Olivia Casanueva

Research Summary

Groundbreaking work in the nematode Caenorhabditis elegans has demonstrated that ageing is not simply a stochastic and progressive decay, but that it is genetically controlled by the longevity pathways. Strikingly, lifespan is highly variable even in genetically identical individuals reared under controlled environmental conditions.

We are interested in finding the mechanisms underlying transcriptional inter-individual variability in genes that modulate lifespan and determining to what extent it explains individual-to-individual differences in the rates of ageing. We are also interested in studying the influence of both stochastic and environmental variability during early life and its long-term effect on health. Dietary restriction (DR), reduced food intake without malnutrition, increases health and function during ageing and protects against ageing-related disease in most organisms. We are interested in understanding how early life nutrition (and DR) can set rates of ageing via epigenetic mechanisms.

Answering these questions requires the development of new technologies that make whole animals centre stage and will have a significant conceptual impact on ageing research and personalized medicine.  

Latest Publications

Autophagy compensates for defects in mitochondrial dynamics.
Haeussler S, Köhler F, Witting M, Premm MF, Rolland SG, Fischer C, Chauve L, Casanueva O, Conradt B

Compromising mitochondrial fusion or fission disrupts cellular homeostasis; however, the underlying mechanism(s) are not fully understood. The loss of C. elegans fzo-1MFN results in mitochondrial fragmentation, decreased mitochondrial membrane potential and the induction of the mitochondrial unfolded protein response (UPRmt). We performed a genome-wide RNAi screen for genes that when knocked-down suppress fzo-1MFN(lf)-induced UPRmt. Of the 299 genes identified, 143 encode negative regulators of autophagy, many of which have previously not been implicated in this cellular quality control mechanism. We present evidence that increased autophagic flux suppresses fzo-1MFN(lf)-induced UPRmt by increasing mitochondrial membrane potential rather than restoring mitochondrial morphology. Furthermore, we demonstrate that increased autophagic flux also suppresses UPRmt induction in response to a block in mitochondrial fission, but not in response to the loss of spg-7, which encodes a mitochondrial metalloprotease. Finally, we found that blocking mitochondrial fusion or fission leads to increased levels of certain types of triacylglycerols and that this is at least partially reverted by the induction of autophagy. We propose that the breakdown of these triacylglycerols through autophagy leads to elevated metabolic activity, thereby increasing mitochondrial membrane potential and restoring mitochondrial and cellular homeostasis.

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PLoS genetics, 16, 3, 19 Mar 2020

DOI: 10.1371/journal.pgen.1008638

PMID: 32191694

Using Genome-Scale Metabolic Networks for Analysis, Visualization, and Integration of Targeted Metabolomics Data.
Hattwell JPN, Hastings J, Casanueva O, Schirra HJ, Witting M

Interpretation of metabolomics data in the context of biological pathways is important to gain knowledge about underlying metabolic processes. In this chapter we present methods to analyze genome-scale models (GSMs) and metabolomics data together. This includes reading and mining of GSMs using the SBTab format to retrieve information on genes, reactions, and metabolites. Furthermore, the chapter showcases the generation of metabolic pathway maps using the Escher tool, which can be used for data visualization. Lastly, approaches to constrain flux balance analysis (FBA) by metabolomics data are presented.

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Methods in molecular biology (Clifton, N.J.), 2104, 1, 2020

DOI: 10.1007/978-1-0716-0239-3_18

PMID: 31953826

Multi-Omics and Genome-Scale Modeling Reveal a Metabolic Shift During C. Elegans Ageing.
Hastings J, Mains A, Virk B, Rodriguez N, Murdoch S, Pearce J, Bergmann S, Le Novère N, Casanueva O

In this contribution, we describe a multi-omics systems biology study of the metabolic changes that occur during aging in . Sampling several time points from young adulthood until early old age, our study covers the full duration of aging and include transcriptomics, and targeted MS-based metabolomics. In order to focus on the metabolic changes due to age we used two strains that are metabolically close to wild-type, yet are conditionally non-reproductive. Using these data in combination with a whole-genome model of the metabolism of and mathematical modeling, we predicted metabolic fluxes during early aging. We find that standard Flux Balance Analysis does not accurately predict measured fluxes nor age-related changes associated with the Citric Acid cycle. We present a novel Flux Balance Analysis method where we combined biomass production and targeted metabolomics information to generate an objective function that is more suitable for aging studies. We validated this approach with a detailed case study of the age-associated changes in the Citric Acid cycle. Our approach provides a comprehensive time-resolved multi-omics and modeling resource for studying the metabolic changes during normal aging in .

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Frontiers in molecular biosciences, 6, 2296-889X, 2019

PMID: 30788345