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The DNA methylation landscape of naturally short-lived killifish
Annual killifish of the genus Nothobranchius are naturally short-lived vertebrates that exhibit a wide range of aging characteristics typically observed in mammals. Here, we provide the first comprehensive whole-genome methylation map for two species, revealing local age-related as well as tissue-specific dynamics in the DNA methylome. Our maps and results support the annual killifish as a model organism and further highlight its value for studying aging including possible health status predictions in vertebrates.
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The cGAS-STING pathway is an in vivo modifier of genomic instability syndromes
Abstract
Mutations in genes involved in DNA damage repair (DDR) often lead to premature aging syndromes.
While recent evidence suggests that inflammation, alongside mutation accumulation and cell death,
may drive disease phenotypes, its precise contribution to in vivo pathophysiology remains unclear. Here,
by modeling Ataxia Telangiectasia (A-T) and Bloom Syndrome in the African turquoise killifish (N.
furzeri), we replicate key phenotypes of DDR syndromes, including infertility, cytoplasmic DNA
fragments, and reduced lifespan. The link between DDR defects and inflammation is attributed to the
activation of the cGAS-STING pathway and interferon signaling by cytoplasmic DNA. Accordingly,
mutating cGAS partially rescues germline defects and senescence in A-T fish. Double mutants also
display reversal of telomere abnormalities and suppression of transposable elements, underscoring
cGAS's non-canonical role as a DDR inhibitor. Our findings emphasize the role of interferon signaling
in A-T pathology and identify the cGAS-STING pathway as a potential therapeutic target for genomic
instability syndromes.
Here, we leverage the turquoise killifish (Nothobranchius furzeri) as an experimental platform
to identify functional modifiers of genomic instability. The killifish has recently emerged as a promising
genetic model for aging, owing to a naturally compressed lifespan (~6-10-fold shorter than mice and
zebrafish, respectively35), and the availability of state-of-the-art genome editing tools36–43 75 . These
features have enabled the identification of novel vertebrate longevity mechanisms (through the
AMP/AMPK pathway or via germline manipulations41,42,44 77 ), and the rapid modeling of human agerelated syndromes (e.g. telomere syndrome36 78 )
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Integrating Iso-seq and RNA-seq data for the reannotation of the killifish telencephalon transcriptome
The short-lived and rapidly aging African turquoise killifish, Nothobranchius furzeri GRZ is a unique model to study vertebrate aging. Current genomic and full-length transcriptomic sequencing lacks full gene annotations, resulting in poor mapping in bulk and single-cell transcriptomic studies. In our efforts to reannotate the transcriptome of the killifish telencephalon, we combined long-read (Smrt-Isoseq) and short-read transcriptome sequencing approaches. A total of 17,008 full-length isoforms, including 6763 novel ones were obtained (51 bp to 7,500 bp). The killifish telencephalon comprises 25% multi-exon genes, while over 50% are mono-exon genes. We discovered novel non-coding and coding sequences in both young and aged telencephali. We integrated long-read and RNA-seq data to construct a comprehensive transcriptome and profiled expression dynamics across the aging telencephalon. Our gene models demonstrate greater detail and accuracy than Ensembl, with more precise polyA locations. Alternative splicing analysis revealed 29 events altered with aging, which involved changes in ribosome function, gap junction and mRNA surveillance pathways. These generated resources pave the way for future functional genomic studies in this biogerontology model.
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Single housing of juveniles accelerates early-stage growth but extends adult lifespan in African turquoise killifish
Abstract
Within the same species, individuals exhibiting faster growth tend to have shorter lifespans, even if their fast growth arises from early-life pharmacological interventions. However, in vertebrates, the impact of the early-life environment on the growth rate and lifespan has not been fully elucidated. In this study, by utilizing the short-lived African turquoise killifish, which is suitable for a comprehensive life-stage analysis in a brief timeframe, we explored the effects of housing density during the juvenile stage on holistic life traits. As a result, we found that lower housing densities resulted in faster growth, but led to longer adult lifespan, which was contrary to the common notion. Furthermore, the single-housed adult fish displayed a longer egg-laying period than did their group-housed counterparts. Our transcriptome analysis also demonstrated that, in terms of internal transcriptional programs, the life stage progression and aging process of single-housed fish were slower than those of group-housed fish. Collectively, our results suggest that sharing housing with others in early life might influence whole-life attributes, potentially leading to specific life history traits beyond the typical relationship between the growth rate and lifespan.
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The killifish germline regulates longevity and somatic repair in a sex-specific manner
Classical evolutionary theories propose tradeoffs among reproduction, damage repair and lifespan. However, the specific role of the germline in shaping vertebrate aging remains largely unknown. In this study, we used the turquoise killifish (Nothobranchius furzeri) to genetically arrest germline development at discrete stages and examine how different modes of infertility impact life history. We first constructed a comprehensive single-cell gonadal atlas, providing cell-type-specific markers for downstream phenotypic analysis. We show here that germline depletion—but not arresting germline differentiation—enhances damage repair in female killifish. Conversely, germline-depleted males instead showed an extension in lifespan and rejuvenated metabolic functions. Through further transcriptomic analysis, we highlight enrichment of pro-longevity pathways and genes in germline-depleted male killifish and demonstrate functional conservation of how these factors may regulate longevity in germline-depleted Caenorhabditis elegans. Our results, therefore, demonstrate that different germline manipulation paradigms can yield pronounced sexually dimorphic phenotypes, implying alternative responses to classical evolutionary tradeoffs.
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The killifish visual system as an in vivo model to study brain aging and rejuvenation
Worldwide, people are getting older, and this prolonged lifespan unfortunately also results in an increased prevalence of age-related neurodegenerative diseases, contributing to a diminished life quality of elderly. Age-associated neuropathies typically include diseases leading to dementia (Alzheimer’s and Parkinson’s disease), as well as eye diseases such as glaucoma and age-related macular degeneration. Despite many research attempts aiming to unravel aging processes and their involvement in neurodegeneration and functional decline, achieving healthy brain aging remains a challenge. The African turquoise killifish (Nothobranchius furzeri) is the shortest-lived reported vertebrate that can be bred in captivity and displays many of the aging hallmarks that have been described for human aging, which makes it a very promising biogerontology model. As vision decline is an important hallmark of aging as well as a manifestation of many neurodegenerative diseases, we performed a comprehensive characterization of this fish’s aging visual system. Our work reveals several aging hallmarks in the killifish retina and brain that eventually result in a diminished visual performance. Moreover, we found evidence for the occurrence of neurodegenerative events in the old killifish retina. Altogether, we introduce the visual system of the fast-aging killifish as a valuable model to understand the cellular and molecular mechanisms underlying aging in the vertebrate central nervous system. These findings put forward the killifish for target validation as well as drug discovery for rejuvenating or neuroprotective therapies ensuring healthy aging.
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