Biology subjects

Jang, H.

Publications and source records attributed to Jang, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Structure-guided design, synthesis, and characterization of C22- and C32-modified FK520 analogs with enhanced activity against human pathogenic fungi

Invasive fungal infections are a leading cause of death worldwide. Translating molecular insights into clinical benefits is challenging because fungal pathogens and their hosts share similar eukaryotic physiology. Consequently, current antifungal treatments have limited efficacy, may be poorly fungicidal in the host, can exhibit toxicity, and are increasingly compromised by emerging resistance. We have established that the phosphatase calcineurin (CaN) is required for invasive fungal disease and an attractive target for antifungal drug development. CaN is a druggable target, and there is vast clinical experience with the CaN inhibitors FK506 and cyclosporin A (CsA). However, while FK506 and its natural analog FK520 exhibit antifungal activity, they are also immunosuppressive in the host and thus not fungal-selective. We leverage our pathogenic fungal CaN-FK506-FKBP12 complex X-ray structures and biophysical data to support structure-based ligand design as well as structure-activity relationship analyses of broad-spectrum FK506/FK520 derivatives with potent antifungal activity and reduced immunosuppressive activity. Here we apply molecular docking studies to develop antifungal C22- or C32-modified FK520 derivatives with improved therapeutic index scores. Among them, the C32-modified FK520 derivative JH-FK-44 (7) demonstrates a significantly improved therapeutic index compared to JH-FK-08, our lead compound to date. NMR binding studies with C32-derivatives are consistent with our hypothesis that C32 modifications disrupt the hydrogen bonding network in the human complex while introducing favorable electrostatic and cation-{pi} interactions with the fungal FKBP12 R86 residue. These findings further reinforce calcineurin inhibition as a promising strategy for antifungal therapy. SignificanceInvasive fungal infections cause significant mortality worldwide, and current antifungal treatments are often ineffective, toxic, or face growing resistance. This research identifies calcineurin (CaN), a critical protein for fungal survival, as a potential target for developing new antifungal drugs. Although existing CaN inhibitors such as FK506 (tacrolimus) and FK520 (ascomycin) possess antifungal properties, their immunosuppressive effects limit their clinical utility. By studying the structure of human and fungal FKBP12-FK506 or FK520 complexes with CaN, we have designed and synthesized modified FK520 derivatives with strong antifungal activity and reduced immunosuppressive effects. These new derivatives are expected to have significantly improved therapeutic profiles, offering hope for more effective and safer antifungal treatments.

microbiology↗

bioRxiv2024

Gradients of Recognition Molecules Shape Synaptic Specificity of a Visuomotor Transformation

Converting sensory information into motor commands is fundamental to most of our actions. In Drosophila, visuomotor transformations are mediated by Visual Projection Neurons (VPNs). These neurons convert object location and motion into directional behaviors downstream through a synaptic gradient mechanism. However, the molecular origins of such graded connectivity remain unknown. We addressed this question in a VPN cell type called LPLC2, which integrates looming motion and transforms it into an escape response through two parallel dorsoventral synaptic gradients at its inputs and outputs. We identified two corresponding dorsoventral expression gradients of cell recognition molecules within the LPLC2 population that regulate this synaptic connectivity. Dpr13 determines synaptic outputs of LPLC2 axons by interacting with its binding partner DIP-{varepsilon} expressed in the Giant Fiber, a neuron that mediates escape. Similarly, beat-VI regulates synaptic inputs onto LPLC2 dendrites by interacting with Side-II expressed in upstream motion-detecting neurons. Behavioral, physiological, and molecular experiments demonstrate that these coordinated molecular gradients control differential synaptic connectivity, enabling the accurate transformation of visual features into motor commands. As within-neuronal-type variation in gene expression is also observed in the mammalian brain, graded expression of cell recognition molecules may represent a common mechanism underlying synaptic specificity.

neuroscience↗

bioRxiv2024

Whole-body PET imaging of SIV using anti-Env probes fails to reveal regions of specific uptake in rhesus macaques

Following the initial reports demonstrating the feasibility of immunoPET imaging of SIV using anti-Env monoclonal antibodies in non-human primates, replication efforts of the imaging system in HIV-infected individuals have yielded conflicting results. Herein, we used 89Zr-7D3 and 89Zr- ITS103.01LS-F(ab)2, two anti-gp120 antibodies for immunoPET imaging of SIV in n=20 rhesus macaques. Despite their demonstrated nanomolar affinity and strong binding specificity to SIV gp120 cell lines, we observed no discernible differences in their binding in primary cells, tissue sections of secondary lymphoid organs, in-vivo probe uptake between SIVmac-infected and uninfected macaques, or ex-vivo validation necropsies. While the probes remained stable in-vivo, only 89Zr-ITS103.01LS-F(ab)2 in chronic plasma retained its binding specificity to SIV gp120, with 89Zr-7D3 experiencing a >97% reduction in binding to gp120 due to competition from endogenous antibodies at the 7D3 binding site. The overall absence of specific uptake suggests inadequate binding potential (ligand affinity x target molarity) for these probes to effectively image SIV or HIV in-vivo, warranting further investigation into the lack of reproducibility observed with earlier non-human primate SIV imaging and conflicting human studies.

immunology↗

bioRxiv2024

Specialized signaling centers direct cell fate and spatial organization in a limb organoid model

Specialized signaling centers orchestrate robust development and regeneration. Limb morphogenesis, for instance, requires interactions between the mesoderm and the signaling center apical-ectodermal ridge (AER), whose properties and role in cell fate decisions have remained challenging to dissect. To tackle this, we developed mouse embryonic stem cells (mESCs)-based heterogeneous cultures and a limb organoid model, termed budoids, comprising cells with AER, surface ectoderm, and mesoderm properties. mESCs were first induced into heterogeneous cultures that self-organized into domes in 2D. Aggregating these cultures resulted in formation of limb bud-like structures in 3D, exhibiting chondrogenesis-based symmetry breaking and elongation. Using our organoids and quantitative in situ expression profiling, we uncovered that AER-like cells support nearby limb mesoderm and fibroblast identities while enhancing tissue polarization that permits distant cartilage formation. Together, our findings provide a powerful model to study aspects of limb morphogenesis, and reveal the ability of signaling center AER cells to concurrently modulate cell fate and spatial organization.

developmental biology↗

bioRxiv2024

A spatially resolved multiomic single-cell atlas of soybean development

Cis-regulatory elements (CREs) precisely control spatiotemporal gene expression in cells. Using a spatially resolved single-cell atlas of gene expression with chromatin accessibility across ten soybean tissues, we identified 103 distinct cell types and 303,199 accessible chromatin regions (ACRs). Nearly 40% of the ACRs showed cell-type-specific patterns and were enriched for transcription factor (TF) motifs defining diverse cell identities. We identified de novo enriched TF motifs and explored conservation of gene regulatory networks underpinning legume symbiotic nitrogen fixation. With comprehensive developmental trajectories for endosperm and embryo, we uncovered the functional transition of the three sub-cell types of endosperm, identified 13 sucrose transporters sharing the DOF11 motif that were co-up-regulated in late peripheral endosperm and identified key embryo cell-type specification regulators during embryogenesis, including a homeobox TF that promotes cotyledon parenchyma identity. This resource provides a valuable foundation for analyzing gene regulatory programs in soybean cell types across tissues and life stages.

plant biology↗

bioRxiv2024

Co-occurring Mutations in Different Genes Can Fuel Oncogenic Signaling and Serve as Metastatic Tumor Markers

Interrogation of big genomic data and integration with large-scale protein-protein interaction networks and pathways, can provide deep patterns that are rare- yet can prompt dramatic phenotypic alterations and serve as clinical signatures. Mapping cancer-specific co-occurring mutation-pair signatures, in primary and metastatic tumors, is indispensable in precision oncology. The additivity of co-occurring driver mutations in different genes (in trans) can lead to powerful proliferation signals. Co-occurring rare in trans combinations can serve as metastasis markers; excluded combinations may indicate candidates for oncogene-induced senescence (OIS), a tumor-suppressive mechanism. Our statistical framework of the pan-cancer mutation profiles of [~]60,000 tumor sequences from the TCGA and AACR GENIE databases, identified 3424 statistically significant different double mutations in non-redundant pathways, that is, have different downstream targets that may promote specific cancers through single or multiple pathways. Our analysis indicates that they are mostly in primary tumors. We list actionable in trans mutations for 2385 metastatic tumors and provide co-occurrence trees of metastatic breast- cancer markers. This innovative work clarifies the mechanistic conceptual basis and establishes the first of its kind tool for identifying and predicting metastasis. Crucially, when coupled with their proliferative functions and pathways, and linked with drugs, it could provide an invaluable metastasis-targeting resource.

systems biology↗

bioRxiv2024

Morphology and synapse topography optimize linear encoding of synapse numbers in Drosophila looming responsive descending neurons.

Synapses are often precisely organized on dendritic arbors, yet the role of synaptic topography in dendritic integration remains poorly understood. Utilizing electron microscopy (EM) connectomics we investigate synaptic topography in Drosophila melanogaster looming circuits, focusing on retinotopically tuned visual projection neurons (VPNs) that synapse onto descending neurons (DNs). Synapses of a given VPN type project to non-overlapping regions on DN dendrites. Within these spatially constrained clusters, synapses are not retinotopically organized, but instead adopt near random distributions. To investigate how this organization strategy impacts DN integration, we developed multicompartment models of DNs fitted to experimental data and using precise EM morphologies and synapse locations. We find that DN dendrite morphologies normalize EPSP amplitudes of individual synaptic inputs and that near random distributions of synapses ensure linear encoding of synapse numbers from individual VPNs. These findings illuminate how synaptic topography influences dendritic integration and suggest that linear encoding of synapse numbers may be a default strategy established through connectivity and passive neuron properties, upon which active properties and plasticity can then tune as needed.

neuroscience↗

bioRxiv2024

Measuring the dynamic balance of integration and segregation underlying consciousness, anesthesia, and sleep

Consciousness requires a dynamic balance of integration and segregation in functional brain networks. An optimal integration-segregation balance depends on two key aspects of functional connectivity: global efficiency (i.e., integration) and clustering (i.e., segregation). We developed a new fMRI-based measure, termed the integration-segregation difference (ISD), which captures both aspects. We used this metric to quantify changes in brain state from conscious wakefulness to loss of responsiveness induced by the anesthetic propofol. The observed changes in ISD suggest a profound shift to segregation in both whole brain and all brain subnetworks during anesthesia. Moreover, brain networks displayed similar sequences of disintegration and subsequent reintegration during, respectively, loss and return of responsiveness. Random forest machine learning models, trained with the integration and segregation of brain networks, identified the awake vs. unresponsive states and their transitions with accuracy up to 93%. We found that metastability (i.e., the dynamic recurrence of non-equilibrium transient states) is more effectively explained by integration, while complexity (i.e., diversity and intricacy of neural activity) is more closely linked with segregation. The analysis of a sleep dataset revealed similar findings. Our results demonstrate that the integration-segregation balance is a useful index that can differentiate among various conscious and unconscious states.

neuroscience↗

bioRxiv2024

Woman the Hunter? Female foragers sometimes hunt, yet gendered divisions of labor are real

Gendered divisions of labor are a feature of every known contemporary hunter-gatherer (forager) society. While gender roles are certainly flexible, and prominent and well-studied cases of female hunting do exist, it is more often men who hunt. A new study (Anderson et al., 2023) surveyed ethnographically known foragers and found that women hunt in 79% of foraging societies, with big-game hunting occurring in 33%. Based on this single type of labor, which is one among dozens performed in foraging societies, the authors question the existence of gendered division of labor altogether. As a diverse group of hunter-gatherer experts, we find that claims that foraging societies lack or have weak gendered divisions of labor are contradicted by empirical evidence. We conducted an in-depth examination of Anderson et al. (2023) data and methods, finding evidence of sample selection bias and numerous coding errors undermining the papers conclusions. Anderson et al. (2023) have started a useful dialogue to ameliorate the popular misconception that women never hunt. However, their analysis does not contradict the wide body of empirical evidence for gendered divisions of labor in foraging societies. Furthermore, a myopic focus on hunting diminishes the value of contributions that take different forms and downplays the trade-offs foragers of both sexes routinely face. We caution against ethnographic revisionism that projects Westernized conceptions of labor and its value onto foraging societies.

evolutionary biology↗

bioRxiv2024

BaYaka mothers balance childcare and subsistence tasks during collaborative foraging in Congo Basin

Across cultures, mothers face trade-offs between childcare and other labor. In hunter-gatherer societies, mothers face this choice on a daily basis when deciding either to take infants on foraging trips or to leave them with caregivers in the village. Yet, it remains unclear how the presence of infants in foraging groups constrains mothers mobility during foraging. Here, we present GPS, energy expenditure and food returns data of 359 foraging trips of 23 BaYaka mothers in the Republic of the Congo. We find that mothers spent more time on out-of-village foraging activities when they took infants along, compared to when they left infants behind. However, infant presence in foraging groups does not affect mothers travel distance, travel range, energy expenditure or food returns. Regardless of infant presence, women travel longer and further in a larger area when foraging in groups, compared to when foraging alone, especially in groups with more adults, females and both kin and non-kin. Our results suggest that BaYaka mothers develop ways to accommodate childcare with foraging activities by combining individual-level and group-level behavioural strategies. Our study highlights that group foraging may allow mothers with infants to maintain high mobility, which may have been a key to human range expansion.

ecology↗

bioRxiv2024

Dynamic evolution of the heterochromatin sensing histone demethylase IBM1

Heterochromatin constitutes a fundamental aspect of genomes that is crucial for maintaining genome stability. In flowering plants, maintenance of heterochromatin relies on a positive feedback loop involving the histone 3 lysine nine methyltransferase (H3K9), KRYPTONITE (KYP), and the DNA methyltransferase, CHROMOMETHYLASE3 (CMT3). An H3K9 demethylase, INCREASED IN BONSAI METHYLATION 1 (IBM1), has evolved to modulate the activity of KYP-CMT3 within transcribed genes. The absence of IBM1 activity results in aberrant methylation of gene bodies, which is deleterious. This study demonstrates extensive genetic and gene expression variations in KYP, CMT3, and IBM1 within and between flowering plant species. IBM1 activity in Arabidopsis thaliana is uniquely regulated by the abundance of H3K9me2 in a repetitive sequence within an intron preceding the histone demethylase domain. This mechanism enables IBM1 to monitor global levels of H3K9me2. We discovered that the methylated intron is prevalent across flowering plants, however, its underlying sequence exhibits dynamic evolution. Its absence in species lacking gene body DNA methylation suggests its primary role in sensing H3K9me2 and preventing its integration into these constitutively expressed genes. Furthermore, our investigation uncovered Arabidopsis thaliana accessions resembling weak ibm1 mutants, several Brassicaceae species with reduced IBM1 expression, and a potential IBM1 deletion. Evolution towards reduced IBM1 activity in some flowering plants could explain the frequent natural occurrence of diminished or lost CMT3 activity, as cmt3 mutants in A. thaliana mitigate the deleterious effects of IBM1.

plant biology↗

bioRxiv2023

Cell cycle progression mechanisms: slower cyclin-D/CDK4 activation and faster cyclin-E/CDK2

Dysregulation of cyclin-dependent kinases (CDKs) impacts cell proliferation, driving cancer. Here, we ask why the cyclin-D/CDK4 complex governs cell cycle progression through the longer G1 phase, whereas cyclin-E/CDK2 regulates the short G1/S phase transition. We consider the experimentally established high-level bursting of cyclin-E, and sustained duration of elevated cyclin-D expression in the cell, available experimental cellular and structural data, and comprehensive explicit solvent molecular dynamics simulations to provide the mechanistic foundation of the distinct activation scenarios of cyclin-D/CDK4 and cyclin-E/CDK2 in the G1 phase and G1/S transition of the cell cycle, respectively. These lead us to propose slower activation of cyclin-D/CDK4 and rapid activation of cyclin-E/CDK2. Importantly, we determine the mechanisms through which this occurs, offering innovative CDK4 drug design considerations. Our insightful mechanistic work addresses the compelling cell cycle regulation question and illuminates the distinct activation speeds in the G1 versus G1/S phases, which are crucial for cell function. StatementOur work provides an unprecedented mechanistic understanding of the distinct activation scenarios of cyclin-D/CDK4 and cyclin-E/CDK2 in cell cycle regulation, underpinning the slower activation of cyclin-D/CDK4 in the more extended G1 phase and the rapid activation of cyclin-E/CDK2 in the brief G1/S transition. Our findings address a long-standing question in cell cycle biology and suggest the design of targeted CDK4 inhibitors.

molecular biology↗

bioRxiv2023

Improved modeling of human vision by incorporating robustness to blur in convolutional neural networks

Whenever a visual scene is cast onto the retina, much of it will appear degraded due to poor resolution in the periphery; moreover, optical defocus can cause blur in central vision. However, the pervasiveness of blurry or degraded input is typically overlooked in the training of convolutional neural networks (CNNs). We hypothesized that the absence of blurry training inputs may cause CNNs to rely excessively on high spatial frequency information for object recognition, thereby causing systematic deviations from biological vision. We evaluated this hypothesis by comparing standard CNNs with CNNs trained on a combination of clear and blurry images. We show that blur-trained CNNs outperform standard CNNs at predicting neural responses to objects across a variety of viewing conditions. Moreover, blur-trained CNNs acquire increased sensitivity to shape information and greater robustness to multiple forms of visual noise, leading to improved correspondence with human perception. Our results provide novel neurocomputational evidence that blurry visual experiences are very important for conferring robustness to biological visual systems.

neuroscience↗

bioRxiv2023

Molecular Mechanism of Regulation of RhoA GTPase by Phosphorylation of RhoGDI

Rho-specific guanine dissociation inhibitors (RhoGDIs) play a crucial role in the regulation of Rho family GTPases. They act as negative regulators that prevent the activation of Rho GTPases by forming complexes with the inactive GDP-bound state of GTPase. Release of Rho GTPase from the RhoGDI-bound complex is necessary for Rho GTPase activation. Biochemical studies provide evidence of a "phosphorylation code", where phosphorylation of some specific residues of RhoGDI selectively releases its GTPase partner (RhoA, Rac1, Cdc42 etc.). This work attempts to understand the molecular mechanism behind this phosphorylation code. Using several microseconds long atomistic molecular dynamics (MD) simulations of the wild-type and phosphorylated states of the RhoA-RhoGDI complex, we propose a molecular-interaction-based mechanistic model for the dissociation of the complex. Phosphorylation induces major structural changes, particularly in the positively charged polybasic region (PBR) of RhoA and the negatively charged N-terminal region of RhoGDI that contribute most to the binding affinity. MM-PBSA binding free energy calculations show a significant weakening of interaction on phosphorylation at the RhoA-specific site of RhoGDI. In contrast, phosphorylation at a Rac1-specific site leads to the strengthening of the interaction confirming the presence of a phosphorylation code. RhoA-specific phosphorylation leads to a reduction in the number of contacts between the PBR of RhoA and the N-terminal region of RhoGDI, which manifests reduction of the binding affinity. Using hydrogen bond occupancy analysis and energetic perturbation network, we propose a mechanistic model for the allosteric response, i.e., long range signal propagation from the site of phosphorylation to the PBR and buried geranylgeranyl group in the form of rearrangement and rewiring of hydrogen bonds and salt bridges. Our results highlight the crucial role of specific electrostatic interactions in manifestation of the phosphorylation code.

biophysics↗

bioRxiv2023

Host-Microbiome Associations in Saliva Predict COVID-19 Severity

Established evidence indicates that oral microbiota plays a crucial role in modulating host immune responses to viral infection. Following Severe Acute Respiratory Syndrome Coronavirus 2 - SARS-CoV-2 - there are coordinated microbiome and inflammatory responses within the mucosal and systemic compartments that are unknown. The specific roles that the oral microbiota and inflammatory cytokines play in the pathogenesis of COVID-19 are yet to be explored. We evaluated the relationships between the salivary microbiome and host parameters in different groups of COVID-19 severity based on their Oxygen requirement. Saliva and blood samples (n = 80) were collected from COVID-19 and from non-infected individuals. We characterized the oral microbiomes using 16S ribosomal RNA gene sequencing and evaluated saliva and serum cytokines using Luminex multiplex analysis. Alpha diversity of the salivary microbial community was negatively associated with COVID-19 severity. Integrated cytokine evaluations of saliva and serum showed that the oral host response was distinct from the systemic response. The hierarchical classification of COVID-19 status and respiratory severity using multiple modalities separately (i.e., microbiome, salivary cytokines, and systemic cytokines) and simultaneously (i.e., multi-modal perturbation analyses) revealed that the microbiome perturbation analysis was the most informative for predicting COVID-19 status and severity, followed by the multi-modal. Our findings suggest that oral microbiome and salivary cytokines may be predictive of COVID-19 status and severity, whereas atypical local mucosal immune suppression and systemic hyperinflammation provide new cues to understand the pathogenesis in immunologically naive populations. Significance StatementThe oral mucosa is one of the first sites encountered by bacterial and viral infections, including SARS-CoV-2. It consists of a primary barrier occupied by a commensal oral microbiome. The primary function of this barrier is to modulate immunity and provide protection against invading infection. The occupying commensal microbiome is an essential component that influences the immune systems function and homeostasis. The present study showed that the host oral immune response performs unique functions in response to SARS-CoV-2 when compared to systemic responses during the acute phase. We also demonstrated that there is a link between oral microbiome diversity and COVID-19 severity. Additionally, the salivary microbiome was predictive of not only disease status but also severity.

immunology↗

bioRxiv2023

Neurodevelopmental disorders and cancer networks share pathways; but differ in mechanisms, signaling strength, and outcome

Neurodevelopmental disorders (NDDs) and cancer are connected, with immunity as their common factor. Their clinical presentations differ; however, individuals with NDDs are more likely to acquire cancer. Schizophrenia patients have [~]50% increased risk; autistic individuals also face an increased cancer likelihood. NDDs are associated with specific brain cell types at specific locations, emerging at certain developmental time windows during brain evolution. Their related mutations are germline; cancer mutations are sporadic, emerging during life. At the same time, NDDs and cancer share proteins, pathways, and mutations. Here we ask exactly which features they share, and how despite their commonality, they differ in outcomes. Our pioneering bioinformatics exploration of the mutations, reconstructed disease-specific networks, pathways, and transcriptome profiles of autism spectrum disorder (ASD) and cancers, points to elevated signal strength in pathways related to proliferation in cancer, and differentiation in ASD. Signaling strength, not the activating mutation, is the key factor in deciding cancer versus NDDs.

systems biology↗

bioRxiv2023

An evolutionary epigenetic clock in plants

Molecular clocks are the basis for dating the divergence between lineages over macro-evolutionary timescales (~105-108 years). However, classical DNA-based clocks tick too slowly to inform us about the recent past. Here, we demonstrate that stochastic DNA methylation changes at a subset of cytosines in plant genomes possess a clock-like behavior. This epimutation-clock is orders of magnitude faster than DNA-based clocks and enables phylogenetic explorations on a scale of years to centuries. We show experimentally that epimutation-clocks recapitulate known topologies and branching times of intra-species phylogenetic trees in the selfing plant A. thaliana and the clonal seagrass Z. marina, which represent two major modes of plant reproduction. This discovery will open new possibilities for high-resolution temporal studies of plant biodiversity.

evolutionary biology↗

bioRxiv2022

Optical Metabolic Imaging Uncovers Sex- and Diet-dependent Lipid Changes in Aging Drosophila Brain

Aging is associated with progressive declines in physiological integrity and functions alongside increases in vulnerability to develop a number of diseases. The brain regulates sensory and motor functions as well as endocrine functions, and age-associated changes in brain are likely prerequisite for the organismal aging. Lipid metabolism has been associated with brain aging, which could be easily intervened by diets and lifestyles. However, the underlying mechanism through which brain lipid metabolism is regulated by diet during aging is elusive. Using stimulated Raman scattering (SRS) imaging combined with deuterium water (D2O) labeling, we visualized that lipid metabolic activities were changed by diet manipulation in aging Drosophila brain. Furthermore, we illuminated that insulin/IGF-1 signaling (IIS) pathway mediates the transformation of brain lipid metabolic changes in both an aging- and a diet-dependent manner. The lipid droplets (LDs) in the brain gradually became inert in both activities of lipid synthesis and mobilization with aging. High sugar diets enhanced the metabolic activity through promoting lipogenesis while dietary restriction increased the metabolic activity in both lipogenesis and lipolysis in brain LDs. However, these effects were impaired in both chico1/+ and dfoxo Drosophila mutants. We also observed that old chico1/+ brains maintained high metabolic activities, whilst the aged dfoxo brains acted exactly the opposite. More interestingly, the sexual dimorphism in brain lipid metabolism was impaired under diet regulation in both chico1/+ and dfoxo mutants. Locally reduced IIS activity in glial cells can mimic the systemic changes in systematic IIS mutants to maintain lipogenesis and lipolysis in aged brains, providing mechanistic insight into the anti-aging effects of IIS pathway. Our results highlight the manipulation of glia-specific IIS activity as a promising strategy in anti-aging treatments.

bioengineering↗