[Show abstract][Hide abstract] ABSTRACT: A number of metabolic disturbances occur in response to the consumption of a high fat western diet. Such metabolic disturbances can include the progressive development of hyperglycemia, hyperinsulemia, obesity, metabolic syndrome, and diabetes. Cumulatively, diet-induced disturbances in metabolism are known to promote increased morbidity and negatively impact life expectancy through a variety of mechanisms. While the impact of metabolic disturbances on the hepatic, endocrine, and cardiovascular systems is well established there remains a noticeable void in understanding the basis by which the central nervous system (CNS) becomes altered in response to diet-induced metabolic dysfunction. In particular, it remains to be fully elucidated which established features of diet-induced pathogenesis (observed in non-CNS tissues) are recapitulated in the brain, and identification as to whether the observed changes in the brain are a direct or indirect effect of peripheral metabolic disturbances. This review will focus on each of these key issues and identify some critical experimental questions which remain to be elucidated experimentally, as well as provide an outline of our current understanding for how diet-induced alterations in metabolism may impact the brain during aging and age-related diseases of the nervous system.
Biochimica et Biophysica Acta 05/2009; · 4.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study examined brain and liver derived proteasome complexes to elucidate if there is a differential susceptibility in proteasome complexes from these tissues to undergo inactivation following exposure to oxidative stressors. It then examined the influence of ageing and dietary restriction (DR) on the observed proteasome inactivation. Studies used a filtration based methodology that allows for enrichment of proteasome complexes with less tissue than is required for traditional chromatography procedures. The results indicate that the brain has much lower levels of overall proteasome activity and exhibits increased sensitivity to hydrogen peroxide mediated inactivation as compared to proteasome complexes derived from the liver. Interestingly, the brain proteasome complexes did not appear to have increased susceptibility to 4-hydroxynonenal (HNE)-induced inactivation. Surprisingly, ageing and DR induced minimal effects on oxidative stress mediated proteasome inhibition. These results indicate that the brain not only has lower levels of proteasome activity compared to the liver, but is also more susceptible to inactivation following exposure to some (but certainly not all) oxidative stressors. This data also suggest that ageing and DR may not significantly modulate the resistance of the proteasome to inactivation in some experimental settings.
Free Radical Research 01/2009; 43(1):28-36. · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dietary restriction (DR), in the absence of malnutrition, is the only intervention known to reliably increase average and maximal lifespan in a variety of organisms including mammals. Because the effects of DR on the heart are poorly understood, in the present study we examined the effects of DR on the ubiquitin-proteasome pathway (UPP) in the heart. In these studies we observed that DR significantly reduced age-related impairments in proteasome-mediated protein degradation, and reduced age-related increases in ubiquitinated, oxidized, and sumoylated protein in the heart. Interestingly, DR did not significantly increase the expression of 20S proteasome subunits or the proteasome maturation factor (POMP-1). These data demonstrate for the first time the effects of aging and DR on proteasome biogenesis and sumoylation in the heart. Cumulatively, our data indicate that DR has many beneficial effects towards the UPP in the heart, and suggests that a preservation of the UPP may be a potential mechanism by which DR mediates beneficial effects on the cardiovascular system.
Mechanisms of Ageing and Development 10/2008; 129(9):515-21. · 3.26 Impact Factor