scholarly journals A combined lifestyle intervention induces a sensitization of the blood transcriptomic response to a nutrient challenge

2021 ◽  
Author(s):  
Thies Gehrmann ◽  
Marian Beekman ◽  
Joris Deelen ◽  
Linda Partridge ◽  
Ondine van de Rest ◽  
...  
Keyword(s):  
Stress Response ◽  
Lifestyle Intervention ◽  
The Elderly ◽  
Cellular Stress Response ◽  
Lifestyle Interventions ◽  
Phenotypic Flexibility ◽  
Transcriptomic Response ◽  
Healthy Elderly ◽  
Fasted State ◽  
Novel Biomarkers

The global population is growing older. As age is a primary risk factor of (multi)morbidity, there is a need for novel indicators to predict, track, treat and prevent the development of disease. Lifestyle interventions have shown promising results in improving the health of participants and reducing the risk for disease, but in the elderly population, such interventions often show less reliable or subtle effects on health outcomes. This is further complicated by a poor understanding of the homeodynamics and the molecular effects of lifestyle interventions, by which their effects of a lifestyle intervention remain obscured. In the Growing Old Together (GOTO) study, we examined the responses of 164 healthy, elderly men and women to a 13-week combined physical and dietary lifestyle intervention. In addition to collecting blood samples at a fasted state, we sampled blood also 30 minutes following a standardized meal. This allows us to investigate an intervention response not only in the traditional fasted state, but also in the blood metabolic and cellular responses to a nutrient challenge. We investigated the transcriptomic and metabolomic responses to this nutrient challenge, how these responses relate to each other, and how this response is affected by the lifestyle intervention. We find that the intervention has very little effect on the fasted blood transcriptome, but that the nutrient challenge induces a large translational inhibition, and an innate immune activation, which together comprise a cellular stress response that is stimulated by the intervention. A sex-specific analysis reveals that although the same set of genes respond in the same direction in both males and females, the magnitude of these effects differ, and are modulated differently by the intervention. On the other hand, the metabolomic response to the nutrient challenge is largely unaffected by the intervention, and the correlation between the metabolomic nutrient response and transcriptomic modules indicates that the change in transcriptomic response to the nutrient challenge is independent from a change in cellular metabolomic environment. This work constitutes a glance at the acute transcriptomic stress response to nutrient intake in blood, and how a lifestyle intervention affects this response in healthy elderly, and may lead to the development of novel biomarkers to capture the phenotypic flexibility of health.

scholarly journals The effect of chronic and acute stressors, and their interaction, on gonadal function: an experimental test during gonadal recrudescence

2017 ◽  
Author(s):  
Mikus Abolins-Abols ◽  
Rachel E. Hanauer ◽  
Kimberly A. Rosvall ◽  
Mark P. Peterson ◽  
Ellen D. Ketterson
Keyword(s):  
Stress Response ◽  
Stress Responses ◽  
Cellular Stress Response ◽  
Gonadal Function ◽  
Transcriptomic Response ◽  
Stress Changes ◽  
Chronic Disturbance ◽  
Gonadal Recrudescence ◽  
Acute Stressor

AbstractOrganisms are expected to invest less in reproduction in response to a stressor, but theory predicts that this effect should depend on the frequency of stressors in the environment. Here we investigated how an acute stressor affected gonadal function in a songbird, and how long-term differences in the stress environment influenced these acute stress responses. We exposed male Dark-eyed Juncos (Junco hyemalis) either to chronic or minimal (control) disturbance during gonadal recrudescence, after which we measured baseline testosterone, testosterone after an acute handling stressor, and the ability to elevate testosterone in response to hormonal stimulation. In a 2x2 design, we then euthanized males from the two chronic treatment groups either immediately or after an acute stressor to investigate the effect of these treatments on the gonadal transcriptome. We found that chronically disturbed birds had marginally lower testosterone. The acute stressor suppressed testosterone in control birds, but not in the chronic disturbance group. The ability to elevate testosterone did not differ between the chronic treatments. Surprisingly, chronic disturbance had a weak effect on the testicular transcriptome, and did not affect transcriptomic response to the acute stressor. The acute stressor, on the other hand, upregulated cellular stress response, and affected expression of genes associated with hormonal stress-response. Overall, we show that both chronic and acute stressors affect reproductive function, and that chronic stress changes how acute stressors affect testosterone physiology. Our findings also suggest that acute and chronic stressors affect testes differently, and that gonadal function is relatively robust to long-term stressors.Summary statementAn acute stressor downregulated testosterone production, but this effect was absent in chronically disturbed birds. The acute stressor had a strong effect on the gonadal transcriptome, whereas chronic disturbance had a negligible effect.

scholarly journals DDRE-06. CELLULAR STRESS RESPONSE IN DIPG THERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii62-ii62
Author(s):  
Sreepradha Sridharan ◽  
Arif Harmanci ◽  
Robert Siddaway ◽  
Tara Dobson ◽  
Jyothishmathi Swaminathan ◽  
...  
Keyword(s):  
Stress Response ◽  
Single Cell ◽  
Synthetic Lethality ◽  
Clonal Evolution ◽  
Single Agent ◽  
Objective Response ◽  
Hdac Inhibitors ◽  
Pediatric Brain Tumor ◽  
Dominant Negative ◽  
Cellular Stress Response

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor of the pons and brainstem. Therefore, there is a desperate need for new therapeutics. Genomic profiling of tumors identified a highly prevalent dominant negative somatic mutation at lysine (K)-27 in histone genes HIST1H3B and H3F3A. Clonal evolution modeling suggests these mutations are truncal, and studies have demonstrated their contribution to tumorigenesis. ONC201, a first-in-class DRD2 antagonist and ClpP agonist is an anticancer drug developed by Oncoceutics, which targets the unfolded protein response (UPR) and integrated stress response (ISR) signaling and is actively being investigated in patients with recurrent H3 K27M-mutant gliomas. In adults with recurrent glioma, single agent studies showed benign-safety, no dose-limiting toxicities and a durable objective response when administered orally. In addition, intra-tumoral drug levels exceeded therapeutic thresholds, and induced tumor cell apoptosis. Based on this and response seen in a pediatric patient with DIPG for whom compassionate use of ONC201 was approved, a multi-arm, non-randomized multi-institutional Phase I clinical trial (NCT03416530) is actively accruing patients. However, the strength of UPR and ISR in DIPGs and their effect on DIPG response to ONC201 is not known. Our group employed bulk/single cell transcriptomic and single cell proteomic approaches to demonstrate substantial heterogeneity in UPR and ISR signaling in human DIPG samples. Consistent with this, DIPG cell lines exhibited considerable variability in sensitivity to ONC201. Single cell profiling identified tumor sub-populations with significant proliferative capacity even after ONC201 exposure. Incomplete response promotes recurrence. To target these cells, we performed a synthetic lethality screen with a library of 360 FDA-approved CNS penetrant compounds, which identified HDAC inhibitors and DNA damage-inducing chemotherapy as having synergy with ONC201. Thus, we suggest that tumor heterogeneity impacts sensitivity to ONC201 and that this can be reduced by combination treatments.

scholarly journals Assessment of Functions of the Autonomic Nervous System in the Elderly with Different Comorbid Factors

2020 ◽  
Author(s):  
Sushma S. ◽  
Medha Y Rao ◽  
Shaikh Mohammed Aslam
Keyword(s):  
Elderly Patients ◽  
Predictive Value ◽  
The Elderly ◽  
Common Symptom ◽  
Deep Breathing ◽  
Isometric Handgrip ◽  
Male Predominance ◽  
Healthy Elderly ◽  
Sensitivity Specificity ◽  
Deep Breathing Test

Abstract Background Studies in healthy elderly patients have shown the prevalence of autonomic dysfunction (AD) in the range of 20 to 30%. However, there is paucity in data pertaining to AD in the elderly in the Indian context. Objective To assess the prevalence of AD in the elderly irrespective of their comorbidity status. Methods A total of 141 elderly patients with or without comorbidities/symptoms of AD were included. Demographic and clinical details of the patients were recorded. Autonomic function tests (AFTs) such as deep breathing test, Valsalva ratio, orthostatic heart rate (OHR), isometric handgrip test, and orthostatic blood pressure were performed based on Ewing’s battery of tests. The sensitivity, specificity, positive predictive value, negative predictive value, and the accuracy of AFTs were evaluated. Results Most patients (n = 85) were aged between 60 and 69 years, with a male predominance (58.87%). Hypertension and diabetes mellitus were the most common comorbidities. Postural hypotension was the most common symptom of AD. With advancing age, symptoms of AD manifested significantly more. Overall, 73.8% of patients had AD, of whom 45.4% had early AD. Number of AD symptoms, glycated hemoglobin (HbA1c) level, and comorbid factors (diabetes and hypertension) were significantly associated with the results of AFTs (p < 0.05). AFTs were highly significant with respect to the results obtained (p < 0.001). Deep breathing test, abnormal in majority of study patients, has a sensitivity of 93.3% and OHR has a specificity of 81.1% to determine AD. Conclusion The study concludes that age itself is an independent predictor of AD, which increases in severity if associated with comorbidities.

scholarly journals Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 99
Author(s):  
Shweta Devi ◽  
Vijay Kumar ◽  
Sandeep Kumar Singh ◽  
Ashish Kant Dubey ◽  
Jong-Joo Kim
Keyword(s):  
Stress Response ◽  
Stress Responses ◽  
Neurodegenerative Disorders ◽  
Cell Damage ◽  
Cellular Stress ◽  
Clinical Manifestations ◽  
Cellular Stress Response ◽  
Dramatic Rise ◽  
Cellular Stress Responses

Neurodegenerative disorders, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), are the most concerning disorders due to the lack of effective therapy and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and endoplasmic reticulum (ER)-stress, which combats with stress conditions. Environmental stress/toxicity weakened the cellular stress response which results in cell damage. Small molecules, such as flavonoids, could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways, such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the potential role of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.

scholarly journals Mitochondrien unter Stress: Die Rolle der Präsequenzprotease MPP

BIOspektrum ◽  
2021 ◽  
Vol 27 (4) ◽  
pp. 390-393
Author(s):  
F.-Nora Vögtle
Keyword(s):  
Stress Response ◽  
Cellular Stress ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Nuclear Genome ◽  
Cellular Stress Response ◽  
Mitochondrial Proteins ◽  
Protein Biogenesis ◽  
Cellular Integrity

AbstractThe majority of mitochondrial proteins are encoded in the nuclear genome, so that the nearly entire proteome is assembled by post-translational preprotein import from the cytosol. Proteomic imbalances are sensed and induce cellular stress response pathways to restore proteostasis. Here, the mitochondrial presequence protease MPP serves as example to illustrate the critical role of mitochondrial protein biogenesis and proteostasis on cellular integrity.

scholarly journals A Comprehensive, Multidisciplinary, Personalized, Lifestyle Intervention Program is Associated with Increased Leukocyte Telomere Length in Children and Adolescents with Overweight and Obesity

Nutrients ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 2682
Author(s):  
George Paltoglou ◽  
Christina Raftopoulou ◽  
Nicolas C. Nicolaides ◽  
Sofia M. Genitsaridi ◽  
Sofia I. Karampatsou ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Telomere Length ◽  
Lifestyle Intervention ◽  
Intervention Program ◽  
Overweight And Obesity ◽  
Initial Assessment ◽  
Biological Aging ◽  
Childhood And Adolescence ◽  
Lifestyle Interventions ◽  
Lifestyle Intervention Program

Leucocyte telomere length (LTL) is a robust marker of biological aging and is associated with obesity and cardiometabolic risk factors in childhood and adolescence. We investigated the effect of a structured, comprehensive, multidisciplinary, personalized, lifestyle intervention program of healthy diet and physical exercise on LTL in 508 children and adolescents (239 males, 269 females; 282 prepubertal, 226 pubertal), aged 10.14 ± 0.13 years. Participants were classified as obese (n = 267, 52.6%), overweight (n = 174, 34.2%), or of normal BMI (n = 67, 13.2%) according to the International Obesity Task Force (IOTF) cutoff points and were studied prospectively for one year. We demonstrated that LTL increased significantly after 1 year of the lifestyle interventions, irrespective of gender, pubertal status, or body mass index (BMI). Waist circumference was the best negative predictor of LTL at initial assessment. The implementation of the lifestyle interventions also resulted in a significant improvement in clinical (BMI, BMI z-score and waist to height ratio) and body composition indices of obesity, inflammatory markers, hepatic enzymes, glycated hemoglobin (HbA1C), quantitative insulin sensitivity check index (QUICKI), and lipid profile in all participants. These findings indicate that the increased LTL may be associated with a more favorable metabolic profile and decreased morbidity later in life.

scholarly journals Effects of Balance Shoes on Balance and Postural Stability in the Elderly: A Crossover, Controlled, Randomized Single-Blind Study

Healthcare ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 179
Author(s):  
Nicolas Amiez ◽  
Carole Cometti ◽  
Éric Mouillon ◽  
Marie José Teisseire ◽  
Pascal Chenut ◽  
...  
Keyword(s):  
Elderly People ◽  
Postural Stability ◽  
The Elderly ◽  
Risk Of Falling ◽  
Limits Of Stability ◽  
Healthy Elderly ◽  
Falling Risk ◽  
Familiarization Period ◽  
Healthy Elderly People ◽  
Single Blind

The risk of falling increases with age. Individuals wearing unadapted shoes present an aggravating risk factor. The objective of this study was to determine the effectiveness of specifically designed balance shoes on balance and postural stability in healthy elderly people compared to that of their usual shoes. In total, 21 healthy individuals aged 65–84 years (76.0 ± 8.0 years) performed balance tests (bipedal with open or closed eyes, unipedal with open eyes, limits of stability, and step cadence) while wearing their (i) personal shoes or (ii) balance shoes (Axis Comfort Development©). Three test sessions were conducted with personal and balance shoes. The first served as the baseline, and the other two were performed after a familiarization period of several days with the personal or balance shoes. The perception of balance shoe efficiency was documented using a questionnaire. The balance shoes significantly improved bipedal balance with closed eyes. Moreover, the familiarization period significantly improved unipedal balance with open eyes. Most subjects felt safer and stabler using balance shoes. The investigated specifically designed balance shoes were effective in elderly individuals in improving postural balance compared to personal shoes. The balance shoes could, therefore, reduce the falling risk in healthy elderly people.

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