In mammalians, advancing age is associated with sarcopenia, the progressive and involuntary loss of muscle mass and strength. Hyperphosphatemia is an aging-related condition involved in several pathologies. The aim of this work was to assess whether hyperphosphatemia plays a role in the age-related loss of mass muscle and strength by inducing cellular senescence in murine myoblasts and to explore the intracellular mechanism involved in this effect. Cultured mouse C₂C₁₂ cells were treated with 10 mM beta-glycerophosphate (BGP] at different periods of time to induce hyperphosphatemia. BGP promoted cellular senescence after 24 h of treatment, assessed by the increased expression of p53, acetylated-p53 and p21 and senescence associated β-galactosidase activity. In parallel, BGP increased ILK expression and activity, followed by mTOR activation and autophagy reduction. Knocking-down ILK expression increased autophagy and protected cells from senescence induced by hyperphosphatemia. BGP also reduced the proliferative capacity of cultured myoblasts. Old mice (24-months-old] presented higher serum phosphate concentration, lower forelimb strength, higher expression of p53 and ILK and less autophagy in vastus muscle than young mice (5-months-old]. In conclusion, we propose that hyperphosphatemia induces senescence in cultured myoblasts through ILK overexpression, reducing their proliferative capacity, which could be a mechanism involved in the development of sarcopenia, since old mice showed loss of muscular strength correlated with high serum phosphate concentration and increased levels of ILK and p53.

Aging is an inevitable physiological challenge occurring in organisms over time, and is also the most important risk factor of neurodegenerative diseases. In this study, we observed cellular and molecular changes of different age mice and LPS-induced Parkinson disease (PD) model. The results showed that behavioral performance and dopaminergic (DA) neurons were declined, accompanied by increased expression of pro-inflammatory factors (TLR2, p-NF-kB-p65, IL-1β and TNF-α), as well as pro-oxidative stress factor gp91phox in aged mice compared with young mice. Aging exaggerated inflammatory M1 microglia, and destroyed the balance between oxidation and anti-oxidation. The intranasal LPS instillation induced PD model in both young and aged mice. The poor behavioral performance and the loss of DA neurons as well as TLR2, p-NF-kB-p65, IL-1β, TNF-α, iNOS and gp91phox were further aggravated in LPS-aged mice. Interestingly, the expression of Nrf2 and HO-1 was up-regulated by LPS only in young LPS-PD mice, but not in aged mice. The results indicate that the synergy of aging process and LPS exposure may prominently aggravate the DA neurons loss caused by more serious neuroinflammation and oxidative stress in the brain.

The perirhinal cortex (PRh) is a critical mediator of recognition memory, and a wealth of evidence points to impairment in PRh function with age. Despite this evidence, age-related deficits in recognition memory are not consistently observed. This may be partially due to the fact that older animals also have well-established deficits in hippocampal function, and many protocols that assess perirhinal function are also sensitive to hippocampal damage. When using one of these protocols, spontaneous object recognition in an open field, we are able to replicate published age-related deficits using pairs of complex objects. However, when using zero-delay object recognition, a task that is more resistant to the influence of changes in hippocampal function, we find no significant age-related differences in recognition memory in the same animals. These data highlight the importance of the protocol used for testing recognition memory, and may place constraints on the role of the PRh in age-related recognition memory impairment as it is typically tested in much of the literature.

It has been reported that aquaporin-4 (AQP4) deficiency impairs transportation between the cerebrospinal fluid and interstitial fluid (ISF) as well as the clearance of interstitial solutes in the superficial brain. However, the effect of AQP4 on ISF flow in the deep brain remains unclear. This study compared the brain ISF flow in the caudate nucleus and thalamus of normal rats (NO) and AQP4 knockout rats (KO) using tracer-based magnetic resonance imaging. The rate of brain ISF flow slowed to different degrees in the two regions of KO rats’ brains. Compared with NO rats, the half-life of ISF in the thalamus of KO rats was significantly prolonged, with a corresponding decrease in the clearance coefficient. The tortuosity of the brain extracellular space (ECS) was unchanged in the thalamus of KO rats. In the caudate nucleus of KO rats, the volume fraction of the ECS and the diffusion coefficient were increased, with significantly decreased tortuosity; no significant changes in brain ISF flow were demonstrated. Combined with a change in the expression of glial fibrillary acidic protein and AQP4 in two brain regions, we found that the effect of AQP4 knockout on ISF flow and ECS structure in these two regions differed. This difference may be related to the distribution of astrocytes and the extent of AQP4 decline. This study provides evidence for the involvement of AQP4 in ISF transportation in the deep brain and provides a basis for the establishment of a pharmacokinetic model of the brain’s interstitial pathway.

Loss-of-function mutations of progranulin are associated with frontotemporal dementia in humans, and its deficiency in mice is a model for this disease but with normal life expectancy and mild cognitive decline on aging. The present study shows that aging progranulin deficient mice develop progressive polydipsia and polyuria under standard housing conditions starting at middle age (6-9 months). They showed high water licking behavior and doubling of the normal daily drinking volume, associated with increased daily urine output and a decrease of urine osmolality, all maintained during water restriction. Creatinine clearance, urine urea, urine albumin and glucose were normal. Hence, there were no signs of osmotic diuresis or overt renal disease, other than a concentrating defect. In line, the kidney morphology and histology revealed a 50% increase of the kidney weight, kidney enlargement, mild infiltrations of the medulla with pro-inflammatory cells, widening of tubules but no overt signs of a glomerular or tubular pathology. Plasma vasopressin levels were on average about 3-fold higher than normal levels, suggesting that the water loss resulted from unresponsiveness of the collecting tubules towards vasopressin, and indeed aquaporin-2 immunofluorescence in collecting tubules was diminished, whereas renal and hypothalamic vasopressin were increased, the latter in spite of substantial astrogliosis in the hypothalamus. The data suggest that progranulin deficiency causes nephrogenic diabetes insipidus in mice during aging. Possibly, polydipsia in affected patients - eventually interpreted as psychogenic polydipsia - may point to a similar concentrating defect.

Metabolic syndrome is an increasing health problem, whose pathogenesis may be associated with genetic factors. The main purpose of our study was to assess relationships between MetS and the presence of the FTO rs9939609, the MC4R rs17782313, and the PPAR-γ rs1801282 polymorphisms in 45-60-year-old women. The study included patients from the general population of the Westpomeranian Province (Poland). The mean age was 54.3 ± 4.2 years. The research procedure involved taking structured history, physical examination, anthropometric measurements, and collecting blood for biochemical and genetic analysis. The patients who met the diagnostic criteria for MetS constituted 38.35% of all participants (sample size: 425 patients). The comparison of blood biochemical parameters revealed numerous differences between the women with MetS and those from the control group. Genetic analysis demonstrated that the T allele of the FTO gene was a factor substantially decreasing the incidence of MetS in the study sample (ORT vs. A = 0.734; 95% CI: 0.555 - 0.970; p < 0.05). Other polymorphisms were not directly related to MetS incidence. Conclusions: 1. MetS-related abnormalities are widespread in the population of 45-60-year-old Polish women. Those most common are the elevated serum total cholesterol and LDL levels, increased insulin resistance and BMI scores, as well as visceral obesity. 2. No direct relationships were demonstrated between MetS and the gene polymorphisms analyzed in our study except for the FTO rs9939609, whose A allele and A/A genotype seemed to predispose to metabolic disorders.

The nucleotide-oligomerization domain (NOD)-like receptor subfamily C3 (NLRC3) is a newly discovered and incompletely characterized member of the NLR family which negatively regulates inflammatory responses. Inflammation is considered a critical pathogenesis in pulmonary hypertension (PH). This is the first study to hypothesize that NLRC3 is closely correlated with PH. Total of 43 PH patients who were diagnosed by right heart catheterization (RHC) and 20 age-matched healthy control subjects were included. Echocardiographic variables and blood biochemical parameters were tested. Results of World Health Organization functional class (WHOFC), Borg dyspnea score and 6-minute walk tests (6MWT) were recorded. Mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were measured from RHC. Serum NLRC3 concentrations were detected by ELISA. ROC curve analysis was used to evaluate the diagnostic value of NLRC3 concentrations in PH. We found that serum NLRC3 concentration was significantly decreased in PH compared to the healthy control group. Serum NLRC3 concentration correlated negatively with mPAP and PVR. In addition, a negative correlation between serum NLRC3 concentration and WHOFC were detected. We proposed a cut-off value of 2.897ng/mL for serum NLRC3 concentration which was able to predict PH with 88% sensitivity and 85% specificity. In conclusion, NLRC3 concentrations in PH were significantly decreased, suggesting that NLRC3 may potentially be a diagnosis index and represent a prognostic factor for PH patients.

Several epidemiological and clinical studies have shown that females with ST-segment elevation myocardial infarction (STEMI) have a higher mortality than males following primary percutaneous coronary intervention (PPCI). Many analyses of sex-based differences following STEMI have revealed conflicting results. Currently, more and more elderly patients with STEMI have undergone emergency interventional therapy. From January 2014 to December 2016, a total of 337 elderly patients with STEMI were enrolled in this study from two chest pain centers, and all patients underwent PPCI. Patients were divided into two groups: elderly females (n=117, mean age 73.4±9.6 years) and elderly males (n=220, mean age 71.7±8.6 years). The prevalence of diabetes was higher in females than in males (29.1% vs. 19.6%,P<0. 01). Typical ischemic chest pain was lower in females than in males (45.3% vs 57.3%, P<0.01). The number of nonsmokers was also significantly higher in females than in males (5.1% vs. 52.3%,P<0. 01). Serum creatinine (sCr) levels (87.6±17.4 umol/L vs 99.5±20.2 umol/L,P<0.01) and body mass index (23.8±2.7 vs 27.3±3.1, P<0.01) were lower in females than in males. The incidences of major adverse cardiac events (MACE) in-hospital showed no significantly difference (P>0.05) between the two groups. However, the cumulative MACE showed a significant difference between the two groups in the 12-month follow-up (16.8% in male vs 12.8% in female, P = 0.04). Our results suggest that the PPCI is safe and effective in elderly female STEMI patients. The cumulative MACE in females are not higher than in males. PPCI are helpful in elderly STEMI patients.

The Bristol Foot Score is considered an instrument for measuring the impact of foot problems and pain. It was developed and validated in United Kingdom. Therefore, this aim was to perform the transcultural adaptation and validation of the Spanish version. The recommended forward/backward translation protocol was applied for the procedure of translation, transcultural adaptation and validation to Spain. Considering each domain and question, internal consistency and reliability were analyzed through the Crombach alpha (α) and intraclass correlation coefficient (ICC) with a 95% confidence interval (95% CI). A very good internal consistency was shown for the 3 domains: concern and pain showed a Cronbach of 0.896, footwear and general foot health of 0.790, mobility 0.887. Each question had a very good test-retest reliability, ranged from 0.721 to 0.963 with no systematic differences (P>0.05) in each question of the Spanish Bristol Foot Score (BFS-S) questionnaire. The test-retest reliability was excellent (ICC 95%): concern and foot pain 0.950 (0.913-0971); footwear and general foot health 0.914 (0.851-0.950), mobility 0.973 (0.953-0.984) and there were no sistematic differences in any domain (P > 0.05). The BFS-S was shown to be a valid and reliable tool with an acceptable use in the Spanish population.

Intracranial and extracranial arterial stenosis, the primary cause of chronic cerebral hypoperfusion (CCH), is a critical reason for the pathogenesis of vascular dementia and Alzheimer’s disease characterized by cognitive impairments. Our previous study demonstrated that limb remote ischemic conditioning (LRIC) improved cerebral perfusion in intracranial arterial stenosis patients. The current study aimed to test whether LRIC promotes angiogenesis and increases phosphorylated endothelial nitric oxide synthase (p-eNOS) activity in CCH rat model. Adult male Sprague-Dawley rats were randomly assigned to three different groups: sham group, bilateral carotid artery occlusion (2VO) group and 2VO+LRIC group. Cerebral Blood Flow (CBF) was measured with laser speckle contrast imager at 4 weeks. Cognitive testing was performed at four and six weeks after 2VO surgery. We demonstrated that LRIC treatment increased cerebral perfusion and improved the CCH induced spatial learning and memory impairment. Immunohistochemistry confirmed that LRIC prevented cell death in the CA1 region, and increased the number of vessels and angiogenesis in the hippocampus after 2VO. Western blot analysis shows that LRIC therapy significantly increased p-eNOS expression in the hippocampus when compared with 2VO rats. Moreover, eNOS inhibitor reduced the effect of LRIC on angiogenesis in the hippocampus and spatial learning and memory function. Our data suggested that LRIC promoted angiogenesis, which is mediated, in part, by eNOS/NO.

Glycation is both a physiological and pathological process which mainly affects proteins, nucleic acids and lipids. Exogenous and endogenous glycation produces deleterious reactions that take place principally in the extracellular matrix environment or within the cell cytosol and organelles. Advanced glycation end product (AGE) formation begins by the non-enzymatic glycation of free amino groups by sugars and aldehydes which leads to a succession of rearrangements of intermediate compounds and ultimately to irreversibly bound products known as AGEs. Epigenetic factors, oxidative stress, UV and nutrition are important causes of the accumulation of chemically and structurally different AGEs with various biological reactivities. Cross-linked proteins, deriving from the glycation process, present both an altered structure and function. Nucleotides and lipids are particularly vulnerable targets which can in turn favor DNA mutation or a decrease in cell membrane integrity and associated biological pathways respectively. In mitochondria, the consequences of glycation can alter bioenergy production. Under physiological conditions, anti-glycation defenses are sufficient, with proteasomes preventing accumulation of glycated proteins, while lipid turnover clears glycated products and nucleotide excision repair removes glycated nucleotides. If this does not occur, glycation damage accumulates, and pathologies may develop. Glycation-induced biological products are known to be mainly associated with aging, neurodegenerative disorders, diabetes and its complications, atherosclerosis, renal failure, immunological changes, retinopathy, skin photoaging, osteoporosis, and progression of some tumors.

Rhythmic auditory cueing has been widely used in gait rehabilitation over the past decade. The entrainment effect has been suggested to introduce neurophysiological changes, alleviate auditory-motor coupling and reduce cognitive-motor interferences. However, a consensus as to its influence over aging gait is still warranted. A systematic review and meta-analysis was carried out to analyze the effects of rhythmic auditory cueing on spatiotemporal gait parameters among healthy young and elderly participants. This systematic identification of published literature was performed according to PRISMA guidelines, from inception until May 2017, on online databases: Web of science, PEDro, EBSCO, MEDLINE, Cochrane, EMBASE, and PROQUEST. Studies were critically appraised using PEDro scale. Of 2789 records, 34 studies, involving 854 (499 young/355 elderly) participants met our inclusion criteria. The meta-analysis revealed enhancements in spatiotemporal parameters of gait i.e. gait velocity (Hedge’s g: 0.85), stride length (0.61), and cadence (1.1), amongst both age groups. This review, for the first time, evaluates the effects of auditory entrainment on aging gait and discusses its implications under higher and lower information processing constraints. Clinical implications are discussed with respect to applications of auditory entrainment in rehabilitation settings.

Stroke is the leading cause of death and adult disability worldwide. Mitochondrial dysfunction has been regarded as one of the hallmarks of ischemia/reperfusion (I/R) induced neuronal death. Maintaining the function of mitochondria is crucial in promoting neuron survival and neurological improvement. In this article, we review current progress regarding the roles of mitochondria in the pathological process of cerebral I/R injury. In particular, we emphasize on the most critical mechanisms responsible for mitochondrial quality control, as well as the recent findings on mitochondrial transfer in acute stroke. We highlight the potential of mitochondria as therapeutic targets for stroke treatment and provide valuable insights for clinical strategies.

The source of dietary nitrate (NO₃) is mainly green, leafy vegetables, partially absorbed into blood through intestinal mucosa. The recycled nitrate is reabsorbed and concentrated by the salivary glands and then secreted into saliva. In 2012, sialin was first discovered as the mammalian membrane nitrate transporter in salivary glands and plays a key role in circulation of inorganic nitrate, providing a scientific basis for further investigation into the circulation and functions of nitrate. Dietary nitrate can be converted to nitrite (NO₂) by oral commensal bacteria under the tongue or in the stomach, following which nitrite is converted to nitric oxide (NO) through non-enzymatic synthesis. Previously, nitrate and nitrite were thought to be carcinogenic due to the potential formation of nitrogen compounds, whereas the beneficial functions of NO₃^--NO₂^--NO pathway were ignored. Under conditions of hypoxia and ischemia, the production of endogenous NO from L-arginine is inhibited, while the activity of exogenous NO₃^--NO₂^--NO is enhanced. Recently, a greater amount of evidence has shown that nitrate and nitrite serve as a reservoir and perform positive biological NO-like functions. Therefore, exogenous dietary nitrate plays an important role in various physiological activities as an effective supplement of nitrite and NO in human body. Here we generally review the source, circulation and bio-functions of dietary nitrate.

Despite its beneficial role on insulin resistance and atherosclerosis, adiponectin has been frequently reported as an independent positive predictor of cardiovascular mortality. Very few information is available regarding adiponectin isoforms and mortality, in particular in advanced aging. Baseline serum levels of Total Adiponectin and its circulating isoforms (HMW-, MMW-, LMW-Adiponectin) were measured in 97 old patients (mean age: 79 years). Patients were followed up for all-cause mortality (study end-point) for an average of 76.4 ± 37.3 months. A positive association was observed for LMW-Ad and all-cause mortality (HR: 1.13, 95% CI: 1.05-1,22, p: 0.002). After multivariate adjustment for age, sex and a previous history of myocardial infarction, higher levels of LMW-Ad were significantly associated with all-cause mortality (HR: 1.11, 95% CI: 1.02-1.21; p: 0.017). Interestingly neither total adiponectin neither the other two circulating isoforms (MMW- and HMW-Ad) showed any significant association with the study end-point. Our data suggest that the association between high serum adiponectin levels and increased mortality rate in elderly is contingent to an unbalanced circulating levels of adiponectin isoforms. The present results support the hypothesis that high levels of Low Molecular Weight adiponectin are a biomarker for mortality risk in very old patients.