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Reviews are paid by on-demand review requests and by donations. Below is this month's longevity research from Biorxiv, Medrxiv, and Arxiv.

New | 1 December 2022 | Biorxiv link | Write review

Listening in everyday life requires attention to be deployed dynamically - when listening is expected to be difficult and when relevant information is expected to occur - to conserve mental resources. Conserving mental resources may be particularly important for older adults who often experience difficulties understanding speech. In the current study, we use electro- and magnetoencephalography to investigate the neural and behavioral mechanics of attention regulation during listening and the effects that aging has on these. We show that neural alpha oscillatory activity indicates when in time attention is deployed (Experiment 1) and that deployment depends on listening difficulty (Experiment 2). Older adults (54-72 years) also show successful attention regulation but appear to utilize timing information differently compared to younger adults (20-33 years). We further show a notable age-group dissociation in recruited brain regions. In younger adults, superior parietal cortex underlies alpha power during attention regulation, whereas, in older adults, alpha power emerges from more ventro-lateral areas (posterior temporal cortex; Experiment 3). This difference in the sources of alpha activity between age groups only occurred during task performance and was absent during rest (Experiment S1). In sum, our study suggests that older adults employ different neural control strategies compared to younger adults to regulate attention in time under listening challenges. | Make paid

New | 30 November 2022 | Biorxiv link | Write review

Cerebrovascular reactivity (CVR), defined as the cerebral blood flow response to a vasoactive stimulus, is an imaging biomarker with demonstrated utility in a range of diseases and in typical development and aging processes. A robust and widely implemented method to map CVR involves using a breath-hold task during a BOLD fMRI scan. Recording end-tidal CO2 (PETCO2) changes during the breath-hold task is recommended to be used as a reference signal for modeling CVR amplitude in standard units (%BOLD/mmHg) and CVR delay in seconds. However, obtaining reliable PETCO2 recordings requires equipment and task compliance that may not be achievable in all settings. To address this challenge, we investigated two alternative reference signals to map CVR amplitude and delay in a lagged general linear model (lagged-GLM) framework: respiration volume per time (RVT) and average gray matter BOLD response (GM-BOLD). In 8 healthy adults with multiple scan sessions, we compare spatial agreement of CVR maps from RVT and GM-BOLD to those generated with PETCO2. We define a threshold to determine whether a PETCO2 recording has ''sufficient'' quality for CVR mapping and perform these comparisons in 16 datasets with sufficient PETCO2 and in 6 datasets with insufficient PETCO2. When PETCO2 quality is sufficient, both RVT and GM-BOLD produce CVR amplitude maps that are nearly identical to those from PETCO2 (after accounting for differences in scale), with the caveat they are not in standard units to facilitate between-group comparisons. CVR delays are comparable to PETCO2 with an RVT regressor but may be underestimated with the average GM-BOLD regressor. Importantly, when PETCO2 quality is insufficient, RVT and GM-BOLD CVR recover reasonable CVR amplitude and delay maps, provided the participant attempted the breath-hold task. Therefore, our framework offers a solution for achieving high quality CVR maps in both retrospective and prospective studies where sufficient PETCO2 recordings are not available and especially in populations where obtaining reliable measurements is a known challenge (e.g., children). Our results have the potential to improve the accessibility of CVR mapping and to increase the prevalence of this promising metric of vascular health. | Make paid

New | 30 November 2022 | Biorxiv link | Write review

The ability to use past experience to effectively guide decision making declines in older adulthood. Such declines have been theorized to emerge from either impairments of striatal reinforcement learning systems (RL) or impairments of recurrent networks in prefrontal and parietal cortex that support working memory (WM). Distinguishing between these hypotheses has been challenging because either RL or WM could be used to facilitate successful decision making in typical laboratory tasks. Here we investigated the neurocomputational basis for age-related decision making deficits using an RL-WM task to disentangle these mechanisms, a computational model to quantify them, and magnetic resonance spectroscopy to link them to their molecular bases. Our results reveal that learning declines in older age are largely attributable to working memory deficits, as might be expected if cortical recurrent networks were unable to sustain persistent activity across multiple trials. Consistent with this, we show that older adults had lower levels of prefrontal glutamate, the excitatory neurotransmitter thought to support persistent activity, compared to younger adults. Individuals with the lowest prefrontal glutamate levels displayed the greatest impairments in working memory after controlling for other anatomical and metabolic factors. Together, our results suggest that reductions in prefrontal glutamate across healthy aging may contribute to failures of working memory systems and impaired decision making in older adulthood. | Make paid

New | 30 November 2022 | Biorxiv link | Write review

Age-related decline in episodic memory performance is a well-replicated finding across numerous studies. Recent studies focusing on aging and individual differences found that the Big Five personality trait Openness to Experience is associated with better episodic memory performance in older adults, but the associated neural mechanisms are largely unclear. Here we investigated the relationship between Openness and memory network function in a sample of 352 participants (143 older adults, 50-80 years; 209 young adults, 18-35 years). Participants underwent functional magnetic resonance imaging (fMRI) during a visual memory encoding task. Functional memory brain-network integrity was assessed using the SAME scores (similarity of activations during memory encoding), which reflect the deviation of a participants memory network activity from prototypical fMRI activity patterns of young adults. Openness was assessed using the NEO Five Factor Inventory (NEO-FFI). Older vs. young adults showed lower memory performance and higher deviation of fMRI activity patterns (i.e., lower SAME scores). Specifically in older adults, high Openness was associated with better memory performance, and mediation analysis showed that this relationship was partially mediated by higher SAME scores. Our results suggest that trait Openness may constitute a protective factor in cognitive aging by better preservation of the brains memory network. | Make paid

New | 29 November 2022 | Biorxiv link | Write review

We recently reported that loss of oligodendrocyte metabolic support through the lactate and pyruvate transporter Monocarboxylate Transporter 1 (MCT1) is well tolerated into adulthood. Only with advanced aging did we observe axonal degeneration and hypomyelination due to loss of MCT1 from oligodendroglia lineage cells. MCT1 is also expressed by other glial subtypes, such as astrocytes and endothelial cells where it has been suggested to be essential for learning and memory tasks. However, the importance of MCT1 in these cell types for long-term axonal metabolic support is still unknown. We therefore addressed whether conditional loss of MCT1 from either of these cell types would lead to widespread axonal degeneration with aging. Using a conditional null approach, similar to what was used for oligodendrocyte MCT1 depletion, we observed that conditional knockout of MCT1 from either astrocytes or endothelial cells did not cause neuronal injury. On the other hand, inducible ubiquitous depletion of MCT1 causes late-onset axonal degeneration, comparable with what was observed in our previous study using the oligodendrocyte lineage MCT1 null mice. In summary, we conclude that unlike oligodendrocyte MCT1, astrocyte MCT1 is not an essential driver of astrocyte mediated axonal energy homeostasis with aging. | Make paid

New | 29 November 2022 | Biorxiv link | Write review

Working memory relies critically on the dorsolateral prefrontal cortex (dlPFC). Morphology and function of the dlPFC, and corresponding working memory performance, are affected early in the aging process. However, these effects are heterogeneous, with nearly half of aged individuals spared of working memory deficits. Translationally relevant model systems are critical for investigating the neurobiological drivers of this variability and identifying why some people experience age-related working memory impairment while others do not. The common marmoset (Callithrix jacchus) is advantageous as a model in which to investigate the biological underpinnings of aging because, as a nonhuman primate, marmosets have a clearly defined dlPFC facilitating investigations of prefrontal-dependent cognitive functions, including working memory, and their short (~10 year) lifespan facilitates longitudinal studies of aging. Here, we conduct the first investigation of synaptic ultrastructure in the dlPFC of the marmoset and investigate whether there are changes to synaptic ultrastructure that are unique to aging with and without working memory impairment. To do this, we characterized working memory capacity in a cohort of marmosets that collectively covered their short lifespan, and found age-related working memory impairment. We also found a remarkable degree of heterogeneity in performance, similar to that found in humans. Utilizing three dimensional reconstruction from serial section electron microscopy, we visualized structural correlates of synaptic efficacy including boutons, mitochondria, and synapses in layer III of the dlPFC of three marmosets: one young adult (YA), one aged cognitively unimpaired (AU), and one aged cognitively impaired (AI). We find that aged marmosets have fewer synapses in dlPFC than young, and this is due to selective vulnerability of small synapses. Next, we tested the hypothesis that violation of the ultrastructural size principle underlies age-related working memory impairment. The ultrastructural size principle states that synaptic efficacy relies on coordinated scaling of synaptic components (e.g., synapses, mitochondria) with presynaptic boutons. While synapses and mitochondria scaled proportionally and were strongly correlated with presynaptic boutons in the YA and AU marmosets, the ultrastructural characteristics of the AI marmoset were alarmingly different. We found that age-related working memory impairment was associated with disproportionately large synapses compared to presynaptic boutons, specifically in those with mitochondria. Remarkably, presynaptic mitochondria and these boutons were completely decorrelated. We posit that this decorrelation results in mismatched energy supply and demand, leading to impaired synaptic transmission. This is the first report of age-related synapse loss in the marmoset, and the first demonstration that violation of the ultrastructural size principle underlies age-related working memory impairment. | Make paid

New | 28 November 2022 | Biorxiv link | Write review

Transcription factors (TFs) have the potential function in regulating gene expression. Transcription factor TFAP2C plays important roles in the regulation of post-implantation embryonic development in mice, the reprogramming process, trophectoderm formation and carcinogenesis, but its role in porcine early embryo development remains unclear. This study was conducted to investigate the role of TFAP2C in porcine early embryo development using siRNA cytoplasmic injection. The RNAseq and immunofluorescence staining were performed to detect gene expression, and ChIP and dual luciferase reporter assays were used to elucidate the mechanism. The results showed that the deficiency of TFAP2C could lead to embryonic development disorder. The percentage of the blastocyst in the TFAP2C knockdown (TFAP2C-KD) group (7.76{+/-}1.86%) was significantly decreased compared to the control group (22.92{+/-}1.97%) (P**<0.01). The RNAseq results showed that 1208 genes were downregulated and 792 genes were upregulated after siRNA injection. The expression of epigenetic modification enzymes KDM5B, SETD2 (P**<0.01) etc. were significantly elevated in TFAP2C-KD group. Meanwhile, the modification levels of H3K4me3, H3K4me2 and H3K9me3 (P*<0.05) were significantly decreased, and the modification levels of H3K36me3 (P**<0.01) and DNA methylation (P**<0.01) were significantly increased in TFAP2C-KD group. DNMT1 was mostly expressed in cytoplasm in the control group, while it was mainly expressed in nuclei in the TFAP2CKD group. In addition, TFAP2C could bind to the promoter region of SETD2, and the mutation of the TFAP2C binding site resulted in increased activity of SETD2 promoter (P**<0.01). The knockdown of TFAP2C affects histone modification and DNA methylation by regulating the expression of SETD2, KDM5B etc. and other genes, thereby inhibiting embryonic development. TFAP2C binds to the promoter region of SETD2 and acts as a hindrance protein. This study fills in the deficiency of TFAP2C in porcine early embryo development and provides theoretical support for animal husbandry production and biomedicine. | Make paid

New | 26 November 2022 | Biorxiv link | Write review

The clearance of insulin from circulation is critical for metabolic homeostasis. Insulin is depleted in the liver by the insulin degrading enzyme (IDE). WDR23 is a substrate receptor of the Cul4-ubiquitin ligase complex and acts as a sophisticated regulator of protein activation and turnover. Here we establish hepatic WDR23 in the regulation of insulin metabolism by regulating IDE. An unbiased proteomic analysis of liver tissue of mice lacking Wdr23 revealed a significant increase in the steady state levels of IDE which accompanied reduced circulating insulin and diminished sensitivity to insulin stimulation. A comparative assessment of the transcriptomic changes in livers from animals with and without WDR23 reveals significant changes in the targets responding to insulin and glucose receptor signaling. Furthermore, phosphorylation of the insulin signaling cascade proteins, IRS-1, AKT, MAPK and mTOR were dysregulated in Wdr23KO mice. These findings are recapitulated in cultured human cell models with genetic ablation of Wdr23 revealing a conserved role for WDR23 from mice to humans. Mechanistically, the cytoprotective transcription factor NRF2, a direct target of WDR23-Cul4 proteostasis, mediates the enhanced transcriptional expression of IDE when WDR23 is ablated. Moreover, an analysis of human genetic variation in WDR23 across a large naturally aging human cohort in the US Health and Retirement Study reveals a significant association of WDR23 with altered hemoglobin A1C (HbA1c) levels in older adults that supports the use of WDR23 as new molecular determinant of metabolic health in humans. | Make paid

New | 26 November 2022 | Biorxiv link | Write review

Mammalian genomes harbor many more enhancers than genes, which greatly complicates the elucidation of cell-state specific regulatory networks. Here, we developed a computational framework for learning enhancer-based gene networks from joint data on enhancer activity and transcript abundance. Dissecting the developmental plasticity of T helper (Th) cells with this approach, we uncovered a highly connected enhancer-gene network that supports graded Th-cell differentiation states, rather than mutual exclusivity of type-1 and type-2 immunity. Machine learning identifies a small number of regulatory enhancer types as network hubs. Hub enhancers in Th1 cells integrate as inputs the expression level of the master regulator transcription factor, T-bet, and STAT signals governed by the cytokine environment. The quantitative balance between cell-intrinsic T-bet, driving phenotypic stability, and environmental cues enabling plasticity explains the heterogeneous reprogramming capacities of individual Th1 cells differentiating during natural infections in vivo. Moreover, we provide a framework for elucidating genome-scale regulatory networks based on enhancer activity. | Make paid

New | 26 November 2022 | Biorxiv link | Write review

The volatile phytohormone ethylene is a major regulator of plant adaptive responses to flooding. In flooded plant tissues, it quickly increases to high concentrations due to its low solubility and diffusion rates in water. The passive, quick and consistent accumulation of ethylene in submerged plant tissues makes it a reliable cue for plants to trigger flood-acclimative responses. However, persistent ethylene accumulation can also have negative effects, notably accelerated leaf senescence. Ethylene is a well-established positive regulator of senescence which is a natural element of plant ageing. However stress-induced senescence hampers the photosynthetic capacity and stress recovery of plants. In submerged Arabidopsis shoots, senescence follows a strict age-dependent pattern starting with the older leaves. Although mechanisms underlying ethylene-mediated senescence have been uncovered, it is unclear how submerged plants avoid an indiscriminate breakdown of leaves despite high systemic accumulation of ethylene. Here we demonstrate in Arabidopsis plants that even though submergence triggers a leaf-age independent activation of ethylene signaling via EIN3, senescence was initiated only in the old leaves. This EIN3 stabilization also led to the overall transcript and protein accumulation of the senescence-promoting transcription factor ORESARA1 (ORE1). ORE1 protein accumulated in both old and young leaves during submergence. However, leaf age-dependent senescence could be explained by ORE1 activation via phosphorylation only in old leaves. Our results unravel a mechanism by which plants regulate the speed and pattern of senescence during environmental stresses like flooding. Such an age-dependent phosphorylation of ORE1 ensures that older expendable leaves are dismantled first, thus prolonging the life of younger leaves and meristematic tissues vital to whole plant survival. | Make paid

New | 25 November 2022 | Biorxiv link | Write review

Background: Tissues need to regenerate to restore function after injury. Yet, this regenerative capacity varies significantly between organs and between species. For example, in the heart, some species retain full regenerative capacity throughout their lifespan but human cardiac cells display limited ability to repair injury. After a myocardial infarction, the function of cardiomyocytes is impaired and reduces the ability of the heart to pump, causing heart failure. Therefore, there is a need to restore the function of an injured heart post myocardial infarction. We investigate in cell culture the role of the YAP, a transcriptional co-regulator with a pivotal role in growth, in driving repair after injury. Methods: We express optogenetic YAP (optoYAP) in three different cell lines. We characterised the behaviour and function of optoYAP using fluorescence imaging and quantitative real-time PCR of downstream YAP target genes. Mutant constructs were generated using site-directed mutagenesis. Nuclear localised optoYAP was functionally tested using wound healing assay and anchorage-independent colony formation assay. Results: Utilising optoYAP, which enables precise control of pathway activation, we show that YAP induces the expression of downstream genes involved in proliferation and migration. optoYAP can increase the speed of wound healing in H9c2 cardiomyoblasts. Interestingly, this is not driven by an increase in proliferation, but by collective cell migration. We subsequently dissect specific phosphorylation sites in YAP to identify the molecular driver of accelerated healing. Conclusions: This study shows that optogenetic YAP is functional in H9c2 cardiomyoblasts and its controlled activation can potentially enhance wound healing in a range of conditions. | Make paid

New | 25 November 2022 | Biorxiv link | Write review

Mitochondria in mammalian cells provide ATP through oxidative phosphorylation. The overproduction of reactive oxygen species (ROS) in mitochondrial cells promotes cancer by modifying gene expression or function. Mating introduces competing mitochondrial (mtDNA) and nuclear DNA (nDNA) gene products, leading to biological differences between males and females for diseases and disorders such as cancer. There is a significant sex bias in aging-related conditions. We aimed to investigate whether sex and age affect mitochondrial protein-coding gene expression in cancer and, if so, to determine the prognosis value in survival outcomes, stemness, and immune cell infiltrates. We compared normal versus primary tumor transcriptomes (bulk RNA-Seq) from The Cancer Genome Atlas (TCGA), and the Genotype-Tissue Expression (GTEx) projects to test these hypotheses. Correlations between gene expression, survival, protective or risk factor, stemness, and immune cell infiltrate were performed in RStudio using UCSC Xena Shiny. Eleven mitochondrial protein-coding genes were altered in brain cancer (MT-ND2, MT-ND1, MT-ATP8, MT-ATP6, MT-CO2, MT-CYB, MT-CO3, MT-ND4L, MT-ND4, MT-ND3, MT-CO1). MT-ND5 and MT-ND6 are disproportionately expressed in female brain tissues. Mitochondrial global polymorphic expression sites of variation were more significant in the 50-59 and 60-79-year-old age groups than in the 20-49-year-old age groups. Pan-cancer survival analysis revealed a 4-component gene signature (MT-CO1, MT-CO2, MT-ND5, and MT-ND6) downregulated in low-grade glioma (LGG). This gene signature increased LGG overall survival, disease-specific survival, and progression-free interval without sex-specific association. However, the correlation with disease-free interval survival was female-specific. The 4-component gene signature was protective in LGG but risky in thymoma cancer and uterine corpus endometrial carcinoma. In LGG, the 4-component gene signature positively correlated with immune monocyte, NK, and B cell infiltrates and negatively correlated with T cell CD4+ Th2, macrophage M1 and M2, myeloid dendritic cell, and neutrophil. We identified a 13-component mitochondrial protein-coding gene signature associated with stemness in kidney chromophobe. A sex-biased effect was observed in mitochondrial protein-coding for brain tissues, with a female bias. However, an aging effect with higher polymorphic site expression was observed in male tissues. We conclude that the differentially expressed mitochondrial protein-coding genes provide new insights into carcinogenesis, helping to identify new prognostic markers. The overexpression of the 4-component gene signature is associated with a better prognosis in LGG, with positive and negative correlations with immune cell infiltrates. | Make paid

New | 25 November 2022 | Biorxiv link | Write review

Intertissue RNA transport has emerged as a novel signaling mechanism. In C. elegans, this is conferred by the systemic RNAi pathway, in which the limiting step is the cellular import of extracellular RNAs via SID-1. To better understand the physiological role of systemic RNAi in vivo, we modified the function of SID-1 through loss-of-function mutation and tissue-specific overexpression of sid-1 in C. elegans. We observed that sid-1 loss-of-function mutants are as healthy as wild-type worms. Conversely, overexpression of sid-1 in intestine, muscle, or neurons rendered worms short-lived. The effects of intestinal sid-1 overexpression were reversed by silencing the components of the systemic RNAi pathway sid-1, sid-2 and sid-5, thus implicating RNA transport. Moreover, silencing the miRNA biogenesis proteins pash-1 and dcr-1 rendered the lifespan of worms with intestinal sid-1 overexpression similar to controls. Lastly, we observed that the lifespan decrease produced by tissue-specific sid-1 overexpression was dependent on the bacterial food source. Collectively, our data support the notion that systemic RNA signaling is tightly regulated, and unbalancing that process provokes a reduction in lifespan. | Make paid

New | 25 November 2022 | Biorxiv link | Write review

Background: An important hallmark of glioblastoma aggressiveness is its altered metabolism of glucose. This metabolic shift wherein the tumor cells employ aerobic glycolysis regardless of oxygen availability via reprogramming of mitochondrial oxidative phosphorylation is known as the Warburg effect. Previous literatures have linked this metabolic reprograming to tumor progression glioblastoma cell proliferation making it a key target for targeted drug therapy. Objective: To evaluate the anti-Warburg efficacies of the triple-drug combination of temozolomide, metformin and epigallocatechin gallate in preclinical glioblastoma models. Methodology: Based on this lacuna, the current study aimed to explore the therapeutic efficacy of the triple-drug combination of temozolomide, metformin and epigallocatechin gallate in attenuating Warburg effect and glucose uptake in glioblastoma both in vitro and in vivo. Results: Our results showed that the triple-drug combination had significantly reduced glucose uptake and reversed the Warburg effect in glioblastoma cells and in the xenograft-induced glioma rat model. Conclusion: Thus, the triple-drug combination would serve as an effective therapeutic regime to hamper glioblastoma progression via altering glucose metabolism and improve the overall prognosis in patient setting. | Make paid

New | 25 November 2022 | Biorxiv link | Write review

Spatially-resolved gene expression profiling provides valuable insight into tissue organization and cell-cell crosstalk; however, spatial transcriptomics (ST) lacks single-cell resolution. Current ST analysis methods require single-cell RNA sequencing data as a reference for a rigorous interpretation of cell states and do not utilize associated histology images. Significant sample variation further complicates the integration of ST datasets, which is essential for identifying commonalities across tissues or altered cellular wiring in disease. Here, we present Starfysh, the first comprehensive computational toolbox for joint modeling of ST and histology data, dissection of refined cell states, and systematic integration of multiple ST datasets from complex tissues. Starfysh uses an auxiliary deep generative model that incorporates archetypal analysis and any known cell state markers to avoid the need for a single-cell-resolution reference in characterizing known or novel tissue-specific cell states. Additionally, Starfysh improves the characterization of spatial dynamics in complex tissues by leveraging histology images and enables the comparison of niches as spatial "hubs" across tissues. Integrative analysis of primary estrogen receptor-positive (ER+) breast cancer, triple-negative breast cancer (TNBC), and metaplastic breast cancer (MBC) tumors using Starfysh led to the identification of heterogeneous patient- and disease-specific hubs as well as a shared stromal hub with varying spatial orientation. Our results show the ability to delineate the spatial co-evolution of tumor and immune cell states and their crosstalk underlying intratumoral heterogeneity in TNBC and revealed metabolic reprogramming shaping immunosuppressive hubs in aggressive MBC. Starfysh is publicly available (https://github.com/azizilab/starfysh). | Make paid

New | 23 November 2022 | Medrxiv link | Write review

Brain-age is an emerging neuroimaging biomarker that represents the aging status of the brain using machine learning techniques from MRI data. It has been successfully applied to the study of different neurological and psychiatric conditions. We hypothesize that patients with migraine may show an increased brain age gap (difference between the age estimated from the MRI data and the chronological age). After building a brain age model from 2,781 healthy subjects, we tested this hypothesis on a dataset with 210 healthy controls and migraine patients. Results showed an increased brain age in chronic migraine patients with respect to healthy controls. | Make paid

New | 23 November 2022 | Medrxiv link | Write review

Recent epidemiological studies suggest that polygenic risk for depression is associated with elevated white blood cell count, indicating shared genetic mechanisms between depression as a psychiatric disorder and the pro-inflammatory states often observed in clinical depression. However, the effects of aging on depressive symptoms and inflammation are not often fully appreciated in these studies, despite known variation across the human lifespan. To investigate the interaction of polygenic risk for depression and age on white blood cell count, we calculated depression polygenic risk scores (PRS) in 324,098 individuals from the UK Biobank (UKB) and 22,758 individuals from the Canadian Longitudinal Study on Aging (CLSA). Linear regression models of white blood cell count were fit to each sample, including interaction effects between age and the depression PRS. Significant age by PRS interaction effects were found in both samples (UKB interaction term: t=-2.9, p=3.7x10-3; CLSA interaction term: t=-2.6, p=9.0x10-3). While the previously reported main positive association between PRS and increasing white blood cell count was observed, we show in this study that the strength of the association diminishes with increasing age. Considering this potential age-dependency, these findings should encourage efforts to uncover genome-wide markers of late-life depression, which are needed to fully understand these age-related interaction effects. | Make paid

New | 23 November 2022 | Biorxiv link | Write review

Malignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations in SMARCB1, a member of the BRG1/BRM-associated factors (BAF) chromatin remodeling complex. Mutations in BAF complex members are common in human cancer, yet their contribution to tumorigenesis remains in many cases poorly understood. Here, we studied derailed regulatory landscapes as a consequence of SMARCB1 loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids revealed a dramatic reshaping of the regulatory landscape upon SMARCB1 reconstitution. Chromosome conformation capture experiments subsequently revealed patient-specific looping of distal enhancer regions with the promoter of the MYC oncogene. This intertumoral heterogeneity in MYC enhancer utilization is also present in patient MRT tissues as shown by combined single-cell RNA-seq and ATAC-seq. We show that loss of SMARCB1 drives patient-specific epigenetic reprogramming underlying MRT tumorigenesis. | Make paid

New | 23 November 2022 | Biorxiv link | Write review

Ecotoxicological studies mainly focus on chemical pollution, however, since past decades, there has been a growing interest for the acoustic pollution. Previous studies on underwater acoustic pollution showed that noise affects vertebrates' behaviour, like fish and marine mammals. However, little is known about other organisms. Consequently, we studied important lacking aspects, well known with chemical pollution: the effect on a key zooplankton species (used as bioindicator) and the effect on fitness (survival and fecundity). We exposed isolated water fleas, Daphnia magna, to chronic boat noise or to a silence broadcasted as control, from birth to death. We measured effects on lifespan and clonal offspring production (e.g., clutch size, number of produced offspring along life). We did not observe any effect of the chronic boat noise exposition on Daphnia's fitness. These results are consistent with results on previous acute noise exposure, but also opposite to other ones found with acute and chronic noise effect. Thus, we discuss how the noise structure and temporal pattern could affect its impacts on aquatic organisms. Our work highlights that noise pollution should be integrated in ecotoxicological studies, but also that some particular aspects of this pollutant should be considered differently than chemical pollutants. | Make paid

New | 23 November 2022 | Biorxiv link | Write review

Recently, there has been a growing interest in the development of pharmacological interventions targeting ageing, as well as on the use of machine learning for analysing ageing-related data. In this work we use machine learning methods to analyse data from DrugAge, a database of chemical compounds (including drugs) modulating lifespan in model organisms. To this end, we created four datasets for predicting whether or not a compound extends the lifespan of C. elegans (the most frequent model organism in DrugAge), using four different types of predictive biological features, based on compound-protein interactions, interactions between compounds and proteins encoded by ageing-related genes, and two types of terms annotated for proteins targeted by the compounds, namely Gene Ontology (GO) terms and physiology terms from the WormBase Phenotype Ontology. To analyse these datasets we used a combination of feature selection methods in a data pre-processing phase and the well-established random forest algorithm for learning predictive models from the selected features. The two best models were learned using GO terms and protein interactors as features, with predictive accuracies of about 82% and 80%, respectively. In addition, we interpreted the most important features in those two best models in light of the biology of ageing, and we also predicted the most promising novel compounds for extending lifespan from a list of previously unlabelled compounds. | Make paid

New | 19 November 2022 | Medrxiv link | Write review

Objective : Continuous renal replacement therapy (CRRT) in patients receiving venovenous extracorporeal membrane oxygenation (VV ECMO) can be accessed via separate venous access (SVA) or directly "in-line" within the ECMO circuit. The objective of this study is to compare the efficacy and safety of SVA versus in-line configuration in patients requiring CRRT and VV ECMO. Design: A retrospective review of 16 subjects receiving CRRT while on VV ECMO support. Setting: Adult ICU at a tertiary academic medical institution. Patients: Critically ill adult subjects with severe respiratory failure undergoing percutaneous VV ECMO and CRRT. Interventions: CRRT with venous access via separate temporary hemodialysis catheter versus direct access in-line with the VV ECMO circuit. Measurements and Results: Subject demographics, ECMO cannulation configuration, duration of CRRT, oxygenator and CRRT filter lifespan, number of interruptions, and dialysis blood flow rate were recorded. Five patients received CRRT via SVA and 11 patients via in-line configuration. There was a higher mean number of days on CRRT in the in-line group (7 vs 12 days, p = 0.32). There was no significant difference in oxygenator lifespan (days) (17.1 vs 14.72, p = 0.597), CRRT filter lifespan (days) (1.68 vs 2.15 p = 0.136), or interruptions per 100 CRRT days (10 vs 11.73, p = 0.834) in SVA vs in-line groups. Percentage days with therapeutic anticoagulation (65 vs 68, p =0.859) and initial dialysis blood flow rate (300 vs 310.91 mL/min, p = 0.258) were similar between configurations. SVA was associated with frequent access site manipulation (60% of patients) and catheter site bleeding (40% of patients). Conclusions: CRRT can be delivered via SVA or in-line configuration in patients requiring VV ECMO with similar efficacy. Separate venous access for CRRT may be associated with higher rates of access associated bleeding and need for access manipulation when compared to in-line configuration. | Make paid

New | 19 November 2022 | Medrxiv link | Write review

Physical activity has a substantial impact on health and mortality. Besides questionnaires that rely on subjective assessment of activity levels, accelerometers can help to objectify an individual's physical activity. Physical activity was assessed with the GT3X activity monitor (ActiGraph LLC, USA) in 797 participants of the Berlin Aging Study II (BASE-II) and compared with questionnaire data obtained from the Rapid Assessment of Physical Activity (RAPA). Of all participants, 760 fulfilled the wear-time based inclusion criteria. Mean age was 75.6 years (SD: 3.8 years, range 66.0 - 94.1 years) and 53% of the included participants were female. Average wear time was 23.2 hours/day (SD 1.3 hours/day). Statistically significant differences between RAPA groups were found for all accelerometric variables except energy expenditure. Post-hoc analysis, however, suggested low agreement between subjective and objective assessment of physical activity. When focusing on the first question of the RAPA questionnaire, participants who reported to be "seldom or never active" showed statistically significant lower activity levels in Vector Magnitude, step counts, and cut-off defined moderate physical activity (p<0.05). Total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides, fasting glucose and hemoglobin A1c were weakly correlated with accelerometric variables (Pearson's r <= 0.25). Results from this study suggest that subjectively assessed data from the RAPA and objectively assessed data from accelerometric variables obtained from the GT3X monitor are partially inconsistent in terms of the physical activity level of the participants. | Make paid

New | 19 November 2022 | Medrxiv link | Write review

Bipolar disorder (BD) has been previously associated with premature mortality and aging, including acceleration of epigenetic aging. Suicide attempts (SA) are greatly elevated in BD and are associated with decreased lifespan, biological aging, and poorer clinical outcomes. We investigated the relationship between GrimAge, an epigenetic clock trained on time-to-death and associated with mortality and lifespan, and SA in two independent cohorts of BD individuals (discovery cohort - controls (n=50), BD individuals with (n=77, BD/SA) and without (n=67, BD/non-SA) lifetime history of SA; replication cohort - BD/SA (n=48) and BD/non-SA (n=47)). An acceleration index for the GrimAge clock (GrimAgeAccel) was computed from blood DNA methylation (DNAm) and compared between groups with multiple general linear models. Differences in epigenetic aging from the discovery cohort were validated in the independent replication cohort. In the discovery cohort, controls, BD/non-SA, and BD/SA significantly differed on GrimAgeAccel (F=5.424, p=0.005), with the highest GrimAgeAccel in BD/SA (p=0.004, BD/SA vs. controls). Within the BD individuals, BD/non-SA and BD/SA differed on GrimAgeAccel in both cohorts (p=0.008) after covariate adjustment. Finally, DNAm-based surrogates revealed possible involvement of plasminogen activator inhibitor 1, leptin, and smoking pack-years in driving accelerated epigenetic aging. These findings pair with existing evidence that not only BD, but also SA, may be associated with an accelerated biological aging and provide putative biological mechanisms for morbidity and premature mortality in this population. | Make paid

New | 19 November 2022 | Medrxiv link | Write review

Most nations worldwide have aging populations. With age, sensory, cognitive and motor abilities decline and the risk for neurodegenerative disorders increases. These multiple impairments influence the quality of life and increase the need for care, thus putting a high burden on society, the economy, and the healthcare system. Therefore, it is important to identify factors that influence healthy aging, in particular ones that are potentially modifiable by each subject through choice of lifestyle. However, large-scale studies that investigate the influence of multiple multi-modal factors on a global description of healthy aging measured by multiple clinical assessments are sparse. Here, we propose a Machine Learning (ML) model that simultaneously predicts multiple cognitive and motor outcome measurements on a personalized level recorded from one learned composite score. This personalized composite score is derived by the model from a large set of multi-modal components from the TREND cohort including genetic, biofluid, clinical, demographic and lifestyle factors. We found that a model based on a single composite score was able to predict cognitive and motor abilities almost as well as a flexible regression model specifically trained for each single clinical score. In contrast to the flexible regression model, our composite score-based model is able to identify factors that globally influence cognitive and motoric abilities as measured by multiple clinical scores. We used the model to identify several risk and protective factors for healthy aging and recover physical exercise as a major, modifiable, protective factor. | Make paid

New | 19 November 2022 | Biorxiv link | Write review

Age-related neural dedifferentiation - reductions in the selectivity and precision of neural representations - contributes to cognitive aging and is thought to result from age increases in neural noise. This research has primarily used fMRI to examine age-related reductions in neural selectivity for different categories of visual stimuli. The present experiment used EEG to examine the link between neural noise and age-related neural dedifferentiation indexed by the scene-selective (P200) and face-selective (N170) ERP components. Young and older adults viewed images of scenes, objects, and faces during a 1-back task. Whereas both the P200 and N170 showed age-related slowing of peak latency, only the P200 showed age-related reductions in amplitude that were independent of visual and contrast acuity. We also examined the relationship between the ERP peak measures and an index of neural noise, namely the 1/f exponent of the frequency power spectrum. For the P200 amplitude, higher levels of neural noise were associated with smaller P200 amplitudes in young, but not older adults. In contrast, there was an age-invariant relationship between neural noise and N170 amplitude in the left hemisphere with higher levels of neural noise being associated reduced N170 amplitudes. While the present findings provide novel empirical evidence broadly consistent with predictions from computational models of neural dedifferentiation, the results also highlight potential limitations of the computational model that necessitate revision. The results also suggest that, at least for the P200, maintaining levels of neural noise similar to young adults might preserve levels of neural selectivity. | Make paid

New | 19 November 2022 | Biorxiv link | Write review

Single nucleotide polymorphisms are the most common type of genetic variation, but how these variants contribute to the evolutionary adaptation of complex phenotypes is largely unknown. Experimental evolution and genome-wide association studies have demonstrated that variation in the PPARgamma-homolog Eip75B is associated with longevity and life-history differences in the fruit fly Drosophila melanogaster. Using RNAi knockdown, we first demonstrate that reduced expression of Eip75B in adults affects lifespan, egg-laying rate and egg volume. We then tested the effect of a naturally occurring SNP variant within a cis-regulatory domain of Eip75B by applying two complementary approaches: a Mendelian randomization approach using lines of the Drosophila Genetic Reference Panel, and allelic replacement using precise CRISPR/Cas9-induced genome editing. Our experiments reveal that this natural polymorphism has a significant pleiotropic effect on fecundity and egg-to-adult viability, but not on longevity or other life-history traits. These results provide a rare functional validation at the nucleotide level and identify a natural allelic variant affecting fitness and life-history adaptation. | Make paid

New | 18 November 2022 | Medrxiv link | Write review

Background: Choroid plexus (CP) within brain ventricles is well known to produce CSF. Additional important CP functions are now recognized including critical modulation of inflammation. Recent MRI studies have demonstrated CP enlargement in human diseases including Multiple Sclerosis and Alzheimers Disease, and in association with neuroinflammation measured using translocator protein (TSPO) PET. The basis of MRI--visible CP enlargement is unknown. Purpose: Based on tissue studies demonstrating CP calcification as a common pathology associated with aging and disease, we hypothesized that previously--unmeasured calcium within CP contributes to MRI--measured CP volume, and may be more specifically associated with neuroinflammation. Materials and Methods: We performed a retrospective analysis of PET--CT studies performed between 2013--2019 on a single scanner using the TSPO radiotracer 11C--PK11195. Subjects included controls (n=43) and patients diagnosed with several non--inflammatory neuropsychiatric conditions (n=46.) Cortical inflammation / microglial activation was quantified as nondisplaceable Binding Potential (BPnd.) CP and ventricle volume were measured using Freesurfer. CP calcium was measured semi--manually via tracing of low--dose CT acquired with PET and automatically using a new CT/MRI method. The contribution of CP calcium, CP overall volume, ventricle volume, subject age, sex and diagnosis to BPnd was assessed using linear regression. Results: 89 subjects (mean age 54+/--7 years; 52 men) were included. Fully--automated CP calcium quantification was accurate (ICC with semi--manual tracing = .98.) The significant predictors of cortical neuroinflammation were subject age (p=.002) and CP calcium volume (p=.041), but not ventricle or CP volume. Conclusion: CP calcium volume can be accurately measured using low--dose CT acquired routinely with PET--CT. CP calcification -- but not CP overall volume -- was associated with cortical inflammation. Unmeasured CP calcification may be relevant to recent reports of CP enlargement in human inflammatory and other diseases. CP calcification may be a specific and relatively easily--acquired biomarker for neuroinflammation and CP pathology. | Make paid

New | 18 November 2022 | Biorxiv link | Write review

The difference between age predicted using anatomical brain scans and chronological age, i.e., the brain-age delta, provides a proxy for atypical aging. Various data representations and machine learning (ML) algorithms have been used for brain-age estimation. However, how these choices compare on performance criteria important for real-world applications, such as; (1) within-site accuracy, (2) cross-site generalization, (3) test-retest reliability, and (4) longitudinal consistency, remains uncharacterized. We evaluated 128 workflows consisting of 16 feature representations derived from gray matter (GM) images and eight ML algorithms with diverse inductive biases. Using four large neuroimaging databases covering the adult lifespan (total N = 2953, 18-88 years), we followed a systematic model selection procedure by sequentially applying stringent criteria. The 128 workflows showed a within-site mean absolute error (MAE) between 4.73-8.38 years, from which 32 broadly sampled workflows showed a cross-site MAE between 5.23-8.98 years. The test-retest reliability and longitudinal consistency of the top 10 workflows were comparable. The choice of feature representation and the ML algorithm both affected the performance. Specifically, voxel-wise feature spaces (smoothed and resampled), with and without principal components analysis, with non-linear and kernel-based ML algorithms performed well. Strikingly, the correlation of brain-age delta with behavioral measures disagreed between within-site and cross-site predictions. Application of the best-performing workflow on the ADNI sample showed a significantly higher brain-age delta in Alzheimer's and mild cognitive impairment patients. However, in the presence of age bias, the delta estimates in the diseased population varied depending on the sample used for bias correction. Taken together, brain-age shows promise, but further evaluation and improvements are needed for its real-world application. | Make paid

New | 18 November 2022 | Biorxiv link | Write review

Protein homeostasis controlled by the 26S proteasome plays a pivotal role in the adaption of plants to environmental stress, contributing to survival and longevity. During ageing in animals, proteasome activity declines resulting in senescence, however, in plants this is so far largely unexplored. Herein, we found that 26S proteasome capacity deteriorates with leaf age, while 20S proteasome activity increases. Interestingly, expression of proteasomal genes increases during leaf senescence, both at the steady-state mRNA level and poly-ribosome associated mRNA level. However, the increase in transcript level does not correlate with protein abundance and proteasome activity in senescing leaves. Furthermore, chemical inhibition of the proteasome results in accelerated leaf senescence. Interestingly, deterioration of proteasome activity in senescent leaves could be restored by cytokinin application. In Arabidopsis, feed-back regulation between proteasome activity and gene expression exists, and we propose that this is the cause for the high amount of proteasomal subunit mRNA during leaf senescence. In sink tissues like mature siliques and seeds, an increased 26S proteasome activity is observed. This increased activity is mainly due to enhanced proteasome assembly. This work provides new insights into the regulation of proteasome activity which deepens our understanding on source-sink relations and their impact on plant yield. | Make paid

New | 18 November 2022 | Biorxiv link | Write review

While enhanced tree growth over the last decades has been reported in forests across the globe, it remains unclear whether it drives persistent biomass increases of the stands, particularly in mature forests. Enhanced tree growth and stand-level biomass are often linked with a simultaneous increase in density-driven mortality and a reduction in tree longevity. Identifying empirical evidence regarding the balance between these processes is challenging due to the confounding effects of stand history, management, and environmental changes. Here, we investigate the link between growth and biomass via the shift in the negative relationship between average tree size and stand density (tree number). We find increasing stand density for a given tree size in unmanaged closed-canopy forests in Switzerland over the past six decades and a positive relationship between growth and stand density - qualitatively consistent with simulations by a mechanistic, cohort-resolving ecosystem model (LM3-PPA). Model simulations show that, in the absence of other disturbances, enhanced growth persistently increases biomass stocks despite simultaneous decreases in carbon residence time and tree longevity, independent of assumptions about the drivers of tree mortality. However, the magnitude of simulated changes critically depends on the shape of the mortality parameterizations. Our analyses reconcile reports of growth-induced reductions of tree longevity with model predictions of persistent biomass increases, and with our finding of a trend towards denser forests in response to growth - also in mature stands. | Make paid