Research Interests: RNA, Neurogenesis, Transcriptomics, Aging, Epigenetics, and 15 moreGene expression, Transcriptome, Biological Sciences, Epigenomics, Brain, Humans, Animals, Male, Animal Model, Cyprinodontiformes, Behavioral Animal Models, Neural Stem Cells, Gene Expression Regulation, Gene expression profiling, and Medical and Health Sciences
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Most research on mechanisms of aging is being conducted in a very limited number of classical model species, i.e., laboratory mouse (Mus musculus), rat (Rattus norvegicus domestica), the common fruit fly (Drosophila melanogaster) and... more
Most research on mechanisms of aging is being conducted in a very limited number of classical model species, i.e., laboratory mouse (Mus musculus), rat (Rattus norvegicus domestica), the common fruit fly (Drosophila melanogaster) and roundworm (Caenorhabditis elegans). The obvious advantages of using these models are access to resources such as strains with known genetic properties, high-quality genomic and transcriptomic sequencing data, versatile experimental manipulation capabilities including well-established genome editing tools, as well as extensive experience in husbandry. However, this approach may introduce interpretation biases due to the specific characteristics of the investigated species, which may lead to inappropriate, or even false, generalization. For example, it is still unclear to what extent knowledge of aging mechanisms gained in short-lived model organisms is transferable to long-lived species such as humans. In addition, other specific adaptations favoring a l...
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SummaryParkinson’s disease (PD) is characterized by phosphorylation and aggregation of the protein α-Synuclein and ensuing neuronal death progressing from the noradrenergic locus coeruleus to midbrain dopaminergic neurons. In 2019, Matsui... more
SummaryParkinson’s disease (PD) is characterized by phosphorylation and aggregation of the protein α-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 ...
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Annual fishes of the genus Nothobranchius inhabit ephemeral habitats in Eastern and Southeastern Africa. Their life cycle is characterized by very rapid maturation, a posthatch lifespan of a few weeks to months and embryonic diapause to... more
Annual fishes of the genus Nothobranchius inhabit ephemeral habitats in Eastern and Southeastern Africa. Their life cycle is characterized by very rapid maturation, a posthatch lifespan of a few weeks to months and embryonic diapause to survive the dry season. The species N. furzeri holds the record of the fastest-maturing vertebrate and of the vertebrate with the shortest captive lifespan and is emerging as model organism in biomedical research, evolutionary biology, and developmental biology. Extensive characterization of age-related phenotypes in the laboratory and of ecology, distribution, and demography in the wild are available. Species/populations from habitats differing in precipitation intensity show parallel evolution of lifespan and age-related traits that conform to the classical theories on aging. Genome sequencing and the establishment of CRISPR/Cas9 techniques made this species particularly attractive to investigate the effects genetic and non-genetic intervention on ...
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SummaryA 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 by using the short-lived... more
SummaryA 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 by using the short-lived vertebrate Nothobranchius furzeri and combining transcriptomics, proteomics and thermal proteome profiling. We found that the correlation between protein and mRNA levels is progressively reduced during aging, and that post-transcriptional mechanisms are responsible for over 40% of these alterations. These changes induce a progressive stoichiometry loss in protein complexes, including ribosomes, which have low thermal stability in brain lysates and whose component proteins are enriched in aggregates found in old brains. Mechanistically, we show that reduced proteasome activity occurs early during brain aging, and is sufficient to induce loss of stoichiometry. Our work thus defines early events in the aging process that can be targeted to prevent loss of ...
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Studies on parental aging are a very attractive field, although it is poorly understood how parental age affects embryonic development and adult traits of the offspring. In this study, we used the turquoise killifish Nothobranchius... more
Studies on parental aging are a very attractive field, although it is poorly understood how parental age affects embryonic development and adult traits of the offspring. In this study, we used the turquoise killifish Nothobranchius furzeri, as is the vertebrate with shortest captive lifespan and an interesting model. The embryos of N. furzeri can follow two distinct developmental pathways either entering diapause or proceeding through direct development. Thus, this embryonic plasticity allows this model to be used to study different factors that could affect their embryonic development, including parental age. The first goal of the present study was to investigate whether parental aging could affect the embryo development. To do this, we collected F1 embryos from two breeder groups (old parents and young parents). We monitored the duration of embryonic development and analyzed genes involved in dorsalization process. The second goal was to investigate if embryonic developmental plas...
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The circadian system is the responsible to organise the internal temporal order in relation to the environment of every process of the organisms producing the circadian rhythms. These rhythms have a fixed phase relationship among them and... more
The circadian system is the responsible to organise the internal temporal order in relation to the environment of every process of the organisms producing the circadian rhythms. These rhythms have a fixed phase relationship among them and with the environment in order to optimise the available energy and resources. From a cellular level, circadian rhythms are controlled by genetic positive and negative auto-regulated transcriptional and translational feedback loops, which generate 24hour rhythms in mRNA and protein levels of the clock components. It has been described about 10% of the genome is controlled by clock genes, with special relevance, due to its implications, to the cell cycle. Ageing is a deleterious process which affects all the organisms' structures including circadian system. The circadian system's ageing may produce a disorganisation among the circadian rhythms, arrhythmicity and, even, disconnection from the environment, resulting in a detrimental situation t...
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Iron is an essential metal cofactor for enzymes involved in many cellular functions such as energy generation and cell proliferation. However, excessive iron concentration leads to increased oxidative stress and toxicity. As such, iron... more
Iron is an essential metal cofactor for enzymes involved in many cellular functions such as energy generation and cell proliferation. However, excessive iron concentration leads to increased oxidative stress and toxicity. As such, iron homeostasis is strictly controlled by two RNA binding proteins known as Iron Regulatory Proteins (IRPs) that regulate at post-transcriptional level the expression of iron management genes. Despite this fine regulation, impairment of iron homeostasis occurs during aging: iron progressively accumulates in several organs and in turn, it exacerbates cellular vulnerability and tissue decay. Moreover, excessive iron accumulation within the CNS is observed in many neurodegenerative diseases. We investigated the age-dependent changes of iron homeostasis using the short lived fish Nothobranchius furzeri. Here, we show that i) both iron content and expression of microRNA family miR-29 increase during adult life and aging in the N. furzeri brain; ii) iron up-reg...
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Research Interests: Electron Microscopy, Plasticity, Aging, Immunohistochemistry, Confocal Microscopy, and 15 moreAge, Mice, Animals, Retina, Neuronal Plasticity, Dendrites, Second Year, Clinical Sciences, Eye, Second Order, Biological markers, Neural pathways, Neurobiology of Aging, Retinal Diseases, and Neurosciences
The S100 protein in nervous tissue appears to play important roles in regulating neuronal differentiation, glial proliferation, plasticity, development, axonal growth, and in neurogenetic processes. In fish, the adult neurogenic activity... more
The S100 protein in nervous tissue appears to play important roles in regulating neuronal differentiation, glial proliferation, plasticity, development, axonal growth, and in neurogenetic processes. In fish, the adult neurogenic activity is much higher than in mammals. In this study, the localization of S100 protein was investigated in the brain of annual teleost fish, Nothobranchius furzeri, which is an emerging model organism for aging research. By immunohistochemical techniques, S100 immunoreactivity (IR) was detected in glial cells, small neurons, and fibers throughout all regions of central nervous system (CNS) with different pattern of distribution. In the telencephalon, S100 IR was seen in the olfactory bulbs and in different areas of the telencephalic hemispheres. In the diencephalon, S100 positivity was observed in the habenular nuclei of the epithalamus, in the cortical thalamic nucleus, in the dorsal, ventral and caudal portions, the latter with the posterior recessus nucleus, and in the diffuse inferior lobe of the hypothalamus, along the diencephalic ventricle and in the dorsal optic tract. In the mesencephalon, S100 IR was observed in the longitudinal tori, in the optic tectum, and along the mesencephalic ventricle. In the rhombencephalon, S100 IR was shown in valvula and body of the cerebellum, and in some nuclei of the medulla oblongata. The results suggest that S100 may play a key role in the maintenance of the CNS and in neurogenesis processes in the adulthood.
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Trk neurotrophin receptors are transmembrane tyrosine kinase proteins known as TrkA, TrkB, and TrkC. TrkA is the high affinity receptor for nerve growth factor, TrkB is the one for both brain-derived neurotrophic factor and... more
Trk neurotrophin receptors are transmembrane tyrosine kinase proteins known as TrkA, TrkB, and TrkC. TrkA is the high affinity receptor for nerve growth factor, TrkB is the one for both brain-derived neurotrophic factor and neurotrophin-4, and TrkC is the preferred receptor for neurotrophin-3. In the adult mammalian brain, neurotrophins are important regulators of neuronal function and plasticity. This study is based on Nothobranchius furzeri, a teleost fish that is becoming an ideal candidate as animal model for aging studies because its life expectancy in captivity is of just 3 months. In adult N. furzeri, all three investigated neurotrophin Trk receptors were immunohistochemically detected in each brain region. TrkA positive neuronal perikarya were localized in the dorsal and ventral areas of the telencephalon and in the cortical nucleus; TrkB immunoreactivity was observed in neuronal perikarya of the dorsal and ventral areas of the telencephalon, the diffuse inferior lobe of the hypothalamus, and Purkinje cells; TrkC positive neuronal perikarya were detected in the most aboral region of the telencephalon, in the magnocellular preoptic nucleus and in few neurons dispersed in the hypothalamus. Numerous positive fibers were widely distributed throughout the brain. Radial glial cells lining the mesencephalic and rhombencephalic ventricles showed immunoreactivity to all three Trks. These findings suggest an involvement of neurotrophins in many aspects of biology of adult N. furzeri.
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Research Interests: Comparative Genomics, Aging, Biomarkers, Comparative Study, Biological Sciences, and 15 moreExperimental evolution, Female, Animals, Laboratory Animals, Male, Drug Screening, Life Expectancy, Biological evolution, Cyprinodontiformes, Model System, Biological markers, Amino Acid Sequence, Embryos, Molecular Sequence Data, and Medical and Health Sciences
Research Interests: Aging, Learning, Biological Sciences, Longevity, Dietary Restriction, and 15 moreBrain, Liver, Animals, Fishes, Animal Model, Inbreeding, Glial Fibrillary Acidic Protein, Biological markers, Caloric Restriction, Intermittent Fasting, Food Deprivation, Lipofuscin, fluorescent dyes, Medical and Health Sciences, and Nerve degeneration
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Nothobranchius is a genus of annual fish broadly distributed in South-Eastern Africa and found into temporary ponds generated during the rain seasons and their lifespan is limited by the duration of their habitats. Here we compared two... more
Nothobranchius is a genus of annual fish broadly distributed in South-Eastern Africa and found into temporary ponds generated during the rain seasons and their lifespan is limited by the duration of their habitats. Here we compared two Nothobranchius species from radically different environments: N. furzeri and N. korthausae. We found a large difference in life expectancy (29- against 71-weeks of median life span, 40- against 80-weeks of maximum lifespan, respectively), which correlates with a diverse timing in the onset of several age dependent processes: our data show that N. korthause longer lifespan is associated to retarded onset of age-dependent liver-neoplasia and slower down-regulation of collagen 1 alpha 2 (COL1A2) expression in the skin. On the other hand, the expression of cyclin B1 (CCNB1) in the brain was strongly age-regulated, but with similar profiles in N. furzeri and N. korthausae. In conclusion, our data suggest that the different ageing rate of two species of the same genus could be used as novel tool to investigate and better understand the genetic bases of some general mechanism leading to the complex ageing process, providing a strategy to unravel some of the genetic mechanisms regulating longevity and age-associate pathologies including neoplasias.
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Life span and aging are substantially modified by natural selection. Across species, higher extrinsic (environmentally related) mortality (and hence shorter life expectancy) selects for the evolution of more rapid aging. However, among... more
Life span and aging are substantially modified by natural selection. Across species, higher extrinsic (environmentally related) mortality (and hence shorter life expectancy) selects for the evolution of more rapid aging. However, among populations within species, high extrinsic mortality can lead to extended life span and slower aging as a consequence of condition-dependent survival. Using within-species contrasts of eight natural populations of Nothobranchius fishes in common garden experiments, we demonstrate that populations originating from dry regions (with short life expectancy) had shorter intrinsic life spans and a greater increase in mortality with age, more pronounced cellular and physiological deterioration (oxidative damage, tumor load), and a faster decline in fertility than populations from wetter regions. This parallel intraspecific divergence in life span and aging was not associated with divergence in early life history (rapid growth, maturation) or pace-of-life syndrome (high metabolic rates, active behavior). Variability across four study species suggests that a combination of different aging and life-history traits conformed with or contradicted the predictions for each species. These findings demonstrate that variation in life span and functional decline among natural populations are linked, genetically underpinned, and can evolve relatively rapidly.