scholarly journals Genome and Epigenome Editing in Mechanistic Studies of Human Aging and Aging-Related Disease

Gerontology ◽  
2016 ◽  
Vol 63 (2) ◽  
pp. 103-117 ◽  
Author(s):  
Cia-Hin Lau ◽  
Yousin Suh
Keyword(s):  
Animal Models ◽  
Genetic Manipulation ◽  
Logic Gate ◽  
Therapeutic Interventions ◽  
Human Aging ◽  
Aging Research ◽  
Epigenome Editing ◽  
Related Disease ◽  
Age Related

The recent advent of genome and epigenome editing technologies has provided a new paradigm in which the landscape of the human genome and epigenome can be precisely manipulated in their native context. Genome and epigenome editing technologies can be applied to many aspects of aging research and offer the potential to develop novel therapeutics against age-related diseases. Here, we discuss the latest technological advances in the CRISPR-based genome and epigenome editing toolbox, and provide insight into how these synthetic biology tools could facilitate aging research by establishing in vitro cell and in vivo animal models to dissect genetic and epigenetic mechanisms underlying aging and age-related diseases. We discuss recent developments in the field with the aims to precisely modulate gene expression and dynamic epigenetic landscapes in a spatial and temporal manner in cellular and animal models, by complementing the CRISPR-based editing capability with conditional genetic manipulation tools including chemically inducible expression systems, optogenetics, logic gate genetic circuits, tissue-specific promoters, and the serotype-specific adeno-associated virus. We also discuss how the combined use of genome and epigenome editing tools permits investigators to uncover novel molecular pathways involved in the pathophysiology and etiology conferred by risk variants associated with aging and aging-related disease. A better understanding of the genetic and epigenetic regulatory mechanisms underlying human aging and age-related disease will significantly contribute to the developments of new therapeutic interventions for extending health span and life span, ultimately improving the quality of life in the elderly populations.

Animal Models of Aging Research: Implications for Human Aging and Age-Related Diseases

2015 ◽  
Vol 3 (1) ◽  
pp. 283-303 ◽  
Author(s):  
Sarah J. Mitchell ◽  
Morten Scheibye-Knudsen ◽  
Dan L. Longo ◽  
Rafael de Cabo
Keyword(s):  
Animal Models ◽  
Human Aging ◽  
Aging Research ◽  
Age Related

scholarly journals Senescence and aging: Causes, consequences, and therapeutic avenues

2017 ◽  
Vol 217 (1) ◽  
pp. 65-77 ◽  
Author(s):  
Domhnall McHugh ◽  
Jesús Gil
Keyword(s):  
Neurodegenerative Disorders ◽  
Cellular Response ◽  
Aging Process ◽  
Normal Development ◽  
Growth Arrest ◽  
The Novel ◽  
Aging Research ◽  
Related Disease ◽  
Age Related ◽  
Stable Growth

Aging is the major risk factor for cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. Although we are far from understanding the biological basis of aging, research suggests that targeting the aging process itself could ameliorate many age-related pathologies. Senescence is a cellular response characterized by a stable growth arrest and other phenotypic alterations that include a proinflammatory secretome. Senescence plays roles in normal development, maintains tissue homeostasis, and limits tumor progression. However, senescence has also been implicated as a major cause of age-related disease. In this regard, recent experimental evidence has shown that the genetic or pharmacological ablation of senescent cells extends life span and improves health span. Here, we review the cellular and molecular links between cellular senescence and aging and discuss the novel therapeutic avenues that this connection opens.

scholarly journals OMICS IN AGING RESEARCH: FROM BIOMARKERS TO SYSTEMS BIOLOGY

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S234-S234
Author(s):  
Daniel Promislow
Keyword(s):  
Natural Variation ◽  
Natural Populations ◽  
Network Models ◽  
Explanatory Gap ◽  
Aging Research ◽  
Evolutionary Forces ◽  
Related Disease ◽  
Diverse Species ◽  
Age Related ◽  
Complex Human Traits

Abstract Advances in whole genome sequencing have dramatically increased our potential to understand what shapes variation in rates of aging and age-related disease in natural populations, but we are still far from realizing this potential. Researchers have identified thousands of genetic markers associated with complex human traits. However, these markers typically explain a very small fraction of the observed variance, leaving an enormous explanatory gap between genotype and phenotype. I will present data from diverse species to illustrate the power of so-called endophenotypes—the epigenome, transcriptome, proteome, and metabolome—to bridge the genotype-phenotype gap. Using multivariate and network models that integrate genetic information with other endophenotype variation, we are closer than ever to understanding the mechanisms that account for natural variation in aging and age-related disease, and the evolutionary forces that have shaped that variation.

scholarly journals Geroprotectors.org: a new, structured and curated database of current therapeutic interventions in aging and age-related disease

Aging ◽  
2015 ◽  
Vol 7 (9) ◽  
pp. 616-628 ◽  
Author(s):  
Alexey Moskalev ◽  
Elizaveta Chernyagina ◽  
João Pedro de Magalhães ◽  
Diogo Barardo ◽  
Harikrishnan Thoppil ◽  
...  
Keyword(s):  
Therapeutic Interventions ◽  
Related Disease ◽  
Age Related

scholarly journals Towards an In Vitro Retinal Model to Study and Develop New Therapies for Age-Related Macular Degeneration

2021 ◽  
Vol 8 (2) ◽  
pp. 18
Author(s):  
Beatrice Belgio ◽  
Federica Boschetti ◽  
Sara Mantero
Keyword(s):  
Animal Models ◽  
Macular Degeneration ◽  
Tensile Testing ◽  
In Vitro Model ◽  
Age Related Macular Degeneration ◽  
Bruch's Membrane ◽  
Bruch’S Membrane ◽  
Age Related ◽  
Vitro Model

Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly worldwide. So far, the etiology and the progression of AMD are not well known. Animal models have been developed to study the mechanisms involved in AMD; however, according to the “Three Rs” principle, alternative methods have been investigated. Here we present a strategy to develop a “Three Rs” compliant retinal three-dimensional (3D) in vitro model, including a Bruch’s membrane model and retina pigment epithelium (RPE) layer. First, tensile testing was performed on porcine retina to set a reference for the in vitro model. The results of tensile testing showed a short linear region followed by a plastic region with peaks. Then, Bruch’s membrane (BrM) was fabricated via electrospinning by using Bombyx mori silk fibroin (BMSF) and polycaprolactone (PCL). The BrM properties and ARPE-19 cell responses to BrM substrates were investigated. The BrM model displayed a thickness of 44 µm, with a high porosity and an average fiber diameter of 1217 ± 101 nm. ARPE-19 cells adhered and spread on the BMSF/PCL electrospun membranes. In conclusion, we are developing a novel 3D in vitro retinal model towards the replacement of animal models in AMD studies.

scholarly journals Constructing the angiome: a global angiogenesis protein interaction network

2012 ◽  
Vol 44 (19) ◽  
pp. 915-924 ◽  
Author(s):  
Liang-Hui Chu ◽  
Corban G. Rivera ◽  
Aleksander S. Popel ◽  
Joel S. Bader
Keyword(s):  
Protein Interaction ◽  
Protein Interaction Network ◽  
Interaction Network ◽  
Age Related Macular Degeneration ◽  
Functional Enrichment ◽  
Therapeutic Interventions ◽  
Signaling Networks ◽  
Growth Factor Signaling ◽  
Age Related

Angiogenesis is the formation of new blood vessels from pre-existing microvessels. Excessive and insufficient angiogenesis have been associated with many diseases including cancer, age-related macular degeneration, ischemic heart, brain, and skeletal muscle diseases. A comprehensive understanding of angiogenesis regulatory processes is needed to improve treatment of these diseases. To identify proteins related to angiogenesis, we developed a novel integrative framework for diverse sources of high-throughput data. The system, called GeneHits, was used to expand on known angiogenesis pathways to construct the angiome, a protein-protein interaction network for angiogenesis. The network consists of 478 proteins and 1,488 interactions. The network was validated through cross validation and analysis of five gene expression datasets from in vitro angiogenesis assays. We calculated the topological properties of the angiome. We analyzed the functional enrichment of angiogenesis-annotated and associated proteins. We also constructed an extended angiome with 1,233 proteins and 5,726 interactions to derive a more complete map of protein-protein interactions in angiogenesis. Finally, the extended angiome was used to identify growth factor signaling networks that drive angiogenesis and antiangiogenic signaling networks. The results of this analysis can be used to identify genes and proteins in different disease conditions and putative targets for therapeutic interventions as high-ranked candidates for experimental validation.

scholarly journals Hormetic Modulation of Aging and Longevity by Mild Heat Stress

Dose-Response ◽  
2005 ◽  
Vol 3 (4) ◽  
pp. dose-response.0 ◽  
Author(s):  
Suresh I. S. Rattan
Keyword(s):  
Heat Stress ◽  
Experimental Studies ◽  
Ultraviolet B ◽  
Mild Stress ◽  
Aging Research ◽  
Maintenance And Repair ◽  
Mild Heat ◽  
Age Related ◽  
Stimulation Of

Aging is characterized by a stochastic accumulation of molecular damage, progressive failure of maintenance and repair, and consequent onset of age-related diseases. Applying hormesis in aging research and therapy is based on the principle of stimulation of maintenance and repair pathways by repeated exposure to mild stress. In a series of experimental studies we have shown that repetitive mild heat stress has anti-aging hormetic effects on growth and various other cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. These effects include the maintenance of stress protein profiles, reduction in the accumulation of oxidatively and glycoxidatively damaged proteins, stimulation of the proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to ethanol, hydrogenperoxide and ultraviolet-B rays, and enhanced levels of various antioxidant enzymes. Anti-aging hormetic effects of mild heat shock appear to be facilitated by reducing protein damage and protein aggregation by activating internal antioxidant, repair and degradation processes.

scholarly journals Interaction of Neuromelanin with Xenobiotics and Consequences for Neurodegeneration; Promising Experimental Models

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 824
Author(s):  
Andrea Capucciati ◽  
Fabio A. Zucca ◽  
Enrico Monzani ◽  
Luigi Zecca ◽  
Luigi Casella ◽  
...  
Keyword(s):  
Animal Models ◽  
Neurodegenerative Diseases ◽  
Brain Aging ◽  
Experimental Models ◽  
Test Tube ◽  
Age Related ◽  
And Function ◽  
Endogenous Metabolites ◽  
High Degree

Neuromelanin (NM) accumulates in catecholamine long-lived brain neurons that are lost in neurodegenerative diseases. NM is a complex substance made of melanic, peptide and lipid components. NM formation is a natural protective process since toxic endogenous metabolites are removed during its formation and as it binds excess metals and xenobiotics. However, disturbances of NM synthesis and function could be toxic. Here, we review recent knowledge on NM formation, toxic mechanisms involving NM, go over NM binding substances and suggest experimental models that can help identifying xenobiotic modulators of NM formation or function. Given the high likelihood of a central NM role in age-related human neurodegenerative diseases such as Parkinson’s and Alzheimer’s, resembling such diseases using animal models that do not form NM to a high degree, e.g., mice or rats, may not be optimal. Rather, use of animal models (i.e., sheep and goats) that better resemble human brain aging in terms of NM formation, as well as using human NM forming stem cellbased in vitro (e.g., mid-brain organoids) models can be more suitable. Toxicants could also be identified during chemical synthesis of NM in the test tube.

scholarly journals Control of Cardiac Function in vivo with a Light-Regulated Drug

2018 ◽  
Author(s):  
Fabio Riefolo ◽  
Carlo Matera ◽  
Aida Garrido-Charles ◽  
Alexandre M. J. Gomila ◽  
Luca Agnetta ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Mammalian Cells ◽  
Acetylcholine Receptors ◽  
Genetic Manipulation ◽  
Muscarinic Acetylcholine Receptors ◽  
Therapeutic Interventions ◽  
Muscarinic Acetylcholine ◽  
First Time

<p>Remote control of physiological functions with light offers the promise of unveiling their complex spatiotemporal dynamics in vivo, and enabling highly focalized therapeutic interventions with reduced systemic toxicity. Optogenetic methods have been implemented in the heart, but the need of genetic manipulation jeopardizes clinical applicability. This study aims at developing, testing and validating the first light-regulated drug with cardiac effects, in order to avoid the requirement of genetic manipulation offered by optogenetic methods. A M2 muscarinic acetylcholine receptors (mAChRs) light-regulated drug (PAI) was designed, synthesized and pharmacologically characterized. The design was based on the orthosteric mAChRs agonist Iperoxo, an allosteric M2 ligand, and a photoswitchable azobenzene linker. PAI can be reversibly photoisomerized between <i>cis</i> and <i>trans</i> configurations under ultraviolet (UV) and visible light, respectively, and it reversibly photoswitches the activity of M2 muscarinic acetylcholine receptors. We have evaluated <i>in vitro</i> photoresponses using a calcium imaging assay in genetically unmodified receptors overexpressed in mammalian cells. Furthermore, using this new chemical tool, we demonstrate for the first time photoregulation of cardiac function <i>in vivo</i> in wildtype frog tadpoles and in rats with a method that does not require genetic manipulation. Such a new approach may enable enhanced spatial and temporal selectivity for cardiovascular drugs.</p>

scholarly journals Quantification of biological aging in young adults

2015 ◽  
Vol 112 (30) ◽  
pp. E4104-E4110 ◽  
Author(s):  
Daniel W. Belsky ◽  
Avshalom Caspi ◽  
Renate Houts ◽  
Harvey J. Cohen ◽  
David L. Corcoran ◽  
...  
Keyword(s):  
Young Adults ◽  
Brain Aging ◽  
Multiple Organ ◽  
Biological Aging ◽  
Research Translation ◽  
Human Aging ◽  
Aging Research ◽  
Cross Sectional ◽  
Age Related ◽  
Organ Systems

Antiaging therapies show promise in model organism research. Translation to humans is needed to address the challenges of an aging global population. Interventions to slow human aging will need to be applied to still-young individuals. However, most human aging research examines older adults, many with chronic disease. As a result, little is known about aging in young humans. We studied aging in 954 young humans, the Dunedin Study birth cohort, tracking multiple biomarkers across three time points spanning their third and fourth decades of life. We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their “biological aging” (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.

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