scholarly journals Using the drug-protein interactome to identify anti-ageing compounds for humans

2018 ◽  
Author(s):  
Matías Fuentealba Valenzuela ◽  
Handan Melike Dönertaş ◽  
Rhianna Williams ◽  
Johnathan Labbadia ◽  
Janet Thornton ◽  
...  
Keyword(s):  
Risk Factor ◽  
Animal Models ◽  
Protein Interactions ◽  
Human Life ◽  
Drug Repurposing ◽  
Developed Countries ◽  
Animal Testing ◽  
Age Related ◽  
Human Ageing ◽  
Hsp 90

AbstractAdvancing age is the dominant risk factor for most of the major killer diseases in developed countries. Hence, ameliorating the effects of ageing may prevent multiple diseases simultaneously. Drugs licensed for human use against specific diseases have proved to be effective in extending lifespan and healthspan in animal models, suggesting that there is scope for drug repurposing in humans. New bioinformatic methods to identify and prioritise potential anti-ageing compounds for humans are therefore of interest. In this study, we first used drug-protein interaction information, to rank 1,147 drugs by their likelihood of targeting ageing-related gene products in humans. Among 19 statistically significant drugs, 6 have already been shown to have pro-longevity properties in animal models (p < 0.001). Using the targets of each drug, we established its association with ageing at multiple levels of biological actions including pathways, functions and protein interactions. Finally, combining all the data, we calculated a comprehensive ranked list of drugs that predicted tanespimycin, an inhibitor of HSP-90, as the top-ranked novel anti-ageing candidate. We experimentally validated the pro-longevity effect of tanespimycin through its HSP-90 target in Caenorhabditis elegans.Author SummaryHuman life expectancy is continuing to increase worldwide, as a result of successive improvements in living conditions and medical care. Although this trend is to be celebrated, advancing age is the major risk factor for multiple impairments and chronic diseases. As a result, the later years of life are often spent in poor health and lowered quality of life. However, these effects of ageing are not inevitable, because very long-lived people often suffer rather little ill-health at the end of their lives. Furthermore, laboratory experiments have shown that animals fed with specific drugs can live longer and with fewer age-related diseases than their untreated companions. We therefore need to identify drugs with anti-ageing properties for humans. We have therefore used computers to search for drugs that affect components and processes known to be important in human ageing. This approach worked, because it was able to re-discover several drugs known to increase lifespan in animal models, plus some new ones, including one that we tested experimentally and validated in this study. These drugs are now a high priority for animal testing and for exploring effects on human ageing.

scholarly journals The AgeGuess database, an open online resource on chronological and perceived ages of people aged 5–100

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Julia A. Barthold Jones ◽  
Ulrik W. Nash ◽  
Julien Vieillefont ◽  
Kaare Christensen ◽  
Dusan Misevic ◽  
...  
Keyword(s):  
Life Expectancy ◽  
Human Life ◽  
Developed Countries ◽  
Biological Age ◽  
Ageing Process ◽  
Birth Cohorts ◽  
Online Resource ◽  
Human Ageing ◽  
Perceived Age ◽  
Citizen Science Project

Abstract In many developed countries, human life expectancy has doubled over the last 180 years. Underlying this higher life expectancy is a change in how we age. Biomarkers of ageing are used to quantify changes in the aging process and to determine biological age. Perceived age is such a biomarker that correlates with biological age. Here we present a unique database rich with possibilities to study the human ageing process. Using perceived age enables us to collect large amounts of data on biological age through a citizen science project, where people upload facial pictures and guess the ages of other people at www.ageguess.org. The data on perceived age we present here span birth cohorts from the years 1877 to 2012. The database currently contains around 220,000 perceived age guesses. Almost 4500 citizen scientists from over 120 countries of origin have uploaded ~4700 facial photographs. Beyond studying the ageing process, the data present a wealth of possibilities to study how humans guess ages and who is better at guessing ages.

scholarly journals Retinoid analogs and polyphenols as potential therapeutics for age-related macular degeneration

2020 ◽  
Vol 245 (17) ◽  
pp. 1615-1625 ◽  
Author(s):  
Tanu Parmar ◽  
Joseph T Ortega ◽  
Beata Jastrzebska
Keyword(s):  
Animal Models ◽  
Macular Degeneration ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Developed Countries ◽  
Natural Compounds ◽  
Scientific Data ◽  
Age Related Macular Degeneration ◽  
Positive Effects ◽  
Age Related

Progressive retinal degeneration manifesting as age-related macular degeneration (AMD) in the elderly affects millions of individuals worldwide. Among various blinding diseases, AMD is the leading cause of central vision impairment in developed countries. Poor understanding of AMD etiology hampers the development of therapeutics against this devastating ocular disease. Currently, daily intravitreal injections of anti-angiogenic drugs, preventing abnormal vessel growth are the only treatment option for wet AMD. However, for dry AMD associated with retinal atrophy, at present there is no cure available. Recent clinical research has demonstrated beneficial effects of plant-derived compounds for various eye disorders. Thus, the ongoing efforts toward discovering efficient treatments preventing or delaying AMD progression focus on implementing a healthy diet rich in vitamins, including vitamin A, E, and C, minerals and carotenoids, in particular lutein and zeaxanthin, to reduce the disease burden. In addition, studies in cell culture and animal models indicated therapeutic potential of dietary polyphenolic compounds present in fruits and vegetables. These natural compounds protect visual function and retinal morphology likely due to their anti-oxidant and anti-inflammatory properties. Although understanding of the exact mechanism of these compounds’ positive effects requires further investigation, they provide non-invasive alternative to battle AMD-like condition. Additionally, studies carried in animal models mimicking AMD-like pathology, examining the pharmacological potential of particular retinoid analogs, demonstrated promising results for their use, and thus they should be considered as an option in developing therapies for AMD. In here, we summarize the most current knowledge regarding developments of therapeutic options to maintain ocular health and prevent vision loss associated with aging. Impact statement Age-related macular degeneration (AMD) is a devastating retinal degenerative disease. Epidemiological reports showed an expected increasing prevalence of AMD in the near future. The only one existing FDA-approved pharmacological treatment involves an anti-vascular endothelial growth factor (VEGF) therapy with serious disadvantages. This limitation emphasizes an alarming need to develop new therapeutic approaches to prevent and treat AMD. In this review, we summarize scientific data unraveling the therapeutic potential of the specific retinoid and natural compounds. The experimental results reported by us and other research groups demonstrated that retinoid analogs and compounds with natural product scaffolds could serve as lead compounds for the development of new therapeutic agents with potential to prevent or slow down the pathogenesis of AMD.

scholarly journals Advances and challenges in geroscience research: An update

2018 ◽  
Vol 105 (4) ◽  
pp. 298-308 ◽  
Author(s):  
A Yabluchanskiy ◽  
Z Ungvari ◽  
A Csiszar ◽  
S Tarantini
Keyword(s):  
Risk Factor ◽  
Chronic Diseases ◽  
Interdisciplinary Approach ◽  
The Elderly ◽  
Vascular Cognitive Impairment ◽  
Developed Countries ◽  
The United States ◽  
Chronic Obstructive ◽  
Age Related ◽  
Wide Range

Aging remains the most pervasive risk factor for a wide range of chronic diseases that afflict modern societies. In the United States alone, incidence of age-related diseases (e.g., cardiovascular disease, stroke, Alzheimer’s disease, vascular cognitive impairment and dementia, cancer, hypertension, type-2 diabetes, chronic obstructive pulmonary disease, and osteoarthritis) is on the rise, posing an unsustainable socioeconomic burden even for the most developed countries. Tackling each and every age-related disease alone is proving to be costly and ineffective. The emerging field of geroscience has posed itself as an interdisciplinary approach that aims to understand the relationship between the biology of aging and the pathophysiology of chronic age-related diseases. According to the geroscience concept, aging is the single major risk factor that underlies several age-related chronic diseases, and manipulation of cellular and systemic aging processes can delay the manifestation and/or severity of these age-related chronic pathologies. The goal of this endeavor is to achieve health improvements by preventing/delaying the pathogenesis of several age-related diseases simultaneously in the elderly population by targeting key cellular and molecular processes of aging instead of managing diseases of aging as they arise individually. In this review, we discuss recent advances in the field of geroscience, highlighting their implications for potential future therapeutic targets and the associated scientific challenges and opportunities that lay ahead.

scholarly journals The Effects of SIRT1 on Alzheimer's Disease Models

2012 ◽  
Vol 2012 ◽  
pp. 1-3 ◽  
Author(s):  
Gizem Donmez
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Animal Models ◽  
Mouse Models ◽  
Neurodegenerative Disorders ◽  
Disease Models ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Age Related

Sirtuins are highly conserved NAD+-dependent enzymes that were shown to have beneficial effects against age-related diseases. Aging is the major risk factor for all neurodegenerative disorders including Alzheimer’s Disease (AD). Sirtuins have been widely studied in the context of AD using different mouse models. In most of these studies, overexpression of SIRT1 has been shown to have protective effects against AD. Therefore, designing therapeutics based on increasing SIRT1 activity might be important for investigating the ways of treatment for this disease. This paper summarizes the recent research on the effect of SIRT1 in AD animal models and also the potential of SIRT1 being a therapeutical target for AD.

scholarly journals The new biology of ageing

2010 ◽  
Vol 365 (1537) ◽  
pp. 147-154 ◽  
Author(s):  
Linda Partridge
Keyword(s):  
Human Life ◽  
Developed Countries ◽  
Model Organisms ◽  
Laboratory Model ◽  
Loss Of Function ◽  
Medical Treatments ◽  
Age Related ◽  
Complex Process ◽  
New Findings ◽  
Clinical Thinking

Human life expectancy in developed countries has increased steadily for over 150 years, through improvements in public health and lifestyle. More people are hence living long enough to suffer age-related loss of function and disease, and there is a need to improve the health of older people. Ageing is a complex process of damage accumulation, and has been viewed as experimentally and medically intractable. This view has been reinforced by the realization that ageing is a disadvantageous trait that evolves as a side effect of mutation accumulation or a benefit to the young, because of the decline in the force of natural selection at later ages. However, important recent discoveries are that mutations in single genes can extend lifespan of laboratory model organisms and that the mechanisms involved are conserved across large evolutionary distances, including to mammals. These mutations keep the animals functional and pathology-free to later ages, and they can protect against specific ageing-related diseases, including neurodegenerative disease and cancer. Preliminary indications suggest that these new findings from the laboratory may well also apply to humans. Translating these discoveries into medical treatments poses new challenges, including changing clinical thinking towards broad-spectrum, preventative medicine and finding novel routes to drug development.

Decoding Protein-protein Interactions: An Overview

2020 ◽  
Vol 20 (10) ◽  
pp. 855-882
Author(s):  
Olivia Slater ◽  
Bethany Miller ◽  
Maria Kontoyianni
Keyword(s):  
Drug Discovery ◽  
Protein Interactions ◽  
Drug Repurposing ◽  
Protein Docking ◽  
Target Space ◽  
Protein Protein Interactions ◽  
X Ray Crystallography ◽  
Protein Protein Interaction ◽  
Interaction Sites ◽  
Long Time

Drug discovery has focused on the paradigm “one drug, one target” for a long time. However, small molecules can act at multiple macromolecular targets, which serves as the basis for drug repurposing. In an effort to expand the target space, and given advances in X-ray crystallography, protein-protein interactions have become an emerging focus area of drug discovery enterprises. Proteins interact with other biomolecules and it is this intricate network of interactions that determines the behavior of the system and its biological processes. In this review, we briefly discuss networks in disease, followed by computational methods for protein-protein complex prediction. Computational methodologies and techniques employed towards objectives such as protein-protein docking, protein-protein interactions, and interface predictions are described extensively. Docking aims at producing a complex between proteins, while interface predictions identify a subset of residues on one protein that could interact with a partner, and protein-protein interaction sites address whether two proteins interact. In addition, approaches to predict hot spots and binding sites are presented along with a representative example of our internal project on the chemokine CXC receptor 3 B-isoform and predictive modeling with IP10 and PF4.

scholarly journals MNBDR: A Module Network Based Method for Drug Repositioning

Genes ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 25
Author(s):  
He-Gang Chen ◽  
Xiong-Hui Zhou
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Drug Response ◽  
Drug Repositioning ◽  
Expression Profiles ◽  
Drug Repurposing ◽  
Recent Decade ◽  
Data Set ◽  
Module Network ◽  
The Cross

Drug repurposing/repositioning, which aims to find novel indications for existing drugs, contributes to reducing the time and cost for drug development. For the recent decade, gene expression profiles of drug stimulating samples have been successfully used in drug repurposing. However, most of the existing methods neglect the gene modules and the interactions among the modules, although the cross-talks among pathways are common in drug response. It is essential to develop a method that utilizes the cross-talks information to predict the reliable candidate associations. In this study, we developed MNBDR (Module Network Based Drug Repositioning), a novel method that based on module network to screen drugs. It integrated protein–protein interactions and gene expression profile of human, to predict drug candidates for diseases. Specifically, the MNBDR mined dense modules through protein–protein interaction (PPI) network and constructed a module network to reveal cross-talks among modules. Then, together with the module network, based on existing gene expression data set of drug stimulation samples and disease samples, we used random walk algorithms to capture essential modules in disease development and proposed a new indicator to screen potential drugs for a given disease. Results showed MNBDR could provide better performance than popular methods. Moreover, functional analysis of the essential modules in the network indicated our method could reveal biological mechanism in drug response.

scholarly journals Impact of neovascular age-related macular degeneration: burden of patients receiving therapies in Japan

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shigeru Honda ◽  
Yasuo Yanagi ◽  
Hideki Koizumi ◽  
Yirong Chen ◽  
Satoru Tanaka ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Productivity Loss ◽  
Work Productivity ◽  
The Elderly ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
Resource Utilisation ◽  
Total Work ◽  
Healthcare Resource Utilisation ◽  
Age Related

AbstractThe chronic eye disorder, neovascular age-related macular degeneration (nAMD), is a common cause of permanent vision impairment and blindness among the elderly in developed countries, including Japan. This study aimed to investigate the disease burden of nAMD patients under treatment, using data from the Japan National Health and Wellness surveys 2009–2014. Out of 147,272 respondents, 100 nAMD patients reported currently receiving treatment. Controls without nAMD were selected by 1:4 propensity score matching. Healthcare Resource Utilisation (HRU), Health-Related Quality of Life (HRQoL), and work productivity loss were compared between the groups. Regarding HRU, nAMD patients had significantly increased number of visits to any healthcare provider (HCP) (13.8 vs. 8.2), ophthalmologist (5.6 vs. 0.8), and other HCP (9.5 vs. 7.1) compared to controls after adjusting for confounding factors. Additionally, nAMD patients had reduced HRQoL and work productivity, i.e., reduced physical component summary (PCS) score (46.3 vs. 47.9), increased absenteeism (18.14% vs. 0.24%), presenteeism (23.89% vs. 12.44%), and total work productivity impairment (33.57% vs. 16.24%). The increased number of ophthalmologist visits were associated with decreased PCS score, increased presenteeism and total work productivity impairment. The current study highlighted substantial burden for nAMD patients, requiring further attention for future healthcare planning and treatment development.

scholarly journals Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases

2021 ◽  
pp. 101414
Author(s):  
Doortje W. Dekens ◽  
Ulrich L.M. Eisel ◽  
Leonie Gouweleeuw ◽  
Regien G. Schoemaker ◽  
Peter P. De Deyn ◽  
...  
Keyword(s):  
Risk Factor ◽  
Brain Diseases ◽  
Lipocalin 2 ◽  
Age Related

scholarly journals Interactions between Apolipoprotein E Metabolism and Retinal Inflammation in Age-Related Macular Degeneration

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 635
Author(s):  
Monica L. Hu ◽  
Joel Quinn ◽  
Kanmin Xue
Keyword(s):  
Risk Factor ◽  
Apolipoprotein E ◽  
Macular Degeneration ◽  
Amyloid Beta ◽  
Complement System ◽  
Genetic Risk ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Retinal Inflammation ◽  
The Complement System

Age-related macular degeneration (AMD) is a multifactorial retinal disorder that is a major global cause of severe visual impairment. The development of an effective therapy to treat geographic atrophy, the predominant form of AMD, remains elusive due to the incomplete understanding of its pathogenesis. Central to AMD diagnosis and pathology are the hallmark lipid and proteinaceous deposits, drusen and reticular pseudodrusen, that accumulate in the subretinal pigment epithelium and subretinal spaces, respectively. Age-related changes and environmental stressors, such as smoking and a high-fat diet, are believed to interact with the many genetic risk variants that have been identified in several major biochemical pathways, including lipoprotein metabolism and the complement system. The APOE gene, encoding apolipoprotein E (APOE), is a major genetic risk factor for AMD, with the APOE2 allele conferring increased risk and APOE4 conferring reduced risk, in comparison to the wildtype APOE3. Paradoxically, APOE4 is the main genetic risk factor in Alzheimer's disease, a disease with features of neuroinflammation and amyloid-beta deposition in common with AMD. The potential interactions of APOE with the complement system and amyloid-beta are discussed here to shed light on their roles in AMD pathogenesis, including in drusen biogenesis, immune cell activation and recruitment, and retinal inflammation.

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