Targeting chromatin aging - the epigenetic impact of longevity-associated interventions

A rapidly growing body of evidence has shown that chromatin undergoes radical alterations as an organism ages, but how these changes relate to aging itself is an open question. It is likely that these processes contribute to genomic instability and loss of transcriptional fidelity, which in turn drives deleterious age-related phenotypes. Interventions associated with increased healthspan and longevity such as reduced insulin/IGF signalling (IIS), inhibition of mTOR and energy depletion resulting in SIRT1/AMPK activation, all have beneficial effects which ameliorate multiple facets of age-associated decline. The impact of these interventions on the epigenome is less certain. In this review we highlight the potential of these interventions to act directly upon the epigenome and promote a youthful chromatin landscape, maintaining genetic and transcriptional memory throughout the lifecourse. We propose that this is a fundamental mechanism through which these interventions are able to curtail the incidence of age-related disease. By revisiting these well characterised interventions, we may be able to identify targetable effectors of chromatin function and use this knowledge to enhance healthspan and longevity in human populations through the measured application of dietary and small molecule interventions

CONDITIONS FOR SUCCESSFUL STRATEGIC ALLIANCES IN THE FOOD INDUSTRY

This paper focuses on strategic fuzzy alliances (SFAs) and the role of trust in business-to-business relationships. First, a theoretical model of governance choice involving strategic alliances is developed, integrating the Shapiro, Sheppard, and Cheraskin (1992) taxonomy of trust into a neoinstitutional framework. Second, this model, based on transaction theory, is then used to generate necessary and sufficient conditions for trust-based agreements. The third component of this paper is an empirical model, which tests the above theory. Finally, managerial implications from the results are discussed.Institutional and Behavioral Economics,

Aging-induced stem cell mutations as drivers for disease and cancer

Aging is characterized by a decrease in genome integrity, impaired organ maintenance, and an increased risk of cancer, which coincide with clonal dominance of expanded mutant stem and progenitor cell populations in aging tissues, such as the intestinal epithelium, the hematopoietic system, and the male germline. Here we discuss possible explanations for age-associated increases in the initiation and/or progression of mutant stem/progenitor clones and highlight the roles of stem cell quiescence, replication-associated DNA damage, telomere shortening, epigenetic alterations, and metabolic challenges as determinants of stem cell mutations and clonal dominance in aging

Critical parameters for efficient sonication and improved chromatin immunoprecipitation of high molecular weight proteins

Solubilization of cross-linked cells followed by chromatin shearing is essential for successful chromatin immunoprecipitation (ChIP). However, this task, typically accomplished by ultrasound treatment, may often become a pitfall of the process, due to inconsistent results obtained between different experiments under seemingly identical conditions. To address this issue we systematically studied ultrasound-mediated cell lysis and chromatin shearing, identified critical parameters of the process and formulated a generic strategy for rational optimization of ultrasound treatment. We also demonstrated that whereas ultrasound treatment required to shear chromatin to within a range of 100–400 bp typically degrades large proteins, a combination of brief sonication and benzonase digestion allows for the generation of similarly sized chromatin fragments while preserving the integrity of associated proteins. This approach should drastically improve ChIP efficiency for this class of proteins

TPA-induced activation of MAP kinase

AbstractThreonine and tyrosine residue phosphorylation of a 42 kDa protein identified as mitogen-activated protein kinase (MAP kinase) was stimulated in extracts from TPA-pretreated cells. It is further shown that TPA pretreatment leads to the enhancement of an activity that will induce reactivation of dephosphorylated/inactivated MAP kinase. This TPA-induced activity induces the threonine and tyrosine phosphorylation of p42 in extracts from unstimulated cells

DNMT inhibitors reverse a specific signature of aberrant promoter DNA methylation and associated gene silencing in AML

<b>Background</b>. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are neoplastic disorders of hematopoietic stem cells. DNA methyltransferase inhibitors (DNMTi), 5-azacytidine (AzaC) and 5-aza-2’-deoxycytidine (Decitabine), benefit some MDS/AML patients. However, the role of DNMTi-induced DNA hypomethylation in regulation of gene expression in AML is unclear.<p></p> <b>Results. </b> We compared the effects of AzaC on DNA methylation and gene expression using whole-genome single-nucleotide bisulfite-sequencing (WGBS) and RNA-sequencing in OCI-AML3 (AML3) cells. For data analysis, we used an approach recently developed for discovery of differential patterns of DNA methylation associated with changes in gene expression, that is tailored to single-nucleotide bisulfite-sequencing data (Washington University Interpolated Methylation Signatures (WIMSi)). By this approach, a subset of genes upregulated by AzaC was found to be characterized by AzaC-induced signature methylation loss flanking the transcription start site. These genes are enriched for genes increased in methylation and decreased in expression in AML3 cells compared to normal hematopoietic stem and progenitor cells. Moreover, these genes are preferentially upregulated by Decitabine in human primary AML blasts, and control cell proliferation, death and development. <p></p> <b>Conclusions.</b> Our WGBS and WIMSi data analysis approach has identified a set of genes whose is methylation and silencing in AML is reversed by DNMTi. These genes are good candidates for direct regulation by DNMTi, and their reactivation by DNMTi may contribute to therapeutic activity. This study also demonstrates the ability of WIMSi to reveal relationships between DNA methylation and gene expression, based on single-nucleotide bisulfite-sequencing and RNA-seq data.<p></p&gt

Fracture toughness of the cancellous bone of FNF femoral heads in relation to its microarchitecture

This study considers the relationship between microarchitecture and mechanical properties for cancellous bone specimens collected from a cohort of patients who had suffered fractured necks of femur. OP is an acute skeletal condition with huge socioeconomic impact [1] and it is associated with changes in both bone quantity and quality [2], which affect greatly the strength and toughness of the tissue [3].Support was provided by the EPSRC (EP/K020196: Point-ofCare High Accuracy Fracture Risk Prediction), the UK Department of Transport under the BOSCOS (Bone Scanning for Occupant Safety) project, and approved by Gloucester and Cheltenham NHS Trust hospitals under ethical consent (BOSCOS – Mr. Curwen CI REC ref 01/179G)

Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment

Background: Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. Results: We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls. Conclusions: This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers

Treatment for femoroacetabular impingement : a qualitative method for exploring equipoise amongst hip arthroscopy surgeons

R : URGENT The published literature suggests uncertainty about whether operative or nonoperative treatments are best for femoroacetabular impingement (FAI). Without the same level of uncertainty (equipoise) amongst surgeons, a RCT will be challenging. A qualitative study was conducted to explore the level of equipoise amongst arthroscopic FAI surgeons. In phase 1, 14 hip arthroscopy surgeons were interviewed and asked to make treatment decisions based on real life cases that included actively recruiting patients to a theoretical RCT. In phase 2, 9 hip arthroscopy hip surgeons participating in a pilot RCT were interviewed about their experiences so far of taking part in a pilot RCT. Five surgeons took part in both phase 1 and 2. Sixteen (89%) surgeons believed that they were in equipoise and that a RCT was required to generate superior scientific evidence and guidelines for the care. Despite this 5 (36%) surgeons showed a lack of active clinical equipoise when faced with real life case scenarios or discussing involvement with a pilot RCT. Some of the reasons behind surgeons’ lack of equipoise, ranged from lack of belief in the FAI pathology, to personal enthusiasm and gut instinct about the efficacy of surgery on one hand; but conservatism on the other. Although many would like a RCT to guide care, there may be particular challenges amongst this same population when actively recruiting patients to a RCT. Qualitative methodology can be used to help design surgical RCTs and address any subsequent difficulties with recruitment