How does the immunomodulatory parasitic worm product ES-62 rewire bone marrow cells to increase healthspan and lifespan in obesity-accelerated ageing?

Around a quarter of the global human population is infected with parasitic worms. Although undoubtedly a public health problem, increasingly there is acceptance that these traditionally unwelcome visitors may actually confer some health benefits. In particular, the evidence, from a combination of studies on human patients and experiments employing mouse models, indicates that worm infection can protect against development of a range of debilitating diseases including allergic (e.g., asthma), autoimmune (e.g.

RA) and cardiovascular conditions. What all these illnesses have in common is an association with persistent, unnecessary inflammatory responses and it is therefore not surprising that the protection afforded by parasitic worms has been correlated with their ability to secrete anti-inflammatory molecules, which can resolve these. One particularly well-characterised molecule is ES-62, which we have previously found to protect against disease development in mouse models of RA, kidney disease and accelerated atherosclerosis associated with systemic lupus erythematosus, and both lung and skin allergy.

A risk factor for the development of many diseases linked with harmful inflammatory responses is ageing, which is itself associated with chronic low-level inflammation and this risk is further increased by obesity. As the human population is becoming both progressively older and increasingly obese, it is thus inevitable that the prevalence of such ailments is rising.

We therefore recently turned our attention to investigating whether ES-62 could act to counter this by assessing its impact on well-being in a C57BL/6J mouse model of obesity-accelerated ageing where animals are fed high calorie diet (HCD) over their lifetime. Not surprisingly, we found ES-62 to inhibit systemic obesity-induced inflammation but a number of other protective effects were noted, intriguingly including within the ageing bone marrow (BM) niche.

The BM contains various types of cells - "stem cells" - which following a process of maturation have the job of replenishing certain cell types in the body, e.g., cells of the immune system and those required for healthy bone and other tissues. As is observed in humans, obesity and ageing led to impairment of stem cell populations in our HCD-fed ageing mice.

This however was significantly reduced in male mice by ES-62 treatment and furthermore, the worm product also protected against the bone loss arising from the changes in BM cells occurring during obesity-accelerated ageing in these animals.

As far as we aware, being able to prevent the effects of ageing on BM cells has not previously been attributed to a parasitic worm product. Our central aim is thus to employ our mouse model of obesity-accelerated ageing to determine how ES-62 achieves this. In particular, we will address the following objectives:

1. Determine whether ES-62's effects on BM cells reflect changes in the expression of particular genes within the cells and how the worm product "rewires" the cellular machinery controlling this. 2. Define how ES-62-mediated changes in gene expression are linked to rescue of defective BM cells.

3. Use BM transfer experiments to determine whether ES-62-conditioned BM promotes improved health in recipient mice and also establish whether its protective effects are due to direct or indirect, for example via the microbiome, interaction with BM cells.

Successful achievement of our objectives will provide knowledge and understanding of the mechanisms underpinning the BM-protective, anti-inflammatory actions of ES-62. ES-62's properties dictate that it is already considered to possess therapeutic potential for a range of illnesses associated with harmful inflammation but our new BM-data clearly suggest that its potential disease-coverage may be even wider, for example, extending to protection against ageing-associated degenerative bone disorders like osteoporosis and malignancies such as leukemia.