Individual cell types in C. elegans age differently and activate distinct cell-protective responses

Roux, Antoine Emile; Yuan, Han; Podshivalova, Katie; Hendrickson, David; Kerr, Rex; Kenyon, Cynthia; Kelley, David

doi:10.1016/j.celrep.2023.112902

Cited by 39 publications

(15 citation statements)

References 81 publications

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“…In general, we observed age-related transcriptomic dysregulation within all retinal cell populations, showing that differentially expressed genes from bulk RNA-seq experiments displayed increased expression across all cell types upon ageing. Similar age-related transcriptional dysregulation has been described in C. elegans using a full organism single-cell atlas for a confined number of genes, although the mechanisms contributing to this altered gene expression remain elusive (Roux et al, 2023). One potential mechanism behind the changes in gene expression across various cell types includes a modified epigenome.…”

Section: Discussionmentioning

confidence: 66%

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Bergmans,

Noel,

Masin

et al. 2024

Preprint

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Age-related vision loss caused by neurodegenerative pathologies in the retina is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short-lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks. Bulk and single-cell RNA-sequencing (scRNA-seq) of three age groups (6-, 12-, and 18-week-old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age-related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterised, confirming the presence of all typical vertebrate retinal cell types. Data integration from age-matched samples between the bulk and scRNA-seq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasises the value of the fast-ageing killifish in elucidating molecular signatures in age-associated retinal disease and vision decline. This study contributes to the understanding of how age-related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age-related pathologies.HighlightsThe aged killifish retina displays several ageing hallmarks, such as oxidative stress, gliosis, and inflammageing, at the transcriptome level.Risk genes for neurodegenerative disorders show dysregulation in the old killifish retina.All vertebrate retinal cell types are present in the killifish retina.Transcriptional dysregulation in the aged killifish retina is observed across cell types.Cell type-specific transcriptomic changes across age highlight increased stress response.

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Section: Discussionmentioning

confidence: 66%

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Bergmans,

Noel,

Masin

et al. 2024

Preprint

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“…In summary, we wished to share ICM-induced senescence with the broader community as a new tool for accelerating research into the cell-intrinsic core of the senescent transcriptional program and the different components that mediate its irreversible nature (or allow for its sporadic bypass). Such rapid and synchronous pharmacological induction of senescence, devoid of paracrine influence, might even serve as a controllable in vitro system for testing antiaging (Browder et al, 2022;Roux et al, 2022) or senolytic approaches (Chaib et al, 2022;Robbins et al, 2020), and we provide a comprehensive characterization of it. The senescent state of the cells was addressed by senescenceassociated β-galactosidase assay (Cell Signaling) according to the manufacturer's instructions.…”

Section: Discussionmentioning

confidence: 99%

Rapid and synchronous chemical induction of replicative‐like senescence via a small molecule inhibitor

Palikyras,

Sofiadis,

Stavropoulou

et al. 2024

Aging Cell

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Cellular senescence is acknowledged as a key contributor to organismal ageing and late‐life disease. Though popular, the study of senescence in vitro can be complicated by the prolonged and asynchronous timing of cells committing to it and by its paracrine effects. To address these issues, we repurposed a small molecule inhibitor, inflachromene (ICM), to induce senescence to human primary cells. Within 6 days of treatment with ICM, senescence hallmarks, including the nuclear eviction of HMGB1 and ‐B2, are uniformly induced across IMR90 cell populations. By generating and comparing various high throughput datasets from ICM‐induced and replicative senescence, we uncovered a high similarity of the two states. Notably though, ICM suppresses the pro‐inflammatory secretome associated with senescence, thus alleviating most paracrine effects. In summary, ICM rapidly and synchronously induces a senescent‐like phenotype thereby allowing the study of its core regulatory program without confounding heterogeneity.

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“…By employing a FACS-based neuron-sorting technique, we selectively analyzed adult neuron-function-related genes and investigated their aging process, which is not easily discernible through whole-worm sequencing 25–27 ( Fig. S6 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, whether daf-2 uses the same or different genes in young and old worms to improve and maintain cognitive function with age is unknown. Recent datasets using whole-animal single-cell RNA-seq have been generated for wild-type and daf-2 worms, and these are sufficient for whole-body aging and pseudobulk analyses 25–27 , but we have found that those data are not deep enough to use specifically for in-depth analysis of neurons, which can be difficult to gather from whole animals. Other data are from larval stages and cannot be extrapolated to aging adults 28 .…”

Section: Introductionmentioning

confidence: 99%

The Neuron-specific IIS/FOXO Transcriptome in Aged Animals Reveals Regulatory Mechanisms of Cognitive Aging

Weng,

Zhou,

Morillo

et al. 2023

Preprint

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Cognitive decline is a significant public health concern in our aging society. In this study, we used the model organism C. elegans to investigate the impact of the IIS/FOXO pathway on age-related cognitive decline. The daf-2 Insulin/IGF-1 receptor mutant exhibits a significant extension of learning and memory span with age compared to wild-type worms, an effect that is dependent on the DAF-16 transcription factor. To determine the mechanisms by which aging daf-2 mutants can maintain learning and memory with age while wild-type worms lose neuronal function, we carried out neuron-specific transcriptomic analysis in aged animals. We observed downregulation of neuronal genes and upregulation of transcriptional regulation genes in aging wild-type neurons. By contrast, IIS/FOXO pathway mutants exhibit distinct neuronal transcriptomic alterations in response to cognitive aging, including upregulation of stress response genes and downregulation of specific insulin signaling genes. We tested the roles of significantly transcriptionally-changed genes in regulating cognitive functions, identifying several novel regulators of learning and memory. These findings suggest a potential mechanism for regulating cognitive function with age and offer insights into novel therapeutic targets for age-related cognitive decline.

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Individual cell types in C. elegans age differently and activate distinct cell-protective responses

Cited by 39 publications

References 81 publications

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Rapid and synchronous chemical induction of replicative‐like senescence via a small molecule inhibitor

The Neuron-specific IIS/FOXO Transcriptome in Aged Animals Reveals Regulatory Mechanisms of Cognitive Aging

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