELISA. ENA-78, ABCA1, and ABCG1 gene expression were tested by RT-PCR. IL-1ß significantly induced the production of ENA-78, IL-8, and RANTES. Fenofibrate at concentrations of 25-50 uM blunted the IL-1ß induced production of ENA-78 (p < 0.05) with no significant effects on RANTES and IL-8. Fenofibrate also reduced the expression of the ENA-78 gene as well as ABCA1 and ABCG1, which are genes involved in angiogenesis. Fenofibrate decreases ENA-78 production and ABCA1/ABCG1 gene expression in RPECs.

Redefinitions of indications for percutaneous nephrostomy.

An analysis of treatment response in 215 patients treated by percutaneous nephrostomy identified obstruction of the urinary tract, complicated by infection and sometimes gram-negative septicemia, as the single most important indication for this intervention. Percutaneous nephrostomy reduced the mortality from gram-negative septicemia from 40% to 8%. Similarly, the length of hospitalization for patients with severe infection complicating urinary tract obstruction was reduced by half in the group undergoing percutaneous nephrostomy. In 43 patients with longstanding obstruction, percutaneous nephrostomy was used to predict recoverable renal function based on the response of renal plasma flow rate to decompression. In 13 patients, percutaneous nephrostomies were used either for the introduction of solvents to dissolve calculi or to serve as pathways for their extraction. Percutaneous nephrostomies in 21 patients were expanded to serve as points of entry for the placement of stent catheters to treat fistulas or bougie catheters to dilate and subsequently catheterize ureteral strictures. While six serious complications were encountered, five of these might have been prevented by meticulous adherence to proper technique.