Primary Prevention of Alzheimer’s Disease (AD)

Alzheimer dementia (AD) is a complex, aging-associated disease whose effects on the brain (an organ made up by nonreplaceable cells) are devastating. Disease is not curable, but progress in pathobiology shows that intervention on aging can make primary prevention of AD feasible. According to the amyloid-cascade hypothesis, mechanisms of AD include: an age-related alteration of free radical metabolism in membranes, leading to a higher yield in the toxic Aβ1-42 peptide and an overwhelming impact on the weaker repair mechanisms of the aging cells. The proposed intervention on aging with anti-AD effects includes a daily assumption of antioxidants (red wine polyphenols enriched with resveratrol), a reinforcement of membrane antioxidant defenses by the assumption of polyunsaturated fatty acids at the first meal after fasting, and an enhancement of cell repair function (at the proteasome and autophagy level by an intermittent feeding regimen and physical exercise plus the assumption of antilipolytic agents during time of fasting). The beneficial effects of diet and physical activity on the endogenous production of protective nerve growth factors are magnified by an enriched environment. Treatment has already been started on healthy individuals at a higher risk of AD in the city of Volterra

Transmural gradient of glycogen metabolism in the normal rat left ventricle.

The changes of glycogen metabolism with the location of tissue within the ventricle wall have been explored in the rat myocardium. The hearts were cut in 100 microns thick serial sections and all sections were analyzed for their content in glycogen, glucose-6-phosphate, UDPG and glycogen enzymes and for glucose incorporation into glycogen and for the 2-deoxyglucose uptake after the intravenous injection of the 14C-labelled sugars. The rate of glycogen turnover was significantly higher in the subendocardial myocardium (P less than 0.01) and the levels of glucose-6-phosphate and the total (i.e. a + b) activity of glycogen phosphorylase were significantly higher in the subepicardial tissue (P less than 0.01 in both instances). No significant transmural gradient of UDPG was found and transmural changes of total (i.e. I + D) synthase activity were barely significant. These changes in glycogen metabolism may be related to regional differences in the cardiac work load and to a differentiation of the subendocardial and subepicardial heart fibers

Protein glycation in the aging male Sprague-Dawley rat: effects of antiaging diet restrictions

Protein glycation and accumulation of advanced glycosylated end-products (AGEs) are supposed to play an important role in the process of aging. Dietary restriction increases life span and delays the onset of most age-associated diseases. Age-dependent changes in glucose homeostasis and glycated plasma proteins and hemoglobin were determined, and AGEs formation was measured as fluorescence in skin and aortic collagens in male Sprague-Dawley rats fed ad libitum or subjected to every-other-day feeding or 40% food restriction. In aging control rats, skin and aortic collagen-linked fluorescence increased with a similar exponential curve (aortic value being always higher), whereas glycated plasma protein and hemoglobin decreased slightly. Dietary restrictions decreased glycated plasma proteins and fluorescent products in skin collagen of younger but not older rats, and did not affect glycated hemoglobin or aortic collagen fluorescence. In conclusion, our data indicate that age-related changes in glucose homeostasis do not play a substantial role in aging; and collagen-linked fluorescence increases significantly during aging, but it may not be sensitive to dietary intervention

Peroxisomes proliferation and pharmacological stimulation of autophagy in rat liver: evidence to support that autophagy may remove the “older” peroxisomes

Like mitochondria, peroxisomes produce reactive oxygen species (ROS), compounds which have been implicated to play an important role in many degenerative diseases and aging itself, and an exaggerated ROS production might occur in altered or older organelles. Growing evidence shows that autophagy, a required function in cell housekeeping during fasting, can remove damaged macromolecules, organelles, and membranes selectively. Proliferation of peroxisomes can be enhanced in liver cells by perfluorooctanoic acid (PFOA), which causes a marked increase of the Acyl-CoA oxidase (ACOX) activity and no significant change in urate oxidase (UOX) activity. The administration of antilipolytic drugs to fasted animals was shown to intensify autophagy. Here we tested the hypothesis that autophagy may distinguish and remove older from younger peroxisomes in rat liver. Male Sprague-Dawley rats were given PFOA (150 mg/kg body weight) or vehicle. Animals were sacrificed at different times following PFOA administration, and 3 h after the induction of autophagy with the antilipolytic agent 3,5-dimethyl pyrazole (DMP, 12 mg/kg body weight). The levels of ACOX and UOX activity were measured in the liver tissue. Results showed that autophagy caused a parallel, significant decrease in both enzymes activity in control rats, and that in PFOA-treated rats the effects were different and changed with PFOA time administration. Changes are compatible with the hypothesis that newly formed ACOX-rich peroxisomes are resistant to pexophagy and that sensitivity to pexophagy increases with increasing peroxisomal “age.” In conclusion, there is indirect evidence supporting the hypothesis that autophagy may recognize and degrade older peroxisomes

Impairment of the priming effect of glucose on insulin secretion from isolated islets of aging rats

The time-dependent potentiation (TDP) of insulin release or priming effect exerted by glucose was evaluated in the islets of Langerhans of mature and old rats. Islets isolated from 12- and 26-month-old male Sprague-Dawley rats and incubated for two consecutive 60-min periods in the presence of various stimulating agents were unable to enhance their insulin responsiveness significantly during the second incubation period and showed other abnormalities in their sensitivity to secretagogues compared with islets from 3-month-old animals. The priming action of glucose plus arginine or isobutylmethylxanthine (IBMX) was not observed in islets from 12-month-old rats, but surprisingly, islets from senescent rats showed a restoration of the beta-cell memory in the presence of IBMX. Interestingly, the islets isolated from 2-month-old animals previously exposed to an intravenous glucose load in vivo released approximately twice as much insulin as the islets taken from fed rats not subjected to the load. This potentiation exerted by the intravenous glucose administration was reduced but not abolished in the islets of glucose-intolerant, 12-month-old rats. In conclusion, the glucose TDP of insulin secretion is impaired in islets of mature and old rats, confirming an early loss of sensitivity of beta-cells to secretagogues during agin

Resveratrol Requires Red Wine Polyphenols for Optimum Antioxidant Activity

Objective: There is substantial evidence that a diet rich in fruit and vegetables may reduce the risk of aging and stress oxidative associated diseases. It has been suggested that benefits associated with fruit and red wine consumption could be due to pooled antioxidant microcomponents in diet. The aim of this study was to investigate the antioxidant activities of pure resveratrol (a well known phytoalexin, RSV) and red wine polyphenols (RWP), using UV-B radiated isolated rat hepatocytes as a model of oxidative stress. Methods: Rat hepatocytes were isolated by the collagenase method. The cells were loaded with resveratrol and/or polyphenols at different concentrations. The production of thiobarbituric acid reactive substances (TBARS) released by UV-B radiated cells and the levels of lipid-soluble antioxidants (Dolichol, Vitamin E, Coenzyme Q9 and Q10) were measured. Results: Resveratrol had pro-oxidant or antioxidant effects depending on (lower or higher) dosage. RWP protection from photolipoperoxidation was dose-dependent and increased with dosage. Combination of the two compounds exhibited synergistic antioxidant effect, and made resveratrol effective both at lower and higher dosages. Conclusions: These results suggest that resveratrol requires red wine polyphenols for optimum antioxidant activity

Mitochondrial myopathy in rats fed with a diet containing beta-guanidine propionic acid, an inhibitor of creatine entry in muscle cells.

In rats with phosphoryl-creatine depletion (fed a standard Randoin-Causeret diet containing 1% beta-guanidine propionic acid) abnormal mitochondria were observed in slow skeletal muscles, often containing paracrystalline inclusions very like those induced by ischaemia or mitochondrial poisons and in human mitochondrial myopathy

Effects of age, diet and obesity on insulin secretion from isolated perfused rat pancreas: Response to glucose, arginine and glucagon-like peptide 1 (7-37)

The insulin secretory responses to glucose, arginine and glucagon-like peptide (GLP)-1-(7- 37 have been evaluated from the isolated perfused pancreas of rats with either acquired or genetic obesity, ie, a) fed ad libitum 14-mo old Sprague-Dawley rats as compared to age-matched animals subjected to two types of dietary restriction (every-other-day feeding, EOD, and 40% restriction? 40% DR), and b) 2.5-mo old genetically obese fa/fa rats as compared to the lean counterpart, In mature fed ad libitum rats, the glucose-stimulated insulin release from the perfused pancreas was increased 5-fold by addition of 0.1 nM GLP-1 (7-37), a subsequent challenge with high glucose resulted in an improvement of the first phase of insulin release, In 40% DR rats, a similar pattern of secretion was observed, with the difference of a lower response to arginine than in fed ad libitum animals, In EOD rats, the overall secretory performance of the perfused pancreas was approximately 50% lower than in the fed ad libitum group but probably adequate to the reduced weight of the animals, In genetically obese young rats, both the response to GLP-1 (7-37) anti the total insulin secretion were higher than in the lean controls. Interestingly, the maximal insulin outputs from the perfused pancreases were observed in both the groups of overweight animals, In conclusion no impairment in the secretory responsiveness of beta-cells occurs in obese animals, Conversely, at least within the age limits of the present study, the endocrine pancreas develops a compensatory ability to match the augmented insulin demand due to the over-weight. In the light of the observed great sensitivity of the isolated perfused pancreas to GLP-1 (7-37), changes in the responsiveness of beta-cells to incretins might be involved in the modulation of the endocrine pancreatic function of obese rats

Effects of the administration of angiotensin II on cardiac glycogen metabolism in the rat.

Changes in glycogen metabolism after an intravenous injection of angiotensin II were investigated in the left and right ventricles of the rat heart, as a function of location within the ventricular wall. Hearts were cut into 100-microns thin section, all of which were analysed for glycogen content, glucose incorporation into glycogen and 2-deoxyglucose uptake and phosphorylation after the intravenous injection of 14C-labelled sugar. In control hearts, glycogen levels were uniform across the wall in both ventricles, while the rate of sugar uptake and phosphorylation, and that of glucose incorporation into glycogen, were significantly higher in the subendocardial myocardium of the left ventricular wall. After angiotensin II administration, heart glycogen levels decreased slightly in the left, but not in the right ventricle, while 2-deoxyglucose uptake and phosphorylation, and glucose incorporation into glycogen, increased 2,5- and 5-fold, respectively. With regard to the distribution across the wall of the left ventricle after angiotensin administration, glycogen levels and glucose incorporation into glycogen were uniformly distributed, whereas sugar phosphorylation was still higher in the subendocardium