Biology subjects

Li, C.

Publications and source records attributed to Li, C..

At least 433 records · Page 24Linked to original sources

bioRxiv2024

A causative SNP in the promoter of myogenin is essential for myogenic differentiation

Single nucleotide polymorphisms (SNPs) widely existing in different breeds genome represent population-specific. Under the influence of long-term evolution and artificial selection, there are a large number of SNPs between western lean-type pig breeds and Chinese indigenous pig breeds, but until now, little is known about their roles in inter-breed differences. Our study revealed SNP rs3471653254 C>T generated from the two types of pigs mentioned above, located in the promoter shared by MyoG and Myoparr, played an important role in the differentiation of myoblast by influencing the enrichment of HOXA5 to regulate the transcription of MyoG and Myoparr. Meanwhile, Myoparr could be used as the sponge of mir-30b-3p which repressed myogenic differentiation and muscle regeneration through targeting MyoD. Our results indicated that SNP rs3471653254 C>T is essential for myogenic differentiation and regeneration and could be used as an ideal site for increasing lean meat production in pigs.

genetics↗

bioRxiv2024

Comparative lifespan and healthspan of nonhuman primate species common to biomedical research

There is a critical need to generate age- and sex-specific survival curves to characterize chronological aging consistently across nonhuman primates (NHP) used in biomedical research. Sex-specific Kaplan-Meier survival curves were computed in 12 translational aging models: baboon, bonnet macaque, chimpanzee, common marmoset, coppery titi monkey, cotton-top tamarin, cynomolgus macaque, Japanese macaque, pigtail macaque, rhesus macaque, squirrel monkey, and vervet/African green. After employing strict inclusion criteria, primary results are based on 12,269 NHP that survived to adulthood and died of natural/health-related causes. A secondary analysis was completed for 32,616 NHP that died of any cause. Results show a pattern of reduced male survival among catarrhines (African and Asian primates), especially macaques, but not platyrrhines (Central and South American primates). For many species, median lifespans were lower than previously reported. An important consideration is that these analyses may offer a better reflection of healthspan than lifespan since research NHP are typically euthanized for humane welfare reasons before their natural end of life. This resource represents the most comprehensive characterization of sex-specific lifespan and age-at-death distributions for 12 biomedically relevant species, to date. These results clarify relationships among NHP ages and provide a valuable resource for the aging research community, improving human-NHP age equivalencies, informing investigators of expected survival rates, providing a metric for comparisons in future studies, and contributing to understanding of factors driving lifespan differences within and among species.

physiology↗

bioRxiv2024

Adipogenin Dictates Adipose Tissue Expansion by Facilitating the Assembly of a Dodecameric Seipin Complex

Adipogenin (Adig) is an evolutionarily conserved microprotein and is highly expressed in adipose tissues and testis. Here, we identify Adig as a critical regulator for lipid droplet formation in adipocytes. We determine that Adig interacts directly with seipin, leading to the formation of a rigid complex. We solve the structure of the seipin/Adig complex by Cryo-EM at 2.98[A] overall resolution. Surprisingly, seipin can form two unique oligomers, undecamers and dodecamers. Adig selectively binds to the dodecameric seipin complex. We further find that Adig promotes seipin assembly by stabilizing and bridging adjacent seipin subunits. Functionally, Adig plays a key role in generating lipid droplets in adipocytes. In mice, inducible overexpression of Adig in adipocytes substantially increases fat mass, with enlarged lipid droplets. It also elevates thermogenesis during cold exposure. In contrast, inducible adipocyte-specific Adig knockout mice manifest aberrant lipid droplet formation in brown adipose tissues and impaired cold tolerance.

cell biology↗

bioRxiv2024

Long-Range Enhancer Networks Gradually Emerge as Key Regulators During Human Cortical Neurogenesis

The chromatin in the human brain cortex shows more enhancer-enhancer contacts than in macaques and mice, yet the organization of these contacts across cellular states and their mechanisms remain unclear. Here, we developed SCOPE-C, a cost-effective technique designed for mapping DNase I Hypersensitive Sites and their spatial interactions, with the potential for scalability to single-cell resolution. Employing SCOPE-C, we generated a comprehensive chromatin map detailing cis-regulatory elements in four cell types during neurogenesis in human, macaque, and mouse fetal cortex. This map introduces a model of long-range enhancer networks that regulate gene transcription during human cortical neurogenesis. In this model, CTCF-mediated loop extrusion forms stripes of enhancer interaction hubs extending up to 10 Mb in human Excitatory Neurons. Enriched with human-specific enhancers and neuropsychiatric disorder-linked SNPs, these remarkably long-range networks predominantly control EN marker genes, suggesting their critical role in robust gene expression during human cortical neurogenesis.

genomics↗

bioRxiv2024

A Hypothalamic Circuit that Modulates Feeding and Parenting Behaviors

Across mammalian species, new mothers undergo considerable behavioral changes to nurture their offspring and meet the caloric demands of milk production1-5. While many neural circuits underlying feeding and parenting behaviors are well characterized6-9, it is unclear how these different circuits interact and adapt during lactation. Here, we characterized the transcriptomic changes in the arcuate nucleus (ARC) and the medial preoptic area (MPOA) of the mouse hypothalamus in response to lactation and hunger. Furthermore, we showed that heightened appetite in lactating mice was accompanied by increased activity of hunger-promoting agouti-related peptide (AgRP) neurons in the ARC. To assess the strength of hunger versus maternal drives, we designed a conflict assay where female mice chose between a food source or a chamber containing pups and nesting material. Although food-deprived lactating mothers prioritized parenting over feeding, hunger reduced the duration and disrupted the sequences of parenting behaviors in both lactating and virgin females. We discovered that ARCAgRP neurons directly inhibit bombesin receptor subtype-3 (BRS3) neurons in the MPOA, a population that governs both parenting and satiety. Selective activation of this ARCAgRP to MPOABRS3 circuit shifted behaviors from parenting to food-seeking. Thus, hypothalamic networks are modulated by physiological states and work antagonistically during the prioritization of competing motivated behaviors.

neuroscience↗

bioRxiv2024

Acupuncture triggers earlier recovery from ischemic stroke than sham needling in a rat model

Summary paragraphAcupuncture, a traditional Chinese medical treatment that has been practiced for over 2,000 years, is widely used around the world [1]. However, its efficacy and distinction from random stimulation are still being questioned [2, 3]. Over the years, many studies have reported either favorable, neutral or even skeptical outcomes regarding the treatment effect of acupuncture on diverse ailments [4-7]. The major question behind this controversy is whether acupuncture is different from random needle insertion and whether its efficacy can be attributed to the placebo effect [8, 9]. Here, we use micro-positron emission tomography (microPET) imaging in a randomized controlled animal study to show that acupuncture facilitates faster recuperation in comparison to sham acupuncture and blank control. Based on the microPET imaging of subjects undergoing daily acupuncture over two weeks duration, we dynamically monitored the metabolic activity levels in different brain regions and found that both acupoint and non-acupoint stimulation could improve ischemic stroke recovery. This finding is consistent with previous reports that both acupuncture and sham needling show a positive effect in the treatment of diseases [4, 5, 8]. More importantly, we further found that rats receiving acupuncture at Baihui (GV20) and Shuigou (GV26), two commonly used acupoints for stroke rehabilitation based on the concept of the meridian system, showed earlier recovery effects than rats receiving sham needling treatment. This difference mainly appeared in regions involved in motor control and was validated by a balance beam walking test. Our findings, in conjunction with a recent electroacupuncture study that revealed a neuroanatomical pathway to mediate the vagal-adrenal anti-inflammatory axis [10], provide quantitative evidence supporting the specificity of acupoints in acupuncture therapy.

neuroscience↗

bioRxiv2024

How do we imagine a speech? A triple network model for situationally simulated inner speech

Inner speech is a silent verbal experience and plays central roles in human consciousness and cognition. Despite impressive studies over the past decades, the neural mechanisms of inner speech remain largely unknown. In this study, we adopted an ecological paradigm called situationally simulated inner speech. Unlike mere imaging speech of words, situationally simulated inner speech involves the dynamic integration of contextual background, episodic and semantic memories, and external events into a coherent structure. We conducted dynamic activation and network analyses on fMRI data, where participants were instructed to engage in inner speech prompted by cue words across 10 different contextual backgrounds. Our seed-based co-activation pattern analyses revealed dynamic involvement of the language network, sensorimotor network, and default mode network in situationally simulated inner speech. Additionally, frame-wise dynamic conditional correlation analysis uncovered four temporal-reoccurring states with distinct functional connectivity patterns among these networks. We proposed a triple network model for deliberate inner speech, including language network for a truncated form of overt speech, sensorimotor network for perceptual simulation and monitoring, and default model network for integration and sense-making processing. HighlightsO_LIIn ten contextual backgrounds, subjects were instructed to perform situationally simulated inner speech based on cue words. C_LIO_LIThe ventral parts of the bilateral somatosensory areas and middle superior temporal gyrus were as centers for seed-based co-activation pattern analyses. C_LIO_LIA triple network model of language network, sensorimotor network, and default mode network was proposed for deliberate inner speech. C_LI

neuroscience↗

bioRxiv2024

Loss of PINK1 causes age-dependent mitochondrial trafficking deficits in nigrostriatal dopaminergic neurons through aberrant activation of p38 MAPK

Mutations in PTEN-induced putative kinase 1 (PINK1) cause early-onset, autosomal-recessive Parkinsons disease (PD). While previous studies showed age-related declines in dopamine release and ATP levels in Pink1-/- mice, the mechanisms remain unclear. Using a novel TH-Mito-Dendra2 transgenic mouse model to label dopaminergic neuron mitochondria, it is found that PINK1 loss leads to age-dependent deficits in mitochondrial axonal trafficking, characterized by reduced anterograde movement and increased static mitochondria in acute brain slices, which more closely mimic in vivo conditions. Pharmacological induction of reactive oxygen species (ROS) and calcium release impaired mitochondrial mobility. Pink1 knockout mice exhibited elevated mitochondrial calcium, ROS levels, and p38 MAPK hyperactivation. Treatment with p38 inhibitor SB202190 restored mitochondrial motility and increased anterograde transport. Our findings suggest that PINK1 loss disrupts mitochondrial trafficking by disturbing calcium homeostasis and ROS production via the p38 pathway, contributing to PD pathogenesis. Table of Contents O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/602426v3_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@1352742org.highwire.dtl.DTLVardef@a48086org.highwire.dtl.DTLVardef@1f209daorg.highwire.dtl.DTLVardef@164ed23_HPS_FORMAT_FIGEXP M_FIG C_FIG Using a novel mouse model with labeled dopaminergic neuron mitochondria, Zhao J. et al. discovered age dependent disruptions in mitochondrial transport. Their research showed progressive deterioration of mitochondrial movement, characterized by reduced anterograde movement and increased static mitochondria. These changes were associated with higher oxidative stress and hyperactivation of p38 MAPK in Parkinsons disease.

neuroscience↗

bioRxiv2024

Cost-effective DNA storage with DNA movable type

In the face of exponential data growth, DNA-based storage offers a promising solution for preserving big-data. However, most existing DNA storage methods, akin to traditional block printing, require costly chemical synthesis for each individual data file, adopting a sequential, one-time-use synthesis approach. To overcome these limitations, we introduce a novel, cost-effective "DNA-Movable-Type Storage" system, inspired by movable type printing. This system utilizes pre-fabricated DNA movable types-short, double-stranded DNA oligonucleotides encoding specific payload, address, and checksum data. These DNA-MTs are enzymatically ligated/assembled into cohesive sequences, termed "DNA movable type blocks", streamlining the assembly process with the automated BISHENG-1 DNA-MT inkjet printer. Using BISHENG-1, we successfully printed, assembled, stored and accurately retrieved 43.7 KB of data files in diverse formats (text, image, audio, and video) in vitro and in vivo, using only 350 DNA-MTs. Notably, each DNA-MT, synthesized once (2 OD), can be used up to 10,000 times, reducing costs to 122 $/MB-outperforming existing DNA storage methods. This innovation circumvents the need to synthesize entire DNA sequences encoding files from scratch, offering significant cost and efficiency advantages. Furthermore, it has considerable untapped potential to advance a robust DNA storage system, better meeting the extensive data storage demands of the big-data era.

bioinformatics↗

bioRxiv2024

SARS-CoV-2 B Epitope-Guided Neoantigen NanoVaccines Enhance Tumor-Specific CD4/CD8 T Cell Immunity Through B Cell Antigen Presentation

Current neoantigen cancer vaccines activate T cell immunity through dendritic cell /macrophage-mediated antigen presentation. It is unclear whether incorporating B cell-mediated antigen presentation into current neoantigen vaccines could enhance CD4/CD8 T cell immunity to improve their anticancer efficacy. We developed a SARS-CoV-2 B cell epitope-guided neoantigen peptide/mRNA cancer nanovaccines (BSARSTNeoAgVax) to improve anticancer efficacy by enhancing tumor-specific CD4/CD8 T cell antitumor immunity through B cell-mediated antigen presentation. BSARSTNeoAgVax crosslinked with B cell receptor, promoted SARS-CoV-2 B cell-mediated antigen presentation to tumor-specific CD4 T cells, increased tumor-specific follicular/non-follicular CD4 T cells, and enhanced B cell-dependent tumor-specific CD8 T cell immunity. BSARSTNeoAgVax achieved superior efficacy in melanoma, pancreatic, and breast cancer models compared to the current neoantigen vaccines. Our study provides a universal platform, SARS-CoV-2 B epitope-guided neoantigen nanovaccines, to improve anticancer efficacy against various cancer types by enhancing CD4/CD8 T cell antitumor immunity through viral-specific B cell-mediated antigen presentation.

immunology↗

bioRxiv2024

BOOST: a robust ten-fold expansion method on hour-scale

Expansion microscopy (ExM) enhances the microscopy resolution by physically expanding biological specimens and improves the visualization of structural and molecular details. Numerous ExM techniques and labeling methods have been developed and refined over the past decade to cater to specific research needs. Nonetheless, a shared limitation among current protocols is the extensive time required for sample processing, particularly for challenging-to-expand biological specimens (e.g., formalin-fixed paraffin-embedded (FFPE) sections and large three-dimensional specimens). Here, we have developed a rapid and robust ExM workflow named BOOST, which leverages a series of novel microwave (MW)-accelerated ExM chemistry, resulting in a single-step linear expansion of [~]10x. Specifically, BOOST facilitates a [~]10-fold expansion of cultured cells, tissue sections, and even the challenging-to-expand FFPE sections under merely 90 minutes with heat and surfactant-based protein denaturation. Furthermore, BOOST employs microwave-assisted proteomic staining and immunostaining to facilitate high-resolution visualization of structural and molecular details with significantly enhanced throughput. Noteworthily, BOOST has pioneered a [~]10-fold expansion of large millimeter-sized three-dimensional specimens in approximately three hours. BOOST offers an easily adaptable workflow based on stable and common reagents, thus boosting the potential adoption of ExM methods in biological investigations.

bioengineering↗

bioRxiv2024

SlNAP2 promoted fruit ripening by directly binding the ACS2 promoter and interacting with EIL3

The ripening process of tomato fruit is affected by a variety of environmental factors and genetic regulators. NAC transcription factors (TFs) function in a multitude of biological processes, while the current knowledge on the participation of NAC TFs in the regulatory network of fruit ripening is relatively limited. In this study, we isolated a NAC TFs, NAP2, which acts as a positive transcription activator in tomato fruit ripening. We also observed a notable delay in the ripening process of SlNAP2 silenced and knockout mutant fruit. In particular, ethylene production was obviously inhibited in SlNAP2 mutant fruit. Y1H and DLR assays showed that SlNAP2 directly binds to the promoter of SlACS2 and activates its transcriptional activity. Furthermore, SlNAP2 and SlEIL3 physically interaction was demonstrated by yeast two-hybrid (Y2H), luciferase complementation (LUC), bimolecular fluorescence complementation (BiFC) and coimmunoprecipitation analysis (CoIP) assays. Meanwhile, the pigment content, firmness and the transcript levels of genes associated with carotenoid and chlorophyll metabolism and cell wall metabolism were also potentially affected by the SlNAP2 deletion; however, it has remained unclear whether these genes are also directly regulated by SlNAP2. Therefore, our findings indicate that SlNAP2 directly binds to SlACS2 promoter to activate its expression and promote ethylene generation, which in turn interacts with EIL3 to enhance the function of ethylene in tomato fruit ripening. Collectively, our data contribute to understanding the interaction of NAC TFs and ethylene in tomato fruit ripening, thereby enhancing our knowledge of the ripening regulatory network that governs tomato fruit maturation.

biochemistry↗

bioRxiv2024

Single-Cell and Spatial Transcriptomic Analyses Deciphering the Three-Layer Architecture of Human Tuberculosis Granulomas

BackgroundGranulomas (defining tuberculosis histopathological feature) are central to the hosts defense against Mycobacterium tuberculosis, critically influencing patient outcomes. However, knowledge of human granulomas structure and function are incomplete. This study employs single-cell and spatial transcriptomics to dissect human granulomas cellular composition, structure, communication and function from 19 pulmonary, lymphatic and skeletal samples. ResultsOur study identified nine key immune-activated/signaling-active cell clusters. Notably, we delineated a three-layered granuloma structure: a core with macrophages (Macro-c09, Macro-c10) and occasional fibroblasts (Fib-c03); a fibroblast-rich (Fib-c01) periphery; and an immune-infiltrated intermediate layer comprising diverse immune-cells recruited by strong signaling-molecules (SPP1/MIF) from core/periphery cells. This study also shows granuloma heterogeneity across individuals and tissues. ConclusionsBy merging scRNA-seq with ST-seq, we offer an intricate single-cell perspective of granulomas spatial-structure and formation mechanisms, identify signaling-molecules and significantly changed genes as potential targets for host-directed tuberculosis immunotherapy, highlight fibroblasts crucial role in granuloma formation, and provide an important reference/improved understanding of TB.

microbiology↗

bioRxiv2024

A new pathway in central metabolism mediates nutrient control of development and antibiotic production by Streptomyces

The amino sugar N-acetylglucosamine (GlcNAc) plays a central role in primary metabolism and is a key signaling molecule for the onset of morphological and chemical differentiation of Streptomyces. The global nutrient-sensory regulator DasR acts as the gatekeeper of development in streptomycetes, and its activity is modulated by aminosugar phosphates. Here, we report the discovery of a novel pathway in aminosugar metabolism that governs GlcNAc sensing. GlcNAc-6P is converted into a toxic metabolite via two new enzyme functions, namely dehydration of N-acetylglucosamine-6-phosphate by NagS to form 6P-Chromogen I, a reaction that has not yet been described in the textbooks, and its subsequent deacetylation by NagA producing a cytotoxic structural analogue of ribose. The latter reveals an unexpected promiscuous activity for GlcNAc-6P deacetylase NagA. The crystal structures of NagS apoenzyme and NagS in complex with its substrate GlcNAc-6P or its inhibitor 6-phosphogluconate were resolved at 2.3 [A], 2.6 [A], and 1.7 [A] resolution, respectively. Detailed in vivo and in vitro studies resolved the key residues of the NagS catalytic site. Thus, we have uncovered a novel pathway in aminosugar metabolism that sheds new light on nutrient-mediated control of development and antibiotic production in Streptomyces.

microbiology↗

bioRxiv2024

Resolving the chromatin impact of mosaic variants with targeted Fiber-seq

Accurately quantifying the functional consequences of non-coding mosaic variants requires the pairing of DNA sequence with both accessible and closed chromatin architectures along individual DNA molecules--a pairing that cannot be achieved using traditional fragmentation-based chromatin assays. We demonstrate that targeted single-molecule chromatin fiber sequencing (Fiber-seq) achieves this, permitting single-molecule, long-read genomic and epigenomic profiling across targeted >100 kilobase loci with [~]10-fold enrichment over untargeted sequencing. Targeted Fiber-seq reveals that pathogenic expansions of the DMPK CTG repeat that underlie Myotonic Dystrophy 1 are characterized by somatic instability and disruption of multiple nearby regulatory elements, both of which are repeat length-dependent. Furthermore, we reveal that therapeutic adenine base editing of the segmentally duplicated {gamma}-globin (HBG1/HBG2) promoters in primary human hematopoietic cells induced towards an erythroblast lineage increases the accessibility of the HBG1 promoter as well as neighboring regulatory elements. Overall, we find that these non-protein coding mosaic variants can have complex impacts on chromatin architectures, including extending beyond the regulatory element harboring the variant.

genomics↗

bioRxiv2024

GlyTrait Brings Insights into Functional Glycosylation

Glycomics research often grapples with the interpretability and biological relevance of glycomics data. Using glycosylation derived traits are promising methods for more in-depth biological insights, yet no such bioinformatic tool exists for such task. Here, we developed GlyTrait, a Python-based framework designed to enhance glycomics analysis through the innovative calculation and interpretation of derived traits from N-glycome data. GlyTrait automates the derivation of biologically significant traits, shifting focus from mere glycan abundances to functional glycan properties such as branching and fucosylation. GlyTrait extends the well-established nomenclatures and definitions of derived traits in the N-glycomics community, allowing for fast exploration and analysis of N-glycome data effortlessly. Furthermore, with the well-designed formula grammar, custom derived traits could be materialized without any knowledge of coding. Besides, a two-step post-filtering process reduces information redundancy, maintaining only the most informative traits. Finally, subsequent statistical and interpretable machine learning analysis provide robust insights into the glycosylation patterns associated with disease states. This comprehensive approach not only improves the statistical power and sensitivity compared to traditional methods, but also enhances the interpretability of glycomics data. GlyTraits efficacy is demonstrated through the re-analysis of published glycoengineered CHO cell lines and visceral leishmaniasis patient data, alongside a newly conducted pilot study for hepatocellular carcinoma (HCC) N-glycan biomarker discovery. We are confident in GlyTraits potential to become an indispensable tool for the glycomics community. Significance StatementGlycomics data is often challenging to interpret and analyze for biological relevance. GlyTrait, a Python-based tool, addresses this by automatically calculating biologically significant traits from N-glycome data, focusing on functional properties like glycan branching and fucosylation rather than mere abundance. This tool enhances data interpretability, reduces redundancy through post-filtering, and employs statistical methods to uncover glycosylation patterns linked to diseases. Demonstrated on various published datasets, as well as a newly conducted pilot study with 165 samples for hepatocellular carcinoma N-glycan biomarker discovery, GlyTrait proves to be a powerful tool. It improves the understanding of glycosylation changes in conditions like cancer, thereby benefiting the glycomics community.

bioinformatics↗

bioRxiv2024

A long non-coding RNA LINC00094 regulates the transcriptional expression of lipid metabolism-related genes as a new member of core regulatory circuitry in esophageal squamous cell carcinoma

LINC00094 as a new supper-enhancer (SE)-related long non-coding RNA is associated with poor overall survival of patients with esophageal squamous cell carcinoma (ESCC). However, the transcriptional regulatory mechanism of LINC00094 and the molecular mechanisms by which LINC00094 affects the phenotype of ESCC remains unclear. Here, we found that LINC00094 promoted the proliferation of ESCC cells both in vitro and in vivo. LINC00094 knockdown significantly reduced the expression profiles of transcription activators including transcription factor 3 (TCF3) and Kruppel like factor 5 (KLF5) and lipid metabolism-related genes. Mechanically, TCF3 and KLF5 formed a core regulatory circuitry (CRC) that bound to the SEs of LINC00094 and to their own SEs to regulate the transcriptional expression in a positive feedback loop. LINC00094 recruited TCF3 and KLF5 to form a ternary complex, which forms a new CRC with TCF3 and KLF5 that regulated its own transcription as well as lipid metabolism-related genes. Knockdown of any or all three genes inhibited the expression of genes related to lipid synthesis and consistently reduced total lipid droplet levels. Treatment with SEs inhibitors (THZ1 and JQ1) effectively inhibited the formation of this CRC and the production of lipid droplets in ESCC cells. The high-risk group of CRC-associated signatures were closely associated with poor prognosis in patients with ESCC. Our findings suggest that LINC00094 is involved in the CRC by forming a complex with TCF3 and KLF5, and this regulation model can affect the phenotype of ESCC cells by controlling the expression of lipid metabolism-related genes. HighlightsO_LIWe identified a novel functional lncRNA-LINC00094 for esophageal squamous cell carcinoma. C_LIO_LILINC00094 forms a complex with the core transcription factors TCF3 and KLF5, thereby forming a core regulatory circuitry to participate in transcriptional regulation in ESCC. C_LIO_LIA core regulatory circuitry mediated by LINC00094 regulates lipid metabolism in ESCC. C_LI

cancer biology↗

bioRxiv2024

Gut metagenomes of Asian octogenarians reveal metabolic potential expansion and distinct microbial species associated with aging phenotypes

While rapid demographic changes in Asia are driving the incidence of chronic diseases related to aging, the limited availability of high-quality in vivo data hampers our ability to understand complex multi-factorial contributions, including gut microbial, to healthy aging. Leveraging the availability of a well-phenotyped cohort of community-living octogenarians in Singapore, we used deep shotgun metagenomic sequencing to do high-resolution taxonomic and functional characterization of their gut microbiomes (n=234). Joint species-level analysis with other Asian cohorts identified a distinct age-associated shift in Asian gut metagenomes, characterized by a reduction in microbial richness, and enrichment of specific Alistipes and Bacteroides species (e.g. Alistipes shahii and Bacteroides xylanisolvens). Functional pathway analysis confirmed that these changes correspond to a metabolic potential expansion in aging towards alternate pathways that synthesize and utilize amino-acid precursors, relative to the dominant microbial guilds that typically produce butyrate in the gut from pyruvate (e.g. Faecalibacterium prausnitzii, Roseburia inulinivorans). Extending these observations to key clinical markers helped identify >10 robust gut microbial associations to inflammation, cardiometabolic and liver health, including potential probiotic species such as Parabacteroides goldsteinii and pathobionts such as Klebsiella pneumoniae, highlighting the role of the microbiome as biomarkers and potential intervention targets for promoting healthy aging.

genomics↗