Biology subjects

Cellerino, A.

Publications and source records attributed to Cellerino, A..

At least 19 recordsLinked to original sources

bioRxiv2026

1,3-1,6 β-glucans reduce aging hallmarks in multiple organs and rapidly induce mitochondrial biogenesis and autophagy via direct effect on the killifish brain and human neurons

The short-lived annual fish Nothobranchius furzeri (Nfu) is a powerful vertebrate model for aging research due to its rapid lifespan and accelerated development of age-associated phenotypes, including gliosis and lipofuscin accumulation. Here, we investigated the effects of dietary 1,3-1,6 {beta}-glucans (BGs), natural polysaccharides derived from Saccharomyces cerevisiae, on aging-related processes across multiple tissues, with particular focus on the brain. Chronic treatment with BG-fortified food reduced several hallmarks of aging in multiple organs. Mechanistically, BG treatment modulated pathways associated with autophagy, lysosomal function, protein oxidation, and inflammation. Both acute and chronic BG administration increased autophagic activity in the aging brain, although lipofuscin accumulation was not affected. To assess whether BGs act directly on neural tissue, we established an ex-vivo Nfu brain culture system that recapitulates the age-dependent decline in autophagy observed in vivo. In this model, acute BG treatment restored impaired autophagy and promoted mitochondrial and lysosomal biogenesis in aged brains. Proteomic analyses revealed increased mitochondrial respiration and modulation of V-ATPase components involved in autophagosome acidification. Depletion of microglia reduced but not eliminated this effect, suggesting direct action of BGs on neurons. To verify the validity of these findings in humans, we performed BG treatment in human iPSC-derived neurons under conditions of impaired autophagy and found an increase in survival. Together, these findings identify {beta}-glucans as modulators of autophagy, mitochondrial function, and inflammation, highlighting their potential to promote healthy aging.

neuroscience↗

bioRxiv2026

Gene function and expression profiling in yeast spores, killifish diapause embryos, and their post-dormant offspring cells

Dormancy is a reversible cellular state characterised by suspended proliferation and increased stress resilience, enabling long-term viability under adverse conditions. Although dormant cells are critical for the life cycle of diverse organisms, from microbes to humans, they are understudied compared to proliferating cells. We present a comparative investigation of dormant cells in two divergent species: spores of fission yeast and diapause embryos of turquoise killifish. A genome-wide screen for genes affecting the lifespan and heat-shock resilience of spores uncovered a trade-off between longevity and heat resistance, and considerable differences in the genetic basis for lifespan between spores and chronologically aging yeast cells. RNA-seq and mass-spectrometry analyses revealed substantial transcriptomic and proteomic changes in spores and diapause embryos, with ribosomal proteins induced as transcripts but repressed as proteins. Transcriptomic regulation of biological processes, but less so of specific genes, is broadly conserved across yeast spores, killifish diapause, and human dormant cancer cells, including the induction of autophagy- and translation-related processes and the repression of cell cycle-related processes. Spores and diapause embryos modulate their transcriptomes and proteomes in response to heat stress and prolonged time. These RNA and protein expression changes are uncoupled and differ from aging-related expression signatures in yeast cells and adult fish. Cells derived from older or stressed spores retain phenotypic differences for several cell divisions, reflected in altered expression signatures, lifespan and stress resilience. Similarly, diapause duration and heat exposure are associated with long-term expression signatures in post-diapause embryos before hatching. This study highlights core biological processes and principles that are remarkably conserved in distinct types of dormant cells.

genetics↗

bioRxiv2025

Resilience to cardiac aging in Greenland shark Somniosus microcephalus

The Greenland shark (Somniosus microcephalus), with a lifespan exceeding 400 years, represents a unique model for studying vertebrate longevity. Here, we characterize its cardiac aging profile and compare it with two other species: the deep-sea shark Etmopterus spinax and the short-lived teleost Nothobranchius furzeri. Histological analysis revealed extensive interstitial and perivascular fibrosis throughout the ventricular myocardium of S. microcephalus, affecting both compact and spongy layers of both sexes. This fibrotic pattern was absent in E. spinax and N. furzeri, suggesting it is a specific feature of S. microcephalus. We also observed extreme lipofuscin accumulation within cardiomyocytes of S. microcephalus, which correlates at the ultrastructural level with abundance of damaged mitochondria and the presence of strikingly enlarged lysosomes filled with electrondense material of likely mitochondrial origin. Additionally, in the myocardium of S. microcephalus we found abundant deposition of the oxidative stress marker 3-nitrotyrosine. Remarkably, despite showing multiple canonical markers of aging such as fibrosis, lipofuscin accumulation, and oxidative damage, S. microcephalus individuals appeared healthy and physiologically uncompromised at the time of capture. These findings suggest that S. microcephalus has evolved resilience to molecular and tissue-level aging hallmarks, supporting sustained cardiac function over centuries and offering new insights into the mechanisms of extreme vertebrate longevity.

cell biology↗

bioRxiv2024

The Aging Synapse: An Integrated Proteomic And Transcriptomic Analysis

An important hallmark of aging is the loss of proteostasis, which can lead to the formation of protein aggregates and mitochondrial dysfunction in neurons. Although it is well known that protein synthesis is finely regulated in the brain, especially at synapses, where mRNAs are locally translated in activity-dependent manner, little is known as to the changes in the synaptic proteome and transcriptome during aging. Therefore, this work aims to elucidate the relationship between transcriptome and proteome at soma and synaptic level during aging. Proteomic and transcriptomic data analysis reveal that, in young animals, proteins and transcripts are correlated and synaptic regulation is driven by changes in the soma. During aging, there is a decoupling between transcripts and proteins and between somatic and synaptic compartments. Furthermore, soma-synapse gradient of ribosomal genes changes upon aging, i.e. ribosomal transcripts are less abundant and ribosomal proteins are more abundant in synaptic compartment of old mice with respect to younglings. Additionally, transcriptomics data highlight a difference in the splicing of certain synaptic mRNA with aging. Taken together, our data provide a valuable resource for the study of the aging synapse.

neuroscience↗

bioRxiv2024

The Greenland shark (Somniosus microcephalus) genome provides insights into extremelongevity

The Greenland shark (Somniosus microcephalus) is the longest-lived vertebrate known, with an estimated lifespan of [~] 400 years. Here, we present a chromosome-level assembly of the 6.45 Gb Greenland shark, rendering it one of the largest non-tetrapod genomes sequenced so far. Expansion of the genome is mostly accounted for by a substantial expansion of transposable elements. Using public shark genomes as a comparison, we found that genes specifically duplicated in the Greenland shark form a functionally connected network enriched for DNA repair function. Furthermore, we identified a unique insertion in the conserved C-terminal region of the key tumor suppressor p53. We also provide a public browser to explore its genome.

genomics↗

bioRxiv2024

Epigenetic clock and lifespan prediction in the short-lived killifish Nothobranchius furzeri

Aging, characterized by a gradual decline in organismal fitness, is the primary risk factor for numerous diseases including cancer, cardiovascular, and neurodegenerative disorders. The inter-individual variability in aging and disease susceptibility has led to the concept of "biological age," an indirect measure of an individuals relative fitness. Epigenetic changes, particularly DNA methylation, have emerged as reliable biomarkers for estimating biological age, leading to the development of predictive models known as epigenetic clocks. Initially created for humans, these clocks have been extended to various mammalian species. Here we set to expand these tools for the short-lived killifish, Nothobranchius furzeri. This species, with its remarkably short lifespan and expression of canonical aging hallmarks, offers a unique model for experimental aging studies. We developed an epigenetic clock for N. furzeri using reduced-representation bisulfite sequencing (RRBS) to analyze DNA methylation in brain and caudal fin tissues across different ages. Our study involved generating comprehensive DNA methylation datasets and employing machine learning to create predictive models based on individual CpG sites and co-methylation modules. These models demonstrated high accuracy in estimating chronological age, with a median absolute error of 3 weeks (7.5% of median lifespan) for a clock based on methylation of individual CpG and 1.5 weeks (3.7% of median lifespan) for an eigenvector-based clock. Our investigation extended to assessing epigenetic age acceleration in different strains and the potential resetting effect of regeneration on fin tissue. Notably, our models indicated that a shorter-lived strain has accelerated epigenetic aging and that regeneration does not reset, but may decelerate epigenetic aging. Additionally, we used longitudinal data to develop an "epigenetic timer" for direct prediction of individual lifespan based on fin biopsies and eigenvector-based method, achieving a median absolute error of 4.5 weeks in the prediction of actual age of death. This surprising result underscores the existence of intrinsic determinants of lifespan established early in life. This study presents the first epigenetic clocks and lifespan predictors for N. furzeri, highlighting their potential as aging biomarkers and sets the stage for future research on life-extending interventions in this model organism.

genomics↗

bioRxiv2023

Transcriptome analysis of different strains of the turquoise killifish Nothobranchius furzeri identifies signatures associated with heritable lifespan differences

The killifish Nothobranchius furzeri is the shortest-lived vertebrate model organism and is characterized by laboratory strains differing in lifespan by more than a factor of two. The genetic architecture underlying this difference is complex and the pathways responsive remain elusive. We performed an analysis in N. furzeri of public transcritomic datasets comprehensive of four different tissues and one embryonic stage in two strains: the shorter-lived GRZ and the longer-lived MZM0410. Remarkably, the two strains differ in their transcriptome profile already at the embryonic stage. The short-lived strain GRZ shows an anticipated aging profile consistently in all tissues investigated, with differences in expression of aging-related genes detected already at sexual maturity. In addition, analysis of a longitudinal dataset revealed that genes whose expression is prognostic of longer lifespan at the individual level are also differentially expressed between strains at an early adult age, suggesting antagonistic pleiotropism.

genomics↗

bioRxiv2023

Tau alters global gene expression affecting chromatin in the early stages of Alzheimer's disease

Recent research revealed that Tau plays critical roles in various neuronal functions. Our previous work demonstrated that destabilization and nuclear delocalization of Tau can alter the expression of glutamatergic genes, thereby mediating early neuronal damage. Upon analysing gene coexpression of AD temporal regions at different stages and the transcriptional output in differentiated neuroblastoma cells, we discovered that changes in Tau availability are linked to global alterations in gene expression that affect multiple neuronal pathways. Comparison with the human AD temporal region showed that the Tau-dependent modulation of gene expression closely resembles an intermediate stage of AD that precedes the definitive AD condition. Furthermore, we identified the chromatin remodelling pathway as being significantly affected by Tau in both our cellular model and AD brains, with reductions in heterochromatin markers. We propose that Tau is able to globally affect the neuronal transcriptome and that its availability is linked to changes in gene expression during intermediate stages of AD development. In addition, we found that the epigenetic pathway is strongly affected by Tau during the progression of AD.

neuroscience↗

bioRxiv2023

A comprehensive atlas of the aging vertebrate brain reveals signatures of progressive proteostasis dysfunction

Aging and neurodegeneration entail diverse cellular and molecular hallmarks. Here, we studied the effects of aging on the transcriptome, translatome, and multiple layers of the proteome in the brain of a short-lived killifish. We reveal that aging causes widespread reduction of proteins enriched in basic amino acids that is independent of mRNA regulation, and it is not due to impaired proteasome activity. Instead, we identify a cascade of events where aberrant translation pausing leads to reduced ribosome availability resulting in proteome remodeling independently of transcriptional regulation. Our research uncovers a vulnerable point in the aging brains biology - the biogenesis of basic DNA/RNA binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity and the biosynthesis of macromolecules. One-Sentence SummaryTranslation pausing reshapes the aging brain proteome, revealing vulnerabilities in the biogenesis of nucleic-acid protein.

systems biology↗

bioRxiv2022

A deep neural network provides an ultraprecise transcriptomic clock of the short-lived fish Nothobranchius furzeri and identifies predictive genes translatable to human aging.

A key and unresolved question in aging research is how to quantify aging at the individual level that led to development of "aging clocks", machine learning algorhythms trained to predict individual age from high-dimensional molecular data under the the assumption that individual deviations of the predicted age from the chronological age contain information on the individual condition (often referred to as "biological age"). A full validation of such clocks as biomarkers for clinical studies of ageing would require a comparison of their predictions with information on actual lifespan and long-term health. Such studies take decades in humans, but could be conducted in a much shorter time-frame in animal models. We developed a transcriptomic clock in the turquoise killifish Nothobranchius furzeri. This species is the shortest-lived vertebrate that can be cultured in captivity and is an emerging model organism for genetic and experimental studies on aging. We developed a proprietary deep learning architecture that autonomously selects a customizable number of input genes to use for its predictions in order to reduce overfitting and increase interpretability, and adopts an adversarial learning framework to identify tissue-independent transcriptional patterns. We called this architecture the Selective Adversarial Deep Neural Network (SA-DNN) and trained it on a multi-tissue transcriptomic dataset of N. furzeri. This SA-DNN predicted age of the test set with an accuracy of 1 day, i.e. less than 1% of the total species lifespan and detected genetic, pharmacological and environmental interventions that are known to influence lifespan in this species. Finally, a human transcriptomic multi-tissue clock that uses as input the orthologs of the genes selected by our SA-DNN in N. furzeri reaches an average error of[~] 3 years rivalling epigenetic clocks. Our SA-DNN represents the prototype of a new class of aging clocks that provide biomarkers applicable to intervention studies in model organisms and humans.

genomics↗

bioRxiv2021

Aging is associated with a degeneration of noradrenergic-, but not dopaminergic-neurons, in the short-lived killifish Nothobranchius furzeri.

Parkinsons disease (PD) is characterized by phosphorylation and aggregation of the protein -Synuclein and ensuing neuronal death progressing from the noradrenergic locus coeruleus to midbrain dopaminergic neurons. In 2019, Matsui and colleagues reported in Cell Reports a spontaneous age-dependent degeneration of dopaminergic neurons and an even greater neurodegeneration of the noradrenergic neurons in the short-lived killifish Nothobranchius furzeri. Given the great possible relevance of a spontaneous model for PD, we set to confirm their results by whole-brain clarification and 3D nuclei reconstruction to quantify total cell numbers. We observed an age dependent neurodegeneration limited to the locus coeruleus and not involving the posterior tuberculum. In addition, we observed the presence of phospho-Synuclein in the soma of locus coeruleus neurons detectable already at a young age and increasing during aging. Our result demonstrates that N. furzeri models the early stages of PD, but not the degeneration of dopaminergic neurons.

neuroscience↗

bioRxiv2021

New lessons on TDP-43 from the killifish N. furzeri

Frontotemporal dementia and amyotrophic lateral sclerosis are fatal and incurable neurodegenerative diseases linked to the pathological aggregation of the TDP-43 protein. This is an essential DNA/RNA binding protein involved in transcription regulation, pre-RNA processing and RNA transport. Having suitable animal models to study the mechanisms of TDP-43 aggregation is crucial to develop treatments against disease. We have previously demonstrated that the killifish Nothobranchius furzeri offers the unique advantage as a model system that it is an organism with compressed lifespan and a conserved ageing phenotype that develops within months, making this organism the available shortest-lived vertebrate with a clear ageing phenotype. Here, we show that the two paralogs of TDP-43 from the killifish N. furzeri share high sequence homology with the human protein and recapitulate its cellular and biophysical behaviour. We prove that, during ageing, N. furzeri TDP-43 spontaneously forms insoluble intracellular TDP-43 aggregates that have amyloid characteristics and colocalize with the stress granule core protein G3BP. Our results propose this organism as a valuable model of TDP-43-related pathologies and show that even minute differences between the human and N. furzeri proteins may help to shed new light onto the role of TDP-43 in RNA recognition and granule formation.

neuroscience↗

bioRxiv2020

The sources of sex differences in aging in annual fishes

Sex differences in lifespan and aging are widespread among animals, with males usually the shorter-lived sex. Despite extensive research interest, it is unclear how lifespan differences between the sexes are modulated by genetic, environmental and social factors. We combined comparative data from natural populations of annual killifishes with experimental results on replicated captive populations, showing that females consistently outlived males in the wild. This sex-specific survival difference persisted in social environment only in two most aggressive species, and ceased completely when social and physical contacts were prevented. Demographically, neither an earlier start nor faster rate of aging accounted for shorter male lifespans, but increased baseline mortality and the lack of mortality deceleration in the oldest age shortened male lifespan. The sexes did not differ in any measure of functional aging we recorded. Overall, we demonstrate that sex differences in lifespan and aging may be ameliorated by modulating social and environmental conditions.

evolutionary biology↗

bioRxiv2019

Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation

A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short-lived vertebrate Nothobranchius furzeri combining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein and mRNA, mainly due to post-transcriptional mechanisms that account for over 40% of the age-regulated proteins. These changes cause a progressive loss of stoichiometry in several protein complexes, including ribosomes, which show impaired assembly / dis-assembly and are enriched in protein aggregates in old brains. Mechanistically, we show that reduction of proteasome activity is an early event during brain aging and is sufficient to induce proteomic signatures of aging and loss of stoichiometry in vivo. Using longitudinal transcriptomic data, we show that the magnitude of early life decline in proteasome levels is the major risk factor for mortality. Our work defines causative events in the aging process that can be targeted to prevent loss of protein homeostasis and delay the onset of age-related neurodegeneration. HighlightsO_LIProgressive loss of stoichiometry affects multiple protein complexes C_LIO_LIRibosomes aggregate in old brains C_LIO_LIPartial reduction of proteasome activity is sufficient to induce loss of stoichiometry C_LIO_LIReduced proteasome levels are a major risk factor for early death in killifish C_LI

systems biology↗

bioRxiv2019

Mitohormetic effects of rotenone drastically depend on age

Hormesis refers to a biphasic intensity-dependent response to stressors where low-intensity or short-duration exposure to potentially noxious stressors induces long-lasting adaptations that have positive physiological effects [1]. It was proposed that life-extending interventions, such as calorie restriction, retard aging via their hormetic action [2]. More recently, it was shown that a transient burst of reactive oxygen species is required to induce the effects of calorie restriction [3], physical exercise [4], inhibition of the insulin/IGF-I pathway [5] and metformin [6]. We have previously shown that partial inhibition of complex I of the respiratory chain by a low dose of the poison rotenone (ROT) administered in middle age increases the lifespan and reverts the transcriptomic signature of aging in a vertebrate species [7], an example of a hormetic effect. Here, we asked whether ROT treatment started at young age induces larger effects on life-span and transcriptome.

pharmacology and toxicology↗

bioRxiv2019

Cell cycle dynamics during diapause entry and exit in an annual killifish revealed by FUCCI technology

BackgroundAnnual killifishes are adapted to surviving and reproducing over alternating dry and wet seasons. During the dry season, all adults die and desiccation-resistant embryos remain encased in dry mud for months or years in a state of quiescence, delaying hatching until their habitats are flooded again. Embryonic development of annual killifishes deviates from canonical teleost development. Epiblast cells disperse during epiboly, and a \"dispersed phase\" precedes gastrulation. In addition, annual fish have the ability to enter diapause and block embryonic development at the dispersed phase (diapause I), mid-somitogenesis (diapause II) and the final phase of development (diapause III).\n\nDevelopmental transitions associated with diapause entry and exit can be linked with cell cycle events. Here we set to image this transitions in living embryos.\n\nResultsTo visibly explore cell cycle dynamics during killifish development in depth, we created a stable transgenic line in Nothobranchius furzeri that expresses two fluorescent reporters, one for the G1 phase and one for the S/G2 phases of the cell cycle, respectively (fluorescent ubiquitination based cell cycle indicator, FUCCI). Using this tool, we observed that, during epiboly, epiblast cells progressively become quiescent and exit the cell cycle. All embryos transit through a phase where dispersed cells migrate, without showing any mitotic activity, possibly blocked in the M phase (diapause I).\n\nThereafter, exit from diapause I is synchronous and cells enter directly into the S phase without transiting through G1. The developmental trajectories of embryos entering diapause and of those that continue to develop are different. In particular, embryos entering diapause have reduced growth along the medio-lateral axis. Finally, exit from diapause II is synchronous for all cells and is characterized by a burst of mitotic activity and growth along the medio-lateral axis such that, by the end of this phase, the morphology of the embryos is identical to that of direct-developing embryos.\n\nConclusionsOur study reveals surprising levels of coordination of cellular dynamics during diapause and provides a reference framework for further developmental analyses of this remarkable developmental quiescent state.\n\nList of AbbreviationsIn this paper, we will refer to several developmental stages or morphological structures using abbreviations. To make the reading easier, we resume here a list of all the abbreviations, to which the reader can refer at any time.

developmental biology↗

bioRxiv2018

Clownfishes are a genetic model of exceptional longevity and reveal molecular convergence in the evolution of lifespan

Standard evolutionary theories of aging postulate that reduced extrinsic mortality leads to evolution of longevity. Clownfishes of the genus Amphiprion live in a symbiotic relationship with sea anemones that provide protection from predation. We performed a survey and identified at least two species with lifespan of over 20 years. Given their small size and ease of captive reproduction, clownfishes lend themselves as experimental models of exceptional longevity.\n\nTo identify genetic correlates of exceptional longevity, we sequenced the transcriptomes of Amphiprion percula and A. clarkii and performed a scan for positively-selected genes (PSGs). These were compared with PSGs detected in long-lived mole rats and short-lived killifishes revealing convergent evolution in processes such as mitochondrial biogenesis. Among individual genes, the Mitochondrial Transcription Termination Factor 1 (MTERF1), was positively-selected in all three clades, whereas the Glutathione S-Transferase Kappa 1 (GSTK1) was under positive selection in two independent clades. For the latter, homology modelling strongly suggested that positive selection targeted enzymatically important residues.\n\nThese results indicate that specific pathways were recruited in independent lineages evolving an exceptionally extended or shortened lifespan and point to mito-nuclear balance as a key factor.

evolutionary biology↗

bioRxiv2018

The age-regulated zinc finger factor ZNF367 is a new modulator of embryonic neurogenesis

Global population aging is one of the major social and economic challenges of contemporary society. During aging the progressive decline in physiological functions has serious consequences for all organs including brain. The age-related incidence of neurodegenerative diseases coincides with the sharp decline of the amount and functionality of adult neural stem cells. Recently, we identified a short list of brain age-regulated genes by means of next-generation sequencing. Among them znf367 codes for a transcription factor that represents a central node in gene coregulation networks during aging but its function, in the central nervous system (CNS), is completely unknown. As proof of concept we analyzed the role of znf367 during neurogenesis. By means of a gene loss of function approach limited to the CNS, we suggested that znf367 might act as a key controller of the neuroblasts cell cycle, particularly in the progression of mitosis and spindle check-point. Using a candidate gene approach, based on a weighted-gene co-expression network analysis, we suggested possible targets of znf367 such as fancd2 and ska3. The age-related decline of znf367 well correlated with its role during embryonic neurogenesis opening new lines of investigation to improved maintenance and even repair of neuronal function.

developmental biology↗