scholarly journals mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

2018 ◽  
Author(s):  
Hannah E. Walters ◽  
Lynne S. Cox
Keyword(s):  
Cardiovascular Disease ◽  
Broad Spectrum ◽  
Molecular Mechanisms ◽  
Mtor Inhibitors ◽  
Chronological Age ◽  
Older Individuals ◽  
Serine Threonine Kinase ◽  
Age Related ◽  
Life Threatening ◽  
Current Therapies

Chronological age represents the greatest risk factor for many life-threatening diseases including neurodegeneration, cancer and cardiovascular disease; ageing also increases susceptibility to infectious disease. Current therapies that effectively tackle individual diseases may have little impact on the overall healthspan of older individuals, who would still be vulnerable to other age-related pathologies. However, recent progress in ageing research has highlighted the accumulation of senescent cells with chronological age as a probable underlying cause of pathological ageing. Cellular senescence is an essentially irreversible proliferation arrest mechanism that has important roles in development, wound healing and preventing cancer, but it may limit tissue function and cause widespread inflammation with age. The serine/threonine kinase mTOR is a regulatory nexus heavily implicated in both ageing and senescence. Excitingly, a growing body of research has highlighted rapamycin and other mTOR inhibitors as promising treatments for a broad spectrum of age-related pathologies, including neurodegeneration, cancer, immunosenescence, osteoporosis, rheumatoid arthritis, age-related blindness, diabetic nephropathy, muscular dystrophy, and cardiovascular disease. In this review, we assess the use of mTOR inhibitors to treat age-related pathologies, discuss possible molecular mechanisms of action where evidence is available, and consider strategies to minimize undesirable side effects. We also emphasize the urgent need for reliable, non-invasive biomarkers of senescence and biological ageing to better monitor the efficacy of any healthy ageing therapy.

scholarly journals mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

2018 ◽  
Vol 19 (8) ◽  
pp. 2325 ◽  
Author(s):  
Hannah Walters ◽  
Lynne Cox
Keyword(s):  
Cardiovascular Disease ◽  
Broad Spectrum ◽  
Molecular Mechanisms ◽  
Mtor Inhibitors ◽  
Chronological Age ◽  
Older Individuals ◽  
Serine Threonine Kinase ◽  
Non Invasive ◽  
Age Related ◽  
Life Threatening

Chronological age represents the greatest risk factor for many life-threatening diseases, including neurodegeneration, cancer, and cardiovascular disease; ageing also increases susceptibility to infectious disease. Current efforts to tackle individual diseases may have little impact on the overall healthspan of older individuals, who would still be vulnerable to other age-related pathologies. However, recent progress in ageing research has highlighted the accumulation of senescent cells with chronological age as a probable underlying cause of pathological ageing. Cellular senescence is an essentially irreversible proliferation arrest mechanism that has important roles in development, wound healing, and preventing cancer, but it may limit tissue function and cause widespread inflammation with age. The serine/threonine kinase mTOR (mechanistic target of rapamycin) is a regulatory nexus that is heavily implicated in both ageing and senescence. Excitingly, a growing body of research has highlighted rapamycin and other mTOR inhibitors as promising treatments for a broad spectrum of age-related pathologies, including neurodegeneration, cancer, immunosenescence, osteoporosis, rheumatoid arthritis, age-related blindness, diabetic nephropathy, muscular dystrophy, and cardiovascular disease. In this review, we assess the use of mTOR inhibitors to treat age-related pathologies, discuss possible molecular mechanisms of action where evidence is available, and consider strategies to minimize undesirable side effects. We also emphasize the urgent need for reliable, non-invasive biomarkers of senescence and biological ageing to better monitor the efficacy of any healthy ageing therapy.

scholarly journals Exploring Epigenetic Age in Response to Intensive Relaxing Training: A Pilot Study to Slow Down Biological Age

2019 ◽  
Vol 16 (17) ◽  
pp. 3074 ◽  
Author(s):  
Pavanello ◽  
Campisi ◽  
Tona ◽  
Lin ◽  
Iliceto
Keyword(s):  
Myocardial Infarction ◽  
Age Estimation ◽  
Healthy Subjects ◽  
Molecular Mechanisms ◽  
Biological Age ◽  
Chronological Age ◽  
Biological Aging ◽  
Epigenetic Clock ◽  
Age Related ◽  
Epigenetic Age

DNA methylation (DNAm) is an emerging estimator of biological aging, i.e., the often-defined “epigenetic clock”, with a unique accuracy for chronological age estimation (DNAmAge). In this pilot longitudinal study, we examine the hypothesis that intensive relaxing training of 60 days in patients after myocardial infarction and in healthy subjects may influence leucocyte DNAmAge by turning back the epigenetic clock. Moreover, we compare DNAmAge with another mechanism of biological age, leucocyte telomere length (LTL) and telomerase. DNAmAge is reduced after training in healthy subjects (p = 0.053), but not in patients. LTL is preserved after intervention in healthy subjects, while it continues to decrease in patients (p = 0.051). The conventional negative correlation between LTL and chronological age becomes positive after training in both patients (p < 0.01) and healthy subjects (p < 0.05). In our subjects, DNAmAge is not associated with LTL. Our findings would suggest that intensive relaxing practices influence different aging molecular mechanisms, i.e., DNAmAge and LTL, with a rejuvenating effect. Our study reveals that DNAmAge may represent an accurate tool to measure the effectiveness of lifestyle-based interventions in the prevention of age-related diseases.

scholarly journals Multimorbidity patterns among COVID-19 deaths: proposal for the construction of etiological models

2020 ◽  
Vol 44 ◽  
pp. 1
Author(s):  
Julián A. Fernández-Niño ◽  
John A. Guerra-Gómez ◽  
Alvaro J. Idrovo
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Respiratory Disease ◽  
High Blood Pressure ◽  
Health Conditions ◽  
Older Individuals ◽  
Age Related ◽  
Probability Of Death ◽  
Polynomial Regressions

Objectives. To describe patterns of multimorbidity among fatal cases of COVID-19, and to propose a classification of patients based on age and multimorbidity patterns to begin the construction of etiological models. Methods. Data of Colombian confirmed deaths of COVID-19 until June 11, 2020, were included in this analysis (n=1488 deaths). Relationships between COVID-19, combinations of health conditions and age were explored using locally weighted polynomial regressions. Results. The most frequent health conditions were high blood pressure, respiratory disease, diabetes, cardiovascular disease, and kidney disease. Dyads more frequents were high blood pressure with diabetes, cardiovascular disease or respiratory disease. Some multimorbidity patterns increase probability of death among older individuals, whereas other patterns are not age-related, or decrease the probability of death among older people. Not all multimorbidity increases with age, as is commonly thought. Obesity, alone or with other diseases, was associated with a higher risk of severity among young people, while the risk of the high blood pressure/diabetes dyad tends to have an inverted U distribution in relation with age. Conclusions. Classification of individuals according to multimorbidity in the medical management of COVID-19 patients is important to determine the possible etiological models and to define patient triage for hospitalization. Moreover, identification of non-infected individuals with high-risk ages and multimorbidity patterns serves to define possible interventions of selective confinement or special management.

Frailty, sarcopenia, and falls in cardiovascular disease

ESC CardioMed ◽  
2018 ◽  
pp. 2950-2954
Author(s):  
Antonio Cherubini ◽  
Massimiliano Fedecostante
Keyword(s):  
Cardiovascular Disease ◽  
Older Adults ◽  
Clinical Manifestations ◽  
Drug Effects ◽  
Adverse Outcomes ◽  
Assessment Tools ◽  
Management Approach ◽  
Older Individuals ◽  
Related Factors ◽  
Age Related

Frailty reflects a state of high vulnerability to stressors, even at low intensity, putting frail older adults at high risk of adverse outcomes. Sarcopenia (i.e. skeletal muscle decline) explains many of the clinical manifestations of the frailty syndrome and is the key component of physical frailty. Many frailty assessment tools are built around the concept of sarcopenia. Frailty is not only a consequence of the ageing process, but cardiovascular disease can contribute to its genesis, also sharing common pathogenetic pathways. Falls are very common in older individuals and are the best example of the interplay between age-related conditions and diseases. Falls, as well as frailty and sarcopenia, are most often multifactorial in nature. Cardiovascular disorders are among the risk factors that have been identified to cause falls in older adults; in particular, unexplained and recurrent falls. Orthostatic hypotension, carotid sinus syndrome, and adverse drug effects are the most important cardiovascular disease-related factors that have been found to be associated with falls in older people. Implementing the comprehensive geriatric assessment, a multidomain and multidisciplinary evaluation and management approach, represents the best strategy to properly manage older patients with cardiovascular disease.

scholarly journals A nonlinear simulation framework supports adjusting for age when analyzing BrainAGE

2018 ◽  
Author(s):  
Trang T. Le ◽  
Rayus Kuplicki ◽  
Brett A. McKinney ◽  
Hung-wen Yeh ◽  
Wesley K. Thompson ◽  
...  
Keyword(s):  
Brain Aging ◽  
Diffusion Tensor ◽  
Machine Learning Algorithms ◽  
Chronological Age ◽  
General Strategy ◽  
Older Individuals ◽  
Regression To The Mean ◽  
Nonlinear Simulation ◽  
Age Related ◽  
The Relationship

AbstractSeveral imaging modalities, including T1-weighted structural imaging, diffusion tensor imaging, and functional MRI can show chronological age related changes. Employing machine learning algorithms, an individual’s imaging data can predict their age with reasonable accuracy. While details vary according to modality, the general strategy is to: 1) extract image-related features, 2) build a model on a training set that uses those features to predict an individual’s age, 3) validate the model on a test dataset, producing a predicted age for each individual, 4) define the “Brain Age Gap Estimate” (BrainAGE) as the difference between an individual’s predicted age and his/her chronological age, and 5) estimate the relationship between BrainAGE and other variables of interest, and 6) make inferences about those variables and accelerated or delayed brain aging. For example, a group of individuals with overall positive BrainAGE may show signs of accelerated aging in other variables as well. There is inevitably an overestimation of the age of younger individuals and an underestimation of the age of older individuals due to ‘regression to the mean’. The correlation between chronological age and BrainAGE may significantly impact the relationship between BrainAGE and other variables of interest when they are also related to age. In this study, we examine the detectability of variable effects under different assumptions. We use empirical results from two separate datasets [training=475 healthy volunteers, aged 18 – 60 years (259 female); testing=489 participants including people with mood/anxiety, substance use, eating disorders and healthy controls, aged 18 – 56 years (312 female)] to inform simulation parameter selection. Outcomes in simulated and empirical data strongly support the proposal that models incorporating BrainAGE should include chronological age as a covariate. We propose either including age as a covariate in step 5 of the above framework, or employing a multistep procedure where age is regressed on BrainAGE prior to step 5, producing BrainAGE Residualized (BrainAGER) scores.

scholarly journals The Cutting Edge: The Role of mTOR Signaling in Laminopathies

2019 ◽  
Vol 20 (4) ◽  
pp. 847 ◽  
Author(s):  
Francesca Chiarini ◽  
Camilla Evangelisti ◽  
Vittoria Cenni ◽  
Antonietta Fazio ◽  
Francesca Paganelli ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Mtor Inhibitors ◽  
Mtor Signaling ◽  
Serine Threonine Kinase ◽  
Partial Lipodystrophy ◽  
Systemic Involvement ◽  
Age Related ◽  
Numerous Cell ◽  
Familial Partial Lipodystrophy ◽  
Mandibuloacral Dysplasia

The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase that regulates anabolic and catabolic processes, in response to environmental inputs. The existence of mTOR in numerous cell compartments explains its specific ability to sense stress, execute growth signals, and regulate autophagy. mTOR signaling deregulation is closely related to aging and age-related disorders, among which progeroid laminopathies represent genetically characterized clinical entities with well-defined phenotypes. These diseases are caused by LMNA mutations and feature altered bone turnover, metabolic dysregulation, and mild to severe segmental progeria. Different LMNA mutations cause muscular, adipose tissue and nerve pathologies in the absence of major systemic involvement. This review explores recent advances on mTOR involvement in progeroid and tissue-specific laminopathies. Indeed, hyper-activation of protein kinase B (AKT)/mTOR signaling has been demonstrated in muscular laminopathies, and rescue of mTOR-regulated pathways increases lifespan in animal models of Emery-Dreifuss muscular dystrophy. Further, rapamycin, the best known mTOR inhibitor, has been used to elicit autophagy and degradation of mutated lamin A or progerin in progeroid cells. This review focuses on mTOR-dependent pathogenetic events identified in Emery-Dreifuss muscular dystrophy, LMNA-related cardiomyopathies, Hutchinson-Gilford Progeria, mandibuloacral dysplasia, and type 2 familial partial lipodystrophy. Pharmacological application of mTOR inhibitors in view of therapeutic strategies is also discussed.

scholarly journals RNA sequencing and bioinformatics analysis of human lens epithelial cells in age-related cataract

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zhongying Wang ◽  
Dongmei Su ◽  
Shanhe Liu ◽  
Guiqian Zheng ◽  
Gaobo Zhang ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Bioinformatics Analysis ◽  
Human Lens ◽  
Older Individuals ◽  
Disease Mechanism ◽  
Anterior Capsule ◽  
Bioinformatics Analyses ◽  
Age Related ◽  
Pathway Analyses

Abstract Background Age-related cataract (ARC) is the main cause of blindness in older individuals but its specific pathogenic mechanism is unclear. This study aimed to identify differentially expressed genes (DEGs) associated with ARC and to improve our understanding of the disease mechanism. Methods Anterior capsule samples of the human lens were collected from ARC patients and healthy controls and used for RNA sequencing to detect DEGs. Identified DEGs underwent bioinformatics analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Subsequently, reverse transcription quantitative RT-qPCR was used to validate the different expression levels of selected genes. Results A total of 698 up-regulated DEGs and 414 down-regulated DEGs were identified in ARC patients compared with controls by transcriptome analysis. Through GO and KEGG bioinformatics analysis, the functions of significantly DEGs and their possible molecular mechanisms were determined. Sequencing results were verified by RT-qPCR as being accurate and reliable. Conclusions This study identified several genes associated with ARC, which improves our knowledge of the disease mechanism.

scholarly journals Altered Glycosylation in the Aging Heart

2021 ◽  
Vol 8 ◽  
Author(s):  
Patricia Franzka ◽  
Lynn Krüger ◽  
Mona K. Schurig ◽  
Maja Olecka ◽  
Steve Hoffmann ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Molecular Mechanisms ◽  
Causes Of Death ◽  
Population Aging ◽  
Functional Decline ◽  
Developed Countries ◽  
Biological Properties ◽  
Quantitative Mass Spectrometry ◽  
Age Related ◽  
Old Mice

Cardiovascular disease is one of the leading causes of death in developed countries. Because the incidence increases exponentially in the aging population, aging is a major risk factor for cardiovascular disease. Cardiac hypertrophy, fibrosis and inflammation are typical hallmarks of the aged heart. The molecular mechanisms, however, are poorly understood. Because glycosylation is one of the most common post-translational protein modifications and can affect biological properties and functions of proteins, we here provide the first analysis of the cardiac glycoproteome of mice at different ages. Western blot as well as MALDI-TOF based glycome analysis suggest that high-mannose N-glycans increase with age. In agreement, we found an age-related regulation of GMPPB, the enzyme, which facilitates the supply of the sugar-donor GDP-mannose. Glycoprotein pull-downs from heart lysates of young, middle-aged and old mice in combination with quantitative mass spectrometry bolster widespread alterations of the cardiac glycoproteome. Major hits are glycoproteins related to the extracellular matrix and Ca2+-binding proteins of the endoplasmic reticulum. We propose that changes in the heart glycoproteome likely contribute to the age-related functional decline of the cardiovascular system.

Protective effects of soy-isoflavones in cardiovascular disease

2008 ◽  
Vol 28 (01/02) ◽  
pp. 85-88 ◽  
Author(s):  
D. Fuchs ◽  
H. Daniel ◽  
U. Wenzel
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Dietary Intervention ◽  
Mononuclear Cells ◽  
Oxidized Ldl ◽  
Proteome Analysis ◽  
Soy Isoflavones ◽  
Protective Effects ◽  
Estrogen Production

SummaryEpidemiological studies indicate that the consumption of soy-containing food may prevent or slow-down the development of cardiovascular disease. In endothelial cells application of a soy extract or a combination of the most abundant soy isoflavones genistein and daidzein both inhibited apoptosis, a driving force in atherosclerosis development, when applied in combination with oxidized LDL or homocysteine. Proteome analysis revealed that the stressorinduced alteration of protein expression profile was reversed by the soy extract or the genistein/daidzein mixture. Only few protein entities that could be functionally linked to mitochondrial dysfunction were regulated in common by both application forms of isoflavones. A dietary intervention with isoflavone-enriched soy extract in postmenopausal women, who generally show strongly increased cardiovascular risk due to diminished estrogen production, led to significant alterations in the steady state levels of proteins from mononuclear blood cells. The proteins identified by proteome analysis revealed that soy isoflavones may increase the anti-inflammatory response in blood mononuclear cells thereby contributing to the atherosclerosispreventive activities of a soy-rich diet. Conclusion: By proteome analysis protein targets were identified in vitro in endothelial cells that respond to soy isoflavones and that may decipher molecular mechanisms through which soy products exert their protective effects in the vasculature.

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