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PubMed2006

[Ageing free radicals and cellular stress].

A number of theories have attempted to account for ageing processes in various species. Following the << rate of living >> theory of Pearl, Harman suggested fifty years ago that the accumulation of oxidants could explain the alteration of physical and cognitive functions with ageing. Oxygen metabolism leads to reactive species, including free radicals, which tend to oxidize surrounding molecules such as DNA, proteins and lipids. As a consequence various functions of cells and tissues can be altered, leading to DNA instability, protein denaturation and accumulation of lipid byproducts. Oxidative stress is an adaptive process which is triggered upon oxidant accumulation and which comprises the induction of protective and survival functions. Experimental evidence suggests that the ageing organism is in a state of oxidative stress, which supports the free radical theory. A number of other theories have been proposed ; some of these are actually compatible with the free radical theory. Caloric restriction is among the best models to increase life span in many species. While the relationship between caloric restriction and corrected metabolic rate is controversial, the decrease in ROS production by mitochondria appears to be experimentally supported. The ROS and mitochondrial theories of ageing appear to be compatible. Genetic models of increased life span, particularly those affecting the Foxo pathway, are usually accompanied by an increased resistance to oxidative insult. The free radical theory is not consistent with programmed senescence theories involving the cell division dependent decrease in telomere length ; however, oxidants are known to alter telomere structure. An appealing view of the role of oxidative stress in ageing is the trade-off principle which states that a phenotypic trait can be evolutionarily conserved because of its positive effects on development, growth or fertility, and despite its negative effect on somatic functions and ageing. It is likely that most cellular stresses which comprise adaptive and toxic functions follow such a rule.

Aging↗

PubMed1980

Studies on the use of activated charcoal and cholestyramine for reducing the body burden of polybrominated biphenyls.

Weanling male rats were exposed to a polybrominated biphenyl (PBB) mixture (Firemaster FF-1) in their diet so that they received 1 mg/kg/day for 6 months. They were then fed a normal diet for 4 months. Following this they were placed on diets containing either activated charcoal (AC) or cholestyramine (CSA) for 6 months to evaluate the usefulness of these compounds in reducing the body burdens of the retained PBBs. Periods of restricted caloric intake were also used in an effort to mobilize PBBs stored in fat. Neither compound nor restricted caloric intake was found to be effective in reducing tissue bromine levels but CSA proved useful in preventing the progression of chronic progressive nephropathy, a spontaneous lesion of aging rats.

Animals↗

PubMed2006

Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition.

While ruling out programmed aging, evolutionary theory predicts a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging. Could it be switched off pharmacologically? This would require identification of a molecular target involved in cell senescence, organism aging and diseases of aging. Notably, cell senescence is associated with activation of the TOR (target of rapamycin) nutrient- and mitogen-sensing pathway, which promotes cell growth, even though cell cycle is blocked. Is TOR involved in organism aging? In fact, in yeast (where the cell is the organism), caloric restriction, rapamycin and mutations that inhibit TOR all slow down aging. In animals from worms to mammals caloric restrictions, life-extending agents, and numerous mutations that increase longevity all converge on the TOR pathway. And, in humans, cell hypertrophy, hyper-function and hyperplasia, typically associated with activation of TOR, contribute to diseases of aging. Theoretical and clinical considerations suggest that rapamycin may be effective against atherosclerosis, hypertension and hyper-coagulation (thus, preventing myocardial infarction and stroke), osteoporosis, cancer, autoimmune diseases and arthritis, obesity, diabetes, macula-degeneration, Alzheimer's and Parkinson's diseases. Finally, I discuss that extended life span will reveal new causes for aging (e.g., ROS, 'wear and tear', Hayflick limit, stem cell exhaustion) that play a limited role now, when quasi-programmed senescence kills us first.

Aging↗

PubMed1982

[Diet with maximum restriction of caloric intake in diabetes mellitus and obesity].

To a group of 40 diabetic patients and obesity, a treatment was conducted by dietetic regimen of maximum restriction of the daily calories, from 3352 to 5028 kilojoules (800 to 1200 kilocal) according to obesity degree. Prior to treatment, only 10 per cent of the patients were with compensated diabetes. The treatment in 10 per cent of them was only a diet and in 5 per cent--insulin and in 85 per cent--peroral drugs. Completely compensated were 90 per cent of the patients subjected only to a diet, and in 10 per cent the inclusion of 5-10 mg maninil daily was necessitated. Body weight reduction with 3650 g was obtained within an average of 24 hospital days. All parameters of lipid metabolism, followed up at the beginning and at the end of the treatment were diminished: total fats (not significantly), cholesterol (significantly in females), triglycerides (significantly in males), betlipoproteins (significantly in females) and ketobodies (significantly for both sexes). In 20 patients with hyperlipoproteinuria, type IV, symptomatic anomaly in lipid metabolism was admitted, because after the treatment, only eight remained with such type of deviations. The dietetic regimen of maximum restriction of the calories applied by the authors, is admitted to be effective, with no risk of ketoacidosis, easy to apply and is recommended for the practice.

Blood Glucose↗

PubMed1987

Dietary restriction: effects on radial maze learning and lipofuscin pigment deposition in the hippocampus and frontal cortex.

Previous studies have shown increased life span and decreased lipofuscin deposition in brain structures when both premature and young adult animals are calorically restricted of an otherwise nutritionally adequate diet. Three-months-old C57BL/6 mice were subjected to 12 months of caloric restriction (2 g/day), and subsequently exposed to a radial maze learning paradigm. Mice in the diet restriction group showed faster learning and higher asymptotic performance on the radial maze task, as well as lower lipofuscin deposition in the neurons of hippocampus and frontal cortex relative to control mice fed ad libitum. The results suggest that dietary restriction has effects on radial maze learning, and this improved behavioral performance was associated with significant reduction in lipofuscin pigment deposition in the neurons of hippocampus and frontal cortex.

Aging↗

PubMed1988

Effects of fasting and refeeding on blood pressure are determined by nutritional state, not by body weight change.

It is commonly assumed that caloric restriction is effective in lowering blood pressure because of the accompanying weight loss and reversal of obesity. However, clinical trials of caloric restriction reporting the greatest falls in blood pressure were those that produced the most rapid weight loss on diets allowing the fewest calories, but the amount of weight loss was unrelated to antihypertensive effect. In obese rats undergoing a supplemented fast, blood pressure fell almost immediately but then stabilized despite continuing weight loss. The depressor effect of fasting was reversed within 2 days of refeeding. Body weight change was no longer correlated with blood pressure change after nutritional state was controlled for. Nutritional state (fed, fasted, refed), but not body weight, has important effects on blood pressure.

Animals↗

PubMed2005

Increased susceptibility to insulin resistance associated with abdominal obesity in aging rats.

OBJECTIVE: Recent data have suggested that the insulin resistance observed with aging may be more related to adiposity than aging per se. We asked whether the insulin resistance observed in aged rats was comparable (both in magnitude and location) to that of fat-fed rats. RESEARCH METHODS AND PROCEDURES: We performed hyperinsulinemic (5 mU/min per kg) euglycemic clamps with tracer in conscious, 6-hour fasted young (YL), fat-fed young (YF), fat-fed old (OF), and calorically restricted old (OL) rats. RESULTS: Intraabdominal fat measurements showed that OF and YF rats were more obese than YL (p OF>YL). Caloric restriction not only prevented age-related obesity but also reduced the ratio of intraabdominal fat to lean body mass (LBM) compared with YL (OL: 0.59+/-0.05 vs. YL: 1.07+/-0.04; p=0.017). Despite similar incremental insulin, YF and OF rats required 40% less infused glucose to maintain euglycemia than YL and OL rats (p<0.001). Insulin-stimulated glucose uptake (Si(Rd): DeltaRd/(DeltaInsulin x Glucose(SS)) was impaired in OF rats (OF: 14.03+/-1.79 vs. YL: 23.08+/-1.87x10(3) dL/min x kg LBM per pM; p=0.004) and improved in OL rats (29.41+/-1.84x10(3) dL/min x kg LBM per pM; p=0.031) compared with YL. Despite greater obesity, YF rats did not exhibit lower SiRd compared with OF rats (p=0.58). In contrast, the ability of insulin to suppress endogenous glucose production (EGP; Si(EGP): DeltaEGP/(DeltaInsulin x GlucoseSS) was not impaired in OF rats (OF vs. YL; p=0.61) but was markedly impaired in YF rats by approximately 75% (1.72+/-0.66x10(3) dL/min x kg per pM; p=0.013). Surprisingly, separate regression analysis for old and young animals revealed that old rats exhibited a significantly steeper regression between Si (Rd and EGP) and adiposity than young rats (p<0.05). Thus, older rats showed a proportionately greater decrement in insulin sensitivity with an equivalent increase in adiposity. DISCUSSION: These data suggest that, in rodents, youth affords significant protection against obesity-induced insulin resistance.

Abdomen↗

PubMed1982

Diet-induced changes in sympathetic nervous system activity: possible implications for obesity and hypertension.

The sympathetic nervous system responds to changes in caloric intake; caloric restriction decreases and carbohydrate administration increases sympathetic nervous system activity in animals and man. Insulin may be a major link between changes in dietary intake and changes in central sympathetic outflow. Caloric restriction reduces, and carbohydrate administration increases blood pressure in spontaneously hypertensive rats, changes consistent with a primary effect of caloric intake on sympathetic nervous system activity. Stimulation of the sympathetic nervous system by overfeeding may contribute to the development and maintenance of hypertension in biologically-predisposed animals and man. The association of obesity and hypertension may reflect chronic overfeeding, although diet-induced changes in sympathetic nervous system activity may affect blood pressure in non-obese individuals as well.

Adolescent↗

PubMed1998

The role of specific macronutrient availability in the effect of food restriction on length of lactational diestrus in rats.

In lactating rats, food restriction for the first two weeks postpartum extends the period of lactational diestrus by about 1 week. In these studies we investigated whether this effect results from caloric restriction or the reduced availability of a specific macronutrient. In Experiment 1 lactating rats nursing litters of eight pups were assigned to one of four conditions: 1) ad lib. fed; 2) protein-restricted; 3) carbohydrate-restricted; and 4) fat-restricted. Animals in all the restricted conditions were given access to 50% of ad lib. intake of the appropriate nutrient for Days 1-14 postpartum and ad lib. access to the other two macronutrients. In Experiment 2, ad lib. supplementation from one macronutrient source was provided to lactating rats given restricted access to a composite diet. No differential effect of specific macronutrient deprivation or supplementation on length of lactational diestrus was observed in these studies. Thus, the results of both studies are consistent with the hypothesis that caloric restriction plays a primary role in inducing the prolongation of lactational diestrus in food-restricted rats.

Animals↗

PubMed1984

Adipocyte blood flow: influence of age, anatomic location, and dietary manipulation.

Adipocyte blood flow in four distinct adipose tissue depots has been measured in conscious, unrestrained, male Sprague-Dawley rats by using the microsphere technique together with cellularity determinations. Blood flow was determined in young rats (90 days old, 387 g mean body wt), spontaneously obese rats (450 days old, 713 g mean body wt), and long-term calorically restricted rats (450 days old, 390 g mean body wt), therefore allowing the comparison of the relative effects of age and fat mass on adipose tissue blood flow. Results of these experiments indicate that while cardiac index remained constant, cardiac output increased in only the obese group, concomitant with increased body fat mass. Spontaneously obese rats exhibited increased adipose tissue depot weight, fat cell lipid, and fat cell size compared with young and restricted groups. Despite significant differences in cell volume, blood flow per cell was remarkably similar between young and obese rats. Long-term caloric restriction, however, was associated with decreased flow per cell. Interdepot comparisons of flow per unit surface area (mm2) or per unit volume (pl) indicate that mesenteric cells receive significantly more blood than cells of the other depots. Our results suggest that adipocyte blood flow is dependent in part on anatomic location, may be further influenced by age or dietary manipulation, and is not a limiting factor in the enlargement of adipocytes during the development of spontaneous obesity.

Adipose Tissue↗

PubMed1978

[Relase of organochloride pesticides during acute weight losses (author's transl)].

The increase of blood organochloride pesticide levels and the urinary excretion have been determined in 4 human subjects undergoing a caloric restriction sequence (500 total K. calories per day) followed by a total starvation period of 36 hours. The severe lipolysis due to the caloric restriction causes an important liberation of fat-soluble pesticides especially DDT and DDE (30 ppb of total DDT equivalents) and an increase of urinary excretion (15 ppb of total DDT equivalents).

Adult↗

PubMed1996

Ethanol ingestion reduces antipneumococcal activity of rat pulmonary surfactant.

Because chronic ethanol ingestion decreases pulmonary clearance of Streptococcus pneumoniae in rats, and extracellular antipneumococcal factors in rat surfactant are important in the early clearance of pneumococci from the rat alveolus, the effects of ethanol ingestion on surfactant bactericidal activity were investigated. Normal surfactant from chow-fed rats showed potent anti-pneumococcal activity, even against bacteria growing in nutrient-rich media under favorable conditions. In contrast, surfactant from ethanol-fed rats and from calorie-restricted control-fed rats had significantly reduced antipneumococcal activity compared with surfactant from chow-fed rats. The reductions in surfactant bactericidal activity produced by ethanol ingestion or caloric restriction did not appear to be mediated through changes in either the total amount or the distribution of fatty acids, the antipneumococcal factors in normal surfactant. Rather, ethanol ingestion, and to a lesser extent caloric restriction, produced a surfactant inhibitor of free fatty acids that was partially characterized as a hydrophobic protein.

Alcohol Drinking↗

PubMed1999

Mitochondrial coenzyme Q content and aging.

The main objective of this study was to determine the nature of the relationship between aging and mitochondrial coenzyme Q (CoQ) content. Mitochondria in the heart, skeletal muscle, kidney and brain of the mouse varied in both the amount of total CoQ (CoQ9 + CoQ10) content as well as in the ratio of the CoQ9 to CoQ10. CoQ content declined with age only in the skeletal muscle. Caloric restriction (CR) resulted in an increase in the amount of CoQ9 in skeletal muscle mitochondria. This effect was partially reversible upon termination of the caloric restriction regimen. Results suggest that a decrease in mitochondrial CoQ content is an integral aspect of aging in skeletal muscle.

Aging↗

PubMed1988

Are cell number and cell proliferation risk factors for cancer?

Relatively little is known about the mechanisms underlying carcinogenesis in humans. Caloric restriction strongly inhibits the development of neoplasia in rodents, and there is evidence of a positive relationship between cancer and body weight in humans. Caloric restriction early in life is also known to permanently diminish organ cellularity. A recent link between adult stature and cancer incidence similarly implicates a lasting effect for growth and possibly for early nutrition in carcinogenesis. It is postulated that cancer risk is proportional to the number of proliferating cells, which in turn depends on both the number of cells and the rate of cell division within the tissue. This hypothesis is consistent with several aspects of human carcinogenesis, including multistage models and the epithelial origin of most cancers.

Body Height↗

PubMed2004

Chronic activation of AMP-activated kinase as a strategy for slowing aging.

Caloric restriction down-regulates insulin secretion and systemic IGF-I activity, and there is reason to suspect that these effects are key mediators of caloric restriction's favorable impact on longevity. Alternative strategies for down-regulating these hormones are thus of great interest; chronic activation of AMP-activated kinase (AMPK)--clinically achievable with the drug metformin--may have utility in this regard. In the liver, AMPK slows hepatic glucose output by down-regulating expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase; in skeletal muscle, it boosts the efficiency of insulin-stimulated glucose uptake by increasing expression of GLUT-4. These effects evidently mandate a down-regulation of insulin secretion. The resulting reduction of hepatic insulin activity can be expected to suppress hepatic production of IGF-I while boosting that of IGFBP-1, thereby decreasing plasma free IGF-I. AMPK can also directly stimulate IGFBP-1 synthesis in hepatocytes, and interfere with the ras/raf/erk pathway of IGF-I signaling. In non-diabetics, metformin therapy is indeed reported to reduce plasma levels of insulin and of free IGF-I; indeed, this is thought to be the mechanism whereby metformin suppresses excess androgen production in PCOS. A pro-longevity effect of the related biguanide phenformin has already been reported in tumor-prone mice, and mouse longevity studies with metformin are currently in progress. The development of AMPK activators which do not share metformin's modest risk of inducing lactic acidosis--apparently reflecting an inhibition of mitochondrial complex 1 that is not intrinsic to AMPK activity--might aid the practical applicability of this pro-longevity strategy.

AMP-Activated Protein Kinases↗

PubMed1954

The effect of undernutrition on cholesterol atherosclerosis in the rabbit.

Experiments were done to determine whether undernutrition with consequent loss of weight or failure to gain weight inhibited the development or promoted the regression of the aortic lesions of experimental cholesterol atherosclerosis in the rabbit. The experiments were conducted in such a way as to determine whether undernourished and adequately nourished rabbits fed the same daily doses of cholesterol would manifest different degrees of atherosclerosis at the end of an experiment. Different experiments tested the effect of undernutrition in young, growing animals that failed to gain weight normally (Experiments 1 and 2); in young rabbits subjected to marked undernutrition both before and during cholesterol feeding (Experiment 3); in fully grown, mature rabbits that lost weight during undernutrition (Experiment 4); and in rabbits that had completed a period of cholesterol feeding before caloric restriction was begun (Experiment 5). In every experiment it was observed that, if two groups of rabbits were fed cholesterol, one group being subjected to caloric restriction while the other received an adequate diet, no difference in aortic atherosclerosis was observed between the two groups at the termination of the experiment. Furthermore, no obvious effect of undernutrition on the regression of atherosclerotic lesions was observed in the rabbit. At the same time, undernutrition was found to promote hypercholesterolemia in the rabbit fed cholesterol. The possible significance of this result was discussed.

Animals↗

PubMed1999

Pathoetiology and prevention of NIDDM lessons from the OLETF rat.

The OLETF rat, a genetic model of spontaneous development of NIDDM, exhibits hyperglycemic obesity with hyperinsulinemia and insulin resistance similar to that in humans. It is still unclear whether a defect in the beta-cell proliferation per se is the primary pathogenetic event in this model rat. To clarify this matter, we used partially pancreatectomized rats as a model. Male rats of 6 weeks of age were allocated at random to two groups: 70% pancreatectomy (Px) and sham-pancreatectomy (sham). Each group was divided into 4 subgroups by the date of sacrifice after surgery. Sustained hyperglycemia was evident in the Px OLETF rats after surgery. This was associated with insufficient proliferation of beta-cells, characterized by a decrease in beta-cell labeling with 5-bromo-2' deoxyuridine in proportion to a decrease in beta-cell mass and reduction in insulin content in the remnant pancreas. Administration of nicotinamide, however, ameliorated the sustained hyperglycemia by increasing beta-cell proliferation. These findings suggest that OLETF rats have a poor capacity for proliferation of pancreatic beta-cells, and that this change may be the critical pathogenetic event prior to the onset of overt diabetes. OLETF rats following long-term caloric restriction and spontaneous exercise training show normal glucose tolerance accompanied by an increase in GIR as shown by a euglycemic clamp. Both exercise training and caloric restriction normalize the abnormalities in the pancreas such as marked hypertrophy of islets and hyperplasia of connective tissues in islets. It is particularly noteworthy that exercise training significantly elevated the beta-cell mass/body weight ratio. This evidence obtained from OLETF rats may be of value when the mechanism of diet and exercise effects on diabetic patients are considered.

Animals↗

PubMed1981

The influence of low calorie (240 kcal/day) protein-carbohydrate diet on serum lipid levels in obese subjects.

Thirteen adult obese subjects (12 women, one man) were placed on a low-calorie diet (240 kcal = 1.02 MJ daily; mixed protein/carbohydrate) for two weeks. Mean weight loss +/- s.d. was 7.9 +/- 1.8 kg. Total serum cholesterol and HDL-cholesterol were significantly decreased after two weeks. Their ratio was unchanged. The direction of the changes in triglyceride levels was related to the pretreatment levels, subjects with a level below 120 mg/dl showed no change or a slight increase, subjects with a level over 120 mg/dl showed a significant decrease. On a normal diet, as well as after two weeks of caloric restriction, a negative correlation existed between serum Tg and the Tg fractional removal rate (K2IVFTT). The mean K2 value increased during weight loss. On a caloric restriction the relative content of linoleic acid decreased and of arachidonic acid increased in serum cholesterol esters and phospholipids. The relative content of palmitic acid increased in CE. The fatty acid composition of Tg was unchanged.

Adolescent↗