Biology subjects

Kenyon, C.

Publications and source records attributed to Kenyon, C..

16 recordsLinked to original sources

bioRxiv2026

Senescent cells induce vascular MHC II to recruit CD4+ T cells and drive inflammation in aging adipose tissue

Adipose tissue exhibits pronounced inflammation during aging, yet the mechanisms sustaining this chronic state are not well understood. By creating an atlas integrating histology, single-nucleus transcriptomics and flow cytometry across the murine lifespan, we find that age-associated inflammation is distinct from the obesity-like inflammatory profile observed at mid-life. Specifically, age-associated inflammation is characterized by a potent interferon-gamma (IFN{gamma}) response signature and the accumulation of T cells. We demonstrate that senescent cells act as an upstream trigger, indirectly initiating an IFN{gamma} response that upregulates vascular MHC II to promote extravasation of CD4+ T cells into the aging tissue. These recruited T cells then act as a critical source of IFN{gamma}, thereby perpetuating a positive feedback loop that maintains chronic immune infiltration and tissue inflammation. These results provide a multi-modal view of adipose aging and identify a mechanism that sustains its age-associated inflammation.

immunology↗

bioRxiv2026

Imageomics defines granular morphological changes of human skin with age and reveals a rejuvenating effect of xenografting

Rejuvenating aging human skin is a major therapeutic goal, but objective, quantitative measures of intrinsic aging are limited. We performed a cross-sectional histological study of UV-protected buttock and abdominal skin in adults spanning multiple decades of life to identify features that reliably track age. Epidermal thickness measured between rete ridges was unchanged, but rete ridge size declined linearly with age: ridges became shorter and thinner in both sites, though rete ridge number decreased only in the abdomen. Consistent with these structural changes, proliferative cells (Ki67+) per ridge and expression of integrin {beta}4 (ITGB4), a putative stem-cell marker, were reduced in aged skin. We combined these biomarkers into a predictive model that estimated skin age more accurately than any single marker. To test whether the model detects longitudinal change, we analyzed aged abdominal skin before and after xenografting onto young or aged mice, a procedure previously reported to rejuvenate human skin in young but not aged recipient mice. Both individual biomarkers and the imaging model indicated rejuvenation regardless of host age; however, notably, engraftment efficiency was lower in aged hosts, with surviving grafts showing younger histological phenotypes. These results provide quantitative criteria for assessing intrinsic skin aging and suggest that the process of engraftment itself is sufficient to induce rejuvenation-like changes.

pathology↗

bioRxiv2025

A FMRF-amide peptide that regulates cell non-autonomous protein homeostasis in C. elegans.

The coordination of protein homeostasis from the brain to periphery is essential for the health and survival of all animals. In C. elegans, glia serve a central role in coordinating organismal protein homeostasis and longevity via the unfolded protein response of the endoplasmic reticulum (UPRER). However, the full extent of the cell non-autonomous response and the identity of the signaling molecules required remained unknown. Here, we show that glial UPRER activation induces robust transcriptomic changes in specific tissue types across the animal, particularly in pathways related to neuropeptide signaling. We performed neuropeptidomics and loss and gain-of-function genetic screens and identified a single neuropeptide, FLP-17, that is sufficient but not necessary to induce cell non-autonomous activation of the UPRER. FLP-17 is sufficient to protect against chronic ER stress and age-dependent protein aggregation. We determined that FLP-17 acts through the receptor, EGL-6, to activate cell non-autonomous UPRER. This work reveals a complex peptidergic signaling network initiated by glial activation of the UPRER to regulate organismal protein homeostasis.

neuroscience↗

bioRxiv2022

The C. elegans Observatory: High-throughput exploration of behavioral aging

Organisms undergo a variety of characteristic changes as they age, suggesting a substantial commonality in the mechanistic basis of aging. Experiments in model organisms have revealed a variety of cellular systems that impact lifespan, but technical challenges have prevented a comprehensive evaluation of how these components impact the trajectory of aging, and many components likely remain undiscovered. To facilitate the deeper exploration of aging trajectories at sufficient scale to enable primary screening, we have created the C. elegans Observatory, an automated system for monitoring the behavior of group-housed C. elegans throughout their lifespans. One Observatory consists of a set of computers running custom software to control an incubator containing custom imaging and motion-control hardware. In its standard configuration, the Observatory cycles through trays of standard 6 cm plates, running four assays per day on up to 576 plates per incubator. High-speed image processing captures a range of behavioral metrics including movement speed and stimulusinduced turning, and a data processing pipeline continuously computes summary statistics. The Observatory software includes a web interface that allows the user to input metadata and to view graphs of the trajectory of behavioral aging as the experiment unfolds. Compared to manual use of a plate-based C. elegans tracker, the Observatory reduces effort required by close to two orders of magnitude. Within the Observatory, reducing function of known lifespan genes with RNA interference (RNAi) gives the expected phenotypic changes, including extended motility in daf-2(RNAi) and progeria in hsf-1(RNAi). Lifespans scored manually from worms raised in conventional conditions match those scored from images captured by the Observatory. We have used the Observatory for a small candidate-gene screen and identified an extended youthful vigor phenotype for tank-1(RNAi) and a progeric phenotype for cdc-42(RNAi). By utilizing the Observatory, it is now feasible to conduct whole-genome screens for an aging-trajectory phenotype, thus greatly increasing our ability to discover and analyze new components of the aging program.

animal behavior and cognition↗

bioRxiv2022

The complete cell atlas of an aging multicellular organism

Here we describe a single-cell atlas of aging for the nematode Caenorhabditis elegans. This unique resource describes the expression across adulthood of over 20,000 genes among 211 groups of cells that correspond to virtually every cell type in this organism. Our findings suggest that C. elegans aging is not random and stochastic in nature, but rather characterized by coordinated changes in functionally related metabolic and stress-response genes in a highly cell-type specific fashion. Aging signatures of different cell types are largely different from one another, downregulation of energy metabolism being the only nearly universal change. Some biological pathways, such as genes associated with translation, DNA repair and the ER unfolded protein response, exhibited strong (in some cases opposite) changes in subsets of cell types, but many more were limited to a single cell type. Similarly, the rates at which cells aged, measured as genome-wide expression changes, differed between cell types; some of these differences were tested and validated in vivo by measuring age-dependent changes in mitochondrial morphology. In some, but not all, cell types, aging was characterized by an increase in cell-to-cell variance. Finally, we identified a set of transcription factors whose activities changed coordinately across many cell types with age. This set was strongly enriched for stress-resistance TFs known to influence the rate of aging. We tested other members of this set, and discovered that some, such as GEI-3, likely also regulate the rate of aging. Our dataset can be accessed and queried at c.elegans.aging.atlas.research.calicolabs.com/.

genomics↗

bioRxiv2022

A Physiology Clock for Human Aging

Why people age at different rates is a fundamental, unsolved problem in biology. We created a model that predicts an individuals age from physiological traits that change with age in the large UK Biobank dataset, such as blood pressure, lung function, strength and stimulus- reaction time. The model best predicted a persons age when it heavily-weighted traits that together query multiple organ systems, arguing that most or all physiological systems (lung, heart, brain, etc.) contribute to the global phenotype of chronological age. Differences between calculated "biological" age and chronological age ({Delta}Age) appear to reflect an individuals relative youthfulness, as people predicted to be young for their age had a lower subsequent mortality rate and a higher parental age at death, even though no mortality data were used to calculate {Delta}Age. Remarkably, the effect of each year of physiological {Delta}Age on Gompertz mortality risk was equivalent to that of one chronological year. A Genome-Wide Association Study (GWAS) of {Delta}Age, and analysis of environmental factors associated with {Delta}Age identified known as well as new factors that may influence human aging, including genes involved in synapse biology and a tendency to play computer games. We identify a small number of readily measured physiological traits that together assess a persons biological age and may be used clinically to evaluate therapeutics designed to slow aging and extend healthy life.

genetics↗

bioRxiv2021

Association between quinolone use in food animals and gonococcal resistance to ciprofloxacin: an ecological study

BackgroundConcentrations of fluoroquinolones up to 200-fold lower than the MIC have been shown to be able to select for antimicrobial resistance in E. coli and Salmonella spp. (the minimum selection concentration - MSC). We aimed to i) establish what the ciprofloxacin MSC is for Neisseria gonorrhoeae and ii) Assess at a country level if the prevalence of gonococcal ciprofloxacin resistance is associated with the concentration of quinolones used in food animal production (an important determinant of long-term low dose ciprofloxacin exposures in humans). Methodsi). To assess if sub-inhibitory ciprofloxacin concentrations could select for de novo generated resistant mutants, susceptible WHO-P was serially passaged at 1, 1/10, 1/100 and 1/1000 of the ciprofloxacin MIC of WHO-P (0.004mg/L) on GC agar plates. ii) Spearmans correlation was used to assess the association between the prevalence of ciprofloxacin resistance in N. gonorrhoeae and the two independent variables - quinolone use for animals and quinolone consumption by humans. ResultsCiprofloxacin concentrations as low as 1/1000 of the MIC of WHO-P were able to select for ciprofloxacin resistance. The prevalence of ciprofloxacin resistance in N. gonorrhoeae was positively associated with quinolone use for food animals ({rho}=0.47; P=0.004; N=34). ConclusionFurther individual level research is required to assess if low doses of ciprofloxacin from ingested foodstuffs are able to select for ciprofloxacin resistance in N. gonorrhoeae and other species.

microbiology↗

bioRxiv2021

Partial reprogramming restores youthful gene expression through transient suppression of cell identity

Transient induction of pluripotent reprogramming factors has been reported to reverse some features of aging in mammalian cells and tissues. However, the impact of transient reprogramming on somatic cell identity programs and the necessity of individual pluripotency factors remain unknown. Here, we mapped trajectories of transient reprogramming in young and aged cells from multiple murine cell types using single cell transcriptomics to address these questions. We found that transient reprogramming restored youthful gene expression in adipocytes and mesenchymal stem cells but also temporarily suppressed somatic cell identity programs. We further screened Yamanaka Factor subsets and found that many combinations had an impact on aging gene expression and suppressed somatic identity, but that these effects were not tightly entangled. We also found that a transient reprogramming approach inspired by amphibian regeneration restored youthful gene expression in aged myogenic cells. Our results suggest that transient pluripotent reprogramming poses a neoplastic risk, but that restoration of youthful gene expression can be achieved with alternative strategies.

systems biology↗

bioRxiv2021

Revisiting the Hayflick Limit: Insights from an Integrated Analysis of Changing Transcripts, Proteins, Metabolites and Chromatin

The process wherein dividing cells exhaust proliferative capacity and enter into replicative senescence has become a prominent model for cellular aging in vitro. Despite decades of study, this cellular state is not fully understood in culture and even much less so during aging. Here, we revisit Leonard Hayflicks original observation of replicative senescence in WI-38 human lung fibroblasts equipped with a battery of modern techniques including RNA-seq, single cell RNA-seq, proteomics, metabolomics, and ATAC-seq. We find evidence that the transition to a senescent state manifests early, increases gradually, and corresponds to a concomitant global increase in DNA accessibility in nucleolar and lamin associated domains. Furthermore, we demonstrate that senescent WI-38 cells acquire a striking resemblance to myofibroblasts in a process similar to the epithelial to mesenchymal transition (EMT) that is regulated by the transcription factors YAP1/TEAD1 and TGF-{beta}2. Lastly, we show that verteporfin inhibition of YAP1/TEAD1 activity in aged WI-38 cells robustly attenuates this gene expression program.

genomics↗

bioRxiv2020

Molecular pathways to high-level azithromycin resistance in Neisseria gonorrhoeae

ObjectivesThe prevalence of azithromycin resistance in Neisseria gonorrhoeae is increasing in numerous populations worldwide. The aim of this study was to characterize the genetic pathways leading to high-level azithromycin resistance. MethodsA customized morbidostat was used to subject two N. gonorrhoeae reference strains (WHO-F and WHO-X) to dynamically sustained azithromycin pressure. We tracked stepwise evolution of resistance by whole genome sequencing. ResultsWithin 26 days, all cultures evolved high-level azithromycin resistance. Typically, the first step towards resistance was found in transitory mutations in genes rplD, rplV and rpmH (encoding the ribosomal proteins L4, L22 and L34 respectively), followed by mutations in the MtrCDE-encoded efflux pump and the 23S rRNA gene. Low-to high-level resistance was associated with mutations in the ribosomal proteins and MtrCDE-encoded efflux pump. However, high-level resistance was consistently associated with mutations in the 23S ribosomal RNA - mainly the well-known A2059G and C2611T mutations, but also at position A2058G. ConclusionsThis study enabled us to track previously reported mutations and identify novel mutations in ribosomal proteins (L4, L22 and L34) that may play a role in the genesis of azithromycin resistance in N. gonorrhoeae.

microbiology↗

bioRxiv2020

A genetic screen identifies processes that couple oocyte maturation to proteostasis in the immortal C. elegans germ lineage

Somatic cells age and die, but the germ-cell lineage is immortal. In C. elegans, germline immortality involves proteostasis renewal at the beginning of each new generation, when oocyte-maturation signals from sperm trigger the clearance of carbonylated proteins and protein aggregates. Here, we explore the cell biology of this proteostasis renewal in the context of a whole-genome RNAi screen. Oocyte maturation signals are known to trigger protein-aggregate removal via lysosome acidification. Our findings suggest that lysosomes are acidified as a consequence of changes in ER activity that permit assembly of the lysosomal V-ATPase, which in turn allows lysosomes to clear the aggregates via microautophagy. We define two functions for mitochondria, both of which appear to be independent of ATP generation. Many genes from the screen also regulate lysosome acidification and age-dependent protein aggregation in the soma, suggesting a fundamental mechanistic link between proteostasis renewal in the germline and somatic longevity.

cell biology↗

bioRxiv2020

Split-wrmScarlet and split-sfGFP: tools for faster, easier fluorescent labeling of endogenous proteins in Caenorhabditis elegans

We create and share a new red fluorophore, along with a set of strains, reagents and protocols, to make it faster and easier to label endogenous C. elegans proteins with fluorescent tags. CRISPR-mediated fluorescent labeling of C. elegans proteins is an invaluable tool, but it is much more difficult to insert fluorophore-size DNA segments than it is to make small gene edits. In principle, high-affinity asymmetrically split fluorescent proteins solve this problem in C. elegans: the small fragment can quickly and easily be fused to almost any protein of interest, and can be detected wherever the large fragment is expressed and complemented. However, there is currently only one available strain stably expressing the large fragment of a split fluorescent protein, restricting this solution to a single tissue (the germline) in the highly autofluorescent green channel. No available C. elegans lines express unbound large fragments of split red fluorescent proteins, and even state-of-the-art split red fluorescent proteins are dim compared to the canonical split-sfGFP protein. In this study, we engineer a bright, high-affinity new split red fluorophore, split-wrmScarlet. We generate transgenic C. elegans lines to allow easy single-color labeling in muscle or germline cells and dual-color labeling in somatic cells. We also describe glonads, a novel expression strategy for the germline, where traditional expression strategies struggle. We validate these strains by targeting split-wrmScarlet to several genes whose products label distinct organelles, and we provide a protocol for easy, cloning-free CRISPR/Cas9 editing. As the collection of split-FP strains for labeling in different tissues or organelles expands, we will post updates at doi.org/10.5281/zenodo.3993663

genetics↗

bioRxiv2019

Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules that Affect Aging Pathways and Extend C. elegans Lifespan

Increased resistance to environmental stress at the cellular level is correlated with the longevity of long-lived mutants and wild-animal species. Moreover, in experimental organisms, screens for increased stress resistance have yielded mutants that are long-lived. To find entry points for small molecules that might extend healthy longevity in humans, we screened [~]100,000 small molecules in a human primary-fibroblast cell line and identified a set that increased oxidative-stress resistance. Some of the hits fell into structurally-related chemical groups, suggesting that they may act on common targets. Two small molecules increased C. elegans stress resistance, and at least 9 extended their lifespan by [~]10-50%. Thus, screening for increased stress resistance in human cells can enrich for compounds with promising pro-longevity effects. Further characterization of these compounds, including a chalcone that promoted stress resistance independently of NRF2, may elucidate new ways to extend healthy human lifespan.

genetics↗

bioRxiv2019

A resource for analyzing C. elegans’ gene expression data using transcriptional gene modules and module-weighted annotations

Identification of gene co-expression patterns (gene modules) is widely used for grouping functionally-related genes during transcriptomic data analysis. An organism-wide atlas of high quality fundamental gene modules would provide a powerful tool for unbiased detection of biological signals from gene expression data. Here, using a method of independent component analysis we call DEXICA, we have defined and optimized 209 modules that broadly represent transcriptional wiring of the key experimental organism C. elegans. Interrogation of these modules reveals processes that are activated in long-lived mutants in cases where traditional analyses of differentially-expressed genes fail to do so. Using this resource, users can easily identify active modules in their gene expression data and access detailed descriptions of each module. Additionally, we show that modules can inform the strength of the association between a gene and an annotation (e.g. GO term). Analysis of \"module-weighted annotations\" improves on several aspects of traditional annotation-enrichment tests and can aid in functional interpretation of poorly annotated genes. Interactive access to the resource is provided at http://genemodules.org/.

bioinformatics↗

bioRxiv2018

Rescue of a developmental arrest caused by a C. elegans heat-shock transcription-factor mutation by loss of ribosomal S6-kinase activity

The widely conserved heat-shock response, regulated by heat shock transcription factors, is not only essential for cellular stress resistance and adult longevity, but also for proper development. However, the genetic mechanisms by which heat-shock transcription factors regulate development are not well understood. In C. elegans, we conducted an unbiased genetic screen to identify mutations that could ameliorate the developmental arrest phenotype of a heat-shock factor mutant. Here we show that loss of the conserved translational activator rsks-1/S6-Kinase, a downstream effector of TOR kinase, can rescue the developmental-arrest phenotype of hsf-1 partial loss-of-function mutants. Unexpectedly, we show that the rescue is not likely caused by reduced translation, nor to activation of any of a variety of stress-protective genes and pathways. Our findings identify an as-yet unexplained regulatory relationship between the heat-shock transcription factor and the TOR pathway during C. elegans development.

genetics↗

bioRxiv2016

Inferring Weighted Gene Annotations from Expression Dat

Annotating genes with information describing their role in the cell is a fundamental goal in biology, and essential for interpreting data-rich assays such as microarray analysis and RNA-Seq. Gene annotation takes many forms, from Gene Ontology (GO) terms, to tissues or cell types of significant expression, to putative regulatory factors and DNA sequences. Almost invariably in gene databases, annotations are connected to genes by a Boolean relationship, e.g., a GO term either is or isnt associated with a particular gene. While useful for many purposes, Boolean-type annotations fail to capture the varying degrees by which some annotations describe their associated genes and give no indication of the relevance of annotations to cellular logistical activities such as gene expression. We hypothesized that weighted annotations could prove useful for understanding gene function and for interpreting gene expression data, and developed a method to generate these from Boolean annotations and a large compendium of gene expression data. The method uses an independent component analysis-based approach to find gene modules in the compendium, and then assigns gene-specific weights to annotations proportional to the degree to which they are shared among members of the module, with the reasoning that the more an annotation is shared by genes in a module, the more likely it is to be relevant to their function and, therefore, the higher it should be weighted. In this paper, we show that analysis of expression data with module-weighted annotations appears to be more resistant to the confounding effect of gene-gene correlations than non-weighted annotation enrichment analysis, and show several examples in which module-weighted annotations provide biological insights not revealed by Boolean annotations. We also show that application of the method to a simple form of genetic regulatory annotation, namely, the presence or absence of putative regulatory words (oligonucleotides) in gene promoters, leads to module-weighted words that closely match known regulatory sequences, and that these can be used to quickly determine key regulatory sequences in differential expression data.

bioinformatics↗