Acute lung injury (ALI) is associated with increased morbidity and mortality in the elderly (> 65 years), but the knowledge about origin and effects of immunosenescence in ALI is limited. Here, we investigated the immune response at pulmonary, systemic and cellular level in young (2-3 months) and old (18-19 months) C57BL/6J mice to localize and characterize effects of immunosenescence in ALI. ALI was induced by intranasal lipopolysaccharide (LPS) application and the animals were sacrificed 24 or 72 h later. Pulmonary inflammation was investigated by analyzing histopathology, bronchoalveolar lavage fluid (BALF) cytometry and cytokine expression. Systemic serum cytokine expression, spleen lymphocyte populations and the gut microbiome were analyzed, as well as activation of alveolar and bone marrow derived macrophages (BMDM) in vitro. Pulmonary pathology of ALI was more severe in old compared with young mice. Old mice showed significantly more inflammatory cells and pro-inflammatory cyto- or chemokines (TNFα, IL-6, MCP-1, CXCL1, MIP-1α) in the BALF, but a delayed expression of cytokines associated with activation of adaptive immunity and microbial elimination (IL-12 and IFNγ). Alveolar macrophages, but not BMDM, of old mice showed greater activation after in vivo and in vitro stimulation with LPS. No systemic enhanced pro-inflammatory cytokine response was detected in old animals after LPS exposure, but a delayed expression of IL-12 and IFNγ. Furthermore, old mice had less CD8⁺ T-cells and NK cells and more regulatory T-cells in the spleen compared with young mice and a distinct gut microbiome structure. The results of our study show an increased alveolar macrophage activation and pro-inflammatory signaling in the lungs, but not systemically, suggesting a key role of senescent alveolar macrophages in ALI. A decrease in stimulators of adaptive immunity with advancing age might further promote the susceptibility to a worse prognosis in ALI in elderly.

Recent research suggests that intestinal microbiota affect the aging process. Glucagon-like peptide 2 (GLP-2), a growth factor found in the intestinal mucosal epithelium, reduces intestinal permeability and affects intestinal microbiota. The relationship between aging, GLP-2, and intestinal microbiota are still not well understood. The current study examined the influence of aging and GLP-2 on the intestinal microbiota of rats. Twelve 3-month old male SD rats were randomly divided into two groups: a young control group (group C) and a young GLP-2 treatment group (group G). Twelve 26-month old male SD rats were randomly divided into two groups: an aged control group (group L) and an aged GLP-2 treatment group (group T). GLP-2 was intraperitoneally injected into rats from group G and group T for 14 days. Plasma GLP-2 concentration was evaluated by ELISA tests. Fresh intestinal stool samples were collected from each group and total fecal bacterial genomic DNA was extracted from the associated rats. The bacterial composition of fecal samples was analyzed by Miseq high-throughput sequencing and comparison with SRA databases. Overall, the diversity of intestinal microbiota significantly decreases with age in SD rats, while GLP-2 has no significant effect on the diversity of intestinal microbiota. Upon aging, there is a reduction in probiotic bacteria and a concomitant increase in pathogenic bacteria in rats. Treatment with GLP-2 results in a significant reduction in the prevalence of pathogenic bacterial genera and an increase in some potential benefit bacteria in aged rats. In addition, treatment with GLP-2 results in an increase in several probiotics and a reduction in the prevalence of pathogenic bacterial genera in young rats.

Hypothermia is considered as a promising neuroprotective treatment for ischemic stroke but with many limitations. To expand its clinical relevance, this study evaluated the combination of physical (ice pad) and pharmacological [transient receptor potential vanilloid channel 1 (TRPV1) receptor agonist, dihydrocapsaicin (DHC)] approaches for faster cooling and stronger neuroprotection. A total of 144 male Sprague Dawley rats were randomized to 7 groups: sham (n=16), stroke only (n=24), stroke with physical hypothermia at 31ºC for 3 h after the onset of reperfusion (n=24), high-dose DHC (H-DHC)(1.5 mg/kg, n=24), low-dose DHC (L-DHC)(0.5 mg/kg, n=32) with (n=8) or without (n=24) external body temperature control at ~38 ºC (L-DHC, 38 ºC), and combination therapy (L-DHC+ ice pad, n=24). Rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Infarct volume, neurological deficits and apoptotic cell death were determined at 24 h after reperfusion. Expression of pro- and anti-apoptotic proteins was evaluated by Western blot. ATP and reactive oxygen species (ROS) were detected by biochemical assays at 6 and 24 h after reperfusion. Combination therapy of L-DHC and ice pad significantly improved every measured outcome compared to monotherapies. Combination therapy achieved hypothermia faster by 28.6% than ice pad, 350% than L-DHC and 200% than H-DHC alone. Combination therapy reduced (p<0.05) neurological deficits by 63% vs. 26% with L-DHC. No effect was observed when using ice pad or H-DHC alone. L-DHC and ice pad combination improved brain oxidative metabolism by reducing (p<0.05) ROS at 6 and 24 h after reperfusion and increasing ATP levels by 42.9% compared to 25% elevation with L-DHC alone. Finally, combination therapy decreased apoptotic cell death by 48.5% vs. 24.9% with L-DHC, associated with increased anti-apoptotic protein and reduced pro-apoptotic protein levels (p<0.001). Our study has demonstrated that combining physical and pharmacological hypothermia is a promising therapeutic approach in ischemic stroke, and warrants further translational investigations.

The mitochondrion is susceptible to neurodegenerative disorders such as Parkinson’s disease (PD). Mitochondrial dysfunction has been considered to play an important role in the dopaminergic degeneration in PD. However, there are no effective drugs to protect mitochondria from dysfunction during the disease development. In the present study, fucoidan, a sulfated polysaccharide derived from Laminaria japonica, was investigated and characterized for its protective effect on the dopamine system and mitochondrial function of dopaminergic neurons in a rotenone-induced rat model of PD. We found that chronic treatment with fucoidan significantly reversed the loss of nigral dopaminergic neurons and striatal dopaminergic fibers and the reduction of striatal dopamine levels in PD rats. Fucoidan also alleviated rotenone-induced behavioral deficits. Moreover, the mitochondrial respiratory function as detected by the mitochondrial oxygen consumption and the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and nuclear transcription factor 2 (NRF2) were reduced in the substantia nigra of PD rats, which were markedly reversed by fucoidan. Oxidative products induced by rotenone were significantly reduced by fucoidan. Taken together, these results demonstrate that fucoidan possesses the ability to protect the dopamine system in PD rats. The neuroprotective effect of fucoidan may be mediated via reserving mitochondrial function involving the PGC-1α/NRF2 pathway. This study provides new evidence that fucoidan can be explored in PD therapy.

Alzheimer’s disease (AD) is a progressive pathology, where dementia symptoms gradually worsen over a number of years. The hallmarks of AD, such as amyloid β-peptide (Aβ) in senile plaque and neurofibrillary tangles, are strongly intertwined with oxidative stress, which is considered one of the common effectors of the cascade of degenerative events. The endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) is the "master regulator" of the antioxidant response and it is known as an indicator and regulator of oxidative stress. The present study aimed to determine the potential neuroprotective activity of caffeic acid phenethyl ester (CAPE), a polyphenolic compound abundant in honeybee, against the neurotoxicity of Aβ_1-42 oligomers (AβO) in mice. An intracerebroventricular (i.c.v.) injection of AβO into the mouse brain triggered increased reactive oxygen species levels, neurodegeneration, neuroinflammation, and memory impairment. In contrast, the intraperitoneal administration of CAPE (10 mg/kg) after i.c.v. AβO-injection counteracted oxidative stress accompanied by an induction of Nrf2 and heme oxygenase-1 via the modulation of glycogen synthase kinase 3β in the hippocampus of mice. Additionally, CAPE treatment decreased AβO-induced neuronal apoptosis and neuroinflammation, and improved learning and memory, protecting mice against the decline in spatial cognition. Our findings demonstrate that CAPE could potentially be considered as a promising neuroprotective agent against progressive neurodegenerative diseases such as AD.

Kif4a, a member of the kinesin superfamily, has been reported to participate in a series of cellular processes such as chromosome condensation and cytokinesis during mitosis. However, the roles of KIF4a in meiosis are still unknown. In present study we found that the Kif4a protein expression decreased in maternal aged mouse oocytes. We then explored the roles of Kif4a in mouse oocyte meiosis by knockdown analysis. Kif4a was enriched at the spindle during mouse oocyte maturation. By specific knock down of the Kif4a using morpholino microinjection, we found that the disruption of Kif4a caused the failure of polar body extrusion. Further analysis indicated that Kif4a might affect the spindle morphology and chromosome alignment in the mouse oocytes, and this might be due to the regulation of tubulin acetylation. Moreover, our results showed that an increased proportion of aneuploidy in the Kif4a knock down oocytes, and this might be due to the loss of kinetochore-microtubule attachment. Taken together, these results suggested that Kif4a possibly regulated mouse oocyte meiosis through its effects on the spindle organization and accurate chromosome segregation, and the loss of Kif4a might be related with aneuploidy of aging oocytes.

Minor changes (~0.1 m/s) in human gait speed are predictive of various measures of decline and can be used to identify at-risk individuals prior to further decline. These associations are possible due to an abundance of human clinical research. However, age-related gait changes are not well defined in rodents, even though rodents are used as the primary pre-clinical model for many disease states as well as aging research. Our study investigated the usefulness of a novel automated system, the CatWalk™ XT, to measure age-related differences in gait. Furthermore, age-related functional declines have been associated with decreases in the reduced to oxidized glutathione ratio leading to a pro-oxidizing cellular shift. Therefore the secondary aim of this study was to determine whether chronic glutathione deficiency led to exacerbated age-associated impairments. Groups of male and female wild-type (gclm^+/+) and knock-out (gclm^-/-) mice aged 4, 10 and 17 months were tested on the CatWalk and gait measurements recorded. Similar age-related declines in all measures of gait were observed in both males and females, and chronic glutathione depletion was associated with some delays in age-related declines, which were further exacerbated. In conclusion, the CatWalk is a useful tool to assess gait changes with age, and further studies will be required to identify the potential compensating mechanisms underlying the effects observed with the chronic glutathione depletion.

Diabetic patients exhibit serum AGE accumulation, which is associated with reactive oxygen species (ROS) production and diabetic cardiomyopathy. ROS-induced PKCδ activation is linked to mitochondrial dysfunction in human cells. However, the role of PKCδ in cardiac and mitochondrial dysfunction caused by AGE in diabetes is still unclear. AGE-BSA-treated cardiac cells showed dose- and time-dependent cell apoptosis, ROS generation, and selective PKCδ activation, which were reversed by NAC and rotenone. Similar tendency was also observed in diabetic and obese animal hearts. Furthermore, enhanced apoptosis and reduced survival signaling by AGE-BSA or PKCδ-WT transfection were reversed by kinase-deficient (KD) of PKCδ transfection or PKCδ inhibitor, respectively, indicating that AGE-BSA-induced cardiomyocyte death is PKCδ-dependent. Increased levels of mitochondrial mass as well as mitochondrial fission by AGE-BSA or PKCδ activator were reduced by rottlerin, siPKCδ or KD transfection, indicating that the AGE-BSA-induced mitochondrial damage is PKCδ-dependent. Using super-resolution microscopy, we confirmed that PKCδ colocalized with mitochondria. Interestingly, the mitochondrial functional analysis by Seahorse XF-24 flux analyzer showed similar results. Our findings indicated that cardiac PKCδ activation mediates AGE-BSA-induced cardiomyocyte apoptosis via ROS production and may play a key role in the development of cardiac mitochondrial dysfunction in rats with diabetes and obesity.

Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly population. SAMP8 mouse model presents accelerated senescence and has been identified as a model of gerontological research. SAMP8 displays a progressive age-related decline in brain function associated with a progressive hearing loss mimicking human aging memory deficits and ARHL. The molecular mechanisms associated with SAMP8 senescence process involve oxidative stress leading to chronic inflammation and apoptosis. Here, we studied the effect of N-acetylcysteine (NAC), an antioxidant, on SAMP8 hearing loss and memory to determine the potential interest of this model in the study of new antioxidant therapies. We observed a strong decrease of auditory brainstem response thresholds from 45 to 75 days of age and an increase of distortion product amplitudes from 60 to 75 days in NAC treated group compared to vehicle. Moreover, NAC treated group presented also an increase of memory performance at 60 and 105 days of age. These results confirm that NAC delays the senescence process by slowing the age-related hearing loss, protecting the cochlear hair cells and improving memory, suggesting that antioxidants could be a pharmacological target for age-related hearing and memory loss.

Diabetes milieu is a complex metabolic disease that has been known to associate with high risk of various neurological disorders. Hyperglycemia in diabetes could dramatically increase neuronal glucose levels which leads to neuronal damage, a phenomenon referred to as glucose neurotoxicity. On the other hand, the impact of hyperglycemia on astrocytes has been less explored. Astrocytes play important roles in brain energy metabolism through neuron-astrocyte coupling. As the component of blood brain barrier, glucose might be primarily transported into astrocytes, hence, impose direct impact on astrocyte metabolism and function. In the present study, we determined the effect of high glucose on the energy metabolism and function of primary astrocytes. Hyperglycemia level glucose (25 mM) induced cell cycle arrest and inhibited proliferation and migration of primary astrocytes. Consistently, high glucose decreased cyclin D1 and D3 expression. High glucose enhanced glycolytic metabolism, increased ATP and glycogen content in primary astrocytes. In addition, high glucose activated AMP-activated protein kinase (AMPK) signaling pathway in astrocytes. In summary, our in vitro study indicated that hyperglycemia might impact astrocyte energy metabolism and function phenotype. Our study provides a potential mechanism which may underlie the diabetic cerebral neuropathy and warrant further in vivo study to determine the effect of hyperglycemia on astrocyte metabolism and function.

Glibenclamide (GBC) is an antidiabetic drug that is in a class of medications known as sulfonylureas, which play critical roles in attenuating brain edema and reducing mortality in ischemic stroke patients. Therapeutic hypothermia (TH) is another robust neuroprotectant that prevents brain swelling and improves the neurological outcomes of stroke patients. However, whether the combination of GBC and TH can be used as a reliable neuroprotectant in ischemic stroke remains largely unknown. We used the middle cerebral artery occlusion (MCAO) rat model as well as oxygen and glucose deprivation-reoxygenation (OGD/R) endothelial cells as ischemic stroke models to investigate the efficacy and mechanisms of treating ischemic stroke with the combination of GBC and TH. The serum glucose, mortality rate, neurobehavioral functions, tight junctions, endothelial cells and inflammatory cytokines were evaluated in the stroke models after treatment with GBC, TH or the combination of them. After 5-hour occlusion and subsequent reperfusion, rats exhibited a large volume of hemispheric swelling and a high mortality rate. Stroke rats treated with the combined therapy did not exhibit hypoglycemia. The combination of GBC and TH exhibited synergistic neuroprotective effects in stroke rats that were associated with greater reductions in edema volume, better improvement in neurobehavioral functions, prevention of tight junction loss, and reduction of expression of the inflammatory cytokines COX-2 and iNOS. In OGD/R endothelia cells, the combination reduced endothelial cell death. This study demonstrated that both GBC and TH are neuroprotective after the severe stroke; however, combined therapy with GBC and TH enhanced the efficiency and efficacy of the effects of TH and GBC in the treatment of ischemia. This combined therapy may facilitate the clinical translation of TH management for severe stroke. The combination of GBC and TH seems to be a feasible and promising clinical strategy to alleviate cerebral injury following severe stroke.

Our study aimed to identify the underlying causes in patients with early onset dementia by clinical and genetic exploration. We recruited a group of 38 patients with early-onset dementia. Firstly, hexanucleotide repeat expansions in C9ORF72 gene were screened in all subjects to exclude the possibility of copy number variation. Then, the whole exome sequencing (WES) was conducted, and the data were analyzed focusing on 89 dementia-related causing and susceptible genes. The effects of identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. There were no pathogenic expansions in C9ORF72 detected. According to the ACMG standards and guidelines, we identified five known pathogenic mutations, PSEN1 P284L, PSEN1c.857-1G>A, PSEN1 I143T, PSEN1 G209E and MAPT G389R, and one novel pathogenic mutation APP K687N. All these mutations caused dementia with the mean onset age of 38.3 (range from 27 to 51) and rapid progression. Eleven variants with uncertain significance were also detected and needed further verification. The clinical phenotypes of dementia are heterogeneous, with both onset ages and clinical features being influenced by mutation position as well as the causative gene. WES can serve as efficient diagnostic tools for different heterogeneous dementia.

The aim of this study was to analyze the prevalence of mild cognitive impairment (MCI) among the aging population (60 years of age and above) in China. Epidemiological investigations on MCI in online Chinese journals were identified manually using the CQVIP, CNKI, and Wanfang databases. Articles from journals published in English were identified using PubMed and Web of Science. Original studies that included prevalence surveys of MCI were selected. Forty-eight relevant studies were included in the analysis, covering 22 provinces in China. Our results showed that the pooled prevalence of MCI in the older Chinese population was 14.71% (95% confidence interval [CI], 14.50-14.92%). The prevalence was 16.72% (95% CI, 15.68-17.71%) in clinical samples vs. 14.61% (95% CI, 14.40-14.83%) in nonclinical samples (χ2=16.60, P<0.01), and 15.20% (95% CI, 14.91-15.49%) in screened samples vs. 14.16% (95% CI, 13.85-14.46%) in diagnosed samples (χ2=22.11, P<0.01). People of older age, of female sex, or living in rural areas or western China were associated with a higher prevalence of MCI. The prevalence of MCI was high in Chinese older adults, and even higher in those who were older, female, or living in rural areas or western China. Future studies are recommended to address the prevalence of MCI in the other 12 provinces of China. Furthermore, diagnostic assessments should be included in the identification of MCI.

Aging is the biggest risk factor for developing many neurodegenerative disorders, including idiopathic Parkinson’s disease (PD). PD is still an incurable disorder and the available medications are mainly directed to the treatment of symptoms in order to improve the quality of life. Oxidative injury has been identified as one of the principal factors involved in the progression of PD and several indications are now reported in the literature highlighting the prominent role of the superoxide radical in inducing neuronal toxicity. It follows that superoxide anions represent potential cellular targets for new drugs offering a novel therapeutic approach to cope with the progression of the disease. In this review we first present a comprehensive overview of the most common cellular reactive oxygen and nitrogen species, describing their cellular sources, their potential physiological roles in cell signalling pathways and the mechanisms through which they could contribute to the oxidative damage. We then analyse the potential therapeutic use of SOD-mimetic molecules, which can selectively remove superoxide radicals in a catalytic way, focusing on the classes of molecules that have therapeutically exploitable properties.

Dimebon (latrepirdine), an old antihistaminic drug, showed divergent results in two large clinical trials in Alzheimer disease (AD), which according to our review might be related to the specific pharmacological properties of the drug and the different patient populations included in both studies. Out of the many pharmacological effects of Dimebon, improvement of impaired mitochondrial function seeems to be most relevant for the substantial effects on cognition and behaviour reported in one of the studies, as these effects are already present at the low concentrations of dimebon measured in plasma and tissues of patients and experimental animals. Since impaired mitochondrial function seems to be the major driving force for the progression of the clinical symptoms and since most of the clinical benefits of dimebon originate from an effect on the symptomatic deterioration, mitochondrial improvement can also explain the lack of efficacy of this drug in another clinical trial where symptoms of the patiets remained stable for the time of the study. Accordingly, it seems worthwhile to reevaluate the clinical data to proof that clinical response is correlated with high levels of Neuropsychiatric Symptoms as these show a good relationship to the individual speed of symptomatic decline in AD patients related to mitochondrial dysfunction.

The population in the United States is aging and presents many challenges in the healthcare world. According to the report released by United States Census Bureau in June 2017, there are around 50 million residents aged 65 years and over as of 2016. Among the multiple healthcare challenges, kidney disease is a significant one because of its high burden, high cost and low awareness. Medicare spending on chronic kidney disease for 65 plus aged patients exceeded $ 50 billion in 2013. Different studies based on different calculations have estimated that at least one-third of chronic kidney disease patients are aged above 65 years. Most of the chronic kidney disease patients have multiple medical co-morbidities but geriatric syndromes are added factors that may be challenging for nephrologists. There is scarcity of well-trained geriatricians and in most instances, nephrologists take over the role of internist or geriatrician. This article outlines the need and importance of collaboration and coordination between geriatrics and nephrology for the best patient care and better healthcare outcomes.

Dietary fats absorbed in the intestine are transported in the circulation as chylomicrons and remnants that have atherogenic potential. Although postprandial lipidemia is increased in older subjects, the specific chylomicron metabolism has not been explored in older subjects nor compared to young subjects, which is the focus of this study. After a 12 h fast, artificially-made emulsions similar to lymph chylomicrons and doubly labeled with radioactive cholesteryl esters and triglycerides were intravenously injected in 23 older (66±4 years) and 20 young (24±3 years) subjects. Sequential blood samples were collected to determine fractional clearance rates (FCR, in min^-1) by compartmental analysis. Older subjects had higher LDL-cholesterol (p<0.001) and triglycerides (p<0.0001) than young subjects; HDL-cholesterol presented no difference. The emulsion cholesteryl-ester FCR was lower in older subjects compared to the young (p=0.0001). The emulsion triglyceride FCR did not differ in the two groups. Tested in vitro, however, the lipolysis of the emulsion triglycerides was less intense in the older than in the young subjects. As delayed removal of remnants, indicated by the pronouncedly smaller cholesteryl ester FCR, is related to the presence of cardiovascular diseases, this can be a risk factor which could accelerate atherogenic complications occurring in aged subjects

Voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) software is widely used in clinical practice in Alzheimer’s disease (AD). The existing VSRAD is based on the normal database with 1.5-tesla MRI scans (VSRAD-1.5T), and its utility for patients have undergone 3-tesla MRI is still controversial. We recruited 19 patients with early AD and 28 healthy controls who had undergone 3-tesla MRI scans at our institute (Cohort 1). We also used the 3-tesla MRI data of 30 patients with early AD and 13 healthy controls from the Japanese Alzheimer’s Disease Neuroimaging Initiative (Cohort 2). We also created a new VSRAD based on 65 normal subjects’ 3-tesla MRI scans (VSRAD-3T), and compared the detectability of AD between VSRAD-1.5T and VSRAD-3T, using receiver operating characteristic curve and area under the curve (AUC) analyses. As a result, there were no significant differences in the detectability of AD between VSRAD-3T and VSRAD-1.5T, except for the whole white matter atrophy score, which showed significantly better AUC in VSRAD-3T than in VSRAD-1.5T in both Cohort 1 (p=0.04) and 2 (p<0.01). Generally, there were better diagnostic values in Cohort 2 than in Cohort 1. The optimal cutoff values varied but were generally lower than in the previously published data. In conclusion, for patients with 3-tesla MRI, the detectability of early AD by the existing VSRAD was not different from that by the new VSRAD based on 3-tesla database. We should exercise caution when using the existing VSRAD for 3-tesla white matter analyses or for setting cutoff values.

Hibernation is a unique physiological state that evolved to survive periods of food shortages. It is characterized by profound decreases in metabolic rate, body temperature and physiological functions. Studies have shown that animals in hibernation can resist neurological damage. Here, we aimed to study whether hypoxia can induce a hibernation-like state in a traditionally non-hibernating animal and whether it is neuroprotective. All procedures were conducted according to international guidelines on laboratory animal safety. Mice C57BL/6 (19-21g) were placed into a 125 mL jar with fresh air and the jar was sealed with a rubber plug. For each run, the tolerance limit was judged by the animals’ appearance for "air hunger”. The animal was removed from the jar as soon as its first gasping breath appeared and was moved to another fresh-air-containing jar of similar volume. This procedure was performed in four runs. The hypoxia exposure significantly decreased oxygen (O₂) consumption, carbon dioxide (CO₂) production, respiratory rate and heart rate. Meanwhile, rectal temperature reached a minimum of 12.7±2.56°C, which is lower than a wide range of ambient temperatures. The mimicked hibernation decreased the infarct size in a focal cerebral ischemia mouse model. Our findings suggest the possibility of inducing suspended animation-like hibernation states for medical applications post injury.