Can studying the mechanism of action of the parasitic worm-derived immunomodulator ES-62, inform on how to slow ageing and improve healthspan?

The introduction of vaccines and drugs to control disease, in combination with greater access to food and improved sanitation, means that people are now living much longer. Currently this increase is staggering, equating to an extra 2.5 years of life per decade. However, improved life expectancy itself amounts to a huge new problem, in that it is not being accompanied by a similar increase in health and wellbeing. This reflects both that like a mechanical machine such as a car engine, the ageing process is naturally associated with a loss of function of its systems due to "wear and tear", but also that improved wealth has resulted in a modern Western life-style, incorporating a high fat diet (HFD) that contributes to age-associated ailments such as type-2 diabetes (T2D), stroke and heart disease. This impact of increased lifespan presenting with associated ill-health has enormous socio-economic implications due to its increasingly global scale, arguing for a need to better understand the process of ageing in the context of health.

Approximately one quarter of the world's population is infected with parasitic worms. Of interest, several recent reports indicate that such infections offer protection against development of conditions such as obesity, cardiovascular disease and T2D in mouse models and that similar protection may also be seen in humans. We have been studying one individual parasitic worm component - ES-62, isolated from the secretory products of the filarial nematode, Acanthocheilonema viteae, and consistent with these studies, ES-62 is highly effective in reducing the cardiovascular disease that arises in a highly susceptible strain of mouse, particularly in response to a high fat diet. Moreover, we have some preliminary data showing that ES-62 may offer some protection against development of the obesity that is associated with development of T2D.

Our studies to date with ES-62 also show it to be effective in inhibiting the development of disease in mouse models of allergy, rheumatoid arthritis and systemic lupus erythematosus. What all of these diseases have in common with cardiovascular disease and T2D is the increasing realization that they are associated with unwanted inflammation. This immediately offers an explanation for ES-62's protective effects, as the parasitic worm-derived molecule possesses a range of anti-inflammatory properties. Furthermore, as ageing is also now being considered as a biological problem in the setting of chronic low-grade inflammation, this raises the possibility of investigating the effect of ES-62 on the ageing process and late-life health and well being (healthspan). Thus, we specifically plan to determine whether ES-62 can slow ageing and improve healthspan using a paradigm where mice will be fed on a high fat diet +/- ES-62. We will use this model to assess the effect of ES-62 treatment on ageing in the context of promotion of gene signatures and signalling pathways known to be associated with ageing/inflammation versus those associated with longevity and healthspan.

In addition to enabling us to establish whether ES-62's anti-inflammatory properties are impacting on the ageing process at the molecular level as predicted, this strategy might allow us to validate novel biomarkers for ageing and even potential sites of therapeutic intervention. With respect to the latter, we have produced synthetic drug-like small molecule analogues (SMAs) of ES-62 during our work on the allergy and autoimmunity models, with a view to using these as a starting point in novel drug development for these conditions. Thus, although the current application is designed to increase understanding of the biology of ageing rather than drug development, we will conduct a small trial with one of these SMAs towards the final year of the project with a view to submitting future grant applications for impact funding for their development as potential therapies.

Advances in medicine allied to better nutrition and sanitation over the last two centuries, have led to a dramatic increase in lifespan, but unfortunately not in late-life health and wellbeing (healthspan). This reflects ageing resulting from accumulation of macromolecular damage and loss of cellular function that causes disease and this is enhanced by the high fat diet (HFD) of modern Western life-style, leading to the metabolic dysfunction that contributes to age-associated co-morbidities such as type-2 diabetes (T2D), stroke and heart disease. The impact of this on quality of life and also its socio-economic implications, argue for a fundamental requirement for better understanding of the processes of healthy versus unhealthy ageing. Emerging studies suggest that parasitic worms may offer protection against development of age-associated co-morbidities and consistent with this, we have shown that ES-62, a molecule secreted by the filarial nematode Acanthocheilonema viteae, greatly reduces aortic plaque development in HFD-fed susceptible gld.ApoE-/- mice. ES-62 targets a number of inflammatory and mTOR-mediated metabolic events e.g., TLR/MyD88 and PI3K/Akt signaling and glycolytic metabolism, which may contribute to the ageing process. We therefore plan to: (i) Measure ES-62's ability to increase life span of HFD-fed male and female C57BL/6 mice and slow ageing as assessed by a panel of functional biomarkers and determine by microarray analysis whether this reflects a particular inflammatory and metabolic gene signature; (ii) Investigate whether ES-62 slows ageing by decreasing low-grade chronic inflammation and/or mTOR signalling whilst inducing cytoprotective, anti-oxidant and autophagy responses; (iii) provide proof-of-concept that a drug-like small molecule analogue can mimic ES-62 activity, to enable future grant applications for impact funding for development of biomarkers and therapeutic interventions.

There are number of potential impacts of this project.

In the short term the research could have academic impact on:
1. Young researcher development: the project will primarily provide the Post-Doctoral Research Assistants (PDRAs) with multidisciplinary research training to facilitate dissection of the molecular and cellular basis of the biology of healthy ageing, but also on assessing potential targets for intervention and investigating ES-62 Small Molecule Analogues (SMAs) as candidate compounds for drug development. In addition, the PDRAs will receive training in project management, oral and written presentation, and multidisciplinary transferable skills, all of which will promote their development as independent scientists and future employability.
2. Knowledge exchange: in addition to providing added value to related ES-62 projects on allergy, arthritis, lupus and atherosclerosis, data dissemination will benefit associated collaborators and also the wider research community working on the biology of healthy ageing. In addition, the project should generate increased understanding of the mechanism of action of ES-62, which will interest both scientists considering the broad therapeutic potential of helminth-derived molecules that modulate or promote evasion of the immune response and also researchers working on anthelmintic therapies. With respect to the latter, helminths infect around one quarter of the global population and also represent a huge economic burden on animal and plant farming.

In the longer term, due to relevant increased understanding, this research could potentially have major socio-economic impacts on age- and life style-associated diseases such as metabolic syndrome/type-2 diabetes/cardiovascular disease. The attendant consequences of such conditions pose a daunting scenario, not only of large-scale poor quality of life and disability but also of consequent reduced economic performance and dramatically increased health costs due to the increasing lifespan of the Western population. Thus these impacts could relate to:
1. Fostering the economic competitiveness of the UK and global biopharma industry: Although the planned research primarily seeks to increase our understanding of the healthy ageing process it could additionally lead to both identification of novel drug targets that biopharma may exploit and ultimately and more directly, to development of ES-62 SMAs as novel drugs for humans and in addition, animals. In addition, any licensing agreement/spin-out company arising out of the IP generated by the project would raise the global profile and economy of the Universities of Glasgow and Strathclyde.
2. Public Services and Policy: Development of ES-62-based SMAs as drugs offers certain advantages such as lack of toxicity and low cost of manufacture. Thus, this research could ultimately impact on regulatory bodies such as the Medicines and Healthcare products Regulatory Agency (MHRA) and the National Institute for Biological Standards and Control (NIBSC) in the UK and also globally, for example, via the USA Federal Drug Agency (FDA) in terms of drug licensing and patient treatment guidelines.
3. Patients: Diseases associated with unhealthy ageing are of dramatically increasing prevalence and if the future development of ES-62-based drugs could improve on existing treatments then this could make a real difference to the quality of life of such patients. Moreover, the information gained may also impact on the development of drugs for a wide range of inflammatory diseases that ES-62 is highly effective against in model systems, potentially benefiting substantial patient cohorts world-wide. Of note, as ES-62 SMAs have already been produced with satisfactory pharmacokinetics and which mimic the protective properties witnessed in most of these models, successful related novel drug development for conditions associated with unhealthy ageing could be short- rather than long-term.