"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."