Old Control Research Articles

Curcumin effects on age-related changes in oral immunity: an in vivo study.

The current study aimed to investigate the effects of ageing on oral immunity using β-defensin (DEFB) 1/2 as a marker and evaluate the effects of curcumin (CUR) on these processes. The study sample included thirty male C57BL/6J mice divided into three groups based on the treatment method used. The young control (YC) and old control (OC) groups received 0·5 % methylcellulose-400 (CUR vehicle) orally for 5 days, whereas the CUR group of older mice received a CUR solution suspended in 0·5 % methylcellulose-400 (dose: 3·0 mg/kg body). DEFB1/2 and immune indicator levels were measured in the saliva and salivary glands post-treatment. The saliva volume and protein content were significantly reduced in the OC group compared with the YC group. CUR administration restored these parameters, decreased DEFB1 expression in the salivary gland and increased DEFB1/2 secretion and DEFB2 expression. These findings were supported by epigenetic gene regulation and partial cytokine activation from changes in WD40 repeat protein 5, TNF alpha and IL-1beta. CUR can partially restore age-related changes in oral immune responses and promote oral health, thereby preventing frailty in the older population through a nutritional therapeutic pathway.

Possible Role of Oxidative Stress and Nrf2/HO-1 Pathway in Pentylenetetrazole-induced Epilepsy in Aged Rats.

To examine the impact of aging on the response of rats to pentylenetetrazole (PTZ)-induction of epilepsy and the possible role of oxidative stress and nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase (HO)-1 pathway in this response. Forty male albino rats were equally allocated into 4 groups; 1) Young control (YC) group, aged 8-12 weeks, 2) Old control (OC) group, aged 24 months, 3) PTZ-Young group: young rats received PTZ (50 mg/Kg, i.p. every other day) for 2 weeks and 4) PTZ-Old group: as group 3 but rats were old. The seizure score stage and latency to the first jerk were recorded in rats. Redox state markers in brain tissues including malondialdehyde (MDA), catalase and total antioxidant capacity (TAC) were evaluated. Also, the expression of Nrf2 and HO-1 genes were measured in the brain tissues. Old rats showed an early and a significant rise in the seizure score with PTZ administration and a significant drop in the seizure latency compared to young rats (P <0.01). Also, old rats showed a significantly higher MDA concentration and a significantly lower TAC and catalase activity than young rats (P <0.01). Moreover, the expression of Nrf2 and HO-1 was significantly lowered in old rats compared to young rats with PTZ administration (P < 0.01). Aging increases the vulnerability of rats to PTZ-induced epilepsy. An effect might come down to the up-regulation of oxidative stress and the down regulation of antioxidant pathways including Nrf2 and HO-1.

MicroRNA profiling of different exercise interventions for alleviating skeletal muscle atrophy in naturally aging rats.

Exercise is an affordable and practical strategy to alleviate several detrimental outcomes from the aging process, including sarcopenia. The elucidation of molecular mechanisms to alleviate sarcopenia is one of the most important steps towards understanding human aging. Although microRNAs (miRNAs) regulate muscle growth, regeneration and aging, the potential role of exercise-mediated miRNAs during the prevention and rehabilitation of skeletal muscle atrophy upon exercise interventions remains unclear. A miRNA profile by miRNA sequencing for gastrocnemius muscle of a 24-month-old aged male rat model mimicking the naturally aging process was established through screening the differentially expressed miRNAs (DEMs) for alleviating aging-induced skeletal muscle atrophy upon optimal exercise intervention. The screened miRNAs and hub genes, as well as biomarkers with the most significantly enriched pathways, were validated by quantitative real-time polymerase chain reaction and western blotting. The sarcopenia index (SI) value and cross-sectional area (CSA) of rats from the old control (OC) group significantly decreased when compared with the youth control (YC) group (P<0.001, P<0.01), whereas an increased SI value and an enlarged CSA of rats from the old-aerobic exercise (OE), old-resistance exercise (OR) and old-mixed exercise (OM) groups were determined (P<0.01, P<0.001, P<0.05; P<0.01, P<0.01, P<0.05). Our results demonstrate that 764 known miRNAs, 201 novel miRNAs and 505 miRNA-mRNA interaction networks were identified to be related to aging-induced muscular atrophy. Among them, 13 miRNAs were differentially expressed (P<0.05 and log2 |fold change|>1) between the YC group and the OC group. Compared with the OC group, 7, 2 and 11 miRNAs were differentially expressed in the OE, OR and OM groups after exercise interventions, respectively. Meanwhile, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the identified DEMs were primarily related to apoptosis, autophagy and the NF-κB/MuRF1 signalling pathways (P<0.05). Meanwhile, four DEMs (miR-7a-1-3p, miR-135a-5p, miR-151-5p and miR-196b-5p), six hub genes (Ar, Igf1, Hif1a, Bdnf, Fak and Nras) and several biomarkers (LC3, Beclin1, p62, Bax, Bcl-2 and NF-κB/MuRF1) with the most significantly enriched pathways were confirmed, which may play a key role in muscular atrophy during the aging process. These findings are closely correlated with the progression of sarcopenia and could act as potential biomarkers for the diagnosis and interventional monitoring of aging-induced skeletal muscle atrophy.

TARGETING SIRT1 RESCUES AGE- AND OBESITY-INDUCED HUMAN MICROVASCULAR DYSFUNCTION

Objective: Experimental evidence suggests a relevant role of SIRT1 in age- and metabolic-related vascular dysfunction. Whether these effects hold true in the human microvasculature is unknown. We aimed to investigate the role of SIRT1 in age- and obesity-related microvascular dysfunction in humans. Design and method: Individuals (n = 95) undergoing laparoscopic surgery were stratified by BMI status (above or below 30 Kg/m2) and age (above or below 40 years) and classified as young control (YC), young obese (YO), old control (OC) and old obese (OO). Endothelial function was assessed in small resistance arteries by pressurized micromyography, before and after incubation with a SIRT1 agonist (SRT1720) and a mitochondria reactive oxygen species (mtROS) scavenger (MitoTEMPO). We assessed vascular levels of mtROS and nitric oxide availability by confocal microscopy and vascular gene expression of SIRT1 and mitochondrial proteins by qPCR. ChIP assay was employed to investigate SIRT1-dependent epigenetic regulation of mitochondrial proteins. Results: Endothelial function showed a graded decrease from YC to OO, with reduced nitric oxide availability and increased mtROS levels. Similarly, SIRT1 and mitochondrial antioxidant proteins (FOXO3 and SOD2) expression levels were reduced while there was a higher expression of pro-oxidant and ageing mitochondria proteins p66Shc and Arginase II. OO, YO and OC endothelial function was rescued by SRT1720 (Figure). The improvement in endothelial function showed a linear relationship with age, BMI and vascular emodelling. The restoration was comparable to the one obtained with mitoTEMPO in the same groups. These effects were explained by SIRT1-dependent chromatin changes leading to reduced p66Shc expression and upregulation of proteins involved in mitochondria respiratory chain: ATP synthase 6, cytochrome B, NADH dehydrogenase 2, NADH dehydrogenase 5. Conclusions: Restoring SIRT1 activity rescues obesity and age-related endothelial dysfunction. Its epigenetic control on mitochondrial pathways influences mtROS levels, NO availability, and the expression of the mitochondria respiratory chain proteins. SIRT1 is a novel central regulator of a homeostatic axis connecting vascular phenotype to systemic metabolism and ageing and to exposure to external adverse stimuli. Early targeting of SIRT1 might represent a crucial strategy to prevent the microvascular dysfunction related to age and obesity.

Cell therapy rescues aging-induced beta-1 adrenergic receptor and GRK2 dysfunction in the coronary microcirculation.

Our past study showed that coronary arterioles isolated from adipose-derived stromal vascular fraction (SVF)-treated rats showed amelioration of the age-related decrease in vasodilation to beta-adrenergic receptor (β-AR) agonist and improved β-AR-dependent coronary flow and microvascular function in a model of advanced age. We hypothesized that intravenously (i.v.) injected SVF improves coronary microvascular function in aged rats by re-establishing the equilibrium of the negative regulators of the internal adrenergic signaling cascade, G-protein receptor kinase 2 (GRK2) and G-alpha inhibitory (Gαi) proteins, back to youthful levels. Female Fischer-344 rats aged young (3 months, n = 24), old (24 months, n = 26), and old animals that received 1 × 107 green fluorescent protein (GFP+) SVF cells (O + SVF, n = 11) 4 weeks prior to sacrifice were utilized. Overnight urine was collected prior to sacrifice for catecholamine measurements. Cardiac samples were used for western blotting while coronary arterioles were isolated for pressure myography studies, immunofluorescence staining, and RNA sequencing. Coronary microvascular levels of the β1 adrenergic receptor are decreased with advancing age, but this decreased expression was rescued by SVF treatment. Aging led to a decrease in phosphorylated GRK2 in cardiomyocytes vs. young control with restoration of phosphorylation status by SVF. In vessels, there was no change in genetic transcription (RNAseq) or protein expression (immunofluorescence); however, inhibition of GRK2 (paroxetine) led to improved vasodilation to norepinephrine in the old control (OC) and O + SVF, indicating greater GRK2 functional inhibition of β1-AR in aging. SVF works to improve adrenergic-mediated vasodilation by restoring the β1-AR population and mitigating signal cascade inhibitors to improve vasodilation.

Effects of high intensity interval training and aging on cardiac muscle apoptosis markers in C57BL/6 Mice

Apoptosis is a specific form of programmed cell death that plays an important role in tissue homeostasis and also occurs during aging. In addition, exercise training may alter apoptosis-related signaling in muscles, including the cardiac muscle. However, the effects of high-intensity interval training (HIIT) on apoptosis markers in the heart have not yet been studied. Thus, the aim of the present study was to investigate the effects of HIIT on Bcl-2 and Bax expression protein levels in young and old cardiac muscles. Four and 24-month old C57BL/6J mice were used as our young adult and old groups, respectively. Animals were randomly assigned to four groups: young control (YC), young trained (YT), old control (OC), and old trained (OT). The trained groups performed HIIT 5 sessions per week for 4 weeks. RNA extraction and synthesis of cDNA was performed, and Bax and Bcl2 heart gene levels were determined by RT-PCR analysis. Training induced significant increases in Bcl-2 gene expression in YT group comparing to the YC group (p = 0.010) and in OT group comparing to OC group (p = 0.002). Training induced non-significant decrease (p > 0.05) in Bax gene expression and in Bax/Bcl-2 ratio in YT group comparing to the YC group and in OT group comparing to OC group. Aging showed no significant effect in Bcl-2 gene expression, Bax gene expression, and Bax/Bcl-2 ratio in CY group comparing to the OC group and in YT group comparing to OT group (p > 0.05). In conclusion, 4 weeks of HIIT increased Bcl-2 level for young and old heart muscles, and no effect of aging was revealed, indicating that HIIT ameliorated anti-apoptotic signaling in the young and old heart of mice.

Exercise-induced changes of gene expression in the cerebellum of aged mice

PurposeExercise has been prescribed to the elderly based on its effect on increasing muscle strength and protein synthesis that prevent sense of balance and/or cognitive functions. However, a few molecular mechanism researches has been conducted on how the vestibular organs, cerebellum, and hippocampus, which are responsible for the deterioration and balance of spatial learning memory due to aging, are affected by exercise. MethodsThe 9-week old and 84-week old C57Bl/6 were assigned randomly to Young-Control (YC), Young-Exercise (YE), Old-Control (OC) and Old-Exercise (OE) groups for 4 -week treadmill running. A Rotarod test was used to evaluate motor coordination function. Moreover, a high-throughput whole transcript expression RNA array approach was applied to the cerebellum of aged mice to explain the novel molecular mechanism of beneficial effect of exercise. ResultsAs results, the motor coordination function was significantly improved in exercise-aged mice. The RNA sequencing analysis showed that the expression of cerebellar genes was significantly changed by aging rather than exercise. Especially, Cers1 was up-regulated in sedentary aged mice and down-regulated in exercise aged mice. Fumonisin B1, inhibition of Cers1, mitigates neuronal cell death induced by doxorubicin. ConclusionThese results provide unraveling specific transcripts and understanding of the exercise-related cerebellum transcriptome in aged mice. Well-designed exercise program might prevent the motor coordination defect in aged model, which development of the exercise protocol for elderly population based on these markers.

Suppression of the gut microbiome ameliorates age-related arterial dysfunction and oxidative stress in mice.

Age-related arterial dysfunction, characterized by oxidative stress- and inflammation-mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases. To investigate whether age-related changes in the gut microbiome may mediate arterial dysfunction, we suppressed gut microbiota in young and old mice with a cocktail of broad-spectrum, poorly-absorbed antibiotics in drinking water for 3-4 weeks. In old mice, antibiotic treatment reversed endothelial dysfunction and arterial stiffening and attenuated vascular oxidative stress and inflammation. To provide insight into age-related changes in gut microbiota that may underlie these observations, we show that ageing altered the abundance of microbial taxa associated with gut dysbiosis and increased plasma levels of the adverse gut-derived metabolite trimethylamine N-oxide. The results of the present study provide the first proof-of-concept evidence that the gut microbiome is an important mediator of age-related arterial dysfunction and therefore may be a promising therapeutic target for preserving arterial function with ageing, thereby reducing the risk of cardiovascular diseases. Oxidative stress-mediated arterial dysfunction (e.g. endothelial dysfunction and large elastic artery stiffening) is the primary mechanism driving age-related cardiovascular diseases. Accumulating evidence suggests the gut microbiome modulates host physiology because dysregulation ('gut dysbiosis') has systemic consequences, including promotion of oxidative stress. The present study aimed to determine whether the gut microbiome modulates arterial function with ageing. We measured arterial function in young and older mice after 3-4weeks of treatment with broad-spectrum, poorly-absorbed antibiotics to suppress the gut microbiome. To identify potential mechanistic links between the gut microbiome and age-related arterial dysfunction, we sequenced microbiota from young and older mice and measured plasma levels of the adverse gut-derived metabolite trimethylamine N-oxide (TMAO). In old mice, antibiotics reversed endothelial dysfunction [area-under-the-curve carotid artery dilatation to acetylcholine in young: 345±16AU vs. old control (OC): 220±34 AU, P<0.01; vs. old antibiotic-treated (OA): 334±15AU; P<0.01vs. OC] and arterial stiffening (aortic pulse wave velocity in young: 3.62±0.15m s-1 vs. OC: 4.43±0.38m s-1 ; vs. OA: 3.52±0.35m s-1 ; P=0.03). These improvements were accompanied by lower oxidative stress and greater antioxidant enzyme expression. Ageing altered the abundance of gut microbial taxa associated with gut dysbiosis. Lastly, plasma TMAO was higher with ageing (young: 2.6±0.4μmol L-1 vs. OC: 7.2±2.0μmol L-1 ; P<0.0001) and suppressed by antibiotic treatment (OA: 1.2±0.2μmol L-1 ; P<0.0001vs. OC). The results of the present study provide the first evidence for the gut microbiome being an important mediator of age-related arterial dysfunction and oxidative stress and suggest that therapeutic strategies targeting gut microbiome health may hold promise for preserving arterial function and reducing cardiovascular risk with ageing in humans.

Fermentation Improves the Preventive Effect of Soybean Against Bone Loss in Senescence-Accelerated Mouse Prone 6.

Osteopenia is a preclinical phase of osteoporosis, it occurs naturally with aging and increases the risk of bone fractures in elderly males. Previous studies have revealed the beneficial effects of soybean on preventing bone loss due to its isoflavone contents. Fermentation alters the soybean isoflavone contents, that is, isoflavone glucosides is hydrolyzed into aglycones. However, it is not clear how these alterations influences the preventive effect of soybean on bone loss. In this study, we fed senescence-accelerated mouse prone 6 (SAMP6), a model of senile osteopenia, with an equal dosage of nonfermented soybean (NS) or fermented soybean, Doenjang (DJ) for 18 weeks. Mice supplemented with DJ showed 1.13-fold higher bone densities and 1.06-fold longer relative bone lengths than those of osteopenic SAMP6 mice old control (OC), while NS-supplemented mice showed no significant improvement. Supplementation with DJ effectively prevented bone loss in the osteopenia model by the improvement of bone formation and reduction of osteoclastogenesis. In addition, we discovered that DJ increased osteogenesis in SAMP6 mice via BMP2-Smad-Runx2 signaling. These results suggest that the fermentation process could enhance bone loss prevention by soybean and dietary supplementation with fermented soybeans may be beneficial for bone health. PRACTICAL APPLICATION: Soybean fermentation improved the preventive effects of soybean on bone loss. Therefore, the consumption of fermented soybean, Doenjang, is a potential alternative for aging-related bone loss therapy.

Adipose-derived cells improve left ventricular diastolic function and increase microvascular perfusion in advanced age.

An early manifestation of coronary artery disease in advanced age is the development of microvascular dysfunction leading to deficits in diastolic function. Our lab has previously shown that epicardial treatment with adipose-derived stromal vascular fraction (SVF) preserves microvascular function following coronary ischemia in a young rodent model. Follow-up studies showed intravenous (i.v.) delivery of SVF allows the cells to migrate to the walls of small vessels and reset vasomotor tone. Therefore we tested the hypothesis that the i.v. cell injection of SVF would reverse the coronary microvascular dysfunction associated with aging in a rodent model. Fischer 344 rats were divided into 4 groups: young control (YC), old control (OC), old + rat aortic endothelial cells (O+EC) and old + GFP+ SVF cells (O+SVF). After four weeks, cardiac function and coronary flow reserve (CFR) were measured via echocardiography, and hearts were explanted either for histology or isolation of coronary arterioles for vessel reactivity studies. In a subgroup of animals, microspheres were injected during resting and dobutamine-stimulated conditions to measure coronary blood flow. GFP+ SVF cells engrafted and persisted in the myocardium and coronary vasculature four weeks following i.v. injection. Echocardiography showed age-related diastolic dysfunction without accompanying systolic dysfunction; diastolic function was improved in old rats after SVF treatment. Ultrasound and microsphere data both showed increased stimulated coronary blood flow in O+SVF rats compared to OC and O+EC, while isolated vessel reactivity was mostly unchanged. I.v.-injected SVF cells were capable of incorporating into the vasculature of the aging heart and are shown in this study to improve CFR and diastolic function in a model of advanced age. Importantly, SVF injection did not lead to arrhythmias or increased mortality in aged rats. SVF cells provide an autologous cell therapy option for treatment of microvascular and cardiac dysfunction in aged populations.

Intermittent parathyroid hormone administration attenuates endothelial dysfunction in old rats.

We have demonstrated that intermittent parathyroid hormone administration can rescue age-related vascular dysfunction by improving endothelial-dependent dilation in the aorta of older rodents. This demonstrates a novel potential benefit of parathyroid hormone administration in aging.

Aging and Endurance Training Alters Mitochondrial Fusion and Fission Dynamics in Rat Skeletal Muscle

Mitochondria undergo constant changes in shape, localization and number regulated by dynamic fusion, fission and motility events. In mammalian cells mitochondrial fusion is largely mediated by mitofusin (Mfn1 and 2) whereas fission is controlled mainly by Fis1 and the dynamin-related protein 1 (Drp1). PURPOSE: To investigate how aging and exercise training affect the gene expression of mitochondrial fusion and fission proteins in rat skeletal muscle. METHODS: Male Sprague-Dawley rats were divided into 6 groups (N=8): young control (YC), young trained (YT); middle-age control (MC), middle-age trained (MT); old control (OC) and old trained (OT). Trained rats ran on treadmill (64%VO2max) at 15 m/min, 5% grade for 45 min/day, 5 days/wk for 12 wks. Rats were killed at 5, 15 and 20 mo of age. Soleus and vastus lateralis (VL) muscles were harvested 48 h after last training bout at rest. RESULTS: Mfn1 mRNA level measured by RT-PCR was decreased in OC vs. YC (P<0.05) in VL, whereas Mfn1 protein content measured by Western blot was lower in OC (P<0.05) in soleus. Mfn2 mRNA level was lowered with age in both muscles (P<0.05). Training increased both Mfn1and Mfn2 mRNA levels (P<0.01) in soleus and VL, but Mfn1/2 protein content was unaltered. Both soleus and VL showed higher Fis1 mRNA levels in MC and OC vs. YC (P<0.01), and elevated mRNA with training was observed in all age groups (P<0.01). Fis1 protein content was also elevated with aging and training in soleus (P<0.01) and VL (P<0.05). Increased Drp1 mRNA and protein levels were observed in OC vs. YC (P<0,01) in both muscles, and with training (P<0.01). Subsarcolemma and intramyofibrial mitochondrial density was not affected by age but increased with training in soleu and VL (P<0.01). CONCLUSION: Mitochondrial fusion protein expression is decreased whereas fission protein expression is elevated with aging in rat skeletal muscle. Endurance training stimulates both fusion and fission proteins expression suggesting a dynamic mitochondrial turnover and biogenesis.

Exercise Training Improves Age-Related Myocardial Metabolic Derangement: Proton Magnetic Resonance Spectroscopy Study in the Rat Model

Background and ObjectivesThe objective of this study was to determine whether long-term exercise training will improve age-related cardiac metabolic derangement using proton magnetic resonance (MR) spectroscopy.Materials and MethodsYoung and old male Fischer 344 rats were assigned to sedentary controls groups {young control (YC) group-3 months of age: YC, n=10; old control (OC) group-22 months of age: OC, n=10}, and an exercise training group (OT, n=5). After 12-week of treadmill exercise training, MR spectroscopy at 4.7 T was performed to assess myocardial energy metabolism: measurements of myocardial creatine-to-water ratio (Scr/Sw) were performed using the XWIN-NMR software.ResultsExercise capacity was 14.7 minutes greater in OT than that in OC (20.1±1.9 minutes in OT, 5.4±2.3 minutes in OC; p<0.001). The 12-week exercise training rendered the old rats a maximum exercise capacity matching that of untrained YC rats (17.9±1.5 minutes in YC, 20.1±1.9 minutes in OT; p>0.05). The creatine-to-water ratios in the interventricular septa of YC did not differ significantly from that of OT (0.00131±0.00025 vs. 0.00127±0.00031; p=0.37). However, OC showed significant reduction in creatine-to-water ratio compared to OT (0.00096±0.00025 vs. 0.00127±0.00031; p<0.001). Mean total creatine concentrations in the myocardium were similar between YC and OT (13.3±3.6 vs. 11.5±4.1 mmol/kg wet weight; p=0.29). In contrast, the mean total creatine concentration of OC was significantly reduced compared to OT (6.8±3.2 vs. 11.5±4.1 mmol/kg wet weight; p=0.03).ConclusionOur findings suggest that long-term exercise training in old rats induced prevention of age-related deterioration in myocardial metabolism.

Arachidonic acid preserves hippocampal neuron membrane fluidity in senescent rats

Previous studies indicate that long-term dietary supplementation with arachidonic acid (AA) in 20-month-old rats (OA) effectively restores performance in a memory task and the induction of long-term potentiation in the hippocampus to the level of young control animals (YC). The present study examined protein mobility using the live cell imaging technique “Fluorescent Recovery After Photobleaching (FRAP)” in YC, old control (OC) and OA neurons in hippocampal slice preparations. Three measures; mobile fraction (Mf), diffusion constant (D) and time constant (τ), were estimated among YC, OC and OA. Each of these parameters was significantly different between OC and YC, suggesting that membrane fluidity is lower in OC than in YC. In contrast, D and τ were comparable in OA and YC, indicating that hippocampal neuronal membranes supplemented with AA were more fluid than those in OC, whereas the fraction of diffusible protein in the bleached region remained smaller than in YC. Long-term administration of AA to senescent rats might help to preserve membrane fluidity and maintain hippocampal plasticity.

Effects of arachidonic acid on the spatial cognition of aged rats

Abstract: To examine the effects of arachidonic acid (AA) on age‐related cognitive deficits, Fischer 344 rats were given an AA‐supplemented powder diet for 12 weeks from 18.6 months old as part of the old AA (OA) group. Other age‐matched rats were fed a non‐AA‐supplemented powder diet as part of the old control (OC) group, and young rats were fed lab pellets as part of the young control (YC) group. When the aged rats reached 20.0 months old, all animals were tested for spontaneous activity in an open field, followed by the Morris water maze place and cue tasks. Escape latencies for the place task showed that the YC rats were fastest, and there was no difference between the OA and OC groups. However, the probe test and the first block of the cue task indicated that the OA rats remembered the location of an invisible platform better than the OC rats. Although the amount of hippocampal AA was larger in the OA rats than in the OC rats, the difference was not significant. The results showed that AA administration to aged animals may alleviate age‐related deficits in spatial cognition.

Attenuation of force deficit after lengthening contractions in soleus muscle from trained rats.

The purposes of this study were 1) to determine the extent to which endurance training reduces the functional deficit induced by lengthening contractions in the soleus (Sol) muscle and 2) to determine whether young and old rats training at a comparable relative exercise intensity would demonstrate a similar protective effect from lengthening-contraction-induced injury. Young (3-mo-old) and old (23-mo-old) male Fischer 344 rats were randomly assigned to either a control or exercise training group [young control (YC), old control (OC), young trained (YT), old trained (OT)]. Exercise training consisted of 10 wk of treadmill running (15% grade, 45 min/day, and 5 days/wk) such that by the end of training the young and old rats were exercising at 27 and 15 m/min, respectively. After training, contractile properties of the Sol muscle were measured in vitro at 26 degrees C. The percent decrease in maximal isometric specific force (P(o)) was determined after a series of 20 lengthening contractions (20% strain from optimal muscle length, 1 contraction every 5 s). After the lengthening-contraction protocol, Sol muscle P(o) was decreased by approximately 26% (19.6 vs. 14.6 N/cm(2)) and 28% (14.8 vs. 9.6 N/cm(2)) in the YC and OC rats, respectively. After exercise training, the reduction in P(o) was significantly (P < 0.05) attenuated to a similar degree ( approximately 13%) in both YT rats (18.7 vs. 16.2 N/cm(2)) and OT rats (15.8 vs. 13.7 N/cm(2)). It is concluded that exercise training attenuates the force deficit after repeated lengthening contractions to a comparable extent in young and old rats training at a similar exercise intensity.

Effect of exercise training on passive stiffness in locomotor skeletal muscle: role of extracellular matrix.

The purpose of this study was to evaluate the effect of endurance exercise training on both locomotor skeletal muscle collagen characteristics and passive stiffness properties in the young adult and old rat. Young (3-mo-old) and senescent (23-mo-old) male Fischer 344 rats were randomly assigned to either a control or exercise training group [young control (YC), old control (OC), young trained (YT), old trained (OT)]. Exercise training consisted of treadmill running at approximately 70% of maximal oxygen consumption (45 min/day, 5 days/wk, for 10 wk). Passive stiffness (stress/strain) of the soleus (Sol) muscle from all four groups was subsequently measured in vitro at 26 degreesC. Stiffness was significantly greater for Sol muscles in OC rats compared with YC rats, but in OT rats exercise training resulted in muscles with stiffness characteristics not different from those in YC rats. Sol muscle collagen concentration and the level of the nonreducible collagen cross-link hydroxylysylpyridinoline (HP) significantly increased from young adulthood to senescence. Although training had no effect on Sol muscle collagen concentration in either age group, it resulted in a significant reduction in the level of Sol muscle HP in OT rats. In contrast, exercise had no effect on HP in the YT animals. These findings indicate that 10 wk of endurance exercise significantly alter the passive viscoelastic properties of Sol muscle in old but not in young adult rats. The coincidental reduction in the principal collagen cross-link HP also observed in response to training in OT muscle highlights the potential role of collagen in influencing passive muscle viscoelastic properties.

Effect of oxidant challenge on contractile function of the aging rat diaphragm.

Although controversial, growing evidence indicates that reactive oxygen species (ROS) alter contractions of skeletal muscle, including the diaphragm. However, the impact of ROS on contractility of the aging diaphragm is unknown. The xanthine oxidase (0.01 U/ml) system was used as an ROS generator, imposing an oxidant challenge. Contractile function [twitch tension; twitch time to peak tension; twitch one-half relaxation time; tension at 10 and 20 Hz; maximal tetanic tension (Po) at 100 Hz] of costal diaphragm fiber bundles from young (4 mo) and old (25 mo) Fischer 344 rats was examined in vitro before and after treatment with control Krebs solution [young control (YC) and old control (OC)], or with xanthine oxidase (XO; 0.01 U/ml) plus hypoxanthine (0.29 mg/ml) substrate [young XO treated (YXO) and old XO treated (OXO)]. Contractile function of fiber bundles was reassessed after oxidant challenge in an unfatigued state (Post-u) or 10 min after a fatiguing stimulation protocol (Post-f). Oxidant challenge in the unfatigued fiber bundles increased twitch tension and tension at 10 and 20 Hz in YXO, but not OXO, without increasing Po. Conversely, XO significantly depressed fatigued diaphragm twitch and low-frequency tension in both OXO and YXO, compared with controls. Po was depressed Post-f in OXO but not YXO. Oxidant challenge also increased twitch one-half relaxation time of the fatigued diaphragm in both age groups. Furthermore, fiber bundles from old rats suffered greater fatigue during the stimulation protocol. We conclude that the response to oxidant challenge and increased contractile demand is impaired in the aging diaphragm.

Rat aortic vasoreactivity is altered by old age and hindlimb unloading

Prolonged bed rest in young adults leads to a number of cardiovascular alterations, including orthostatic intolerance and decreased exercise capacity. Similar changes occur with advanced age. These modifications of cardiovascular function have been suggested to be causally related to changes in peripheral vascular reactivity. Using rat hindlimb unloading as an animal model of physical inactivity, this study was designed to determine whether prolonged decreases in weight-bearing activity induce changes in vascular reactivity that are similar to those occurring in senescent rats and whether the imposition of inactivity on old rats further modifies any age-related alterations in vasomotor responsiveness. Responses to vasoactive compounds were examined in vitro by using isolated abdominal aortic rings. Maximal isometric contractile force evoked by the vasoconstrictors KCl, norepinephrine (NE), and arginine vasopressin was lower in aortic segments from young hindlimb-unloaded (YHU), old control (OC), and old hindlimb-unloaded (OHU) rats compared with that from young control (YC) rats. Sensitivity [mean effective concentration (EC50)] to KCl was enhanced in segments from both old and unloaded animals compared with YC rats, but EC50 values for the other constrictors were not different among groups. Vasorelaxation responses induced by acetylcholine (10(-7) M NE preconstriction) were lower in vessel rings from OC (1 x 10(-7) to 3 x 10(-6) M), YHU (10(-7) to 10(-5) M), and OHU (10(-7) to 10(-5) M) rats than those from YC animals. In addition, vessel rings from OC, YHU, and OHU rats were less sensitive to sodium nitroprusside-induced relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)