ABSTRACT
BACKGROUND: Dementia is prevalent in aged populations and is associated with disability and distress for those affected. Therapeutic benefits of drugs targeting dementia are small. Impaired nutrient sensing pathways have been implicated in the pathogenesis of dementia and may offer a novel treatment target. AIMS: This systematic review collated evidence for novel therapeutic compounds that modify nutrient sensing pathways, particularly the sirtuin pathway, in preventing cognitive decline or improving cognition in normal ageing, mild cognitive impairment (MCI), and dementia. METHODS: PubMed, Embase and Web of Science databases were searched using key search terms. Articles were screened using Covidence systematic review software. The risk of bias was assessed using the Systematic Review Center for Laboratory animal Experimentation (SYRCLE)'s risk of bias tool for animal studies and Cochrane Risk of Bias tool v 2.0 for human studies. RESULTS: Out of 3841 articles, 68 were included describing 38 different novel therapeutic compounds that modulate the nutrient sensing pathway via the sirtuin pathway. In animal models (58 studies), all investigated novel therapeutic compounds showed cognitive benefits. Ten studies were human intervention trials targeting normal ageing (1 study) and dementia populations (9 studies). Direct sirtuin (silent mating type information regulation 2 homolog) 1 (SIRT1) activators Resveratrol and Nicotinamide derivatives improved cognitive outcomes among human subjects with normal cognition and MCI. CONCLUSION: Animal studies support that modulation of the sirtuin pathway has the potential to improve cognitive outcomes. Overall, there is a clear lack of translation from animal models to human populations.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Sirtuins , Humans , Aged , Alzheimer Disease/drug therapy , Cognition , NutrientsABSTRACT
Background: Since the outbreak of COVID-19 pandemic the interindividual variability in the course of the disease has been reported, indicating a wide range of factors influencing it. Factors which were the most often associated with increased COVID-19 severity include higher age, obesity and diabetes. The influence of cytokine storm is complex, reflecting the complexity of the immunological processes triggered by SARS-CoV-2 infection. A modern challenge such as a worldwide pandemic requires modern solutions, which in this case is harnessing the machine learning for the purpose of analysing the differences in the clinical properties of the populations affected by the disease, followed by grading its significance, consequently leading to creation of tool applicable for assessing the individual risk of SARS-CoV-2 infection. Methods: Biochemical and morphological parameters values of 5,000 patients (Curisin Healthcare (India) were gathered and used for calculation of eGFR, SII index and N/L ratio. Spearman's rank correlation coefficient formula was used for assessment of correlations between each of the features in the population and the presence of the SARS-CoV-2 infection. Feature importance was evaluated by fitting a Random Forest machine learning model to the data and examining their predictive value. Its accuracy was measured as the F1 Score. Results: The parameters which showed the highest correlation coefficient were age, random serum glucose, serum urea, gender and serum cholesterol, whereas the highest inverse correlation coefficient was assessed for alanine transaminase, red blood cells count and serum creatinine. The accuracy of created model for differentiating positive from negative SARS-CoV-2 cases was 97%. Features of highest importance were age, alanine transaminase, random serum glucose and red blood cells count. Conclusion: The current analysis indicates a number of parameters available for a routine screening in clinical setting. It also presents a tool created on the basis of these parameters, useful for assessing the individual risk of developing COVID-19 in patients. The limitation of the study is the demographic specificity of the studied population, which might restrict its general applicability.
ABSTRACT
Background: Dementia is a global challenge with 10 million individuals being diagnosed every year. Currently, there are no established disease-modifying treatments for dementia. Impaired nutrient sensing has been implicated in the pathogenesis of dementia. Compounds that inhibit the glycogen synthase kinase-3 (GSK3) pathway have been investigated as a possible treatment to attenuate the progression of the disease, particularly the suppression of the hyper-phosphorylation process of the tau protein. Aims: Systematically summarizing compounds which have been tested to inhibit the GSK3 pathway to treat cognitive impairment and dementia. Methods: PubMed, Embase and Web of Science databases were searched from inception until 28 July 2021 for articles published in English. Interventional animal studies inhibiting the GSK3 pathway in Alzheimer's disease (AD), Parkinson's dementia, Lewy body dementia, vascular dementia, mild cognitive impairment (MCI) and normal cognitive ageing investigating the change in cognition as the outcome were included. The Systematic Review Centre for Laboratory animal Experimentation's risk of bias tool for animal studies was applied. Results: Out of 4,154 articles, 29 described compounds inhibiting the GSK3 pathway. All studies were based on animal models of MCI, AD or normal cognitive ageing. Thirteen out of 21 natural compounds and five out of nine synthetic compounds tested in MCI and dementia animal models showed an overall positive effect on cognition. No articles reported human studies. The risk of bias was largely unclear. Conclusion: Novel therapeutics involved in the modulation of the GSK3 nutrient sensing pathway have the potential to improve cognitive function. Overall, there is a clear lack of translation from animal models to humans.
ABSTRACT
Nicotinamide adenine dinucleotide (NAD+) is an important natural molecule involved in fundamental biological processes, including the TCA cycle, OXPHOS, ß-oxidation, and is a co-factor for proteins promoting healthy longevity. NAD+ depletion is associated with the hallmarks of ageing and may contribute to a wide range of age-related diseases including metabolic disorders, cancer, and neurodegenerative diseases. One of the central pathways by which NAD+ promotes healthy ageing is through regulation of mitochondrial homeostasis via mitochondrial biogenesis and the clearance of damaged mitochondria via mitophagy. Here, we highlight the contribution of the NAD+-mitophagy axis to ageing and age-related diseases, and evaluate how boosting NAD+ levels may emerge as a promising therapeutic strategy to counter ageing as well as neurodegenerative diseases including Alzheimer's disease. The potential use of artificial intelligence to understand the roles and molecular mechanisms of the NAD+-mitophagy axis in ageing is discussed, including possible applications in drug target identification and validation, compound screening and lead compound discovery, biomarker development, as well as efficacy and safety assessment. Advances in our understanding of the molecular and cellular roles of NAD+ in mitophagy will lead to novel approaches for facilitating healthy mitochondrial homoeostasis that may serve as a promising therapeutic strategy to counter ageing-associated pathologies and/or accelerated ageing.
