Age-induced Deterioration Research Articles

Cardiovascular aging: from cellular and molecular changes to therapeutic interventions.

Progressive age-induced deterioration in the structure and function of the cardiovascular system involves cardiac hypertrophy, diastolic dysfunction, myocardial fibrosis, arterial stiffness, and endothelial dysfunction. These changes are driven by complex processes that are interconnected, such as oxidative stress, mitochondrial dysfunction, autophagy, inflammation, fibrosis, and telomere dysfunction. In recent years, the advances in research of cardiovascular aging, including the wide use of animal models of cardiovascular aging, elucidated an abundance of cell signaling pathways involved in these processes and brought into sight possible interventions, which span from pharmacological agents, such as metformin, sodium-glucose cotransporter 2-inhibitors, rapamycin, dasatinib and quercetin, to lifestyle changes.

Age- and time-dependent mitochondrial genotoxic and myopathic effects of beta-guanidinopropionic acid, a creatine analog, on rodent skeletal muscles.

Beta-guanidinopropionic acid (GPA) is a creatine analog suggested as a treatment for hypertension, diabetes, and obesity, which manifest primarily in older adults. A notable side effect of GPA is the induction of mitochondrial DNA deletion mutations. We hypothesized that mtDNA deletions contribute to muscle aging and used the mutation promoting effect of GPA to examine the impact of mtDNA deletions on muscles with differential vulnerability to aging. Rats were treated with GPA for up to 4months starting at 14 or 30months of age. We examined quadriceps and adductor longus muscles as the quadriceps exhibits profound age-induced deterioration, while adductor longus is maintained. GPA decreased body and muscle mass and mtDNA copy number while increasing mtDNA deletion frequency. The interactions between age and GPA treatment observed in the quadriceps were not observed in the adductor longus. GPA had negative mitochondrial effects in as little as 4weeks. GPA treatment exacerbated mtDNA deletions and muscle aging phenotypes in the quadriceps, an age-sensitive muscle, while the adductor longus was spared. GPA has been proposed for use in age-associated diseases, yet the pharmacodynamics of GPA differ with age and include the detrimental induction of mtDNA deletions, a mitochondrial genotoxic stress that is pronounced in muscles that are most vulnerable to aging. Further research is needed to determine if the proposed benefits of GPA on hypertension, diabetes, and obesity outweigh the detrimental mitochondrial and myopathic side effects.

Detection of internal defects of concrete structures based on statistical evaluation of healthy part of concrete by the noncontact acoustic inspection method

A noncontact acoustic inspection method was developed to perform measurements from a long distance (usually about 5 to 7 m but even over 30 m) and detect internal defects (up to 10 cm in depth) of concrete structures using a long-range acoustic device and a laser Doppler vibrometer. An algorithm was also proposed to detect internal defects of concrete by combining two acoustic features, the vibrational energy ratio and spectral entropy obtained by our measurement. However, in actual concrete structures, it is difficult to distinguish a boundary between a healthy part and a defective part owing to influences such as the shape of internal defects, age-induced deterioration, and the surface condition of concrete. Therefore, we propose a method to statistically evaluate the distribution of the healthy part of concrete and extract the healthy part to identify the defective part. By this proposed method, the actual concrete floor slab bridge was measured from 33 m away and some internal defects were detected and visualized. Furthermore, a result for a railroad tunnel was compared with the Schmidt hammer rebound value and elastic wave velocity to verify the validity of the proposed method.

Mir-195: Roadblock for Reprogramming Aged Cells

Advanced age remains the greatest known risk factor for human diseases. According to a National Institute on Aging report, it is anticipated that people aged 65 or older will number nearly 1.5 billion by 2050, representing 16% of the world’s population and a dramatic increase in the economic burden of providing care to patients with senile chronic diseases. Recent evidence strongly supports the current hypotheses that age-induced deterioration of tissue stem cells play an important role in initiation of several aging-associated disorders including heart failure, Alzheimer’s disease, and Parkinson’s disease.

Sildenafil Ameliorates Advanced Glycation End Products-Induced Mitochondrial Dysfunction in HT-22 Hippocampal Neuronal Cells.

ObjectiveAccumulation of advanced glycation end-products (AGE) and mitochondrial glycation is importantly implicated in the pathological changes of the brain associated with diabetic complications, Alzheimer disease, and aging. The present study was undertaken to determine whether sildenafil, a type 5 phosphodiesterase type (PDE-5) inhibitor, has beneficial effect on neuronal cells challenged with AGE-induced oxidative stress to preserve their mitochondrial functional integrity.MethodsHT-22 hippocampal neuronal cells were exposed to AGE and changes in the mitochondrial functional parameters were determined. Pretreatment of cells with sildenafil effectively ameliorated these AGE-induced deterioration of mitochondrial functional integrity.ResultsAGE-treated cells lost their mitochondrial functional integrity which was estimated by their MTT reduction ability and intracellular ATP concentration. These cells exhibited stimulated generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential, induction of mitochondrial permeability transition, and release of the cytochrome C, activation of the caspase-3 accompanied by apoptosis. Western blot analyses and qRT-PCR demonstrated that sildenafil increased the expression level of the heme oxygenase-1 (HO-1). CoPP and bilirubin, an inducer of HO-1 and a metabolic product of HO-1, respectively, provided a similar protective effects. On the contrary, the HO-1 inhibitor ZnPP IX blocked the effect of sildenafil. Transfection with HO-1 siRNA significantly reduced the protective effect of sildenafil on the loss of MTT reduction ability and MPT induction in AGE-treated cells.ConclusionTaken together, our results suggested that sildenafil provides beneficial effect to protect the HT-22 hippocampal neuronal cells against AGE-induced deterioration of mitochondrial integrity, and upregulation of HO-1 is involved in the underlying mechanism.

Defects in β-cell Ca2+ dynamics in age-induced diabetes.

Little is known about the molecular mechanisms underlying age-dependent deterioration in β-cell function. We now demonstrate that age-dependent impairment in insulin release, and thereby glucose homeostasis, is associated with subtle changes in Ca(2+) dynamics in mouse β-cells. We show that these changes are likely to be accounted for by impaired mitochondrial function and to involve phospholipase C/inositol 1,4,5-trisphosphate-mediated Ca(2+) mobilization from intracellular stores as well as decreased β-cell Ca(2+) influx over the plasma membrane. We use three mouse models, namely, a premature aging phenotype, a mature aging phenotype, and an aging-resistant phenotype. Premature aging is studied in a genetically modified mouse model with an age-dependent accumulation of mitochondrial DNA mutations. Mature aging is studied in the C57BL/6 mouse, whereas the 129 mouse represents a model that is more resistant to age-induced deterioration. Our data suggest that aging is associated with a progressive decline in β-cell mitochondrial function that negatively impacts on the fine tuning of Ca(2+) dynamics. This is conceptually important since it emphasizes that even relatively modest changes in β-cell signal transduction over time lead to compromised insulin release and a diabetic phenotype.

Old flies have a robust central oscillator but weaker behavioral rhythms that can be improved by genetic and environmental manipulations.

Sleep–wake cycles break down with age, but the causes of this degeneration are not clear. Using a Drosophila model, we addressed the contribution of circadian mechanisms to this age-induced deterioration. We found that in old flies, free-running circadian rhythms (behavioral rhythms assayed in constant darkness) have a longer period and an unstable phase before they eventually degenerate. Surprisingly, rhythms are weaker in light–dark cycles and the circadian-regulated morning peak of activity is diminished under these conditions. On a molecular level, aging results in reduced amplitude of circadian clock gene expression in peripheral tissues. However, oscillations of the clock protein PERIOD (PER) are robust and synchronized among different clock neurons, even in very old, arrhythmic flies. To improve rhythms in old flies, we manipulated environmental conditions, which can have direct effects on behavior, and also tested a role for molecules that act downstream of the clock. Coupling temperature cycles with a light–dark schedule or reducing expression of protein kinase A (PKA) improved behavioral rhythms and consolidated sleep. Our data demonstrate that a robust molecular timekeeping mechanism persists in the central pacemaker of aged flies, and reducing PKA can strengthen behavioral rhythms.

An Estimation of a Power Threshold Required for Elderly Subjects to Perform a Sit-to-stand

The age-induced deterioration of skeletal muscle power is related to a decline in functional independence in the elderly. In fact, power, the rate of force production, has been shown to have a stronger correlation with ADL performance and fall prevention than strength. Using a force platform and high speed photography, we have developed a regression equation to estimate power during a 30s chair stand test. The y-intercept for this equation, which was used as an estimate of peak power necessary to perform a single chair stand, was 3.71 ± 1.45 W·kg−1. Therefore, we tested the hypothesis that approximately 4 W·kg−1 was necessary to rise from a chair. PURPOSE: To estimate a power threshold associated with the ability to rise from a chair using our previously published regression equation based on body weight and chair stand performance. METHODS: Participants included 554 community-dwelling (CD) adults (74.01±6.7yrs) and 39 extended-care facility (ECF) residents (86.13±6.31yrs). Subjects were instructed to perform chair rises at maximum speed for 30 seconds or until they elected to stop the test due to fatigue or discomfort. The test was performed with the participant's arms held across the chest and for a stand to be counted the subject was required to reach a fully upright position. Peak lower body power was predicted using our regression equation with body weight and number of stands as the predictor variables. RESULTS: Fourteen CD and 12 ECF subjects were unable to perform at least 1 sitto- stand. The minimum peak power outputs for the 540 CD and 27 ECF subjects who performed at least 1 chair rise during the test were 4.22 and 4.23 W·kg−1, respectively. CONCLUSION: These results support the hypothesis that a peak lower body power of approximately 4 W·kg−1 was necessary to perform a single chair rise. However, the actual power output necessary for the performance of a chair stand was above the 3.71 ± 1.45 W·kg−1 predicted by our equation and the 4 W·kg−1 we hypothesized.

Application of PLC to dynamic control system for liquid He cryogenic pumping facility on JT-60U NBI system

The control system of the cryogenic facility in the JT-60 NBI system has been replaced by employing the PLC (Programmable Logic Controller) and SCADA (Supervisory Control And Data Acquisition) system. The original control system was constructed about 20 years ago by specifying the DCS (Distributed Control System) computer to deal with ∼400 feedback loops. Recently, troubles on this control system have increased due to its age-induced deterioration. To maintain the high reliability of the cryogenic facility, a new control system has been planned with the PLC and SCADA systems. Their attractive features include high market availability and cost-effectiveness, however, the use of PLC for such a large facility with ∼400 feedback loops has not been established because of insufficient processing capability of the early PLC. Meanwhile, the recent progress in the PLC enables to use the FBD (function block diagram) programming language for 500 function blocks. By optimizing the function blocks and connecting them in the FBD language, the feedback loops have been successfully replaced from DCS to PLC without a software developer. Moreover, an oscillation of the liquid He level, which often occurs during the cooldown mode of the cryopumps, can be automatically stabilized by easily adding a new process program in the PLC. At present, the new control system has worked well.

Deterioration of contractile properties of muscle fibres in elderly subjects is modulated by the level of physical activity

The impact of ageing on force and velocity of human skeletal muscle fibres has been extensively studied. As discrepancies have been reported, it is still unclear whether or not a deterioration of the capacity of muscle fibres to develop force and shortening is involved in determining weakness and decrease in shortening velocity of skeletal muscle of elderly people. We compared myosin heavy chain (MHC) isoform distribution of vastus lateralis muscle, and specific force (Po/CSA) and maximum shortening velocity (Vo) of skeletal muscle fibres among one population of young controls (CTRL) and three populations of elderly (EL) subjects with very variable levels of physical activity: sedentary (EL-SED, n = 3); controls (EL-CTRL, n = 4); endurance trained (EL-END, n = 3). Muscle phenotype was progressively faster in the order EL-END --> CTRL --> EL-CTRL --> EL-SED. Po/CSA and Vo also varied among the different populations of elderly subjects generally showing a decreasing deterioration with increasing activity levels. The results suggest that discrepancies observed so far in age-induced deterioration of contractile properties of muscle fibres could depend on the different activity levels of the populations of elderly subjects enrolled in the studies.

Fracture, aging, and disease in bone

From a public health perspective, developing a detailed mechanistic understanding of the well-known increase with age in fracture risk of human bone is essential. This also represents a challenge from materials science and fracture mechanics viewpoints. Bone has a complex, hierarchical structure with characteristic features ranging from nanometer to macroscopic dimensions; it is therefore significantly more complex than most engineering materials. Nevertheless, by examining the micro-/nanostructural changes accompanying the process of aging using appropriate multiscale experimental methods and relating them to fracture mechanics data, it is possible to obtain a quantitative picture of how bone resists fracture. As human cortical bone exhibits rising ex vivo crack-growth resistance with crack extension, its fracture toughness must be evaluated in terms of resistance-curve (R-curve) behavior. While the crack initiation toughness declines with age, the more striking finding is that the crack-growth toughness declines even more significantly and is essentially absent in bone from donors exceeding 85 years in age. To explain such an age-induced deterioration in the toughness of bone, we evaluate its fracture properties at multiple length scales, specifically at the molecular and nano dimensions using vibrational spectroscopies, at the microscale using electron microscopy and hard/soft x-ray computed tomography, and at the macroscale using R-curve measurements. We show that the reduction in crack-growth toughness is associated primarily with a degradation in the degree of extrinsic toughening, in particular involving crack bridging, and that this occurs at relatively coarse size scales in the range of tens to hundreds of micrometers. Finally, we briefly describe how specific clinical treatments, e.g., with steroid hormones to treat various inflammatory conditions, can prematurely damage bone, thereby reducing its fracture resistance, whereas regulating the level of the cytokine Transforming Growth Factor-β can offer significant improvements in the stiffness, strength, and toughness of bone and as such may be considered a therapeutic target to treat increased bone fragility induced by aging, drugs, and disease.

Ameliorative effects of nucleosides on senescence acceleration and memory deterioration in senescence-accelerated mice

We investigated the effects of a mixture of dietary nucleosides and nucleotides (NS+NT) on memory in senescence-accelerated mice (SAM). Memory retention was studied with passive avoidance and active avoidance tests. In old mice, the time of passive avoidance was significantly higher in the NS+NT group than in the control group at days 1 and 7. However, such an effect of NS+NT was not observed in young mice. In the active avoidance test, the incidence of successful avoidance in old mice was significantly higher in the NS+NT group than in the control group at days 1 and 2. The percentages of specific brain cells containing lipofuscin were significantly lower in NS+NT groups than in the control groups in both young and old mice. The number of monovacuoles and multiple vacuoles in specific brain regions tended to be lower in NS+NT than in control groups, with significant differences in the microvacuoles of the middle cortex of young mice and in the multiple vacuoles in the hind cortex of old mice. These results suggest that increased dietary NS+NT may be associated with decreases in the age-induced deterioration of brain morphology and certain memory tasks.

A Nucleoside-Nucleotide Mixture May Reduce Memory Deterioration in Old Senescence-Accelerated Mice

We investigated the effects of a mixture of dietary nucleosides and nucleotides (NS + NT) on memory in 1- and 7-mo-old senescence-accelerated mice (SAM). Memory retention was studied with passive avoidance (step-through) and active avoidance (shuttle) tests. For 14 wk, mice in the control groups were fed a 20 g of casein/100 g diet, whereas the NS + NT groups were fed this diet supplemented with a 0.5 g of NS + NT mixture/100 g. All mice were killed at wk 14, and we studied the brain histopathology. Lipofuscin, monovacuoles and multiple vacuoles of various brain regions were measured. Body weight, food intake and ambulatory activity did not differ between the control and NS + NT groups. In old mice, the time of passive avoidance was significantly higher in the NS + NT group than in the control group at d 1 and 7 (P: < 0.05). However, such an effect of NS + NT was not observed in young mice. In the active avoidance test, the incidence of successful avoidance in old mice was higher in the NS + NT group than in the control group at d 1 and 2 (P: < 0.05). The percentages of specific brain cells containing lipofuscin were lower in NS + NT groups than in the control groups in both young and old mice (P: < 0.05). The number of monovacuoles and multiple vacuoles in specific brain regions tended to be lower (P: = 0.1-0.25) in NS + NT than in control groups, with significant differences in the microvacuoles of the middle cortex of young mice and in the multiple vacuoles in the hind cortex of old mice (P: < 0. 05). These results suggest that increased dietary NS + NT may be associated with decreases in the age-induced deterioration of brain morphology and certain memory tasks.

Parameters of calcium homeostasis in normal neuronal ageing.

The last decade has witnessed a significant turn in our understanding of the mechanisms responsible for the decline of cognitive functions in aged brain. As has been demonstrated by detailed morphological reassessments, the senescence-related changes in cognition cannot be attributed to a simple decrease in the number of neurons. It is becoming clearer that a major cause of age-induced deterioration of brain capability involves much subtler changes at the level of synapses. These changes are either morphological, i.e. reduction in the number of effective synapses and/or functional alterations, i.e. changes in the efficacy of remaining synapses. Important questions are now raised regarding the mechanisms which mediate these synaptic changes. Clearly, an important candidate is calcium, the cytotoxic role of which is already firmly established. The wealth of evidence collected so far regarding the changes of Ca2+ homeostasis in aged neurons shows that the overall duration of cytoplasmic Ca2+ signals becomes longer. This is the most consistent result, demonstrated on different preparations and using different techniques. What is not yet clear is the underlying mechanism, as this result could be explained either through an increased Ca2+ influx or because of a deficit in the Ca2+ buffering/clearance systems. It is conceivable that these prolonged Ca2+ signals may exert a local excitotoxic effect, removing preferentially the most active synapses. Uncovering of the role of Ca2+ in the synaptic function of the aged brain presents an exciting challenge for all those involved in the neurobiology of the senescent CNS.

B-50/GAP-43 phosphorylation in hippocampal slices from aged rats: Effects of phosphatidylserine administration

Phosphorylation of the presynaptic protein B-50/GAP-43, a substrate of protein kinase C (PKC), has been implicated in neuronal mechanisms related to learning and memory. We evaluated both basal (5 mM KCl) and stimulated (30 mM KCl) B-50/GAP-43 phosphorylation in 32P-prelabeled hippocampal slices obtained from adult and senescent male Sprague-Dawley rats. The in situ B-50/GAP-43 phosphorylation was assayed by quantitative immunoprecipitation. There was no age-related difference in B-50/GAP-43 basal phosphorylation. However, B-50/GAP-43 phosphorylation in depolarized slices from aged rats was significantly decreased relative to that of adult animals. Aged rats were treated with either tris buffer or sonicated suspension of phosphatidylserine (PS) in tris buffer (15 mg/kg IP for 7 and 17 days). PS did not affect basal and high K +-induced B-50/GAP-43 phosphorylation in the 7-day treatment. However, after 17 days, PS restored the K +-induced B-50/GAP-43 phosphorylation. It is proposed that repeated PS administrations might be beneficial to the age-induced deterioration of endogenous B-50/GAP-43 phosphorylation by acting on Ca + + homeostatic mechanisms and/or PKC.