This review focuses on the emerging evidence that attenuation of the production of reactive oxygen species and inhibition of inflammatory pathways play a central role in the antiaging cardiovascular effects of caloric restriction. Particular emphasis is placed on the potential role of the plasma membrane redox system in caloric restriction-induced pathways responsible for sensing oxidative stress and increasing cellular oxidative stress resistance. We propose that caloric restriction increases bioavailability of NO, decreases vascular reactive oxygen species generation, activates the Nrf2/antioxidant response element pathway, inducing reactive oxygen species detoxification systems, exerts antiinflammatory effects, and, thereby, suppresses initiation/progression of vascular disease that accompany aging.

Mechanisms Underlying Caloric Restriction and Lifespan Regulation Implications for Vascular Aging

The Sir2 histone deacetylases are important for gene regulation, metabolism, and longevity. A unique feature of these enzymes is their utilization of NAD+ as a cosubstrate, which has led to the suggestion that Sir2 activity reflects the cellular energy state. We show that SIRT1, a mammalian Sir2 homologue, is also controlled at the transcriptional level through a mechanism that is specific for this isoform. Treatment with the glycolytic blocker 2-deoxyglucose (2-DG) decreases association of the redox sensor CtBP with HIC1, an inhibitor of SIRT1 transcription. We propose that the reduction in transcriptional repression mediated by HIC1, due to the decrease of CtBP binding, increases SIRT1 expression. This mechanism allows the specific regulation of SIRT1 in response to nutrient deprivation.

https://www.pnas.org/content/pnas/104/3/829.full.pdf

Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex

The plasma membrane redox system in aging

Calorie restriction attenuates age-related alterations in the plasma membrane antioxidant system in rat liver.

Transcriptional regulation of the antioxidant response element (ARE) by Nrf2 is important for the cellular adaptive response to toxic insults. New data show that primary skin-derived fibroblasts from the long-lived Snell dwarf mutant mouse, previously shown to be resistant to many toxic stresses, have elevated levels of Nrf2 and of multiple Nrf2-sensitive ARE genes. Dwarf-derived fibroblasts exhibit many of the traits associated with enhanced activity of Nrf2/ARE, including higher levels of glutathione and resistance to plasma membrane lipid peroxidation. Treatment of control cells with arsenite, an inducer of Nrf2 activity, increases their resistance to paraquat, hydrogen peroxide, cadmium, and UV light, rendering these cells as stress resistant as untreated cells from dwarf mice. Furthermore, mRNA levels for some Nrf2-sensitive genes are elevated in at least some tissues of Snell dwarf mice, suggesting that the phenotypes observed in culture may be mirrored in vivo. Augmented activity of Nrf2 and ARE-responsive genes may coordinate many of the stress resistance traits seen in cells from these long-lived mutant mice.

Nrf2 Signaling, a Mechanism for Cellular Stress Resistance in Long-Lived Mice

Pulmonary arterial endothelial cells possess transplasma membrane electron transport (TPMET) systems that transfer intracellular reducing equivalents to extracellular electron acceptors. As one asp...

Nicholas J. Kettenhofen

Papers

Intracellular redox status affects transplasma membrane electron transport in pulmonary arterial endothelial cells