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Below is this month's longevity research from Biorxiv, Medrxiv, and Arxiv.

New | 22 April 2023 | Biorxiv link | Write review

Myeloid cell metabolic reprogramming is a hallmark of inflammatory disease, however, its role in inflammation-induced hypercoagulability is poorly understood. Using novel myeloid cell-based global haemostasis assays and murine models of immunometabolic disease, we evaluated the role of inflammation-associated metabolic reprogramming in regulating blood coagulation. Glycolysis was essential for enhanced activated myeloid cell tissue factor expression and decryption, driving increased cell-dependent thrombin generation in response to inflammatory challenge. Similarly, inhibition of glycolysis enhanced activated macrophage fibrinolytic activity via reduced plasminogen activator inhibitor 1 (PAI-1)-activity. Macrophage polarisation or activation markedly increased endothelial protein C receptor (EPCR) expression on monocytes and macrophages, leading to increased myeloid cell-dependent protein C activation. Importantly, inflammation-dependent EPCR expression on tissue-resident macrophages was also observed in vivo. Adipose tissue macrophages from obese mice fed a high-fat diet exhibited significantly enhanced EPCR expression and APC generation compared to macrophages isolated from the adipose tissue of healthy mice. Similarly, the induction of colitis in mice prompted infiltration of EPCR+ innate myeloid cells within inflamed colonic tissue that were absent from the intestinal tissue of healthy mice. Collectively, this study identifies immunometabolic regulation of myeloid cell hypercoagulability, opening new therapeutic possibilities for targeted mitigation of thrombo-inflammatory disease. | Make paid

New | 22 April 2023 | Biorxiv link | Write review

Organisms utilize gene regulatory networks (GRNs) to make fate decisions, but the regulatory mechanisms of transcription factors (TFs) in GRNs are exceedingly intricate. A longstanding question in this field is how these tangled interactions synergistically contribute to decision-making procedures. To comprehensively understand the role of regulatory logic in cell fate decisions, we constructed a logic-incorporated GRN model and examined its behavior under two distinct driving forces (noise-driven and signal-driven). Under the noise-driven mode, we distilled the relationship among fate bias, regulatory logic, and noise profile. Under the signal-driven mode, we bridged regulatory logic and progression-accuracy trade-off, and uncovered distinctive trajectories of reprogramming influenced by logic motifs. In differentiation, we characterized a special logic-dependent priming stage by the solution landscape. Finally, we applied our findings to decipher three biological instances: hematopoiesis, embryogenesis, and trans-differentiation. Orthogonal to the classical analysis of expression profile, we harnessed noise patterns to construct the GRN corresponding to fate transition. Our work presents a generalizable framework for top-down fate-decision studies and a practical approach to the taxonomy of cell fate decisions. | Make paid

New | 22 April 2023 | Biorxiv link | Write review

RNA Binding Proteins (RBPs) interact with RNA and ubiquitously regulate RNA transcripts during their life cycle. Previous works showed that RBPs play fundamental roles in the progression of angiogenesis-related diseases. However, the role of RBPs in skeletal endothelium-dependent bone formation and osteogenesis is unclear. Here, we show that RBP-Ybx1 was strongly reduced in bone vasculature of OVX mice. Endothelial cell-specific deletion of Ybx1 impaired CD31hiEMCNhi endothelium morphology and resulted in low bone mass, while its overexpression promoted angiogenesis-dependent osteogenesis and ameliorated bone loss in OVX mice. Mechanistically, Ybx1 deletion disrupted CD31, EMCN and BMP4 stability in an m5C-dependent manner and blocked endothelial-derived BMP4 release, thereby inhibiting osteogenic differentiation of BMSCs. Administration of recombinant BMP4 protein restored impaired bone formation in Ybx1i{Delta}EC mice. Finally, tail vein injection of CD31-modified PEG-PLGA carrying sciadopitysin, a natural Ybx1 agonist, pharmacologically partially reversed CD31hiEMCNhi vessels decline and improved bone mass both in OVX and aging animals. These findings demonstrated the role of RBP-Ybx1 in angiogenesis-dependent bone formation and provided a novel therapeutic approach for ameliorating osteoporosis. | Make paid

New | 22 April 2023 | Biorxiv link | Write review

Intracellular pathogens and other endosymbionts reprogram host cell transcription to suppress immune responses and recalibrate biosynthetic pathways. This reprogramming is critical in determining the outcome of infection or colonisation. Here, we combine pooled CRISPR knockout screening with dual host-microbe single-cell RNA-sequencing to identify the molecular mediators of these transcriptional interactions, a method we term dual perturb-seq. Applying dual perturb-seq to the intracellular pathogen Toxoplasma gondii, we are able to identify previously uncharacterised effector proteins and directly infer their function from the transcriptomic data. We show that TgGRA59 contributes to the export of other effector proteins from the parasite into the host cell and identify a novel effector, TgSOS1, that is necessary for sustained host STAT6 signalling and thereby contributes to parasite immune evasion and persistence. Together, this work demonstrates a novel tool that can be broadly adapted to interrogate host-microbe transcriptional interactions and reveal mechanisms of infection and immune evasion. | Make paid

New | 22 April 2023 | Biorxiv link | Write review

A causal relationship exists among the aging process, organ decay and dis-function, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed EklfK74R/K74R or Eklf(K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/ EKLF has been generated that possesses extended lifespan and healthy characteristics including cancer resistance. We show that the high anti-cancer capability of the Eklf(K74R) mice are gender-, age- and genetic background-independent. Significantly, the anti-cancer capability and extended lifespan characteristics of Eklf(K74R) mice could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells. Targeted/global gene expression profiling analysis has identified changes of the expression of specific proteins and cellular pathways in the leukocytes of the Eklf(K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a novel hematopoietic/ blood system for long-term anti-cancer and, potentially, for anti-aging. | Make paid

New | 22 April 2023 | Biorxiv link | Write review

The pro-inflammatory state of macrophages is crucial in conferring its role in combating tumor cells. That state is closely associated with metabolic reprogramming. Here we identified key metabolic genes regulating macrophage pro-inflammatory activation in a pooled metabolic gene knockout CRISPR screen. We found that KEAP1 and ACOD1 are strong regulators of the pro-inflammatory state, and therefore developed human ACOD1 knockout macrophages with our induced pluripotent stem cell-derived CAR-macrophage (CAR-iMAC) platform. The engineered iMACs showed stronger and more persistent polarization toward the pro-inflammatory state, more ROS production, and more potent phagocytosis and cytotoxic functions against cancer cells in vitro. Upon transplantation to ovarian or pancreatic cancer mouse models, ACOD1 depleted CAR-iMACs exhibited enhanced capacity in repressing tumors in vivo and prolonged the lifespan of mice. In addition, combining ACOD1-depleted CAR-iMACs with immune check point inhibitors (ICIs), such as the anti-CD47 antibody or anti-PD1 antibody resulted in stronger tumor suppressing effect. Mechanistically, the depletion of ACOD1 reduced the immunometabolite itaconate, allowing KEAP1 to prevent NRF2 from entering the nucleus to activate the anti-inflammatory program. This study demonstrates that ACOD1 is a new myeloid target for cancer immunotherapy and metabolically engineered human iPSC-derived CAR-iMACs exhibit enhanced polarization and anti-tumor functions in adoptive cell transfer therapies. | Make paid

New | 21 April 2023 | Biorxiv link | Write review

Objective: Obesity-induced metabolic dysfunction, tissue remodeling, and chronic inflammation in visceral white adipose-tissue (WAT) are correlated with insulin resistance, type II diabetes, and metabolic disease pathogenesis. In this work, we sought to establish spatio-temporal context of adipose tissue macrophage (ATM) reprogramming during obesity. Methods: We captured single-cell RNA-sequencing, spatial transcriptomics, and histological imagining of murine WAT over the course of diet-induced obesity to study macrophage phenotype dynamics. We developed a straightforward mathematical approach to integrating multi-modal data to quantify obesity-induced changes to WAT organization. We aligned ATM phenotypes with crown-like structures (CLS) in early obesity and used spatial network analysis to uncover signaling mechanisms implicated in CLS formation. Results: We identified novel diversity of the lipid-associated macrophage (LAM) phenotype, whose transcriptional profile, signaling mechanisms, and spatial context serve as indicators of CLS formation in early obesity. We demonstrated that dysregulation of lipid-metabolic signaling is a critical turning point in the monocyte-LAM lineage and identified novel ligand-receptor mechanisms including Apoe, Lrp1, Lpl and App that serve as hallmarks of nascent CLS in WAT. Conclusions: Multi-modal spatio-temporal profiling demonstrates that LAMs disproportionately accumulate in CLS and are preceded by a transition-state macrophage phenotype with monocytic origins. We identified novel ligand-receptor interactions implicated in nascent CLS regions which may guide future cellular-reprogramming interventions for obesity-related sequelae. | Make paid

New | 21 April 2023 | Biorxiv link | Write review

Background: Neurophysiological studies with awake macaques typically require chronic cranial implants. Headpost and connector-chamber implants are used to allow head stabilization and to house connectors of chronically implanted electrodes, respectively. New Method: We present long-lasting, modular, cement-free headpost implants made of titanium that consist of two pieces: a baseplate and a top part. The baseplate is implanted first, covered by muscle and skin and allowed to heal and osseointegrate for several weeks to months. The percutaneous part is added in a second, brief surgery. Using a punch tool, a perfectly round skin cut is achieved providing a tight fit around the implant without any sutures. We describe the design, planning and production of manually bent and CNC-milled baseplates. We also developed a remote headposting technique that increases handling safety. Finally, we present a modular, footless connector chamber that is implanted in a similar two-step approach and achieves a minimized footprint on the skull. Results: Twelve adult male macaques were successfully implanted with a headpost and one with the connector chamber. To date, we report no implant failure, great headpost stability and implant condition, in four cases even more than 9 years post-implantation. Comparison with Existing Methods: The methods presented here build on several related previous methods and provide additional refinements to further increase implant longevity and handling safety. Conclusions: Optimized implants can remain stable and healthy for at least 9 years and thereby exceed the typical experiment durations. This minimizes implant-related complications and corrective surgeries and thereby significantly improves animal welfare. | Make paid

New | 20 April 2023 | Biorxiv link | Write review

Hand drawing involves multiple neural systems for planning and precise control of sequential movements, making it a valuable cognitive test for older adults. However, conventional visual assessment of drawings may not capture intricate nuances that could help track cognitive states. To address this issue, we utilized a deep-learning model, PentaMind, to examine cognition-related features from hand-drawn images of intersecting pentagons. PentaMind, trained on 13,777 images from 3,111 participants in three aging cohorts, explained 23.3% of the variance in global cognitive scores, a comprehensive hour-long cognitive battery. The model's performance, which was 1.92 times more accurate than conventional visual assessment, significantly improved the detection of cognitive decline. The improvement in accuracy was due to capturing additional drawing features that we found to be associated with motor impairments and cerebrovascular pathologies. By systematically modifying the input images, we discovered several important drawing attributes for cognition, including line waviness. Our results demonstrate that hand-drawn images can provide rich cognitive information, enabling rapid assessment of cognitive decline and suggesting potential clinical implications in dementia. | Make paid

New | 20 April 2023 | Biorxiv link | Write review

Musical training can offset age-related decline of speech perception in noisy environments. However, whether functional compensation or functional preservation the older musicians adopt to counteract the adverse effects of aging is unclear yet, so do older non-musicians. Here, we employed the fundamental brain organization feature named functional lateralization, and calculated network-based lateralization indices (LIs) of resting-state functional connectivity (FC) in 23 older musicians (OM), 23 older non-musicians (ONM), and 24 young non-musicians (YNM). OM outperformed ONM and almost equalized YNM in speech-in-noise/speech tasks. In parallel, ONM exhibited reduced lateralization than YNM in LI of intrahemispheric FC (LI_intra) in cingulo-opercular network (CON) and interhemispheric heterotopic FC (LI_he) in language network (LAN). Moreover, OM showed higher neural alignment to YNM (i.e., similar lateralization pattern) than ONM in LI_intra in CON, LAN, frontoparietal network (FPN) and default mode network (DMN) and LI_he in DMN. These findings suggest that musical training contributes to the preservation of youth-like lateralization in older adults. Furthermore, stronger left-lateralized and lower alignment-to-young of LI_intra in somatomotor network (SMN) and dorsal attention network (DAN) and LI_he in DMN correlated with better speech performance in ONM. In contrast, stronger right-lateralized LI_intra in FPN and DAN and higher alignment-to-young of LI_he in LAN correlated with better performance in OM. Thus, functional preservation and compensation of lateralization may play different roles in speech perception in noise for the elderly with and without musical expertise, respectively. Our findings provide insight into successful aging theories from the unique perspective of functional lateralization and speech perception. | Make paid

New | 19 April 2023 | Biorxiv link | Write review

Upregulation of nuclear factor {kappa}B (NF{kappa}B) signaling is a hallmark of aging and a major cause of age-related chronic inflammation. NF{kappa}B activity plays a critical role in transcriptional regulation and cell fate determination; however, its physiological function in inflammatory aging remains unclear. Here, we demonstrate that dysfunction of negative feedback regulators of NF{kappa}B, I{kappa}B and A20, alters the NF{kappa}B nuclear dynamics from oscillatory to sustained, thereby promoting cellular senescence. Sustained NF{kappa}B activity by I{kappa}B downregulation enhances inflammatory gene expression through increased NF{kappa}B-DNA binding, promotes purine catabolism by downregulating hypoxanthine phosphoribosyltransferase, and arrests the cell cycle. This regulatory mechanism was confirmed in aged mice heart tissues, suggesting that prolonged nuclear localization of NF{kappa}B drives chronic inflammation and metabolic rewiring associated with aging. | Make paid

New | 19 April 2023 | Biorxiv link | Write review

Sensory processing consists in the integration and interpretation of somatosensory information. It builds upon proprioception but is a distinct function requiring complex processing by the brain over time. Currently little is known about the effect of aging on sensory processing ability, nor the influence of other covariates such as motor function, proprioception, or cognition. In this study, we measured upper limb passive and active sensory processing, motor function, proprioception, and cognition in 40 healthy younger adults and 54 older adults. We analyzed age differences across all measures and evaluated the influence of covariates on sensory processing through regression. Our results showed larger effect sizes for age differences in sensory processing (r=0.38) compared to motor function (r=0.18-0.22) and proprioception (r=0.10-0.27), but smaller than for cognition (r=0.56-0.63). Aside from age, we found no evidence that sensory processing performance was related to motor function or proprioception, but active sensory processing was related to cognition ({beta}=0.30-0.42). In conclusion, sensory processing showed an age-related decline, while some proprioceptive and motor abilities were preserved across age. | Make paid

New | 19 April 2023 | Biorxiv link | Write review

Aged skin is prone to viral infections, but the mechanisms responsible for this immunosenescent immune risk are unclear. We observed that aged murine and human skin expressed reduced antiviral proteins (AVPs) and circadian regulators including Bmal1 and Clock. Bmal1 and Clock were found to control rhythmic AVP expression in skin and such circadian-control of AVPs was diminished by disruption of immune cell interleukin 27 signaling and deletion of Bmal1/Clock genes in mouse skins, as well as siRNA-mediated knockdown of CLOCK in human primary keratinocytes. We found that treatment of circadian enhancing agents, nobiletin and SR8278, reduced infection of herpes simplex virus 1 (HSV1) in epidermal explants and human keratinocytes in a Bmal1/Clock-dependent manner. Circadian enhancing treatment also reversed susceptibility of aging murine skin and human primary keratinocytes to viral infection. These findings reveal an evolutionarily conserved and age-sensitive circadian regulation of cutaneous antiviral immunity, underscoring circadian restoration as an antiviral strategy in aging populations. | Make paid

New | 19 April 2023 | Biorxiv link | Write review

Respiratory viruses can transmit by multiple modes, including contaminated surfaces, commonly referred to as fomites. Efficient fomite transmission requires that a virus remain infectious on a given surface material over a wide range of environmental conditions, including different relative humidities. Prior work examining the stability of influenza viruses on surfaces has relied upon virus grown in media or eggs, which does not mimic the composition of virus-containing droplets expelled from the human respiratory tract. In this study, we examined the stability of the 2009 pandemic H1N1 (H1N1pdm09) virus on a variety of nonporous surface materials at four different humidity conditions. Importantly, we used virus grown in primary human bronchial epithelial (HBE) cultures from different donors to recapitulate the physiological microenvironment of expelled viruses. We observed rapid inactivation of H1N1pdm09 on copper under all experimental conditions. In contrast to copper, viruses were stable on polystyrene plastic, stainless steel, aluminum, and glass, at multiple relative humidity conditions, but greater decay on ABS plastic was observed at short time points. However, the half-lives of viruses at 23% relative humidity were similar among non-copper surfaces and ranged from 4.5 to 5.9 hours. Assessment of H1N1pdm09 longevity on nonporous surfaces revealed that virus persistence was governed more by differences among HBE culture donors than by surface material. Our findings highlight the potential role of an individuals respiratory fluid on viral persistence and could help explain heterogeneity in transmission dynamics. | Make paid

New | 18 April 2023 | Biorxiv link | Write review

Here we report a novel strategy to rejuvenate dentate gyrus cells in old mice. This approach involves the activation of folate receptor by the use of simple compounds such as folate or a peptide that binds to the folate receptor . The injection of folate or folate-mimicking peptide into the brain brought about a significant enhancement of cognition. Likewise, the dentate gyrus cells of these mice showed increased plasticity and DNA methylation levels. On the basis of our findings, we propose that the activation of folate receptor through folate or by folate-mimicking peptides enhance neural plasticity and memory performance in a similar fashion to that previously reported in the literature for Yamanaka Factors (YF). However, in marked contrast with the long-term cyclic treatment used for cell partial reprogramming with YF, our method involves only a single injection of very simple small compounds. Our observations may facilitate future studies aimed at improving the clinical translation of cell partial rejuvenation methods into the field of neurodegenerative disorders. | Make paid

New | 18 April 2023 | Biorxiv link | Write review

Aged skin is prone to viral infections, but the mechanisms responsible for this immunosenescent immune risk are unclear. We observed that aged murine and human skin expressed reduced antiviral proteins (AVPs) and circadian regulators including Bmal1 and Clock. Bmal1 and Clock were found to control rhythmic AVP expression in skin and such circadian-control of AVPs was diminished by disruption of immune cell interleukin 27 signaling and deletion of Bmal1/Clock genes in mouse skins, as well as siRNA-mediated knockdown of CLOCK in human primary keratinocytes. We found that treatment of circadian enhancing agents, nobiletin and SR8278, reduced infection of herpes simplex virus 1 (HSV1) in epidermal explants and human keratinocytes in a Bmal1/Clock-dependent manner. Circadian enhancing treatment also reversed susceptibility of aging murine skin and human primary keratinocytes to viral infection. These findings reveal an evolutionarily conserved and age-sensitive circadian regulation of cutaneous antiviral immunity, underscoring circadian restoration as an antiviral strategy in aging populations. | Make paid

New | 18 April 2023 | Biorxiv link | Write review

The transcription factor SPT5 physically interacts with MYC oncoproteins and is essential for efficient transcriptional activation of MYC targets in cultured cells. Here we use Drosophila to address the relevance of this interaction in a living organism. Spt5 displays moderate synergy with Myc in fast proliferating young imaginal disc cells. During later development, Spt5-knockdown has no detectable consequences on its own, but strongly enhances eye defects caused by Myc-overexpression. Similarly, Spt5-knockdown in larval type 2 neuroblasts has only mild effects on brain development and survival of control flies, but dramatically shrinks the volumes of experimentally induced neuroblast tumors and significantly extends the lifespan of tumor-bearing animals. This beneficial effect is still observed when Spt5 is knocked down systemically and after tumor initiation, highlighting SPT5 as a potential drug target in human oncology. | Make paid

New | 16 April 2023 | Biorxiv link | Write review

In animals, early-life starvation can program gene expression changes that result in profound effects on adult phenotypes. For C. elegans nematodes, passage through the stress-resistant dauer diapause stage due to early-life starvation establishes a cellular memory that manifests as increased metabolism and decreased fecundity compared to continuously developed adults. To further investigate the connection between metabolism and reproduction, we supplemented the diet of postdauer adults with different fatty acids and examined their life history traits. Here, we show that dietary oleic acid (OA) supplementation uniquely increases the fecundity of both postdauer and continuously developed adults in a DAF-12 steroid signaling dependent manner, potentially through the increased expression of fat-7 {Delta}9-desaturase and vit-2 vitellogen genes. In addition, OA may rescue increased ferroptosis in postdauer germ lines and has complex effects on adult lifespan depending on life history. Together, our results suggest a model where OA modifies DAF-12 activity to positively regulate fecundity, metabolism, and lifespan in adults. | Make paid

New | 16 April 2023 | Biorxiv link | Write review

The complex biological mechanisms underlying human brain aging remain incompletely understood. To investigate this, we utilized multimodal magnetic resonance imaging and artificial intelligence (AI) to examine the genetic heterogeneity of the brain age gap (BAG) derived from gray matter volume (GM-BAG), white matter tract (WM-BAG), and functional connectivity (FC-BAG). Sixteen significant genomic loci were identified, with GM-BAG loci showing abundant associations with neurodegenerative and neuropsychiatric traits, WM-BAG for cancer and Alzheimer's disease (AD), and FC-BAG for only insomnia. The gene-drug-disease network further corroborated these associations by highlighting genes linked to GM-BAG for the treatment of neurodegenerative and neuropsychiatric disorders, and WM-BAG genes for cancer therapy. GM-BAG showed the highest enrichment of heritability in conserved regions, while in WM-BAG, the 5' untranslated regions exhibited the highest heritability enrichment; oligodendrocytes and astrocytes showed significant heritability enrichment in WM and FC-BAG, respectively. Notably, Mendelian randomization identified risk causal effects of triglyceride-to-lipid ratio in VLDL and type 2 diabetes on GM-BAG, and AD on WM-BAG. These findings suggest that interventions targeting these factors and diseases may ameliorate human brain health. Overall, our results provide valuable insights into the genetic heterogeneity of human brain aging, with potential implications for lifestyle and therapeutic interventions. | Make paid

New | 16 April 2023 | Biorxiv link | Write review

Despite their biological importance, the role of stem cells in human aging remains to be elucidated. In this work, we applied a machine learning methodology to GTEx transcriptome data and assigned stemness scores to 17,382 healthy samples from 30 human tissues aged between 20 and 79 years. We found that ~60% of the studied tissues present a significant negative correlation between the subject's age and stemness score. The only significant exception to this pattern was the uterus, where we observed an increased stemness with age. Moreover, we observed a global trend of positive correlations between cell proliferation and stemness. When analyzing the tissues individually, we found that ~50% of human tissues present a positive correlation between stemness and proliferation and 20% a negative correlation. Furthermore, all our analyses show negative correlations between stemness and cellular senescence, with significant results in ~80% of the tissues analyzed. Finally, we also observed a trend that hematopoietic stem cells derived from old patients might have more stemness. In short, we assigned stemness scores to human samples and show evidence of a pan-tissue loss of stemness during human aging, which adds weight to the idea that stem cell deterioration contributes to human ageing. | Make paid

New | 15 April 2023 | Biorxiv link | Write review

The antagonistic pleiotropy hypothesis posits that natural selection for pleiotropic mutations that confer earlier or more reproduction but impair the post-reproductive life causes aging. This hypothesis of the evolutionary origin of aging is supported by case studies but lacks unambiguous genomic evidence. Here we genomically test this hypothesis using the genotypes, reproductive phenotypes, and death registry of 276,406 UK Biobank participants. We observe a strong, negative genetic correlation between reproductive traits and lifespan. Individuals with higher polygenetic scores for reproduction (PGS_R) have lower survivorships to age 76 (SV76), and PGS_R increased over birth cohorts from 1940 to 1969. Similar trends are found from individual genetic variants examined. PGS_R and SV76 remain negatively correlated upon the control of the offspring number, revealing horizontal pleiotropy between reproduction and lifespan. Intriguingly, regardless of PGS_R, having two children maximizes SV76. These and other findings strongly support the antagonistic pleiotropy hypothesis of aging in humans. | Make paid

New | 15 April 2023 | Biorxiv link | Write review

Senescence, the deterioration of organismal function with advancing age, is a puzzling biological phenomenon. While actuarial senescence (i.e., age-dependent increases in mortality rates) is well described across some taxa, reproductive senescence (i.e. age-dependent declines in reproduction) is less understood, especially in males, with mixed patterns reported across studies. To examine the evidence for male reproductive senescence, we investigated how advancing male age affects ejaculate traits across non-human animals via a meta-analysis yielding 1814 effect sizes from 379 studies. We found no evidence for a general pattern of reproductive senescence. Instead, we found high heterogeneity for how reproduction changes with male age across animals. Some of this heterogeneity (>10%) was associated with biological factors. For example, there were taxonomical differences for some ejaculate traits- sperm motility declined with male age in lab rodents and fish, whereas ejaculate size improved with male age in bulls, fish, and insects. Some methodological factors were also important in explaining this heterogeneity: studies sampling a larger proportion of a species' lifespan were more likely to detect senescence in ejaculate traits, emphasising the need to examine the full life cycle of species to document senescence. Contrary to predictions, we reveal that the evidence for senescence in ejaculate traits is sporadic. Our findings will help generate novel hypotheses and identify more effective methodological approaches for studying male reproductive senescence. | Make paid

New | 15 April 2023 | Biorxiv link | Write review

Single-cell RNA-seq (scRNA-seq) technologies have been broadly utilized to reveal molecular mechanisms of respiratory pathology and physiology at single-cell resolution. Here, we established single-cell meta-analysis (scMeta-analysis) by integrating data from 8 public datasets, including 104 lung scRNA-seq samples with clinicopathological information and designated a cigarette smoking lung atlas. The atlas revealed early carcinogenesis events and defined the alterations of single-cell transcriptomics, cell population, and fundamental properties of biological pathways induced by smoking. In addition, we developed two novel scMeta-analysis methods: VARIED (Visualized Algorithms of Relationships In Expressional Diversity) and AGED (Aging-related Gene Expressional Differences). VARIED analysis revealed expressional diversity associated with smoking carcinogenesis. AGED analysis revealed differences in gene expression related to both aging and smoking states. The scMeta-analysis pave the way to utilize publicly -available scRNA-seq data and provide new insights into the effects of smoking and into cellular diversity in human lungs, at single-cell resolution. | Make paid

New | 15 April 2023 | Biorxiv link | Write review

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland with generally very unfavourable outcome. Two molecular subgroups, C1A and C1B, have been previously identified with a significant association with patient survival. In this work, we study chromatin state organization characterized by histone modifications using ChIP-sequencing in adult ACC. We describe the super-enhancer landscape of ACC, characterized by H3K27ac, and identify super-enhancer regulated genes that play a significant role in tumorigenesis. We show that the super-enhancer landscape reflects differences between the molecular subgroups C1A and C1B and identify networks of master transcription factors mirroring these differences. Additionally, we study the effects of molecules THZ1 and JQ1 previously reported to affect super-enhancer-driven gene expression in ACC cell lines. Our results reveal that the landscape of histone modifications in ACC is linked to its molecular subgroups and thus provide the groundwork for future analysis of epigenetic reprogramming in ACC. | Make paid

New | 14 April 2023 | Biorxiv link | Write review

DNA methylation is influenced by genetic and non-genetic factors. Here, we chart quantitative trait loci (QTLs) that modulate levels of methylation at highly conserved CpGs using liver methylome data from mouse strains belonging to the BXD Family. A regulatory hotspot on chromosome 5 had the highest density of trans-acting methylation QTLs (trans-meQTLs) associated with multiple distant CpGs. We refer to this locus as meQTL.5a. The trans-modulated CpGs showed age-dependent changes, and were enriched in developmental genes, including several members of the MODY pathway (maturity onset diabetes of the young). The joint modulation by genotype and aging resulted in a more ''aged methylome'' for BXD strains that inherited the DBA/2J parental allele at meQTL.5a. Further, several gene expression traits, body weight, and lipid levels mapped to meQTL.5a, and there was a modest linkage with lifespan. DNA binding motif and protein-protein interaction enrichment analysis identified the hepatic nuclear factor, Hnf1a (MODY3 gene in humans), as a strong candidate. The pleiotropic effects of meQTL.5a could contribute to variation in body size and metabolic traits, and influence CpG methylation and epigenetic aging that could have an impact on lifespan. | Make paid

New | 14 April 2023 | Biorxiv link | Write review

Aging is an inevitable process of cellular and physiological decline. These markers of age can be measured on the molecular and functional level. Wearable devices offer a non-invasive continuous measure of physiological and behavioural features and how they pertain to aging. Wearable data can be used to extrapolate information derived from epigenetic biological age predictions and its underlying biology. LifeQ-enabled wearable devices were worn for 40 days to harvest data on 48 human participants. Thereafter blood was drawn and methylation levels determined using the Illumina EPIC array. Multiple epigenetic clock ages were calculated and compared with wearable features. Activity minutes correlated with VO2 max (p = 0.003), subendocardial viability ratio (SEVR, p < 0.01), blood pressure index (BPI, p = 0.02), resting heart rate (RHR, p < 0.01) and heart outflow (HO, p < 0.01). Sedentary time correlated with RHR (p < 0.01), VO2 max (p = 0.01), SEVR (p = 0.04), and HO (p = 0.04). VO2 max, SEVR, small artery resistance (SAR), BPI and large artery stiffness index (LASI) correlated with multiple epigenetic age clock outputs and chronological age but were most strongly correlated with PCPhenoAge. VO2 max, (p = 0.04) RHR (p < 0.01) and LASI (p = 0.04) were significantly correlated with PCPhenoAge acceleration. Weighted gene correlation network analysis (WGCNA) of the differentially methylated positions of PCPhenoAge acceleration was used to construct modules, identifying 3 modules correlating with wearable features. Behavioural features impact physiological state, measured by the wearable, which are associated with epigenetic age and age acceleration. Signal from the underlying biology of age acceleration can be picked up by the wearable, presenting a case that wearable devices can capture portions of biological aging. | Make paid

New | 14 April 2023 | Biorxiv link | Write review

Biogenesis of inclusion bodies (IBs) facilitates protein quality control (PQC). Canonical aggresomes execute degradation of misfolded proteins while non-degradable amyloids quarantine into Insoluble Protein Deposits. Lewy Bodies (LBs) are well-known neurodegenerative IBs of alpha-Synuclein associated diseases like Dementia with Lewy bodies (DLB) and Parkinson's disease. Intriguingly, the PQC benefits and drawbacks associated with LBs remain underexplored. Here, we report that the crosstalk between LBs and aggresome-like IBs of alpha-Synuclein (Syn-aggresomes) buffers amyloidogenic alpha-Synuclein load in primary neurons and mitotic cell models. Using cellular biochemistry, genetic knockdown, and microscopy tools we find that LBs possess unorthodox PQC-capacities of self-quarantining the Syn-amyloids, and being degradable upon receding fresh amyloidogenesis. Syn-aggresomes equilibrate biogenesis of LBs by facilitating spontaneous and opportunistic turnover of soluble alpha-Synuclein and Syn-amyloids, respectively. However, LBs overgrow at the perinucleus once amyloidogenesis sets in and are misidentified by cytosolic BICD2 as cargos for motor-protein dynein. Simultaneously, microtubules surrounding the perinuclear LBs are distorted, misbalancing the dynein motor-force on nucleoskeleton leading to lamina injuries. Like typical Laminopathies, nucleocytoplasmic mixing, DNA-damage, and deregulated transcription of stress chaperones defeat the proteostatic purposes of LBs. We confirmed the lamina disintegrities in brain sections of Parkinson's disease patients. Together, our study provides insights into the intricate complexities of proteostatic possibilities associated with alpha-Synuclein inclusions and offers understanding on the proteostasis-sensitivity of LB-containing aging neurons via lamina-injuries. | Make paid

New | 14 April 2023 | Biorxiv link | Write review

Telomeres play central roles in senescence, aging and chromosome integrity. Using ONT long read sequencing we have assembled the genomes of Meloidogyne incognita, M. javanica and M. arenaria, the three most devastating plant-parasitic nematodes at unparalleled contiguity. The telomeric repeat (TTAGGC)n, evolutionarily conserved in nematodes, was not found in these genomes. Furthermore, no evidence for a telomerase enzyme or for orthologs of C. elegans telomere-associated proteins could be found. Instead, we identified species-specific composite repeats mostly present at one end of contigs. These repeats were G-rich, oriented and transcribed, similarly to known telomeric repeats. Using FISH we confirmed these repeats were present at one single end of M. incognita chromosomes. The discovery of a new kind of telomeric repeat in these species highlights the evolutionary diversity of chromosome protection systems despite their central roles and opens new perspectives towards the development of more specific control methods against these pests. | Make paid

New | 13 April 2023 | Medrxiv link | Write review

Vaccination rates against SARS-CoV-2 in children aged five to 11 years remain low in many countries. The current benefit of vaccination in this age group has been questioned given that the large majority of children have now experienced at least one SARS-CoV-2 infection. However, protection from infection, vaccination or both wanes over time. National decisions on offering vaccines to this age group have tended to be made without considering time since infection. There is an urgent need to evaluate the additional benefits of vaccination in previously infected children and under what circumstances those benefits accrue. We present a novel methodological framework for estimating the potential benefits of COVID-19 vaccination in previously infected children aged five to 11, accounting for waning. We apply this framework to the UK context and for two adverse outcomes: hospitalisation related to SARS-CoV-2 infection and Long Covid. We show that the most important drivers of benefit are: the degree of protection provided by previous infection; the protection provided by vaccination; the time since previous infection; and future attack rates. Vaccination can be very beneficial for previously infected children if future attack rates are high and several months have elapsed since the previous major wave in this group. Benefits are generally larger for Long Covid than hospitalisation, because Long Covid is both more common than hospitalisation and previous infection offers less protection against it. Our framework provides a structure for policy makers to explore the additional benefit of vaccination across a range of adverse outcomes and different parameter assumptions. It can be easily updated as new evidence emerges. | Make paid

New | 13 April 2023 | Medrxiv link | Write review

Health agencies rely upon survey-based physical measures to estimate the prevalence of key global health indicators such as hypertension. Such measures are usually collected by non-healthcare worker personnel and are potentially subject to measurement error due to variations in interviewer technique and setting, termed "interviewer effects". In the context of physical measurements, particularly in low- and middle-income countries, interviewer-induced biases have not yet been examined. Using blood pressure as a case study, we aimed to determine the relative contribution of interviewer effects on the total variance of blood pressure measurements in three large nationally-representative health surveys from the Global South. We utilized 169,681 observations between 2008 and 2019 from three health surveys (Indonesia Family Life Survey, National Income Dynamics Study of South Africa, and Longitudinal Aging Study in India). In a linear mixed model, we modeled systolic blood pressure as a continuous dependent variable and interviewer effects as random effects alongside individual factors as covariates. To quantify the interviewer effect-induced uncertainty in hypertension prevalence, we utilized a bootstrap approach comparing sub-samples of observed blood pressure measurements to their adjusted counterparts. Our analysis revealed that the proportion of variation contributed by in- terviewers to blood pressure measurements was statistically significant but small: approximately 0.24-2.2% depending on the cohort. Thus, hypertension prevalence estimates were not substantially impacted at national scales. However, individual extreme interviewers could account for measurement divergences as high as 12%. Thus, highly biased interviewers could have important impacts on hypertension estimates at the sub-district level. | Make paid