Neurobiol Aging. 2010 Jun 10.
 [Impact of aging and caloric restriction on white matter]  Effects of aging and calorie restriction on white matter in rhesus macaques.
Bendlin BB, Canu E, Willette A, Kastman EK, McLaren DG, Kosmatka KJ, Xu G, Field AS, Colman RJ, Coe CL, Weindruch RH, Alexander AL, Johnson SC.
Geriatric Research Educational and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI, USA; University of Wisconsin School of Medicine and Public Health, Department of Medicine, Madison, WI, USA.
Abstract:
Rhesus macaques on a calorie restricted diet (CR) develop less age-related disease, have virtually no indication of diabetes, are protected against sarcopenia, and potentially live longer. Beneficial effects of caloric restriction likely include reductions in age-related inflammation and oxidative damage. Oligodendrocytes are particularly susceptible to inflammation and oxidative stress, therefore, we hypothesized that CR would have a beneficial effect on brain white matter and would attenuate age-related decline in this tissue. CR monkeys and controls underwent diffusion tensor imaging (DTI). A beneficial effect of CR indexed by DTI was observed in superior longitudinal fasciculus, fronto-occipital fasciculus, external capsule, and brainstem. Aging effects were observed in several regions, although CR appeared to attenuate age-related alterations in superior longitudinal fasciculus, frontal white matter, external capsule, right parahippocampal white matter, and dorsal occipital bundle. The results, however, were regionally specific and also suggested that CR is not salutary across all white matter. Further evaluation of this unique cohort of elderly primates to mortality will shed light on the ultimate benefits of an adult-onset, moderate CR diet for deferring brain aging.
 

Int J Mol Med. 2011 Jan;27(1):95-102. doi: 10.3892/ijmm.2010.556. Epub 2010 Nov 10.
[Findings on the effect of intermittent fasting on the diabetic syndrome] Intermittent fasting modulation of the diabetic syndrome in sand rats. III. Post-mortem investigations.
Belkacemi L, Selselet-Attou G, Bulur N, Louchami K, Sener A, Malaisse WJ.
Laboratoire de Technologie Alimentaire et Nutrition, Université de Mostaganem, Mostaganem, Algeria.
Abstract:
The present report concerns several post-mortem variables examined in sand rats that were either maintained on a vegetal diet (control animals) or exposed first during a 20-day transition period to a mixed diet consisting of a fixed amount of a hypercaloric food and decreasing amounts of the vegetal food and then to a 30-day experimental period of exposure to the hypercaloric food. During the latter period, all animals were either given free access to food or fasting daily for 15 h, i.e. from 5.00 p.m. to 8.00 a.m. The body weight, liver wet weight, pancreas wet weight, plasma glucose and haemoglobin A1c concentration, plasma insulin concentration, insulinogenic index, insulin resistance HOMA, plasma cholesterol and triglyceride concentration, liver triglyceride and phospholipid content were all measured. Pancreatic islet (insulin, GLUT2) and liver (lipid droplets) histology were also examined. The main findings consisted in a lower body weight of fasting than non-fasting animals, a higher liver weight in non-diabetic and diabetic rats than in control non-fasting (but not so in fasting) animals, a decrease of pancreas weight in non-diabetic and diabetic as distinct from control animals, a fasting-induced decrease in plasma glucose, plasma insulin and insulin resistance HOMA, plasma cholesterol and triglyceride concentration and triglyceride liver content.
 

Rejuvenation Res. 2010 Nov 3. 

[Reprogramming of Differentiated Cells to Stem-Like Self-Renewal States]  Pharmacological Mimicking of Caloric Restriction Elicits Epigenetic Reprogramming of Differentiated Cells to Stem-Like Self-Renewal States.

Oliveras-Ferraros C, Vazquez-Martin A, Menendez JA.
Catalan Institute of Oncology (ICO) , Girona, Catalonia, Spain .
Abstract:
Abstract Networks of oncogenes and tumor suppressor genes that control cancer cell proliferation also regulate stem cell renewal and possibly stem cell aging. Because (de)differentiation processes might dictate tumor cells to retrogress to a more stem-like state in response to aging-relevant epigenetic and/or environmental players, we recently envisioned that cultured human cancer cells might be used as reliable models to test the ability of antiaging interventions for promoting the initiation and maintenance of self-renewing divisions. Cancer cell lines naturally bearing undetectable amounts of stem/progenitor-like cell populations were continuously cultured in the presence of the caloric restriction mimetic metformin for several months. Microarray technology was employed to profile expression of genes related to the identification, growth, and differentiation of stem cells. Detection of functionally related gene groups using a pathway analysis package provided annotated genetic signatures over- and underexpressed in response to pharmacological mimicking of caloric restriction. By following this methodological approach, we recently obtained data fitting a model in which, in response to chronic impairment of cellular bioenergetics imposed by metformin-induced mitochondrial uncoupling as assessed by the phosphorylation state of cAMP-response element binding protein (CREB), tumor cells can retrogress from a differentiated state to a more CD44(+) stem-like primitive state epigenetically governed by the Polycomb-group suppressor BMI1-a crucial "stemness" gene involved in the epigenetic maintenance of adult stem cells. These findings might provide a novel molecular avenue to investigate if antiaging benefits from caloric restriction mimetics might relate to their ability to epigenetically reprogram stemness while prolonging the capacity of stem-like cell states to proliferate, differentiate, and replace mature cells in adult aging tissues.

 

Curr Pharm Des. 2010;16(7):877-83.
[Dietary antidioxidant effects on free radical-related diseases]  The hormetic role of dietary antioxidants in free radical-related diseases.
Calabrese V, Cornelius C, Trovato A, Cavallaro M, Mancuso C, Di Rienzo L, Condorelli D, De Lorenzo A, Calabrese EJ.
Department of Chemistry, University of Catania, Catania, Italy. calabres@unict.it
Abstract:
Regular consumption of cruciferous vegetables or spices is associated with a reduced incidence of cancer and reduction of markers for neurodegenerative damage. Furthermore, greater health benefit may be obtained from raw as opposed to cooked vegetables. Nutritional interventions, by increasing dietary intake of fruits and vegetables, can retard and even reverse age-related declines in brain function and cognitive performance. The mechanisms through which dietary supplementation with antioxidants may be useful to prevent free radical-related diseases is related to their ability to counteract toxic production of both reactive oxygen and nitrogen species, along with the up-regulation of vitagenes, such as members of the heat shock protein (Hsp) family heme oxygenase-1 and Hsp70. The most prominent dietary factor that affects the risk of many different chronic diseases is energy intake - excessive calorie intake increases the risk. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against diseases, in part, by hormetic mechanisms that increase cellular stress resistance. This biphasic dose-response relationship, referred to here as hormesis, display low-dose stimulation and a high-dose inhibition. Despite the current interest in hormesis by the toxicology community, quantitatively similar U-shaped dose responses have long been recognized by researchers to be involved with factors affecting memory, learning, and performance, as well as nutritional antioxidants and oxidative stress-mediated degenerative reactions. Dietary polyphenols present strong cytoprotective effects, however under uncontrolled nutritional supplementation gene induction effects and the interaction with detoxification responses can have negative consequences through the generation of more reactive and harmful intermediates.
 

Cell Metab. 2010 Dec 1;12(6):662-7.
[Reduction of oxidative stress through caloric restriction]  Calorie Restriction Reduces Oxidative Stress by SIRT3-Mediated SOD2 Activation.
Qiu X, Brown K, Hirschey MD, Verdin E, Chen D.
Department of Nutritional Science & Toxicology, University of California, Berkeley, CA 94720, USA.
Abstract:
A major cause of aging and numerous diseases is thought to be cumulative oxidative stress, resulting from the production of reactive oxygen species (ROS) during respiration. Calorie restriction (CR), the most robust intervention to extend life span and ameliorate various diseases in mammals, reduces oxidative stress and damage. However, the underlying mechanism is unknown. Here, we show that the protective effects of CR on oxidative stress and damage are diminished in mice lacking SIRT3, a mitochondrial deacetylase. SIRT3 reduces cellular ROS levels dependent on superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme. SIRT3 deacetylates two critical lysine residues on SOD2 and promotes its antioxidative activity. Importantly, the ability of SOD2 to reduce cellular ROS and promote oxidative stress resistance is greatly enhanced by SIRT3. Our studies identify a defense program that CR provokes to reduce oxidative stress and suggest approaches to combat aging and oxidative stress-related diseases.
 

Biochem Biophys Res Commun. 2010 Dec 3. 
[ Adipose and liver stress reduced through caloric restriction]Caloric restriction decreases ER stress in liver and adipose tissue in ob/ob mice.
Tsutsumi A, Motoshima H, Kondo T, Kawasaki S, Matsumura T, Hanatani S, Igata M, Ishii N, Kinoshita H, Kawashima J, Taketa K, Furukawa N, Tsuruzoe K, Nishikawa T, Araki E.
Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Abstract:
Endoplasmic reticulum (ER) stress plays a crucial role in the development of insulin resistance and diabetes. Although caloric restriction (CR) improves obesity-related disorders, the effects of CR on ER stress in obesity remain unknown. To investigate how CR affects ER stress in obesity, ob/ob mice were assigned to either ad libitum (AL) (ob-AL) or CR (ob-CR) feeding (2 g food/day) for 1-4 weeks. The body weight (BW) of ob-CR mice decreased to the level of lean AL-fed littermates (lean-AL) within 2 weeks. BW of lean-AL and ob-CR mice was less than that of ob-AL mice. Ob-CR mice showed improved glucose tolerance and hepatic insulin action compared with ob-AL mice. Levels of ER stress markers such as phosphorylated PKR-like ER kinase (PERK) and eukaryotic translation initiation factor 2α and the mRNA expression of activating transcription factor 4 were significantly higher in the liver and epididymal fat from ob-AL mice compared with lean-AL mice. CR for 2 and 4 weeks significantly reduced all of these markers to less than 35% and 50%, respectively, of the levels in ob-AL mice. CR also significantly reduced the phosphorylation of insulin receptor substrate (IRS)-1 and c-Jun NH(2)-terminal kinase (JNK) in ob/ob mice. The CR-mediated decrease in PERK phosphorylation was similar to that induced by 4-phenyl butyric acid, which reduces ER stress in vivo. In conclusion, CR reduced ER stress and improved hepatic insulin action by suppressing JNK-mediated IRS-1 serine-phosphorylation in ob/ob mice.
 

J Mol Med. 2010 Dec 8. [Epub ahead of print]
[Improved post-ischemic recovery and cardiac metabolism through caloric restriction]  Improved cardiac metabolism and activation of the RISK pathway contributes to improved post-ischemic recovery in calorie restricted mice.
Sung MM, Soltys CL, Masson G, Boisvenue JJ, Dyck JR.
Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada.
Abstract:
Recent evidence has suggested that activation of AMP-activated protein kinase (AMPK) induced by short-term caloric restriction (CR) protects against myocardial ischemia-reperfusion (I/R) injury. Because AMPK plays a central role in regulating energy metabolism, we investigated whether alterations in cardiac energy metabolism contribute to the cardioprotective effects induced by CR. Hearts from control or short-term CR mice were subjected to ex vivo I/R and metabolism, as well as post-ischemic functional recovery was measured. Even in the presence of elevated levels of fatty acids, CR significantly improved recovery of cardiac function following ischemia. While rates of fatty acid oxidation or glycolysis from exogenous glucose were similar between groups, improved functional recovery post-ischemia in CR hearts was associated with high rates of glucose oxidation during reperfusion compared to controls. Consistent with CR improving energy supply, hearts from CR mice had increased ATP levels, as well as lower AMPK activity at the end of reperfusion compared to controls. Furthermore, in agreement with the emerging concept that CR is a non-conventional form of pre-conditioning, we observed a significant increase in phosphorylation of Akt and Erk1/2 at the end of reperfusion. These data also suggest that activation of the reperfusion salvage kinase (RISK) pathway also contributes to the beneficial effects of CR in reducing post-ischemia contractile dysfunction. These findings also suggest that short-term CR improves post-ischemic recovery by promoting glucose oxidation, and activating the RISK pathway. As such, pre-operative CR may be a clinically relevant strategy for increasing ischemic tolerance of the heart.
 

Toxicol Appl Pharmacol. 2010 Nov 28. [Epub ahead of print]
[Effects of Atorvastat treatment on the liver] Reduction of liver Fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after Atorvastatin treatment.
Vilà L, Rebollo A, Ađalsteisson GS, Alegret M, Merlos M, Roglans N, Laguna JC.
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona.
Abstract:
Consumption of beverages that contain fructose favors the increasing prevalence of metabolic syndrome alterations in humans, including non-alcoholic fatty liver disease (NAFLD). Although the only effective treatment for NAFLD is caloric restriction and weight loss, existing data show that atorvastatin, a hydroxymethyl-glutaryl-CoA reductase inhibitor, can be used safely in patients with NAFLD and improves hepatic histology. To gain further insight into the molecular mechanisms of atorvastatin's therapeutic effect on NAFLD, we used an experimental model that mimics human consumption of fructose-sweetened beverages. Control, fructose (10% w/v solution) and fructose+atorvastatin (30 mg/kg/day) Sprague-Dawley rats were sacrificed after 14 days. Plasma and liver tissue samples were obtained to determine plasma analytes, liver histology, and the expression of liver proteins that are related to fatty acid synthesis and catabolism, and inflammatory processes. Fructose supplementation induced hypertriglyceridemia and hyperleptinemia, hepatic steatosis and necroinflammation, increased the expression of genes related to fatty-acid synthesis and decreased fatty acid β-oxidation activity. Atorvastatin treatment completely abolished histological signs of necroinflammation, reducing the hepatic expression of metallothionein-1 and nuclear factor kappa B binding. Furthermore, atorvastatin reduced plasma (x0.74) and liver triglyceride (x0.62) concentrations, decreased the liver expression of carbohydrate response element binding protein transcription factor (x0.45) and its target genes, and increased the hepatic activity of the fatty acid β-oxidation system (x1.15). These effects may be related to the fact that atorvastatin decreased the expression of fructokinase (x0.6) in livers of fructose-supplemented rats, reducing the metabolic burden on the liver that is imposed by continuous fructose ingestion.