OXIDATIVE CAPACITY OF AGED RAT MUSCLE AND LIVER FOLLOWING LONG-TERM MODERATE EXERCISE AND CALORIC RESTRICTION

Caloric restriction (CR) slows the aging process, extends lifespan, and exerts neuroprotective effects. It is widely accepted that CR attenuates β-amyloid (Aβ) neuropathology in models of Alzheimer’s disease (AD) by so-far unknown mechanisms. One promising process induced by CR is autophagy, which is known to degrade aggregated proteins such as amyloids. In addition, autophagy positively regulates glucose uptake and may improve cerebral hypometabolism—a hallmark of AD—and, consequently, neural activity. To evaluate this hypothesis, APPswe/PS1delta9 (tg) mice and their littermates (wild-type, wt) underwent CR for either 16 or 68 weeks. Whereas short-term CR for 16 weeks revealed no noteworthy changes of AD phenotype in tg mice, long-term CR for 68 weeks showed beneficial effects. Thus, cerebral glucose metabolism and neuronal integrity were markedly increased upon 68 weeks CR in tg mice, indicated by an elevated hippocampal fluorodeoxyglucose [18F] ([18F]FDG) uptake and increased N-acetylaspartate-to-creatine ratio using positron emission tomography/computer tomography (PET/CT) imaging and magnet resonance spectroscopy (MRS). Improved neuronal activity and integrity resulted in a better cognitive performance within the Morris Water Maze. Moreover, CR for 68 weeks caused a significant increase of LC3BII and p62 protein expression, showing enhanced autophagy. Additionally, a significant decrease of Aβ plaques in tg mice in the hippocampus was observed, accompanied by reduced microgliosis as indicated by significantly decreased numbers of iba1-positive cells. In summary, long-term CR revealed an overall neuroprotective effect in tg mice. Further, this study shows, for the first time, that CR-induced autophagy in tg mice accompanies the observed attenuation of Aβ pathology.

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Impact of long-term caloric restriction on cardiac senescence: Caloric restriction ameliorates cardiac diastolic dysfunction associated with aging

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2010.10.018 ◽

2011 ◽

Vol 50 (1) ◽

pp. 117-127 ◽

Cited By ~ 106

Author(s):

Ken Shinmura ◽

Kayoko Tamaki ◽

Motoaki Sano ◽

Mitsushige Murata ◽

Hiroyuki Yamakawa ◽

...

Keyword(s):

Diastolic Dysfunction ◽

Caloric Restriction

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Caloric restriction increases muscle and liver mitochondrial oxidative capacity in young but not in old rats

Clinical Nutrition ◽

10.1016/s0261-5614(03)80160-7 ◽

2003 ◽

Vol 22 ◽

pp. S43

Author(s):

R. Barazzoni ◽

M. Zanetti ◽

L. Visintin ◽

G. Biolo ◽

M. Stebel ◽

...

Keyword(s):

Caloric Restriction ◽

Oxidative Capacity ◽

Mitochondrial Oxidative Capacity ◽

Old Rats

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Long-Term Caloric Restriction Ameliorates the Decline in Diastolic Function in Humans

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2005.08.069 ◽

2006 ◽

Vol 47 (2) ◽

pp. 398-402 ◽

Cited By ~ 248

Author(s):

Timothy E. Meyer ◽

Sándor J. Kovács ◽

Ali A. Ehsani ◽

Samuel Klein ◽

John O. Holloszy ◽

...

Keyword(s):

Diastolic Function ◽

Caloric Restriction

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Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice

Physiological Genomics ◽

10.1152/physiolgenomics.00084.2006 ◽

2006 ◽

Vol 27 (3) ◽

pp. 187-200 ◽

Cited By ~ 79

Author(s):

Colin Selman ◽

Nicola D. Kerrison ◽

Anisha Cooray ◽

Matthew D. W. Piper ◽

Steven J. Lingard ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Caloric Restriction ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Proton Nuclear Magnetic Resonance ◽

Cellular Transport ◽

Expression Of Genes ◽

Transcriptional Changes

Caloric restriction (CR) increases healthy life span in a range of organisms. The underlying mechanisms are not understood but appear to include changes in gene expression, protein function, and metabolism. Recent studies demonstrate that acute CR alters mortality rates within days in flies. Multitissue transcriptional changes and concomitant metabolic responses to acute CR have not been described. We generated whole genome RNA transcript profiles in liver, skeletal muscle, colon, and hypothalamus and simultaneously measured plasma metabolites using proton nuclear magnetic resonance in mice subjected to acute CR. Liver and muscle showed increased gene expressions associated with fatty acid metabolism and a reduction in those involved in hepatic lipid biosynthesis. Glucogenic amino acids increased in plasma, and gene expression for hepatic gluconeogenesis was enhanced. Increased expression of genes for hormone-mediated signaling and decreased expression of genes involved in protein binding and development occurred in hypothalamus. Cell proliferation genes were decreased and cellular transport genes increased in colon. Acute CR captured many, but not all, hepatic transcriptional changes of long-term CR. Our findings demonstrate a clear transcriptional response across multiple tissues during acute CR, with congruent plasma metabolite changes. Liver and muscle switched gene expression away from energetically expensive biosynthetic processes toward energy conservation and utilization processes, including fatty acid metabolism and gluconeogenesis. Both muscle and colon switched gene expression away from cellular proliferation. Mice undergoing acute CR rapidly adopt many transcriptional and metabolic changes of long-term CR, suggesting that the beneficial effects of CR may require only a short-term reduction in caloric intake.

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Abstract P138: Long-term Effects Of Severe Caloric Restriction To The Heart Function

Hypertension ◽

10.1161/hyp.78.suppl_1.p138 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Aline M De Souza ◽

Jonathas Almeida ◽

Nataliia Shults ◽

Hong Ji ◽

Kathryn Sandberg

Keyword(s):

Cardiovascular Disease ◽

Caloric Restriction ◽

Heart Function ◽

Left Ventricular ◽

Structure And Function ◽

Long Term Effects ◽

Isolated Hearts ◽

Ad Libitum ◽

And Function

Severe caloric restriction (sCR) increases the risk for acute cardiovascular disease. Less understood are the long-term effects on cardiovascular disease risk after the sCR period has ended. We investigated the effects of sCR on heart structure and function months after refeeding (sCR-Refed). Female Fischer rats (3-months-old) were maintained on (CT) ad libitum or a 60% caloric restricted diet for 2 weeks. Thereafter, all rats received ad libitum chow for 3 months and they were analyzed by precision ultrasound to assess their heart function. After imaging, the animals were sacrificed and the hearts were subjected to ischemia-reperfusion (I/R) using a Langendorff preparation. After 2 weeks of sCR, rats lost 15% of their initial body weight (BW) [% (100*(Final-Initial/Initial)): CT, 1.5±0.8 vs sCR, -15.4±1.1; p<0.001;n=8]. After 3 months of refeeding, there was no detectable difference in BW between CT and sFR-Refed groups. Isolated hearts from the sCR-Refed rats exhibited worse myocardial pathology after I/R compared to CT rats. The parallel orientation of myofibers and striations normally present in cardiomyocytes was lost in sCR-Refed rats. Further analysis revealed uneven blood-filling of the microcirculatory vessels and prominent interstitial edema of the myocardium. Hearts from sCR-Refed rats had more atrophied cardiomyocytes than CT [Atrophied/Total (%): CT, 0.2±0.1 vs sCR-Refed, 50.6±1.1; p<0.001; n=5]. The number of arrhythmic events during a 30 min ischemic interval in isolated hearts doubled after 2 weeks on the sCR diet ( data not shown ) and remained doubled 3 months later [Arrhythmias (% of time): CT, 34±8 vs sCR-Refed, 68±9; p=0.02; n=8]. Ultrasound imaging showed no difference in stroke volume, coronary perfusion pressure and left ventricular mass. However, the thickness of the left ventricular posterior wall was significantly reduced in sCR-Refed rats [(mm): CT, 2.55 ±0.03 vs sCR-Refed, 2.10±0.04; p=0.002; n=4]. These findings indicate heart structure and function remained damaged months after the sCR period ended and BW was restored. These studies have adverse cardiovascular risk implications for who are subjected either voluntarily (crash diets) or involuntarily (very low food security) to periods of inadequate caloric intake.

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Effect of pre- and postnatal growth and post-weaning activity on glucose metabolism in the offspring

Journal of Endocrinology ◽

10.1530/joe-14-0600 ◽

2014 ◽

Vol 224 (2) ◽

pp. 171-182 ◽

Cited By ~ 15

Author(s):

Neele S Dellschaft ◽

Marie-Cecile Alexandre-Gouabau ◽

David S Gardner ◽

Jean-Philippe Antignac ◽

Duane H Keisler ◽

...

Keyword(s):

Caloric Restriction ◽

Young Adulthood ◽

Postnatal Growth ◽

Late Gestation ◽

Leptin Resistance ◽

Metabolic Phenotype ◽

Obesogenic Environment ◽

Appetite Control ◽

Pregnant Sheep

Maternal caloric restriction during late gestation reduces birth weight, but whether long-term adverse metabolic outcomes of intra-uterine growth retardation (IUGR) are dependent on either accelerated postnatal growth or exposure to an obesogenic environment after weaning is not established. We induced IUGR in twin-pregnant sheep using a 40% maternal caloric restriction commencing from 110 days of gestation until term (∼147 days), compared with mothers fed to 100% of requirements. Offspring were reared either as singletons to accelerate postnatal growth or as twins to achieve standard growth. To promote an adverse phenotype in young adulthood, after weaning, offspring were reared under a low-activity obesogenic environment with the exception of a subgroup of IUGR offspring, reared as twins, maintained in a standard activity environment. We assessed glucose tolerance together with leptin and cortisol responses to feeding in young adulthood when the hypothalamus was sampled for assessment of genes regulating appetite control, energy and endocrine sensitivity. Caloric restriction reduced maternal plasma glucose, raised non-esterified fatty acids, and changed the metabolomic profile, but had no effect on insulin, leptin, or cortisol. IUGR offspring whose postnatal growth was enhanced and were obese showed insulin and leptin resistance plus raised cortisol. This was accompanied by increased hypothalamic gene expression for energy and glucocorticoid sensitivity. These long-term adaptations were reduced but not normalized in IUGR offspring whose postnatal growth was not accelerated and remained lean in a standard post-weaning environment. IUGR results in an adverse metabolic phenotype, especially when postnatal growth is enhanced and offspring progress to juvenile-onset obesity.

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Sexual dimorphism in liver mitochondrial oxidative capacity is conserved under caloric restriction conditions

AJP Cell Physiology ◽

10.1152/ajpcell.00203.2007 ◽

2007 ◽

Vol 293 (4) ◽

pp. C1302-C1308 ◽

Cited By ~ 50

Author(s):

A. Valle ◽

R. Guevara ◽

F. J. García-Palmer ◽

P. Roca ◽

J. Oliver

Keyword(s):

Sexual Dimorphism ◽

Energy Expenditure ◽

Oxidative Damage ◽

Caloric Restriction ◽

Oxidative Capacity ◽

Complex Iii ◽

Female Rats ◽

Oxidative Balance ◽

Wide Range ◽

Mitochondrial Oxidative Capacity

Caloric restriction (CR) without malnutrition has been shown to increase maximal life span and delay the rate of aging in a wide range of species. It has been proposed that reduction in energy expenditure and oxidative damage may explain the life-extending effect of CR. Sex-related differences also have been shown to influence longevity and energy expenditure in many mammalian species. The aim of the present study was to determine the sex-related differences in rat liver mitochondrial machinery, bioenergetics, and oxidative balance in response to short-term CR. Mitochondria were isolated from 6-mo-old male and female Wistar rats fed ad libitum or subjected to 40% CR for 3 mo. Mitochondrial O2 consumption, activities of the oxidative phosphorylation system (complexes I, III, IV, and V), antioxidative activities [MnSOD, glutathione peroxidase (GPx)], mitochondrial DNA and protein content, mitochondrial H2O2 production, and markers of oxidative damage, as well as cytochrome C oxidase and mitochondrial transcription factor A levels, were measured. Female rats showed a higher oxidative capacity and GPx activity than males. This sexual dimorphism was not modified by CR. Restricted rats showed slightly increased oxygen consumption, complex III activity, and GPx antioxidant activity together with lower levels of oxidative damage. In conclusion, the sexual dimorphism in liver mitochondrial oxidative capacity was unaffected by CR, with females showing higher mitochondrial functionality and ROS protection than males.

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