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Aging is a major international concern that brings formidable socioeconomic and healthcare challenges. Small molecules capable of improving the health of older individuals are being explored. Small molecules that enhance cellular stress resistance are a promising avenue to alleviate declines seen in human aging. Tomatidine, a natural compound abundant in unripe tomatoes, inhibits age-related skeletal muscle atrophy in mice. Here we show that tomatidine extends lifespan and healthspan in C. elegans , an animal model of aging which shares many major longevity pathways with mammals. Tomatidine improves many C. elegans behaviors related to healthspan and muscle health, including increased pharyngeal pumping, swimming movement, and reduced percentage of severely damaged muscle cells. Microarray, imaging, and behavioral analyses reveal that tomatidine maintains mitochondrial homeostasis by modulating mitochondrial biogenesis and PINK-1/DCT-1-dependent mitophagy. Mechanistically, tomatidine induces mitochondrial hormesis by mildly inducing ROS production, which in turn activates the SKN-1/Nrf2 pathway and possibly other cellular antioxidant response pathways, followed by increased mitophagy. This mechanism occurs in C. elegans , primary rat neurons, and human cells. Our data suggest that tomatidine may delay some physiological aspects of aging, and points to new approaches for pharmacological interventions for diseases of aging.

Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates PARP1 and leads to accelerated aging in Caenorhabditis elegans. In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response.

Left ventricular ejection fraction (LVEF) is the most frequently used parameter in the assessment of heart failure (HF). Cardiac index (CI) is considered a potential alternative to LVEF despite limited evidence. We aimed to assess and compare the predictive accuracy of LVEF and echocardiographically-assessed CI in HF patients. A single-centre, retrospective cohort study was conducted in patients hospitalized for acute HF from 2010-2016. Cox proportional hazard models including either LVEF or CI were created to predict all cause death, cardiovascular (CV) death, or first HF-readmission. Of 334 patients included in the analysis, 58.7% exhibited HF with reduced LVEF (HFrEF). Left ventricular ejection fraction did not show correlation with any endpoint, while CI was predictive of HF-readmission in the entire cohort. Both the LVEF-based and CI-based models demonstrated moderate discriminative accuracy when predicting all-cause death, CV death, or HF-readmission. Left ventricular ejection fraction proved to be an independent predictor of CV mortality in HFrEF-patients, while CI was predictive of HF-readmission in the non-HFrEF group. Left ventricular ejection fraction seemed to be associated more closely with disease severity in HFrEF, and CI in the non-HFrEF group, in this real-life cohort of elderly HF patients. The LVEF-based and CI-based predictive models have clinically similar predictive accuracy for mortality and HF-readmission, thus CI may be a potential alternative to LVEF in the assessment of left ventricular function. Cardiac index may be an important new tool in the assessment of HF patients with midrange or preserved LVEF.

Introduction Analyses of off‐label use of acetylcholinesterase inhibitors (AChEIs) in mild cognitive impairment (MCI) has produced mixed results. Post hoc analyses of observational cohorts, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), have reported deleterious effects in AChEI‐treated subjects (AChEI+). Here, we used neuroimaging biomarkers to determine whether AChEI+ subjects had a greater rate of neurodegeneration than untreated (AChEI–) subjects while accounting for baseline differences. Methods We selected 121 ADNI MCI AChEI+ subjects and 151 AChEI– subjects with a magnetic resonance imaging (MRI) scan; 82 AChEI+ and 110 AChEI– also had a fluorodeoxyglucose (FDG) scan. A subset (83 AChEI+ and 98 AChEI–) had cerebrospinal fluid (CSF) or amyloid positron emission tomography (PET) assessment for amyloid positivity. Linear regression models were used to compare the effect of treatment on changes in Mini‐Mental State Examination and Clinical Dementia Rating‐Sum of Boxes scores. We used standard regression in SPM (for baseline) and the SPM toolbox sandwich estimator, SwE (for longitudinal) for comparisons of AChEI+ and AChEI– FDG PET and MRI data. Results At baseline, the AChEI+ group had significantly reduced cortical gray matter density (GMD) and more hypometabolism than AChEI– subjects. The greater rate of atrophy and hypometabolic changes over time in AChEI+ compared to AChEI– subjects did not survive correction for baseline differences. AChEI+ participants were more likely to be amyloid‐positive and have lower GMD and FDG standardized uptake value ratio than AChEI– at baseline. AChEI+ subjects showed greater atrophy over time, which remained significant after controlling for amyloid status. Discussion Our data suggest that the observed differences in rates of cognitive decline, atrophy, and hypometabolism are likely the result of significant baseline differences between the groups. Furthermore, the data indicate no treatment effect of AChEI (positive of negative), rather that physicians prescribe AChEI to subjects who present with more severe clinical impairment. This alone may account for the negative effect seen previously in the ADNI population of AChEI use among MCI subjects.

Ageing of the brain is accompanied by variable degrees of cognitive decline. Estrogens have profound effects on brain ageing by exerting neurotrophic and neuroprotective types of action. Furthermore, exercise has also been claimed to play a role in the non-pharmacological prevention of psycho-neuronal decline with ageing. In the present study the question was asked whether chronic physical exercise might substitute the action of estrogens in aged rats. We compared the effects of 17β-estradiol (E2) treatment and long-term moderate physical exercise in ageing (15 months, early stage of ageing) and old (27 months) female rats, on cognitive functions and the relevant intracellular molecular signaling pathways in the hippocampus. Results showed that both treatments improved attention and memory functions of the 15 months old rats. Like E2, physical training enhanced the level of brain derived nerve growth factor and the activation of PKA/Akt/CREB and MAPK/CREB pathways. The treatments also enhanced the levels of synaptic molecules synaptophysin and synapsin I, which could explain the improved cognitive functions. In the 27 months old rats the behavioral and molecular effects of E2 were indistinguishable from those found in the 15 months old animals but the effects of physical exercise in most of the measures proved to be practically ineffective. It is concluded that the effectiveness of regular and moderate intensity physical exercise is age-dependent while the action of E2 treatment is comparable between the ageing and old female rats on maintaining cognition and its underlying molecular mechanisms.

Purpose Sigma-1 receptors are involved in learning and memory processes. We assessed sigma-1 receptor expression and memory function in two animal models of cognitive impairment. Procedures Male Wistar-Hannover rats were either lesioned by unilateral injection of N -methyl- D -aspartic acid in the nucleus basalis, or deprived of rapid eye movement sleep for 48 h, using the modified multiple platform method. Sigma-1 receptor expression was examined with the positron emission tomography radiotracer [ 11 C]SA4503, immunohistochemistry, and Western blotting. Results Cortical tracer uptake after 1 week was not significantly affected by lesioning. Immunohistochemistry revealed moderate increases of sigma-1 receptors at bregma level −2.8, in parietal cortex layer V of the lesioned hemisphere. Sleep deprivation lowered passive avoidance test scores and reduced [ 11 C]SA4503 accumulation and sigma-1 receptor expression in pons. Conclusions Cholinergic lesioning causes an increase of sigma-1 receptor expression in a small cortical area which may be neuroprotective. Sleep deprivation decreases receptor expression in midbrain and pons.

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates in the brain. Extracellular vesicles (EVs), including exosomes, are small 50–150 nm membrane vesicles that have recently been implicated in the prion-like spread of self-aggregating proteins. Here we report that EVs isolated from AD patient cerebrospinal fluid and plasma, from the plasma of two AD mouse models, and from the medium of neural cells expressing familial AD presenilin 1 mutations, destabilize neuronal Ca 2+ homeostasis, impair mitochondrial function, and sensitize neurons to excitotoxicity. EVs contain a relatively low amount of Aβ but have an increased Aβ42/ Aβ40 ratio; the majority of Aβ is located on the surface of the EVs. Impairment of lysosome function results in increased generation of EVs with elevated Aβ42 levels. EVs may mediate transcellular spread of pathogenic Aβ species that impair neuronal Ca 2+ handling and mitochondrial function, and may thereby render neurons vulnerable to excitotoxicity. Alzheimer’s disease: How the cellular sickness spreads A deadly game of cellular ‘tag’ might underlie the degenerative spread of damage between brain cells in Alzheimer’s patients. Mark Mattson from the National Institute on Aging in Maryland and colleagues investigated a hallmark of Alzheimer’s disease: the proliferation of tangled amyloid β protein clusters between brain cells. They found that small pouches of the outer membrane of brain cells—called extracellular vesicles-shuttled a particularly damaging form of amyloid β between cells. Extracellular vesicles were isolated from the fluid surrounding the brain in Alzheimer’s patients; when normal brain cells were exposed to these vesicles, cellular function in the exposed brain cells turned aberrant, occasionally leading to cell death. Understanding the propagation of Alzheimer’s disease pathology within the brain might uncover markers for detecting the disease earlier, and perhaps a window to intervene and halt the damage.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates in the brain. Extracellular vesicles (EVs), including exosomes, are small 50-150 nm membrane vesicles that have recently been implicated in the prion-like spread of self-aggregating proteins. Here we report that EVs isolated from AD patient cerebrospinal fluid and plasma, from the plasma of two AD mouse models, and from the medium of neural cells expressing familial AD presenilin 1 mutations, destabilize neuronal Ca 2+ homeostasis, impair mitochondrial function, and sensitize neurons to excitotoxicity. EVs contain a relatively low amount of Aβ but have an increased Aβ42/ Aβ40 ratio; the majority of Aβ is located on the surface of the EVs. Impairment of lysosome function results in increased generation of EVs with elevated Aβ42 levels. EVs may mediate transcellular spread of pathogenic Aβ species that impair neuronal Ca 2+ handling and mitochondrial function, and may thereby render neurons vulnerable to excitotoxicity.

Alzheimer's Disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates in the brain. Extracellular vesicles (EVs) are small 50-150 nanometer membrane vesicles that have recently been implicated in the prion-like spread of self-aggregating proteins. Here we report that EVs isolated from AD patient CSF and plasma, from the plasma of two AD mouse models, and from the medium of neural cells expressing familial AD presenilin 1 mutations, destabilize neuronal Ca homeostasis, impair mitochondrial function, and sensitize neurons to excitotoxicity. EVs contain a relatively low amount of Aβ but have an increased Aβ42/ Aβ40 ratio; the majority of Aβ is located on the surface of the EVs. Impairment of lysosome function results in increased generation EVs with elevated Aβ42 levels. EVs may mediate transcellular spread of pathogenic Aβ species and that impair neuronal Ca handling and mitochondrial function, and may thereby render neurons vulnerable to excitotoxicity.

Probiotics have already proven beneficial effects in the treatment of several intestinal infections, but the underlying mechanisms how the probiotics can affect responses of porcine IPEC-J2 enterocytes to oxidative stress remained to be elucidated. The immunmodulatory effect of five bacterial strains ( Lactobacillus plantarum 2142 , Lactobacillus casei Shirota , Bifidobacterium animalis subsp. lactis BB-12 , Bacillus amyloliquefaciens CECT 5940 and Enterococcus faecium CECT 4515) on 1 mM peroxide-triggered upregulation of interleukin (IL)-8 and tumor necrosis factor alpha (TNF-α) level was screened by q RT-PCR. Our data revealed that spent culture supernatant (SCS) of L. plantarum 2142 had significant lowering effect on IL-8 and TNF-α level with concomitant promoting activity on protective Hsp70 gene expression. According to our results, lactic acid (racemic, d - and l -lactic acid) and acetic acid produced by lactobacilli had no protective effect in quenching upregulation of proinflammatory cytokines. Furthermore, L. plantarum 2142-specific supernatant peptides were detected by gel electrophoresis and capillary zone electrophoresis.