Biology subjects

Ezcurra, M.

Publications and source records attributed to Ezcurra, M..

12 recordsLinked to original sources

bioRxiv2026

A defined microbial community remodels host metabolism and pathogen resistance in Caenorhabditis elegans

The microbiome is an important regulator of metabolism and health, yet the mechanisms by which microbial communities influence host physiological state remain incompletely understood. Here we used a defined host-microbiota model consisting of Caenorhabditis elegans and an 11-member bacterial consortium representative of its natural microbiota (DefNatMta). We investigated how this native microbial community influences host metabolism and physiology relative to the standard laboratory diet, E. coli OP50. Transcriptomic analyses revealed remodelling of host pathways associated with lipid metabolism, immunity and xenobiotic detoxification. Comparison with fasting-responsive transcriptional programmes showed that the DefNatMta response is distinct from fasting or caloric restriction. DefNatMta enhanced resistance to Staphylococcus aureus infection, and this protective effect was consistent with roles for the conserved host defence regulators PMK-1/p38 MAPK and HLH-30/TFEB. Additionally, DefNatMta reduced lipid accumulation, modified expression of lipid metabolism genes, and altered fatty acid composition, including enrichment of monomethyl branched-chain fatty acids and polyunsaturated fatty acids. Together, these findings demonstrate that a defined microbial community can induce transcriptional, metabolic and physiological remodelling in the host. Our results are consistent with microbial communities shaping host metabolic state and immune competence.

physiology↗

bioRxiv2025

A hierarchy of causes of death in senescent C. elegans

In experimental gerontology, lifespan is often interpreted as a metric of the rate of the overall aging process. However, interventions that increase lifespan can result from suppression of one or more individual late-life pathologies. Here we show how, in the nematode Caenorhabditis elegans, such pathologies can compete in a hierarchical fashion to cause death, such that removal of one cause of death can unmask another. Under standard culture conditions, a major cause of death in elderly C. elegans is infection by their bacterial food source. We report that only when such infection is prevented is lifespan extended by suppression of a second senescent pathology, teratoma-like uterine tumors. Thus, as in mammals, lifespan in wild-type C. elegans can be limited by naturally-occurring neoplasia. By contrast, blocking bacterial infection attenuated the life-shortening effects of vitellogenesis, and did not unmask a life-shortening effect of distal gonad degeneration. Thus, depending on the masking or unmasking of competing causes of mortality in the hierarchy of causes of death, nematode lifespan limitation in different contexts can reflect action of distinct life-limiting senescent pathologies. This underscores how increases in lifespan do not necessarily reflect a reduction in overall aging rate.

pathology↗

bioRxiv2025

A novel C. elegans respirometry assay using low-cost optical oxygen sensors

Measurement of the oxygen consumption rate (OCR), or respirometry, is a powerful and comprehensive method for assessing mitochondrial function both in vitro and in vivo. Respirometry at the whole-organism level has been repeatedly performed in the model organism Caenorhabditis elegans, typically using high throughput microplate-based systems over traditional Clark-type respirometers. However, these systems are highly specialised, costly to purchase and operate, and inaccessible to many researchers. Here, we develop a respirometry assay using low-cost commercially available optical oxygen sensors (PreSens OxoPlates(R)) and fluorescence plate readers (the BMG FLUOstar), as an alternative to more costly standard respirometry systems. This assay uses standard BMG FLUOstar protocols and a set of custom scripts to perform repeated measurements of the C. elegans OCR, with the optional use of respiratory inhibitors or other interventions. We validate this assay by demonstrating the linearity of basal OCRs in samples with highly variable numbers of animals, and by examining the impact of respiratory inhibitors with previously demonstrated efficacy in C. elegans: carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (a mitochondrial uncoupler) and sodium azide (a Complex IV inhibitor). Using this assay, we demonstrate that the sequential use of FCCP and sodium azide leads to an increase in the sodium azide-treated (non-mitochondrial) OCR, indicating that the sequential use of respiratory inhibitors, as standard in intact cell respirometry, may produce erroneous estimates of non-mitochondrial respiration in C. elegans and thus should be avoided.

cell biology↗

bioRxiv2024

A gut-microbiota-muscle axis that protects against age-related motor decline by regulating mitochondrial fission in C. elegans

Across diverse taxa, the composition of the microbiota is associated with lifelong host health. A mechanistic understanding of how microbial communities influence host physiology could lead to microbiota-based interventions for lifelong health. Here, we have developed a new host-microbiota model system utilising the model organism C. elegans combined with a defined natural microbiota (DefNatMta) consisting of 11 bacteria isolated from wild C. elegans, to study host-microbiota interactions in a more natural setting. We show that DefNatMta colonises the C. elegans gut, forming a stable and distinct gut microbiota. Using DefNatMta, we find a gut microbiota-muscle axis by which the microbiota affects age-related motility and muscular strength and protects against age-related decline in motor function. The gut microbiota-muscle axis acts by altering metabolism and mitochondrial network dynamics in muscle, and requires dynamin-related protein 1 DRP-1, a regulator of mitochondrial fission to protect against age-related motility decline. Our study demonstrates a gut microbiota-muscle axis and microbiota-mitochondria communication affecting age-related muscle function.

physiology↗

bioRxiv2024

New tools to monitor Pseudomonas aeruginosa infection and biofilms in vivo in C. elegans.

Antimicrobial resistance is a growing health problem. Pseudomonas aeruginosa is a pathogen of major concern because of its multidrug resistance and global threat, especially in health-care settings. The pathogenesis and drug resistance of P. aeruginosa depends on its ability to form biofilms, making infections chronic and untreatable as the biofilm protects against antibiotics and host immunity. A major barrier to developing new antimicrobials is the lack of in vivo biofilm models. Standard microbiological testing is usually performed in vitro using planktonic bacteria, without representation of biofilms, reducing translatability. Here we develop tools to study both infection and biofilm formation by P. aeruginosa in vivo to accelerate development of strategies targeting infection and pathogenic biofilms. Using the nematode Caenorhabditis elegans and P. aeruginosa reporters combined with in vivo imaging we show that fluorescent P. aeruginosa reporters that form biofilms in vitro can be used to visualise tissue infection. Using automated tracking of C. elegans movement, we find that that the timing of this infection corresponds with a decline in health endpoints. In a mutant strain of P. aeruginosa lacking RhlR, a transcription factor that controls quorum sensing and biofilm formation, we find reduced capacity of P. aeruginosa to form biofilms, invade host tissues and negatively impact healthspan and survival. Our findings suggest that RhlR could be a new antimicrobial target to reduce P. aeruginosa biofilms and virulence in vivo and C. elegans could be used to more effectively screen for new drugs to combat antimicrobial resistance.

microbiology↗

bioRxiv2024

Phytoene and phytoene-rich microalgae extracts extend lifespan in C. elegans and protect against amyloid-beta toxicity in an Alzheimers disease model

The role of foods is shifting from focusing on the provision of energy and basic nutrients to also include bioactive compounds that prevent the development of chronic age-related diseases. Microalgae offer a source of nutritional compounds with important health effects, and have the potential for production of health-promoting products, without increasing agricultural land use and negatively impacting the environment. Here we investigate the health effects of microalgal extracts with high levels of the colourless carotenoid phytoene. Phytoene is widely available from dietary sources and can be detected across different tissues in the human body. However, it is usually regarded as a precursor for the synthesis of other carotenoids, rather than a bioactive molecule. We utilised the model organism C. elegans to show that phytoene-rich extracts from Chlorella sorokiniana and Dunaliella bardawil have anti-ageing properties. The extracts protect against oxidative damage and amyloid-{beta}42 proteotoxicity (a major pathology of Alzheimers disease), and extends lifespan. We show that pure phytoene also has these anti-ageing effects, suggesting that phytoene is a bioactive molecule with positive effects on ageing and longevity.

physiology↗

bioRxiv2024

Machine learning predicts lifespan and underlying causes of death in aging C. elegans

Senescence (aging) leads to senescent pathology that causes death, and genes control aging by determining such pathology. Here we investigate how senescent pathology mediates the effect of genotype on lifespan in C. elegans by means of a data-driven approach, using machine learning (ML). To achieve this we gathered extensive data on how diverse determinants of lifespan (sex, nutrition, genotype) affect patterns of age-related pathology. Our findings show that different life-extending treatments result in distinct patterns of suppression of senescent pathology. By analysing the differential effects on pathology and lifespan, our ML models were able to predict >70% of lifespan variation. Extent of pathology in the pharynx and intestine were the most important predictors of lifespan, arguing that elderly C. elegans die in part due to late-life disease in these organs. Notably, the mid-life pathogenetic burst characteristic of hermaphrodite senescence is absent from males.

genetics↗

bioRxiv2020

C. elegans hermaphrodites undergo semelparous reproductive death

Ageing in the nematode Caenorhabditis elegans is unusual in terms of the severity and early onset of senescent pathology, particularly affecting organs involved in reproduction (Ezcurra et al., 2018; Garigan et al., 2002; Herndon et al., 2002). In post-reproductive C. elegans hermaphrodites, intestinal biomass is converted into yolk leading to intestinal atrophy and yolk steatosis (Ezcurra et al., 2018; Sornda et al., 2019). We recently showed that post-reproductive mothers vent yolk which functions as a milk (yolk milk), supporting larval growth that is consumed by larvae (Kern et al., 2020). This form of massive reproductive effort involving biomass repurposing leading to organ degeneration is characteristic of semelparous organisms (i.e. that exhibit only a single reproductive episode) ranging from monocarpic plants to Pacific salmon where it leads to rapid death (reproductive death) (Finch, 1990; Gems et al., 2020). Removal of the germline greatly increases lifespan in both C. elegans and Pacific salmon, in the latter case by suppressing semelparous reproductive death (Hsin and Kenyon, 1999; Robertson, 1961). Here we present evidence that reproductive death occurs in C. elegans, and that it is suppressed by germline removal, leading to extension of lifespan. Comparing three Caenorhabditis sibling species pairs with hermaphrodites and females, we show that lactation and massive early pathology only occurs in the former. In each case, hermaphrodites are shorter lived and only in hermaphrodites does germline removal markedly increase lifespan. Semelparous reproductive death has previously been viewed as distinct from ageing; however, drawing on recent theories of ageing (Blagosklonny, 2006; de Magalhaes and Church, 2005; Maklakov and Chapman, 2019), we argue that it involves exaggerated versions of programmatic mechanisms that to a smaller extent contribute to ageing in non-semelparous species. Thus, despite the presence of reproductive death, mechanisms of ageing in C. elegans are informative about ageing in general.

genetics↗

bioRxiv2020

Neuronal SKN-1B Modulates Nutritional Signalling Pathways and Mitochondrial Networks to Control Satiety

The feeling of hunger or satiety results from integration of the sensory nervous system with other physiological and metabolic cues. This regulates food intake, maintains homeostasis and prevents disease. In C. elegans, chemosensory neurons sense food and relay information to the rest of the animal via hormones to control food-related behaviour and physiology. Here we identify a new component of this system, SKN-1B which acts as a central food-responsive node, ultimately controlling satiety and metabolic homeostasis. SKN-1B, an ortholog of mammalian NF-E2 related transcription factors (Nrfs), acts in two hypothalamus-like ASI neurons to sense food, communicate nutritional status to the organism, and control satiety and exploratory behaviours. It achieves this by modulating endocrine signalling pathways (IIS and TGF-{beta}), and by promoting a robust mitochondrial network. Our data suggest a food-sensing and satiety role for mammalian Nrf proteins.

animal behavior and cognition↗

bioRxiv2018

A family of transcription factors that limit lifespan: ETS factors have conserved roles in longevity

Increasing average population age, and the accompanying burden of ill health, is one of the public health crises of our time. Understanding the basic biology of the ageing process may help ameliorate the pathologies that characterise old age. Ageing can be modulated, often through changes in gene expression where regulation of transcription plays a pivotal role. Activities of Forkhead transcription factors (TFs) are known to extend lifespan, but detailed knowledge of the broader transcriptional networks that promote longevity is lacking. This study focuses on the E twenty-six (ETS) family of TFs. This family of TFs is large, conserved across metazoa, and known to play roles in development and cancer, but the role of its members in ageing has not been studied extensively. In Drosophila, an ETS transcriptional repressor, Aop, and an ETS transcriptional activator, Pnt, are known to genetically interact with Foxo and activating Aop is sufficient to extend lifespan. Here, it is shown that Aop and Foxo effect a related gene-expression programme. Additionally, Aop can modulate Foxos transcriptional output to moderate or synergise with Foxo activity depending on promoter context, both in vitro and in vivo. In vivo genome-wide mRNA expression analysis in response to Aop, Pnt or Foxo indicated, and further experiments confirmed, that combinatorial activities of the three TFs dictate metabolic status, and that direct reduction of Pnt activity is sufficient to promote longevity. The role of ETS factors in longevity was not limited to Pnt and Aop. Knockdown of Ets21c or Eip74EF in distinct cell types also extended lifespan, revealing that lifespan is limited by transcription from the ETS binding site in multiple cellular contexts. Reducing the activity of the C. elegans ETS TF Lin-1 also extended lifespan, a finding that corroborates established evidence of roles of this TF family in ageing. Altogether, these results reveal the ETS family of TFs as pervasive and evolutionarily conserved brokers of longevity.

genetics↗

bioRxiv2017

Autophagy-dependent gut-to-yolk biomass conversion generates visceral polymorbidity in aging C. elegans

Aging (senescence) is characterized by the development of numerous pathologies, some of which limit lifespan. Key to understanding aging is discovery of the mechanisms (etiologies) that cause senescent pathology. In Caenorhabditis elegans a major senescent pathology of unknown etiology is atrophy of its principal metabolic organ, the intestine. Here we identify a cause of not only this pathology, but also of yolky lipid accumulation and redistribution (a form of senescent obesity): autophagy-mediated conversion of intestinal biomass into yolk. Inhibiting intestinal autophagy or vitellogenesis rescues both visceral pathologies, and can also extend lifespan. This defines a disease syndrome leading to polymorbidity and contributing to late-life mortality. Activation of gut-to-yolk biomass conversion by insulin/IGF-1 signaling (IIS) promotes reproduction and senescence. This illustrates how major, IIS-promoted senescent pathologies in C. elegans can originate not from damage accumulation, but from continued action of a wild-type function (vitellogenesis), consistent with the recently proposed hyperfunction theory of aging.

physiology↗

bioRxiv2017

Monsters in the uterus: A parthenogenetic quasi-program causes teratoma-like tumors during aging in wild-type C. elegans

Many diseases whose frequency increases with advancing age are caused by aging (senescence), but the mechanisms of senescence remain poorly understood. According to G.C. Williams and M.V. Blagosklonny, a major etiological determinant of senescence is late-life, wild-type gene action and non-adaptive execution of biological programs (or quasi-programs). These generate a wide range of senescent pathologies causing illness and death. Here we investigate the etiology of a prominent senescent pathology in the nematode C. elegans, uterine tumors, in the light of the Williams Blagosklonny theory. Uterine tumors develop from unfertilized, immature oocytes which execute incomplete embryogenetic programs. This includes extensive endomitosis, leading to formation of chromatin masses and cellular hypertrophy. The starting point of pathogenesis is exhaustion of sperm stocks. The timing of this transition between program and quasi-program can be altered by blocking sperm production (causing earlier tumors) or supplying additional sperm by mating (delaying tumor onset). Other pathophysiological determinants are yolk consumption by tumors, and bacterial proliferation within tumors. Uterine tumors resemble mammalian ovarian teratomas (tera, Greek: monster) in that both develop from oocytes that fail to mature after meiosis I, and both are the result of quasi-programs. Moreover, older but not younger uterine tumors show expression of markers of later embryogenesis, i.e. are teratoma-like. These results show how uterine tumors in C. elegans form as the result of run-on of embryogenetic quasi-programs. They also suggest fundamental etiological equivalence between teratoma and some forms of senescent pathology, insofar as both are caused by quasi-programs.

developmental biology↗