The parasitic worm product ES-62 promotes health- and life-span in a high calorie diet-accelerated mouse model of ageing

Crowe, J. et al. (2020) The parasitic worm product ES-62 promotes health- and life-span in a high calorie diet-accelerated mouse model of ageing. PLoS Pathogens, 16(3), e1008391. (doi: 10.1371/journal.ppat.1008391) (PMID:32163524) (PMCID:PMC7108737)

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Abstract

Improvements in hygiene and health management have driven significant increases in human lifespan over the last 50 years. Frustratingly however, this extension of lifespan has not been matched by equivalent improvements in late-life health, not least due to the global pandemic in type-2 diabetes, obesity and cardiovascular disease, all ageing-associated conditions exacerbated and accelerated by widespread adoption of the high calorie Western diet (HCD). Recently, evidence has begun to emerge that parasitic worm infection might protect against such ageing-associated co-morbidities, as a serendipitous side-effect of their evolution of pro-survival, anti-inflammatory mechanisms. As a novel therapeutic strategy, we have therefore investigated the potential of ES-62, an anti-inflammatory secreted product of the filarial nematode Acanthocheilonema viteae, to improve healthspan (the period of life before diseases of ageing appear) by targeting the chronic inflammation that drives metabolic dysregulation underpinning ageing-induced ill-health. We administered ES-62 subcutaneously (at a dose of 1 μg/week) to C57BL/6J mice undergoing HCD-accelerated ageing throughout their lifespan, while subjecting the animals to analysis of 120 immunometabolic responses at various time-points. ES-62 improved a number of inflammatory parameters, but markedly, a range of pathophysiological, metabolic and microbiome parameters of ageing were also successfully targeted. Notably, ES-62-mediated promotion of healthspan in male and female HCD-mice was associated with different mechanisms and reflecting this, machine learning modelling identified sex-specific signatures predictive of ES-62 action against HCD-accelerated ageing. Remarkably, ES-62 substantially increased the median survival of male HCD-mice. This was not the case with female animals and unexpectedly, this difference between the two sexes could not be explained in terms of suppression of the chronic inflammation driving ageing, as ES-62 tended to be more effective in reducing this in female mice. Rather, the difference appeared to be associated with ES-62's additional ability to preferentially promote a healthier gut-metabolic tissue axis in male animals.

Item Type:Articles
Additional Information:Funding: The study was funded by linked awards to MMH and CS (BB/M029727/1) and WH (BB/ M029662/1) from the Biotechnology and Biological Sciences Research Council (https://bbsrc.ukri.org).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and Lumb, Miss Felicity and Crowe, Dr Jenny and Selman, Professor Colin and Harnett, Professor William and Doonan, Dr James and Tarafdar, Ms Anuradha and Mulvey, Ms Lorna and Babayan, Dr Simon and Pineda, Dr Miguel
Creator Roles:
Crowe, J.Data curation, Formal analysis, Investigation, Methodology, Writing – review and editing
Lumb, F. E.Data curation, Formal analysis, Investigation, Methodology, Writing – review and editing
Doonan, J.Formal analysis, Investigation, Methodology, Writing – review and editing
Tarafdar, A.Investigation, Methodology, Writing – review and editing
Pineda, M. A.Investigation, Methodology, Writing – review and editing
Mulvey, L.Investigation, Methodology, Writing – review and editing
Babayan, S. A.Data curation, Formal analysis, Investigation, Methodology, Writing – review and editing
Selman, C.Conceptualization, Formal analysis, Funding acquisition, Methodology, Supervision, Writing – original draft, Writing – review and editing
Harnett, W.Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review and editing
Harnett, M. M.Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review and editing
Authors: Crowe, J., Lumb, F. E., Doonan, J., Broussard, M., Tarafdar, A., Pineda, M. A., Landabaso, C., Mulvey, L., Hoskisson, P. A., Babayan, S. A., Selman, C., Harnett, W., and Harnett, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Copyright Holders:Copyright © 2020 Crowe et al.
First Published:First published in PLoS Pathogens 16(3):e1008391
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172179Can studying the mechanism of action of the parasitic worm-derived immunomodulator ES-62, inform on how to slow ageing and improve healthspan?Margaret HarnettBiotechnology and Biological Sciences Research Council (BBSRC)BB/M029727/1III - Immunology