Parasitic worm-derived ES-62 promotes health- and life-span in high calorie diet-fed mice

Abstract

The recent extension of human lifespan has not been matched by equivalent improvements in late-life health due to the corresponding increase in ageingassociated comorbidities and obesity, conditions exacerbated by the widespread adoption of the high calorie Western diet (HCD). Chronic low-grade inflammation underpins ageing-induced ill-health and thus we have focused on ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae that we have previously shown to have potent anti-inflammatory properties, as a novel therapeutic strategy. ES-62 was tested in a mouse model of HCD-accelerated ageing and found to ameliorate pathophysiological, inflammatory and metabolic parameters, when administered at only 1 µg/week. Strikingly, ES-62 also substantially increased the median survival of male HCD-mice. This extension was not observed with female mice and indeed, ES-62 treatment resulted in distinct gender-specific healthspan signatures. Combined with a machine learning approach, such signatures signpost candidate parameters key to promoting both healthspan and lifespan.Adoption of the modern Western diet (high fat and high sugar) has significantly contributed to a global pandemic in metabolic syndrome, obesity, type-2 diabetes and cardiovascular disease; ageing-associated conditions that impact on both wellbeing (healthspan) and lifespan 1,2 . This increasing major public health problem reflects, at least in part, that such a high calorie diet (HCD) disrupts the gut microbiome, with the consequent intestinal inflammation and loss of barrier integrity driving chronic systemic inflammation that appears to dysregulate immunometabolic pathways, accelerating the ageing process and reducing lifespan 1,3-7 . Interestingly, epidemiological data suggest that Western diet-associated diseases are rising fastest in in the developing world 2,8 , regions where parasitic worms (helminths) and other infectious agents are being eradicated 9 . Helminths promote their survival by releasing excretory-secretory (ES) products that, by dampening inflammation and promoting tissue repair, act to prevent worm expulsion but also limit host pathology 10 . Thus, the relatively rapid eradication of these parasites appears to have resulted in hyper-active host immune systems, characterised by chronic low-grade inflammation that may (further) contribute to development of obesity and associated metabolic syndrome co-morbidities, as well as allergic and autoimmune inflammatory disorders, in developing and urbanised countries 10 . Whilst this has questioned the wisdom of current mass parasite eradication programs, it has emphasised the potential of utilising worm infections or ES to treat a wide range of noncommunicable diseases that are characterised by chronic inflammation [11][12][13] . Indeed, we have shown that a single, defined ES protein, ES-62, can suppress pathology in mouse models of allergic and autoimmune inflammatory diseases 9,10,14-16 . ES-62 achieves this by virtue of immunomodulatory phosphorylcholine groups attached...

Synthetic small molecule analogues of the immunomodulatory Acanthocheilonema viteae product ES-62 promote metabolic homeostasis during obesity in a mouse model

“…Regarding gut damage, we found evidence of HCD-induced ileum damage (reduced villus length at d160) that was protected against by SMA treatment, particularly in female animals. Again, these gut data largely mirror what we have observed with ES-62 [40].…”

“…We found no protection against steatosis but reduced fibrosis in both sexes, although this was only statistically significant in female mice. These data for both steatosis and fibrosis mirror what we observed when treating HCD-fed mice with ES-62 [40], although with the parent molecule, protection against fibrosis in the male mice also reached statistical significance.…”

“…Presumably it is less obvious in SMA-treated mice because overall, they develop less visceral adipose tissue (we only examined retroperitoneal adipose tissue) or at least the increase is delayed, as shown in the present study for retroperitoneal tissue. Interestingly, overall the SMAs appear to be more effective than ES-62 in dealing with rising blood glucose levels although we did not test the early day timepoint with the parent molecule [40]. We did not observe any protective effect of the SMAs on glucose clearance in female mice in the current study but such animals appear to show somewhat less impairment of this in response to HCD than males.…”

“…Thus, examining day 116 tissue for immune cell and cytokine profiles during this earlier time point may be warranted. Nevertheless, in spite of detecting some reductions in inflammatory-and increases in anti-inflammatory-markers in the ES-62 study referred to earlier [40], these changes did not appear to be the key factors that improved healthspan or lifespan in ageing animals. Rather a more convincing casesupported by a machine learning approachwas provided by metabolic changes and improved gut health/reduced gut dysbiosis.…”

“…Possibly at least some of the variation we have observed with respect to both factors could relate to sex-specific differences in hormone levels and it could therefore be interesting to investigate the effects of hormonal intervention in our system. We have also observed sex-specific responses to ES-62 treatment with this model [40] but as far as we are aware, this has not been reported with other defined helminth-derived molecules that are protective in mouse models of inflammatory diseases.…”