scholarly journals In vivo Pooled Screening: A Scalable Tool to Study the Complexity of Aging and Age-Related Disease

2021 ◽  
Vol 2 ◽  
Author(s):  
Martin Borch Jensen ◽  
Adam Marblestone
Keyword(s):  
Biological Aging ◽  
Living Animal ◽  
Related Disease ◽  
Open Questions ◽  
Age Related ◽  
Cellular Mediators ◽  
Direct Administration ◽  
Shed Light ◽  
Systemic Signals

Biological aging, and the diseases of aging, occur in a complex in vivo environment, driven by multiple interacting processes. A convergence of recently developed technologies has enabled in vivo pooled screening: direct administration of a library of different perturbations to a living animal, with a subsequent readout that distinguishes the identity of each perturbation and its effect on individual cells within the animal. Such screens hold promise for efficiently applying functional genomics to aging processes in the full richness of the in vivo setting. In this review, we describe the technologies behind in vivo pooled screening, including a range of options for delivery, perturbation and readout methods, and outline their potential application to aging and age-related disease. We then suggest how in vivo pooled screening, together with emerging innovations in each of its technological underpinnings, could be extended to shed light on key open questions in aging biology, including the mechanisms and limits of epigenetic reprogramming and identifying cellular mediators of systemic signals in aging.

scholarly journals IN VIVO ANALYSIS OF REPORTER ALLELES REVEALS INCREASED VARIABILITY OF GENE EXPRESSION IN CELLS AND ANIMALS WITH AGE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S101-S101
Author(s):  
Nikolay Burnaevskiy ◽  
Bryan Sands ◽  
Soo Yun ◽  
Alexander Mendenhall
Keyword(s):  
Gene Expression ◽  
Analytical Framework ◽  
Biological Aging ◽  
Early Event ◽  
Quantitative Microscopy ◽  
C Elegans ◽  
Age Related ◽  
Stochastic Events ◽  
Noise In Gene Expression

Abstract As a major risk factor for a multitude of chronic diseases aging is being increasingly recognized as a necessary therapeutic target for preventive medicine. Yet, despite tremendous progress in our understanding of the genetic determinants of longevity, proximal causes of aging remain incompletely understood. In part, this may be due to a plethora of factors, such as various types of stochastic macromolecular damage that affect individual cells and individual animals. Indeed, recent studies point to an increase of cell-to-cell variability in gene expression within old tissues, supporting the idea that stochastic events contribute to the aging process. Therefore, more single-cell focused studies are needed for a complete understanding of biological aging. Here, we utilized quantitative microscopy for analysis of gene expression in individual aging cells, in vivo in C. elegans. Using transcriptional reporters, fluorescently tagged proteins and a quantitative analytical framework adapted from yeast, we have found that young C. elegans exhibit very little stochastic or signaling noise in gene expression. However, using quantitative microscopy, we directly observed dysregulation of gene expression with age in vivo. Specifically, the stoichiometric ratios of proteins that are tightly regulated among the youthful populace start deviating in a cell autonomous fashion. Importantly, we find that an increase of gene expression variation is a relatively early event in the aging of C. elegans, readily observed before median lifespan. Hence, we suggest that incoherent cell-to-cell variation in gene expression arising with age can be an immediate causal factor for age-related loss of robust tissue function.

scholarly journals Key Signaling Pathways in Aging and Potential Interventions for Healthy Aging

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 660
Author(s):  
Mengdi Yu ◽  
Hongxia Zhang ◽  
Brian Wang ◽  
Yinuo Zhang ◽  
Xiaoying Zheng ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Adenosine Monophosphate ◽  
Sirtuin 1 ◽  
Public Health Issue ◽  
Biological Aging ◽  
Related Disease ◽  
Age Related ◽  
General Decline

Aging is a fundamental biological process accompanied by a general decline in tissue function. Indeed, as the lifespan increases, age-related dysfunction, such as cognitive impairment or dementia, will become a growing public health issue. Aging is also a great risk factor for many age-related diseases. Nowadays, people want not only to live longer but also healthier. Therefore, there is a critical need in understanding the underlying cellular and molecular mechanisms regulating aging that will allow us to modify the aging process for healthy aging and alleviate age-related disease. Here, we reviewed the recent breakthroughs in the mechanistic understanding of biological aging, focusing on the adenosine monophosphate-activated kinase (AMPK), Sirtuin 1 (SIRT1) and mammalian target of rapamycin (mTOR) pathways, which are currently considered critical for aging. We also discussed how these proteins and pathways may potentially interact with each other to regulate aging. We further described how the knowledge of these pathways may lead to new interventions for antiaging and against age-related disease.

scholarly journals Natural extract and its fractions isolated from the marine bacterium Pseudoalteromonas flavipulchra STILL-33 have antioxidant and antiaging activities in Schizosaccharomyces pombe

2020 ◽  
Vol 20 (3) ◽  
Author(s):  
Muhammad Eka Prastya ◽  
Rika Indri Astuti ◽  
Irmanida Batubara ◽  
Hiroshi Takagi ◽  
Aris Tri Wahyudi
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Fission Yeast ◽  
Aging Process ◽  
Marine Bacterium ◽  
Mitochondrial Activity ◽  
Oxygen Species ◽  
Related Disease ◽  
Age Related

ABSTRACT Investigations into the potential for pharmacological inhibition of the aging process and the onset of age-related disease are increasingly garnering attention. Here, we analyzed the antiaging properties of natural compounds derived from several marine bacteria in vitro and in vivo using the fission yeast Schizosaccharomyces pombe. The Pseudoalteromonas flavipulchra STILL-33 extract exhibited high antioxidant and antiglycation activities in vitro. We then characterized two antioxidant active fractions isolated from this extract. In addition, we showed that the P. flavipulchra STILL-33 extract or either of its two active fractions (Fractions 1 and 2) could extend the longevity of fission yeast. Moreover, the particular extract and two active fractions were found to induce mitochondrial activity and to delay the G1 phase of the fission yeast cell cycle, perhaps by improving the aging process. The P. flavipulchra STILL-33 extract and Fraction 1 also increased the expression of the catalase-encoding ctt1+ gene and thereby decreased the reactive oxygen species level. Structural analysis showed that Fraction 1 was dominated by l-arginine and ipriflavone, and we showed indeed that the two corresponding commercial products increase the fission yeast lifespan. As for Fraction 2 was identified as the putative structure of butamben. Together, these results should facilitate the discovery of additional antiaging compounds from P. flavipulchra and ultimately the development of novel antiaging compounds for pharmaceutical use.

scholarly journals Systematic Review of Studies on Telomere Lengths in Patients with Multiple Sclerosis

2020 ◽  
Author(s):  
Jan Bühring ◽  
Michael Hecker ◽  
Brit Fitzner ◽  
Uwe Klaus Zettl
Keyword(s):  
Multiple Sclerosis ◽  
Meta Analysis ◽  
Individual Variability ◽  
Biological Aging ◽  
Specific Cell ◽  
List Type ◽  
Healthy Controls ◽  
Telomere Attrition ◽  
Related Disease ◽  
Age Related

AbstractBACKGROUNDTelomeres are protective cap structures at the end of chromosomes that are essential for maintening genomic stability. Accelerated telomere shortening is related to premature cellular senescence. Shortened telomere lengths (TL) have been implicated in the pathogenesis of various chronic immune-mediated and neurological diseases.OBJECTIVEWe aimed to systematically review the current literature on the association of TL as a measure of biological age and multiple sclerosis (MS).METHODSA comprehensive literature search was conducted to identify original studies that presented data on TL in samples from MS patients. Quantitative and qualitative information was extracted from the articles to summarize and compare the studies.RESULTSA total of 51 articles were screened, and 7 of them were included in this review. In 6 studies, average TL were analyzed in peripheral blood cells, whereas in one study, bone marrow-derived cells were used. Four of the studies reported significantly shorter leukocyte TL in at least one MS subtype in comparison to healthy controls (p=0.003 in meta-analysis). Shorter telomeres in MS patients were found to be associated, independently of age, with greater disability, lower brain volume, increased relapse rate and more rapid conversion from relapsing to progressive MS. However, it remains unclear how telomere attrition in MS may be linked to oxidative stress, inflammation and age-related disease processes.CONCLUSIONSDespite few studies in this field, there is substantial evidence on the association of TL and MS. Variability in TL appears to reflect heterogeneity in clinical presentation and course. Further investigations in large and well-characterized cohorts are warranted. More detailed studies on TL of individual chromosomes in specific cell types may help to gain new insights into the pathomechanisms of MS.HighlightsThe relationship between aging and the pathophysiology and course of MS is not fully understoodWe have identified seven studies that analyzed telomere lengths (TL) in patients with MSOur meta-analysis revealed significantly shorter leukocyte TL in MS patients compared to healthy controlsThere is evidence that individual variability in biological aging reflects clinical heterogeneity in MSThe potential use of TL as a biomarker of age-related disease mechanisms deserves further investigation

scholarly journals p16-3MR: a novel model to study cellular senescence in cigarette smoke-induced lung injuries during aging

2021 ◽  
Author(s):  
Irfan Rahman ◽  
Gagandeep Kaur ◽  
Isaac Sundar
Keyword(s):  
Cigarette Smoke ◽  
Cellular Senescence ◽  
Biological Aging ◽  
In Vivo Model ◽  
Chronic Obstructive ◽  
Suitable Model ◽  
Obstructive Pulmonary Disease ◽  
Age Related ◽  
Chronic Smoking

Abstract Cellular senescence and lung aging are associated with the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). COPD progresses with aging, and chronic smoking is the key susceptibility factor in lung pathological changes concurrent with biological aging. However, these processes involving cigarette smoke (CS)-mediated lung cellular senescence are difficult to distinguish. One of the impediments to study cellular senescence in relation to age-related lung pathologies is the lack of a suitable in vivo model. In view of this, we provide evidence that supports the suitability of p16-3MR mice to study cellular senescence in CS-mediated and age-related lung pathologies. p16-3MR mice has a trimodal reporter fused to the promoter of p16INK4a gene that enables detection, isolation and selective elimination of senescent cells, thus making it a suitable model to study cellular senescence. To determine its suitability in CS-mediated lung pathologies, we exposed young (12-14 months) and old (17-20 months) p16-3MR mice to 30-day CS exposure and studied the expression of senescent genes (p16, p21 and p53) and SASP-associated markers (MMP9, MMP12, PAI-1, and FN-1) in air- and CS-exposed mouse lungs. Our results showed that this model could detect cellular senescence using luminescence and isolate cells undergoing senescence with the help of tissue fluorescence in CS-challenged young and old mice. Our results from the expression of senescence markers and SASP-associated genes in CS-challenged young and old p16-3MR mice were comparable with increased lung cellular senescence and SASP in COPD. We further showed age-dependent alteration in the (i) tissue luminescence and fluorescence, (ii) mRNA and protein expressions of senescent markers and SASP genes, and (iii) SA-β-gal activity in CS-challenged young and old p16-3MR mice as compared to their air controls. Overall, we showed that p16-3MR is a competent model to study cellular senescence in age-related pathologies and could help understand the pathobiology of cellular senescence in lung conditions like COPD and fibrosis.

scholarly journals Identifying Significant Biological Markers in Klotho Gene Variants Across Wide Ranging Taxonomy

2015 ◽  
Vol 5 (1) ◽  
pp. 11
Author(s):  
Tommy Rodriguez
Keyword(s):  
Transmembrane Protein ◽  
Genetic Regulation ◽  
Comparative Sequence Analysis ◽  
Biological Aging ◽  
Altered State ◽  
Telomere Attrition ◽  
Related Disease ◽  
Age Related ◽  
Evolutionary Context ◽  
Klotho Protein

<p class="1Body">Biological aging is marked by progressively degenerative physiological change that causes damage to tissues and organs. Errors in biopolymers accumulate over time; mitochondrial dysfunction, telomere attrition, and wider genomic instability lead to an altered state of intercellular communication. In this investigation, my focus will be aimed at examining and identifying specifically critical biomarkers in genetic variants of KLOTHO (a transmembrane protein involved in the genetic regulation of age-related disease) among organisms with varied life spans that range across wide taxonomical rankings. Here, I investigate the correlation between lower and higher frequency a-amino acid compositions in Klotho protein factors within a grouped methodology; as to also include several demonstrative techniques in comparative sequence analysis for inferring relatedness in evolutionary context.</p>

scholarly journals Identification, Expression, and Roles of the Cystine/Glutamate Antiporter in Ocular Tissues

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Renita M. Martis ◽  
Luis J. Knight ◽  
Paul J. Donaldson ◽  
Julie C. Lim
Keyword(s):  
Knockout Mouse ◽  
Redox Balance ◽  
Ocular Tissues ◽  
Age Related ◽  
Neural Tissues ◽  
The Brain ◽  
Oxidative State ◽  
Shed Light

The cystine/glutamate antiporter (system xc-) is composed of a heavy chain subunit 4F2hc linked by a disulphide bond to a light chain xCT, which exchanges extracellular cystine, the disulphide form of the amino acid cysteine, for intracellular glutamate. In vitro research in the brain, kidney, and liver have shown this antiporter to play a role in minimising oxidative stress by providing a source of intracellular cysteine for the synthesis of the antioxidant glutathione. In vivo studies using the xCT knockout mouse revealed that the plasma cystine/cysteine redox couple was tilted to a more oxidative state demonstrating system xc- to also play a role in maintaining extracellular redox balance by driving a cystine/cysteine redox cycle. In addition, through import of cystine, system xc- also serves to export glutamate into the extracellular space which may influence neurotransmission and glutamate signalling in neural tissues. While changes to system xc- function has been linked to cancer and neurodegenerative disease, there is limited research on the roles of system xc- in the different tissues of the eye, and links between the antiporter, aging, and ocular disease. Hence, this review seeks to consolidate research on system xc- in the cornea, lens, retina, and ocular humours conducted across several species to shed light on the in vitro and in vivo roles of xCT in the eye and highlight the utility of the xCT knockout mouse as a tool to investigate the contribution of xCT to age-related ocular diseases.

scholarly journals p16-3MR: a novel model to study cellular senescence in cigarette smoke-induced lung injuries during aging

2021 ◽  
Author(s):  
Gagandeep Kaur ◽  
Isaac K. Sundar ◽  
Irfan Rahman
Keyword(s):  
Cigarette Smoke ◽  
Cellular Senescence ◽  
Biological Aging ◽  
Chronic Obstructive ◽  
Suitable Model ◽  
Obstructive Pulmonary Disease ◽  
Age Related ◽  
Lung Injuries ◽  
Chronic Smoking

ABSTRACTCellular senescence and lung aging are associated with the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). COPD progresses with aging, and chronic smoking is the key susceptibility factor in lung pathological changes concurrent with biological aging. However, these processes involving cigarette smoke (CS)-mediated lung cellular senescence are difficult to distinguish. One of the impediments to study cellular senescence in relation to age-related lung pathologies is the lack of a suitable in vivo model. In view of this, we provide evidence that supports the suitability of p16-3MR mice to study cellular senescence in CS-mediated and age-related lung pathologies. p16-3MR mice has a trimodal reporter fused to the promoter of p16INK4a gene that enables detection, isolation and selective elimination of senescent cells, thus making it a suitable model to study cellular senescence. To determine its suitability in CS-mediated lung pathologies, we exposed young (12-14 months) and old (17-20 months) p16-3MR mice to 30-day CS exposure and studied the expression of senescent genes (p16, p21 and p53) and SASP-associated markers (MMP9, MMP12, PAI-1, and FN-1) in air- and CS-exposed mouse lungs. Our results showed that this model could detect cellular senescence using luminescence and isolate cells undergoing senescence with the help of tissue fluorescence in CS-challenged young and old mice. Our results from the expression of senescence markers and SASP-associated genes in CS-challenged young and old p16-3MR mice were comparable with increased lung cellular senescence and SASP in COPD. We further showed age-dependent alteration in the (i) tissue luminescence and fluorescence, (ii) mRNA and protein expressions of senescent markers and SASP genes, and (iii) SA-β-gal activity in CS-challenged young and old p16-3MR mice as compared to their air controls. Overall, we showed that p16-3MR is a competent model to study cellular senescence in age-related pathologies and could help understand the pathobiology of cellular senescence in lung conditions like COPD and fibrosis.

scholarly journals CHIP Deficiency Decreases Longevity, with Accelerated Aging Phenotypes Accompanied by Altered Protein Quality Control

2008 ◽  
Vol 28 (12) ◽  
pp. 4018-4025 ◽  
Author(s):  
Jin-Na Min ◽  
Ryan A. Whaley ◽  
Norman E. Sharpless ◽  
Pamela Lockyer ◽  
Andrea L. Portbury ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Degradation ◽  
Cellular Senescence ◽  
Protein Quality ◽  
Functional Decline ◽  
Protein Quality Control ◽  
Biological Aging ◽  
Control Mechanisms ◽  
Age Related

ABSTRACT During the course of biological aging, there is a gradual accumulation of damaged proteins and a concomitant functional decline in the protein degradation system. Protein quality control is normally ensured by the coordinated actions of molecular chaperones and the protein degradation system that collectively help to maintain protein homeostasis. The carboxyl terminus of Hsp70-interacting protein (CHIP), a ubiquitin ligase/cochaperone, participates in protein quality control by targeting a broad range of chaperone substrates for proteasome degradation via the ubiquitin-proteasome system, demonstrating a broad involvement of CHIP in maintaining cytoplasmic protein quality control. In the present study, we have investigated the influence that protein quality control exerts on the aging process by using CHIP−/− mice. CHIP deficiency in mice leads to a markedly reduced life span, along with accelerated age-related pathophysiological phenotypes. These features were accompanied by indications of accelerated cellular senescence and increased indices of oxidative stress. In addition, CHIP−/− mice exhibit a deregulation of protein quality control, as indicated by elevated levels of toxic oligomer proteins and a decline in proteasome activity. Taken together, these data reveal that impaired protein quality control contributes to cellular senescence and implicates CHIP-dependent quality control mechanisms in the regulation of mammalian longevity in vivo.

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