Longevity Of Rats Research Articles

Yohimbine ameliorates liver inflammation and fibrosis by regulating oxidative stress and Wnt/β-catenin pathway

Background and purposeChronic liver injury, caused by various aetiologies, causes recurrent tissue damage, culminating in decreased liver regenerative ability and resulting in fibrosis followed by cirrhosis. In this study, the anti-fibrotic activity of Yohimbine hydrochloride (YHC) was investigated using various in vitro models and in vivo models. MethodsTo assess the anti-inflammatory, antioxidant, and anti-fibrotic effects of YHC, lipopolysaccharide or TGF-β induced differentiation or lipid-induced oxidative-stress models were employed using HLECs, HSC-LX2, and HepG2 cells. Further, thioacetamide (TAA) induced hepatic inflammation/fibrosis models were utilized to validate the YHC's anti-fibrotic activity in rats. ResultsInflammation/differentiation experiments in HLECs and HSC-LX2 revealed that YHC treatment significantly (p < 0.001) mitigated the lipopolysaccharide or TGF-β induced upregulation of inflammatory and fibrotic markers expression respectively. In addition, YHC dose-dependently reduced the TGF-β induced migration and palmitic acid-induced oxidative stress in HepG2 cells. Further, TAA administration (5 weeks) in vivo rat model showed increased inflammatory marker levels/expression, oxidative stress, and pathological abnormalities. Additionally, TAA administration (9 weeks) elevated the fibrotic marker expression, collagen deposition in liver tissues, and shortened longevity in rats. Treatment with YHC dose-dependently mitigated the TAA-induced abnormalities in both inflammation and fibrosis models and improved the survival of the rats. Further mechanistic approaches revealed that TAA administration elevated the JNK, Wnt components and β-catenin expression in hepatic stellate cells and animal tissues. Further treatment with YHC significantly modulated the JNK/Wnt/β-catenin signaling. Moreover, the β-catenin nuclear translocation results showed that β-catenin levels were significantly elevated in the nuclear fraction of TAA control samples and reduced in YHC-treated samples. ConclusionYohimbine treatment significantly improved inflammation and fibrosis by inhibiting differentiation, oxidative stress, and collagen deposition by partly modulating the JNK/Wnt/β-catenin pathway. These results might serve as a foundation for proposing yohimbine as a potential lead compound for liver fibrosis.

Mitochondrial health is enhanced in rats with higher vs. lower intrinsic exercise capacity and extended lifespan

The intrinsic aerobic capacity of an organism is thought to play a role in aging and longevity. Maximal respiratory rate capacity, a metabolic performance measure, is one of the best predictors of cardiovascular- and all-cause mortality. Rats selectively bred for high-(HCR) vs. low-(LCR) intrinsic running-endurance capacity have up to 31% longer lifespan. We found that positive changes in indices of mitochondrial health in cardiomyocytes (respiratory reserve, maximal respiratory capacity, resistance to mitochondrial permeability transition, autophagy/mitophagy, and higher lipids-over-glucose utilization) are uniformly associated with the extended longevity in HCR vs. LCR female rats. Cross-sectional heart metabolomics revealed pathways from lipid metabolism in the heart, which were significantly enriched by a select group of strain-dependent metabolites, consistent with enhanced lipids utilization by HCR cardiomyocytes. Heart–liver–serum metabolomics further revealed shunting of lipidic substrates between the liver and heart via serum during aging. Thus, mitochondrial health in cardiomyocytes is associated with extended longevity in rats with higher intrinsic exercise capacity and, probably, these findings can be translated to other populations as predictors of outcomes of health and survival.

INVESTIGATING EFFECTS OF 7,8-DISUBSTITUTED DERIVATIVE OF THEOPHYLLINE (BENOPHYLLINE) ON FREE-RADICAL OXIDATION IN RENAL INJURY OF RATS

This article highlights the pharmacological study of new 7,8-disubstituted derivative of theophylline, the substance conditionally named benophylline. Based on the literature data and previous studies of compounds of this class, it has been concluded that studying the effect of benophylline on the pro-antioxidant system under simulated pathologies is of great interest and importance.&#x0D; The study of antihypoxic action of 7,8-disubstituted theophylline in rats was carried out under modelled normobaric hypoxia with hypercapnia (in an enclosed space). It has been found out the application of 7-n-methylbenzyl-8-substituted polyphosphonates increases the longevity of rats in the conditions described above that evidences the improvement of metabolic processes in mitochondrial respiratory chain.&#x0D; Based on the results of screening studies, we selected 7,8-disubstituted derivative of theophylline (benophylline) as a leading substance for further investigation. The purpose of the study was to evaluate the efficacy of benophylline for the pharmacological correction of free radical processes in experimental renal damage in rats based on the evaluation of the expression of lipid peroxidation and antioxidant protection.&#x0D; Materials and methods: blood serum, homogenate and rat kidney tissues were the study materials. The study of the protective effect of benophylline on the functional state of the kidneys was investigated on experimental model of acute renal injury by introducing 50% water solution of glycerol (myoglobin nephropathy). Pathogenesis of this model was described in the methodological recommendations by C. Yu. Shtrygol, V. M. Lysovoi, I. A. Zupanetz et al. in «Methods of experimental modeling of kidney damage for pharmacological research». The content of TBK-R was determined spectrophotometrically by reaction with thiobarbituric acid.&#x0D; Glutathione recovered activity was determined spectrophotometrically in reaction with Elman's reagent using the method of Beutler E. D. et al. The catalase activity was assessed by the method of M.A. Koroluk et al. The influence of benophylline on the morphological state of the renal parenchyma was assessed on the modeled myoglobin nephropathy. The activity of gamma-glutamyltranspeptidase in serum was evaluated photometrically using a reagent test kit (“Filisit”). Statistical processing of the results was performed using the STATISTICA 8.0 software package, with the mean value, standard error of the mean confidence interval (p≤0.05). The microscopic study of microproducts was performed under the Granum microscope. Micrographs were taken with a Granum DMC 310 digital camera. The images were processed on a Pentium 2.4 GHz computer using Toup View software.&#x0D; Research results: Under the influence of benophylline, the processes of LPO and AOP became normalized, the expressiveness of degradation of the nephrocytes decreased, the microscopic picture of renal excretion in all rats got normalized. At the same time, 62.5% of the rats had the morphological condition of kidneys close to the intact control, and 37.5% of the animals were noticed to demonstrate a significant decrease in the dyscirculatory abnormalities, inflammatory manifestations and signs of nephrocyte regeneration.&#x0D; Conclusions: The ability of benophylline to inhibit the processes of free radical oxidation and to enhance antioxidant protection has been found out. The study has shown benophylline enhances regenerative effect kidney tissues.

Contribution of Innate and Adaptive Exercise Capacity as Determinants of Health and Longevity in Rats

Exercise capacity is a complex trait comprised of an inborn ability (i.e. innate component) in addition to that acquired in response to physical activity (i.e. adaptive component). In humans, it is near impossible to conduct an experiment that identifies which of these two components, innate or adaptive, is the leading mechanistic determinant underlying healthy aging and longevity. As a solution, we developed rat genetic models of both forms of exercise capacity via two‐way artificial selection: the innate (Low Capacity Runners LCR, High Capacity Runners HCR) and the adaptive (Low Response Trainers LRT, High Response Trainers HRT) to test our general thesis that low capacity for energy transfer underlies complex disease risk, accelerated aging, and diminished longevity. In previous work we showed that compared to HCR, LCR rats had 28–45 % shorter lifespan and that VO2max, maximal running capacity, and gains in body weight (↑% fat, ↓% lean) across lifespan predicted survivability.Conclusion 1: In rats, innate exercise capacity links with health and lifespanNow we aim to test the hypothesis that low adaptive capacity will have similar predictability features to the innate component. Here we studied 72 female and male LRT/HRT rats, representing the extremes of low and high adaptive capacity from generation 20 of selection, for treadmill exercise capacity across lifespan. As young adults (3 mo. old), female LRT and HRT in the non‐trained condition were similar for maximal running distance (605 ± 126 vs. 550 ± 137 meters, respectively) but due to bigger body mass, LRT &gt; HRT for work performed (joules). Male LRT at 3 mo. old were significantly heavier, had higher running capacity and thus performed more work compared to HRT.Conclusion 2: When young, low adaptive capacity rats have greater body mass and perform more workAfter 8 weeks of endurance treadmill training, female HRT increased running distance by 437 ± 126 m and work performed by 269 ± 85 J. Whereas female LRT had no change in running capacity (−92 ± 100 m) or work performed (−2%). Male LRT and HRT demonstrated the same training response pattern for running capacity and work as females.Conclusion 3: As adults, high adaptive capacity rats improve both running capacity and work with training whereas low adaptive capacity rats do notAll rats were then left sedentary in home cages and re‐tested for exercise capacity at 22 mo. old. Using an NMR based analyzer, aged LRT females weighed 35 g more and had 5% less lean body mass and 35% greater body fat compared to aged HRT. Aged LRT males were 40 g heavier than HRT but with no significant differences in % lean or % fat body composition. With aging, all rats showed a significant decrease in running distance and capacity to perform work. However, aged female HRT ran 431 ± 143 m compared to 237 ± 55 m for aged female LRT, an equivalent to performing 58% more work. Aged male HRT ran 232 ± 73 m compared to 149 ± 59 m for aged male LRT, equating to 40% greater work performed by HRT compared to LRT.Conclusion 4: When aged, high adaptive capacity rats retain greater running capacity and can perform more work relative to their low adaptive capacity counterpartsTogether these data suggest that rats bred with low capacity for innate or low adaptive response to exercise are greater risk for premature aging and reduced survivability.Support or Funding InformationSupported by NIH grant P40OD021331 (LGK/SLB), Glenn Foundation for Medical Research N020308 (LGK). This work utilized Core Services supported by grant DK089503 of NIH to the University of Michigan.

Effect of zinc supplementation on E-ADA activity, seric zinc, and cytokines levels of Trypanosoma evansi infected wistar rats

The aim of this study was to evaluate the effect of zinc supplementation on the ecto-adenosine deaminase activity (E-ADA), zinc seric levels and cytokines (TNF-α, IL-1, IL-6, and IL -10) on rats experimentally infected by Trypanosoma evansi. Four groups with 10 rats each were used as negative controls (groups A and B), while the animals from the groups C and D were infected intraperitoneally with 0.1 mL of cryopreserved blood containing 1.4 × 104 of trypanosomes. Animals of groups B and D received two doses of Zinc (Zn) at 5 mg kg−1, subcutaneously, on the 2nd and 7th day post-infection (PI). Blood samples were collected on days 5 (n = 5) and 15 PI (n = 5). Zn supplementation was able to increase the rat's longevity and to reduce their parasitemia. It was observed that seric Zn levels were increased on infected animals under Zn supplementation. Animals that were infected and supplemented with Zn showed changes in E-ADA activity and in cytokine levels (P < 0.05). Zn supplementation of healthy animals (Group B), increased the E-ADA activity, as well as reduced the concentration of cytokines. Infected animals from groups C and D showed increased levels of cytokines. Finally, we observed that Zn supplementation led to a modulation on cytokine's level in rats infected by T. evansi, as well as in E-ADA activity.

Maternal caloric restriction prior to pregnancy increases the body weight of the second-generation male offspring and shortens their longevity in rats.

Maternal undernutrition can affect offspring's physical status and various health parameters that might be transmittable across several generations. Many studies have focused on undernutrition throughout pregnancy, whereas maternal undernutrition prior to pregnancy is not sufficiently studied. The objective of our study was to explore the effects of food restriction prior to and during pregnancy on body weight and longevity of the second generation offspring. Adult female Wistar rats ("F0" generation) were 50% food restricted for one month prior to pregnancy (pre-pregnancy) or during pre-pregnancy and pregnancy. The third group was fed normally (control). The first generation offspring were normally fed until the 6(th) month of age to produce the second generation offspring; namely, the first-generation female rats were mated with male breeders from outside the experiment. The second generation offspring thus obtained were observed until natural death (up to 36 months). Compared to the controls, the second-generation male offspring whose "grandmothers (F0 females)" undernourished only during pre-pregnancy were significantly heavier from the 8(th) month of age, whereas no significant weight difference was found in the male offspring whose "grandmothers" were food-restricted during pre-pregnancy and pregnancy. Shorter lifespan was observed in the second-generation male offspring of "grandmothers" that were food-restricted either during pre-pregnancy or during pre-pregnancy and pregnancy. By contrast, no differences in body weight and lifespan were observed in all second-generation female offspring. In conclusion, maternal caloric restriction prior to pregnancy increases the body weight and shortens the longevity of the second-generation male offspring, indicating the sex-dependent transgenerational effect of maternal caloric restriction.

Deletion of growth hormone receptor gene but not visceral fat removal decreases expression of apoptosis-related genes in the kidney—potential mechanism of lifespan extension

Mice homozygous for the targeted disruption of the growth hormone (GH) receptor (Ghr) gene (GH receptor knockout; GHRKO; KO) are hypoinsulinemic, highly insulin sensitive, normoglycemic, and long-lived. Visceral fat removal (VFR) is a surgical intervention which improves insulin signaling in normal (N) mice and rats and extends longevity in rats. We have previously demonstrated decreased expression level of certain pro-apoptotic genes in skeletal muscles and suggested that this may contribute to the regulation of longevity in GHRKO mice. Alterations in apoptosis-related genes expression in the kidneys also may potentially lead to lifespan extension. In this context, we decided to examine the renal expression of the following genes: caspase-3, caspase-9, caspase-8, bax, bad, bcl-2, Smac/DIABLO, Apaf-1, p53, and cytochrome c1 (cyc1) in male GHRKO and N mice subjected to VFR or sham surgery, at approximately 6 months of age. The kidneys were collected 2 months after VFR. As a result, caspase-3, caspase-9, and bax expressions were decreased in KO mice as compared to N animals. Expressions of Smac/DIABLO, caspase-8, bcl-2, bad, and p53 did not differ between KOs and N mice. VFR did not change the expression of the examined genes in KO or N mice. In conclusion, endocrine abnormalities in GHRKO mice result in decreased expression of pro-apoptotic genes and VFR did not alter the examined genes expression in N and KO mice. These data are consistent with a model in which alterations of GH signaling and/or insulin sensitivity lead to increased lifespan mediated by decreased renal expression of pro-apoptotic genes.

Renal pro-apoptotic proteins are reduced by growth hormone resistance but not by visceral fat removal

Growth hormone (GH) receptor knockout (GHRKO) mice are highly insulin sensitive and long-lived. Surgical visceral fat removal (VFR) improves insulin signaling in normal mice and rats and extends longevity in rats. We have previously demonstrated decreased expression of certain pro-apoptotic genes in kidneys of GHRKO mice and suggested that this could contribute to the increased longevity of these animals. The aim of the present study was to examine the level of the following proteins: caspase-3, caspase-9, caspase-8, bax, bad, phospho-bad, bcl-2, Smac/DIABLO, Apaf-1, phospho-p53 (pp53) and cytochrome c in male GHRKO and normal (N) mice subjected to VFR or sham surgery, at approximately six months of age. The kidneys were collected two months after VFR. Caspase-3, caspase-8, bax, bad, Smac/DIABLO, Apaf-1 and pp53 levels were decreased in GHRKO mice as compared to N animals. VFR did not change the level of any of the examined proteins. The decreased renal levels of pro-apoptotic proteins could contribute to the extended life-span caused by targeted disruption of the GH receptor gene but are apparently not involved in mediating the effects of VFR.

Protein restriction in lactation confers nephroprotective effects in the male rat and is associated with increased antioxidant expression

Telomere shortening has been implicated in the aging process and various age-associated disorders, including renal disease. Moreover, oxidative stress has been identified as an initiator of accelerated telomere shortening. We have shown previously that maternal protein restriction during lactation leads to reduced renal telomere shortening, reduced albuminuria, and increased longevity in rats. Here we address the hypothesis that maternal protein restriction during lactation is nephroprotective and associated with increased expression of antioxidative enzymes and decreased age-dependent renal telomere shortening. Newborn rats were suckled by a dam fed either a control (20% protein) or low-protein (8% protein) diet. All animals were weaned onto standard chow. Offspring that had been suckled by protein-restricted mothers had reduced albuminuria, N-acetyl-glucosaminidase, and urinary aldosterone excretion. These animals also did not show significant age-dependent renal telomere shortening and hence had significantly longer telomeres at 12 mo of age. This lack of renal telomere shortening was associated with increased levels of the antioxidant enzymes manganese superoxide dismutase, glutathione peroxidase, and glutathione reductase. These findings suggest that beneficial effects of slow growth during lactation are associated with increased antioxidant capacity and prevention of age-dependent telomere shortening in the kidney.

Intentional Weight Loss Reduces Mortality Rate in a Rodent Model of Dietary Obesity

We used a rodent model of dietary obesity to evaluate effects of caloric restriction-induced weight loss on mortality rate. Research Measures and Procedures: In a randomized parallel-groups design, 312 outbred Sprague-Dawley rats (one-half males) were assigned at age 10 weeks to one of three diets: low fat (LF; 18.7% calories as fat) with caloric intake adjusted to maintain body weight 10% below that for ad libitum (AL)-fed rat food, high fat (HF; 45% calories as fat) fed at the same level, or HF fed AL. At age 46 weeks, the lightest one-third of the AL group was discarded to ensure a more obese group; the remaining animals were randomly assigned to one of three diets: HF-AL, HF with energy restricted to produce body weights of animals restricted on the HF diet throughout life, or LF with energy restricted to produce the body weights of animals restricted on the LF diet throughout life. Life span, body weight, and leptin levels were measured. Animals restricted throughout life lived the longest (p < 0.001). Life span was not different among animals that had been obese and then lost weight and animals that had been nonobese throughout life (p = 0.18). Animals that were obese and lost weight lived substantially longer than animals that remained obese throughout life (p = 0.002). Diet composition had no effect on life span (p = 0.52). Weight loss after the onset of obesity during adulthood leads to a substantial increase in longevity in rats.

Is early life body weight a predictor of longevity and tumor risk in rats?

Heavy body weight (BW) is thought to be associated with reduced longevity and age-associated diseases, including cancer, both in laboratory rodents and humans. To further investigate the interactions between BW, longevity and spontaneous tumor development, we measured the correlations between BW in early life, BW in middle life, and parameters of life span and tumorigenesis in male and female outbred rats. The data show that BW at the ages of both 3 and 12 months are significant predictors of longevity in rats. Heavier female rats tend to live longer than the lighter female rats, while in male those who were light at 3 months but heavy at 12 month had the best longevity. BW at the age 3 months was not predictive of tumor growth but being heavier at the age of 1 year did confer an increased risk of tumor development for both male and female rats.

Biosynthetic human parathyroid hormone (1-34) effects on bone quality in aged ovariectomized rats.

For the first time, PTH (1-34) was found to significantly affect bone quality, femora length, and body weight of aged, ovariectomized rats. Specifically, we examined the effects of biosynthetic human PTH (1-34) in 9 month-old rats that were ovariectomized and dosed for the ensuing 6 months with 8 or 40 microg/kg PTH. Bone content, architecture, and quality of axial and appendicular skeletal sites were analyzed by computed tomography (QCT), histomorphometry, and biomechanical testing. The large sample size (n = 26-35) of this study was useful in confirming the anabolic, dose-dependent effects of PTH at trabecular and cortical bone sites. Longitudinal analysis of tibias by QCT confirmed a small age-dependent reduction in bone density, with further reductions observed for ovariectomized controls (OVX). Subtle but deleterious effects of ovariectomy on bone quality are described. Additionally, the strength of the femoral neck was shown not to differ between baseline, sham-operated controls, or OVX in this model, suggesting limited utility of this measurement in aged rats. Both doses of PTH induced substantial gains above OVX, in bone mass and connectivity for the proximal tibia, distal femur, proximal femur, and spine. Ovariectomy significantly decreased the toughness of vertebral bone. However, PTH at 8 microg/kg reversed this deleterious effect on bone quality, while 40 microg/kg PTH significantly improved both toughness and brittleness beyond baseline controls. Cortical bone analyses at the femoral or tibial diaphysis confirmed the PTH stimulation of endosteal and periosteal bone formation with resulting increase in cortical thickness, moment of inertia, strength, and stiffness of the femur. PTH treatment significantly improved the intrinsic properties, Young's modulus and toughness, of the femur compared with OVX. At 40 microg/kg PTH, bone mass and strength were typically greater than sham or baseline controls, confirming that PTH is functionally anabolic at trabecular and cortical bone sites. Interestingly, PTH dose-dependently increased the femora length, in the absence of differences between baseline, sham, and OVX controls. PTH slightly increased body weight above OVX. In addition, PTH did not interfere with the beneficial effects of ovariectomy on rat longevity.

Sexual performance and longevity.

Sexually inactive ("low-performing," LP) and highly active ("high-performing," HP) rats were selected from a sexually inexperienced population. Saline control LP rats (n = 44) lived 134.58 +/- 2.29 weeks, their HP peers (n = 49) lived 151.24 +/- 1.36 weeks. Life-long treatment with 0.25 mg/kg (-)deprenyl, a selective inhibitor of MAO-B that also stimulates action potential-transmitter release coupling in the catecholaminergic neurons in the brain (catecholaminergic activity enhancer, CAE, effect), enhanced the sexual and learning performance of both LP and HP rats and prolonged their life. LP rats (n = 48) treated with (-)deprenyl lived 152.54 +/- 1.36 weeks and HP rats on (-)deprenyl (n = 50) lived 185.30 +/- 1.96 weeks. As an indicator of the basic activity of catecholaminergic neurons, the resting release of dopamine from the striatum, substantia nigra, and tuberculum olfactorium, and of norepinephrine from the locus coeruleus, was measured in 2-, 4-, 8-, 16-, and 32-week-old male and female rats. The release of transmitters between weaning and the second month of age, i.e., during the crucial developmental phase of life, was significantly higher than either before or after that period, indicating that a CAE mechanism starts working with high intensity after weaning, lasts until the completion of full scale sexual development, and shows an unparalleled decay thereafter. It was concluded that the CAE regulation in the brain, stimulated by (-)deprenyl, controls general activity and consequently the longevity of rats.

The effects of overfeeding and moderate dietary restriction on Sprague-Dawley rat survival, pathology, carcinogenicity, and the toxicity of pharmaceutical agents

Ad libitum (AL) overfeeding is the most significant uncontrolled variable effecting the rodent bioassay. There is a highly significant correlation between food consumption, the resultant body weight, and two-year survival in laboratory rats. We have studied the effects of AL overfeeding, moderate dietary restriction (DR) and several modified diets on Sprague-Dawley (SD) rat longevity, spontaneous disease, carcinogenesis and the toxicity of pharmaceuticals. AL feeding of diets varying in protein, fiber and metabolizable energy content did not significantly alter two-year rat survival. Moderate DR (within the range of reported AL food intake) of all diets tested significantly improved survival and delayed the onset of spontaneous degenerative disease and diet-related tumors compared to AL-fed rats. Moderate DR resulted in a similar incidence of spontaneous tumors by 2 years, however, the tumors were more likely to be incidental and not result in early mortality. There was a decreased, age-adjusted incidence of pituitary and mammary gland tumors, but tumor volume and growth time was similar between AL and DR groups indicating similar tumor progression with a delay in tumor onset. Moderate DR did not change Phase I and Phase II drug metabolizing enzyme levels and did not significantly alter the toxicological response to 5 pharmaceuticals tested at maximum tolerated doses (MTDs). Additional studies with 4 pharmaceutical candidates did demonstrate that moderate DR allowed higher doses of compounds to be given before classical MTDs were observed. However, toxicokinetic studies of two of these compounds demonstrated steady state systemic exposures that were either equal of higher in the moderate DR fed rats. These and other data indicate that the moderate DR fed SD rat is a more appropriately controlled rodent model for toxicity and carcinogenicity studies to assess human safety of candidate pharmaceuticals.

Changes in various tissues in the arterial wall of spontaneously hypertensive rats.

1. Using stroke-prone spontaneously hypertensive rats (SHRSP), stroke-resistant spontaneously hypertensive rats (SHRSR) and Wistar-Kyoto rats (WKY), vascular complications and the longevity of rats were investigated. 2. SHRSP aged more than 9.5 months tended to suffer from severe vascular complications such as periarteritis nodosa (PN) of mesenteric artery, while SHRSR very rarely showed severe vascular complications and WKY did not show any complications, because of the different level of systolic blood pressure. 3. Among some tissues PN tended to occur early in the small arteries of the testes and then in mesenteric artery, when these tissues of SHRSP were investigated microscopically. 4. Concerning the influence of systolic blood pressure on arterial smooth muscle layer, the deviation force of this layer was larger in SHRSR compared to WKY (44.7 times in Y axis), which was calculated mathematically and physically using computer analysis. 5. The arterial wall area of PN was enlarged, resulting in the low ratio of lumen/wall. The ratio of arterial lumen/wall was lower in SHRSP when compared to the age-matched WKY. 6. In search for myocardial ischaemia, ECG was recorded. There were positive correlations between PQ interval or SV1 + RV5 and age in the three strains of rats. ST depression more than 1 mm on ECG was most prevalent in old SHRSP, indicating probably the presence of myocardial ischaemia.

Methionine restriction increases blood glutathione and longevity in F344 rats.

Little is known about the biochemical mechanisms responsible for the biological aging process. Our previous results and those of others suggest that one possible mechanism is based on the loss of glutathione (GSH), a multifunctional tripeptide present in high concentrations in nearly all living cells. The recent finding that life-long dietary restriction of the GSH precursor methionine (Met) resulted in increased longevity in rats led us to hypothesize that adaptive changes in Met and GSH metabolism had occurred, leading to enhanced GSH status. To test this, blood and tissue GSH levels were measured at different ages throughout the life span in F344 rats on control or Met-restricted diets. Met restriction resulted in a 42% increase in mean and 44% increase in maximum life span, and in 43% lower body weight compared to controls (P < 0.001). Increases in blood GSH levels of 81% and 164% were observed in mature and old Met-restricted animals, respectively (P < 0.001). Liver was apparently the source for this increase as hepatic GSH levels decreased to 40% of controls. Except for a 25% decrease in kidney, GSH was unchanged in other tissues. All changes in GSH occurred as early as 2 months after the start of the diet. Altogether, these results suggest that dramatic adaptations in sulfur amino acid metabolism occur as a result of chronic Met restriction, leading to increases in blood GSH levels and conservation of tissue GSH during aging.

Calcium supplement and longevity in rats

Calcium supplement and longevity in rats

EFFECTS OF DIETARY RESTRICTION ON AGE-ASSOCIATED PATHOLOGIC CHANGES IN F-344 RATS

Since McCay et al. reported beneficial effects of caloric restriction on longevity in rats (McCay et al. 1935), the influence of dietary factors on longevity and spontaneously occurring pathological lesions have been studied in experimental animals for several decades by many authors (Berg and Simms 1961; Maeda et al. 1985; Tannenbaum 1945; Tucker 1979; Yu et al. 1985). Food or caloric restriction inhibits the development of some tumors or age-related pathological lesions such as chronic nephropathy and myocardiopathy. However, there are few available data explaining a rational relationship between food restriction and hematological, biochemical, or pathological findings in Fischer rats.

Food Restriction, Circadian Disorder and Longevity of Rats and Mice

Evidence that food restriction alters circadian rhythms as it prolongs the healthful life of rats and mice is reviewed. Because rhythms in different variables are changed in different ways, the circadian organization that is characteristic of freely feeding animals is disrupted. In the case of daily food restriction (meal feeding), the extent of disruption depends on the timing of the meal in relation to the daily light-dark schedule. Recent studies indicate that the extension of life span by a given level of food restriction is similar regardless of mealtime, whether fixed or shifted at weekly intervals throughout life. Such results suggest that the effects of food restriction on circadian organization are not involved in the effect on survival. On the other hand, changes in any given rhythm (such as an increased amplitude and a decreased overall average of body temperature) could point to the mechanism by which longevity is increased.

Longevity of cold-exposed rats: a reevaluation of the "rate-of-living theory"

It has been postulated that increased energy expenditure results in shortened survival. To test this "rate-of-living theory" we examined the effect of raising energy expenditure by means of cold exposure on the longevity of rats. Male 6-mo-old SPF Long-Evans rats were gradually accustomed to immersion in cool water (23 degrees C). After 3 mo they were standing in the cool water for 4 h/day, 5 days/wk. They were maintained on this program until age 32 mo. The cold exposure resulted in a 44% increase in food intake (P less than 0.001). Despite their greater food intake, the cold-exposed rats' body weights were significantly lower than those of control animals from age 11 to 32 mo. The average age at death of the cold-exposed rats was 968 +/- 141 days compared with 923 +/- 159 days for the controls. The cold exposure appeared to protect against neoplasia, particularly sarcomas; only 24% of the necropsied cold-exposed rats had malignancies compared with 57% for the controls. The results of this study provide no support for the concept that increased energy expenditure decreases longevity.