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Age-related changes in motor unit activation properties remain unclear for locomotor muscles such as quadriceps muscles, although these muscles are preferentially atrophied with aging and play important roles in daily living movements. The present study investigated and compared detailed motor unit firing characteristics for the vastus lateralis muscle during isometric contraction at low to moderate force levels in the elderly and young. Fourteen healthy elderly men and 15 healthy young men performed isometric ramp-up contraction to 70 % of the maximal voluntary contractions (MVC) during knee extension. Multichannel surface electromyograms were recorded from the vastus lateralis muscle using a two-dimensional grid of 64 electrodes and decomposed with the convolution kernel compensation technique to extract individual motor units. Motor unit firing rates in the young were significantly higher (~+29.7 %) than in the elderly (p < 0.05). There were significant differences in firing rates among motor units with different recruitment thresholds at each force level in the young (p < 0.05) but not in the elderly (p > 0.05). Firing rates at 60 % of the MVC force level for the motor units recruited at <20 % of MVC were significantly correlated with MVC force in the elderly (r = 0.885, p < 0.0001) but not in the young (r = 0.127, p > 0.05). These results suggest that the motor unit firing rate in the vastus lateralis muscle is affected by aging and muscle strength in the elderly and/or age-related strength loss is related to motor unit firing/recruitment properties.

Testosterone deficiency is associated with a higher incidence of cardiovascular diseases in men. However, its effect on cell senescence, which plays a causal role in vascular aging, remains unclear. Here, we tested the hypothesis that testosterone alleviated vascular smooth muscle cell (VSMC) senescence and collagen synthesis via growth arrest-specific protein 6 (Gas6)/Axl- and Akt/FoxO1a-dependent pathways. Testosterone significantly ameliorated angiotensin II-induced VSMC senescence and collagen overexpression. In addition, testosterone inhibited angiotensin II-induced matrix metalloproteinase-2 (MMP-2) activity, which played a pivotal role in facilitating age-related collagen deposition. Testosterone increased the expression of tissue inhibitor of metalloproteinase-2 but decreased the expression of MMP-2 and membrane type-1 metalloproteinase which contributed to increase MMP-2 activity. The effects on VSMCs senescence and collagen synthesis were mediated by restoration of angiotensin II-induced downregulation of Gas6 and Axl expression and a subsequent reduction of Akt and FoxO1a phosphorylation. The effects of testosterone were reversed by a Gas6 blocker, Axl-Fc, and a specific inhibitor of Axl, R428. Treatment of VSMCs with PI3K inhibitor LY294002 abrogated the downregulating effect of testosterone on MMP-2 activity. Furthermore, when FoxO1a expression was silenced by using a specific siRNA, the inhibitory effect of testosterone on MMP-2 activity was revered as well, that indicated this process was Akt/FoxO1a dependence. Taken together, Gas6/Axl and Akt/FoxO1a were involved in protective effects of testosterone on VSMCs senescence and collagen synthesis. Our results provide a novel mechanism underlying the protective effect of testosterone on vascular aging and may serve as a theoretical basis for testosterone replacement therapy.

Data shows that inflammation during pregnancy significantly exerts a long-term influence on offspring, such as increasing the risk of adult cognition decline in animals. However, it is unclear whether gestational inflammation affects the neurobehavioral and neurobiochemical outcomes in the mother-self during aging. In this study, pregnant CD-1 mice intraperitoneally received lipopolysaccharide (LPS) in two doses (25 and 50 g/kg, respectively) or normal saline daily during gestational days 15-17. At the age of 15 months, a battery of behavioral tasks was employed to evaluate their species-typical behaviors, sensorimotor ability, anxiety levels, and spatial learning and memory abilities. An immunohistochemical method was utilized preliminarily to detect neurobiochemical indicators consisting of amyloid-β, phosphorylated tau, presynaptic proteins synaptotagmin-1 and syntaxin-1, glial fibrillary acidic protein (GFAP), and histone-4 acetylation on the K8 site (H4K8ac). The behavioral results showed that LPS exposure during pregnancy exacerbated a decline in 15-month-old CD-1 mice's abilities to nest, their sensorimotor and spatial learning and memory capabilities, and increased their anxiety levels. The neurobiochemical results indicated that gestational LPS exposure also intensified age-related hippocampal changes, including increased amyloid-β42, phosphorylated tau, synaptotagmin-1 and GFAP, and decreased syntaxin-1 and H4K8ac. Our results suggested that the inflammatory insult during pregnancy could be an important risk factor for the development of Alzheimer's disease, and the H4K8 acetylation might play an important role in the underlying mechanism. This study offers a perspective for improving strategies that support healthy development and successful aging.

Ankle proprioceptive information is integrated by the central nervous system to generate and modulate muscle contractions for maintaining standing balance. This study evaluated the association of ankle joint proprioception with objective and self-report measures of balance, mobility, and physical function across the adult life span. Seven hundred and ninety participants (age range 24-97 years, 362 women) who completed ankle proprioception assessment between 2010 and 2014 were included in the present study from the population-based cohort of the Baltimore Longitudinal Study of Aging (BLSA), USA. Outcome measures included ankle joint proprioception measured as threshold for perception of passive movement (TPPM); single leg stance time; perceived difficulty for standing balance; usual, fastest, and narrow-path gait speed; walking index; short physical performance battery score; and self-reported activity restriction due to fear of falling. Descriptive variables included age, sex, body mass index, education, strength, and cognition. Analyses of covariance (ANCOVA) in general linear model (GLM) or multinomial logistic regression analyses were performed, as appropriate, to test the hypothesis that balance, mobility, and physical function were significantly different according to TPPM quintiles even after adjusting for relevant covariates. Those with TPPM >2.2° consistently demonstrated poor balance, mobility, and physical function. However, with increase in challenge (single leg stance, fastest walking speed, and SPPB), TPPM >1.4° was associated with significantly worse performance. In conclusion, ankle proprioceptive acuity has an overall graded relationship with objective and self-report measures of balance, mobility, and physical function. However, the cutoff proprioceptive acuity associated with substantial decline or inability to perform could depend on the challenge induced.

Stress-induced premature senescence (SIPS) is quite similar to replicative senescence that is committed by cells exposed to various stress conditions viz. ultraviolet radiation (DNA damage), hydrogen peroxide (oxidative stress), chemotherapeutic agents (cytotoxic threat), etc. Here, we report that cristacarpin, a natural product obtained from the stem bark of Erythrina suberosa, promotes endoplasmic reticulum (ER) stress, leading to sub-lethal reactive oxygen species (ROS) generation and which eventually terminates by triggering senescence in pancreatic and breast cancer cells through blocking the cell cycle in the G1 phase. The majority of cristacarpin-treated cells responded to conventional SA-β-gal stains; showed characteristic p21(waf1) upregulation along with enlarged and flattened morphology; and increased volume, granularity, and formation of heterochromatin foci-all of these features are the hallmarks of senescence. Inhibition of ROS generation by N-acetyl-L-cysteine (NAC) significantly reduced the expression of p21(waf1), confirming that the modulation in p21(waf1) by anti-proliferative cristacarpin was ROS dependent. Further, the elevation in p21(waf1) expression in PANC-1 and MCF-7 cells was consistent with the decrease in the expression of Cdk-2 and cyclinD1. Here, we provide evidence that cristacarpin promotes senescence in a p53-independent manner. Moreover, cristacarpin treatment induced p38MAPK, indicating the ROS-dependent activation of the MAP kinase pathway, and thus abrogates the tumor growth in mouse allograft tumor model.

Apathy defined as a mental state characterized by a lack of goal-directed behavior is prevalent and associated with poor functioning in older adults. The main objective of this study was to identify factors contributing to the distinct dimensions of apathy (cognitive, emotional, and behavioral) in older adults without dementia. One hundred and fifty participants (mean age, 80.42) completed self-rated questionnaires assessing apathy, emotional distress, anticipatory pleasure, motivational systems, physical functioning, quality of life, and cognitive functioning. Data were analyzed using partial least squares variance-based structural equation modeling in order to examine factors contributing to the three different dimensions of apathy in our sample. Overall, the different facets of apathy were associated with cognitive functioning, anticipatory pleasure, sensitivity to reward, and physical functioning, but the contribution of these different factors to the three dimensions of apathy differed significantly. More specifically, the impact of anticipatory pleasure and physical functioning was stronger for the cognitive than for emotional apathy. Conversely, the impact of sensibility to reward, although small, was slightly stronger on emotional apathy. Regarding behavioral apathy, again we found similar latent variables except for the cognitive functioning whose impact was not statistically significant. Our results highlight the need to take into account various mechanisms involved in the different facets of apathy in older adults without dementia, including not only cognitive factors but also motivational variables and aspects related to physical disability. Clinical implications are discussed.

Epigenetic regulation through DNA methylation (5mC) plays an important role in development, aging, and a variety of diseases. Genome-wide studies of base- and strand-specific 5mC are limited by the extensive sequencing required. Targeting bisulfite sequencing to specific genomic regions through sequence capture with complimentary oligonucleotide probes retains the advantages of bisulfite sequencing while focusing sequencing reads on regions of interest, enables analysis of more samples by decreasing the amount of sequence required per sample, and provides base- and strand-specific absolute quantitation of CG and non-CG methylation levels. As an example, an oligonucleotide capture set to interrogate 5mC levels in all rat RefSeq gene promoter regions (18,814) and CG islands, shores, and shelves (18,411) was generated. Validation using whole-genome methylation standards and biological samples demonstrates enrichment of the targeted regions and accurate base-specific quantitation of CG and non-CG methylation for both forward and reverse genomic strands. A total of 170 Mb of the rat genome is covered including 6.6 million CGs and over 67 million non-CG sites, while reducing the amount of sequencing required by ~85 % as compared to existing whole-genome sequencing methods. This oligonucleotide capture targeting approach and quantitative validation workflow can also be applied to any genome of interest.

Obesity and fitness have been associated with older adults' physical independence. We aimed to investigate the independent and combined associations of physical fitness and adiposity, assessed by body mass index (BMI) and waist circumference (WC) with the projected ability for physical independence. A total of 3496 non-institutionalized older adults aged 65 and older (1167 male) were included in the analysis. BMI and WC were assessed and categorized according to established criteria. Physical fitness was evaluated with the Senior Fitness Test and individual test results were expressed as Z-scores. Projected ability for physical independence was assessed with the 12-item composite physical function scale. Logistic regression was used to estimate the odds ratio (OR) for being physically dependent. A total of 30.1 % of participants were classified as at risk for losing physical independence at age 90 years. Combined fitness and fatness analysis demonstrated that unfit older adults had increased odds ratio for being physically dependent in all BMI categories (normal: OR = 9.5, 95 %CI = 6.5-13.8; overweight: OR = 6.0, 95 %CI = 4.3-8.3; obese: OR = 6.7, 95 %CI = 4.6-10.0) and all WC categories (normal: OR = 10.4, 95%CI = 6.5-16.8; middle: OR = 6.2, 95 %CI = 4.1-9.3; upper: OR = 7.0, 95 %CI = 4.8-10.0) compared to fit participants that were of normal weight and fit participants with normal WC, respectively. No increased odds ratio was observed for fit participants that had increased BMI or WC. In conclusion, projected physical independence may be enhanced by a normal weight, a normal WC, or an increased physical fitness. Adiposity measures were not associated with physical independence, whereas fitness is independently related to physical independence. Independent of their weight and WC status, unfit older adults are at increased risk for losing physical independence.

The aim of the study was to determine whether gait characteristics were associated with endothelial cell inflammation, oxidative stress, and apoptosis and with circulating biomarkers of inflammation and antioxidant capacity in older patients with symptomatic peripheral artery disease (PAD). Gait measurements of 231 symptomatic men and women with PAD were assessed during a 4-m walk test. Patients were further characterized on endothelial effects of circulating factors present in the sera using a cell culture-based bioassay on primary human arterial endothelial cells and on circulating inflammatory and vascular biomarkers. In a multivariate regression model for gait speed, the significant independent variables were age (p < 0.001), intercellular cell adhesion molecule-1 (ICAM-1) (p < 0.001), diabetes (p = 0.003), sex (p = 0.003), and history of cerebrovascular accidents (p = 0.021). In multivariate analyses for gait cadence, the significant independent predictors included high-sensitivity C-reactive protein (HsCRP) (p < 0.001), diabetes (p = 0.001), and hypertension (p = 0.001). In a multivariate regression model for gait stride length, the significant independent variables were HsCRP (p < 0.001), age (p < 0.001), ICAM-1 (p < 0.001), hypertension (p = 0.002), cellular reactive oxygen species production (p = 0.007), and sex (p = 0.008). Higher levels of circulating biomarkers of inflammation and endothelial cell oxidative stress were associated with slower gait speed, slower cadence, and shorter stride length in older symptomatic patients with PAD. Additionally, this profile of impaired gait was more evident in older patients, in women, and in those with diabetes, hypertension, and history of cerebrovascular accidents.

Stimulus over-selectivity describes a phenomenon where only a subset of the relevant stimuli present in the environment, control an individual's behavior. The current experiment explored the degree to which over-selectivity increases in old age. The level of over-selectivity in a visual discrimination task in 60 individuals aged 60-89 years was assessed, as well as the degree to which this reflected attentional control. In addition, the intellectual functioning and cognitive flexibility of the participants were assessed. Results showed that, as age increased, three effects were revealed: levels of stimulus over-selectivity increased, IQ scores decreased, and cognitive flexibility decreased. However, over-selectivity was not related to IQ or cognitive flexibility, and appeared related most to attentional impairments. Thus, ageing is related to significant declines in effective stimulus control. These effects can have a serious impact on the physical and psychological health of old adults, as well as their quality of life, and, therefore, this area of research warrants further exploration. The results are discussed in relation to the attention-deficit and comparator theory of over-selectivity.