Repurposing Proteostasis-Modifying Drugs to Prevent or Treat Age-Related Dementia: A Systematic Review

Background: Dementia has a significant impact on quality of life of older individuals. Impaired proteostasis has been implicated as a potential cause of dementia, that can be therapeutically targeted to improve patient outcomes. This review aimed to collate all current evidence of the potential for targeting proteostasis with repurposed drugs as an intervention for age-related dementia and cognitive decline.Methods: PubMed, Web of Science and Embase databases were searched from inception until 4th July 2017 for studies published in English. Interventional studies of repurposed proteostasis-modifying drugs in Alzheimer's disease (AD), Parkinson's disease (PD), Lewy Body disease, vascular dementia, and cognitive aging, in either animal models or humans with change in cognition as the outcome were included. The SYRCLE and Cochrane tools were used to assess risk of bias for included studies.Results: Overall 47 trials, 38 animal and 9 human, were isolated for inclusion in this review. Drugs tested in animals and humans included lithium, rapamycin, rifampicin, and tyrosine kinase inhibitors. Drugs tested only in animals included Macrophage and Granulocyte-Macrophage Colony Stimulating Factors, methylene blue, dantrolene, geranylgeranylacetone, minocycline and phenylbutyric acid. Lithium (n = 10 animal, n = 6 human) and rapamycin (n = 12 animal, n = 1 human) were the most studied proteostasis modifying drugs influencing cognition. Nine of ten animal studies of lithium showed a statistically significant benefit in Alzheimer's models. Rapamycin demonstrated a significant benefit in models of vascular dementia, aging, and Alzheimer's, but may not be effective in treating established Alzheimer's pathology. Lithium and nilotinib had positive outcomes in human studies including Alzheimer's and Parkinson's patients respectively, while a human study of rifampicin in Alzheimer's failed to demonstrate benefit. Microdose lithium showed a strongly significant benefit in both animals and humans. While the risk of bias was relatively low in human studies, the risk of bias in animal studies was largely unclear.Conclusion: Overall, the collective findings support the hypothesis that targeting proteostasis for treatment of dementia may be beneficial, and therefore future studies in humans with repurposed proteostasis modifying drugs are warranted. Larger human clinical trials focusing on safety, efficacy, tolerability, and reproducibility are required to translate these therapeutics into clinical practice

Understanding the circumgalactic medium is critical for understanding galaxy evolution

Galaxies evolve under the influence of gas flows between their interstellar medium and their surrounding gaseous halos known as the circumgalactic medium (CGM). The CGM is a major reservoir of galactic baryons and metals, and plays a key role in the long cycles of accretion, feedback, and recycling of gas that drive star formation. In order to fully understand the physical processes at work within galaxies, it is therefore essential to have a firm understanding of the composition, structure, kinematics, thermodynamics, and evolution of the CGM. In this white paper we outline connections between the CGM and galactic star formation histories, internal kinematics, chemical evolution, quenching, satellite evolution, dark matter halo occupation, and the reionization of the larger-scale intergalactic medium in light of the advances that will be made on these topics in the 2020s. We argue that, in the next decade, fundamental progress on all of these major issues depends critically on improved empirical characterization and theoretical understanding of the CGM. In particular, we discuss how future advances in spatially-resolved CGM observations at high spectral resolution, broader characterization of the CGM across galaxy mass and redshift, and expected breakthroughs in cosmological hydrodynamic simulations will help resolve these major problems in galaxy evolution.Comment: Astro2020 Decadal Science White Pape

Immune capacity determines outcome following surgery or trauma:a systematic review and meta-analysis

PURPOSE: Immunological functions are altered following physical injury. The magnitude of the immunological response is dependent on the initial injury. However, variability in the immune response exists within and between patients where only some patients are at risk of developing complications such as systemic inflammatory response syndrome after injury. This systematic review and meta-analysis assessed whether lipopolysaccharide (LPS) induced cytokine production capacity of leucocytes can be used as a functional test to predict the risk of developing complications after injury. METHODS: Medline, Embase and Web of Science were systematically searched to identify articles that investigated the association between LPS induced cytokine production capacity in leucocytes and any clinical outcome after surgery or trauma. Where sufficient information was supplied, a meta-analysis was performed to determine the overall clinical outcomes. RESULTS: A total of 25 articles out of 6765 abstracts identified through the literature search were included in this review. Most articles described a positive association between cytokine production capacity and the development of inflammatory complications (n = 15/25). Coincidingly, the meta-analysis demonstrated that TNFα (Hedges g: 0.63, 95% CI 0.23, 1.03), IL-6 (Hedges g: 0.76, 95% CI 0.41, 1.11) and IL-8 (Hedges g: 0.93, 95% CI 0.46, 1.39) production capacity was significantly higher, one day after injury, in patients who developed inflammatory complications compared to patients who did not following trauma or surgical intervention. No significant difference was observed for IL-1β. CONCLUSION: The associations of elevated LPS-induced cytokine production capacity with the risk of developing inflammatory complications are consistent with previous theories that proposed excessive inflammation is accompanied by anti-inflammatory mechanisms that results in a period of immunosuppression and increased risk of secondary complications. However, immunological biomarkers for risk stratification is still a developing field of research where further investigations and validations are required

Unresolved inflammation during hospitalization is associated with post-discharge institutionalization and mortality in geriatric rehabilitation inpatients: The RESORT cohort

10.1016/j.exger.2021.111597Experimental Gerontology15611159

Senescence in tissue samples of humans with age-related diseases: A systematic review

10.1016/j.arr.2021.101334Ageing Research Reviews6810133

Cellular senescence and chronological age in various human tissues:A systematic review and meta-analysis

Senescent cells in tissues and organs are considered to be pivotal to not only the aging process but also the onset of chronic disease. Accumulating evidence from animal experiments indicates that the magnitude of senescence can vary within and between aged tissue samples from the same animal. However, whether this variation in senescence translates across to human tissue samples is unknown. To address this fundamental question, we have conducted a systematic review and meta-analysis of all available literature investigating the magnitude of senescence and its association with chronological age in human tissue samples. While senescence is higher in aged tissue samples, the magnitude of senescence varies considerably depending upon tissue type, tissue section, and marker used to detect senescence. These findings echo animal experiments demonstrating that senescence levels may vary between organs within the same animal

Prevalence of sarcopenia in inpatients 70 years and older using different diagnostic criteria

Aim: To compare prevalence rates of sarcopenia applying multiple diagnostic criteria in hospitalized older patients. Design: Observational, longitudinal EMPOWER study. Methods: A total of 378 hospitalized inpatients aged 70 years and older were recruited. Muscle mass and strength were measured using bioelectrical impedance analysis and handheld dynamometer respectively. Nine commonly used diagnostic criteria for sarcopenia were applied. Analyses were stratified for sex. Results: Mean age was 79.7 years (SD 6.43) and 50.8% were males. Depending on the applied criterion, prevalence of sarcopenia ranged between 12.0-75.9% in males and 3.1-75.3% in females. Males had a higher prevalence of sarcopenia compared with females in all but one of the applied diagnostic criteria. In males, highest prevalence of sarcopenia was found using muscle mass as diagnostic criterion while in females this was observed when using muscle strength. Five male and one female hospitalized older patients were sarcopenic according to all applied diagnostic criteria

Prevalence of sarcopenia in inpatients 70 years and older using different diagnostic criteria

Aim: To compare prevalence rates of sarcopenia applying multiple diagnostic criteria in hospitalized older patients. Design: Observational, longitudinal EMPOWER study. Methods: A total of 378 hospitalized inpatients aged 70 years and older were recruited. Muscle mass and strength were measured using bioelectrical impedance analysis and handheld dynamometer respectively. Nine commonly used diagnostic criteria for sarcopenia were applied. Analyses were stratified for sex. Results: Mean age was 79.7 years (SD 6.43) and 50.8% were males. Depending on the applied criterion, prevalence of sarcopenia ranged between 12.0-75.9% in males and 3.1-75.3% in females. Males had a higher prevalence of sarcopenia compared with females in all but one of the applied diagnostic criteria. In males, highest prevalence of sarcopenia was found using muscle mass as diagnostic criterion while in females this was observed when using muscle strength. Five male and one female hospitalized older patients were sarcopenic according to all applied diagnostic criteria