• Parasitic worm secretion molecule ES-62 substantially extends male mouse lifespan but not female.
  • ES-62 improves male mouse gut health, which may contribute to lifespan extension.

Parasitic worms called helminths infect people’s intestines when their eggs get transmitted through contaminated food or water. And there’s an interesting link between age-related diseases associated with high calorie, Western diets — like obesity, type-2 diabetes, and cardiovascular disease — and the presence of helminths, or lack thereof. These diseases are rising fastest in regions where helminths have been eradicated. This has led some researchers to ponder whether something about what helminths release, such as excretory-secretory products, to promote their survival could have once had a preventative effect on these age-related diseases. 

Harnett and colleagues from the University of Glasgow in the United Kingdom published a study in PLoS Pathogens testing whether administering a helminth excretory-secretory factor (ES-62) under the skin of mice fed a high-calorie diet improved health and lifespan. They found that giving mice ES-62 substantially increased high-calorie diet-fed male mouse survival by 10% but not female. The scientists found this ES-62 sex-specific difference was due primarily to ES-62’s gut health promotion. If these ES-62 benefits translate from mice to humans, they may provide a means to improve gut health and potentially the number of healthy years people live without disease (healthspan).

Researchers Test the Effect of a Parasitic Worm Secretion

Since parasitic worm infections are not an ideal way to reap the benefits of helminth intestinal infestations, Harnett and colleagues pinpointed ES-62 administration as a method to combat hyper-active mouse immune systems that go along with high-calorie diets. They had previously shown that ES-62 can resolve inflammation by normalizing the aberrant signaling of a protein playing a central role in immune responses called MyD88. So, this research team sought to determine whether administering ES-62 under the skin could curtail the excessive immune responses and inflammation in mice fed a high-calorie diet to extend lifespan and improve health.

ES-62 Substantially Extends Male Mouse Lifespan

The team from the University of Glasgow began by administering ES-62 to see whether it improved the lifespans of mice fed a high-calorie diet. To do so, they administered the mice with 1 µg of ES-62 each week starting at nine weeks old and kept track of how long they survived. What they saw was that ES-62 extended the lives of male, but not female mice, by over 70 days (or greater than 10%).

(Crowe et al., 2020 | PLoS Pathogens) ES-62 administration extended male median lifespan more than 70 days and greater than 10%. The survival curve on the left indicates no significant ES-62 administration effect on survival when data from both sexes were combined. The graph in the middle shows the 10% increased median male lifespan with administering ES-62, and the curve on the right shows no substantial ES-62 effect for female survival.

Harnett and colleagues then wanted to know how exactly ES-62 was influencing male mouse lifespan. So, what they did was analyze organ health to find whether ES-62 extended male lifespan by improving organ function. But they weren’t able to identify an organ-specific mechanism to explain ES-62’s male lifespan promoting effects, which led them to a more generalized examination of gut health.

ES-62 Improved Male Mouse Gut Health

Since high-calorie diet-related gut inflammation is linked to insulin resistance, obesity, and also accelerated aging, Harnett and colleagues checked if the effects of ES-62 on lifespan were due to effects on gut inflammation. When the researchers administered ES-62 to high-calorie diet mice, they saw significant protection against age-related intestinal degradation in males but not females.

Harnett and colleagues then examined if there was a link between ES-62’s preservation of male intestinal integrity and gut bacterial composition — the microbiome. Their analyses indicate that ES-62 administration does in fact normalize the gut’s bacterial composition in high-calorie diet-fed male mice toward that of standard diet-fed males. From these results, Harnett and colleagues proposed that ES-62-mediated lifespan extension is linked to improved gut health.

(Crowe et al., 2020 | PLoS Pathogens) ES-62 normalizes gut bacterial composition in high-calorie diet-fed mice, especially in males. From left to right: the left column shows young mouse bacterial composition (d56), the next column shows the gut bacterial composition of older mice fed a standard chow diet, the next column illustrates the composition of older mice fed a high-calorie diet (labeled PBS), and the right column shows the gut bacterial composition of mice administered ES-62. The ES-62 administration normalized the male mouse microbiome toward its composition with a normal, chow diet.

The Future of ES-62 Research

Emerging evidence from fruit fly research indicates that ES-62-mediated lifespan extension relates to improved gut health and that intestinal barrier integrity mediates limited lifespan. Results from the study corroborate this evidence as ES-62 extended male lifespan and enhanced gut health as it pertains to intestinal barrier integrity and bacterial composition. This also indicates that gut health could be used in the future as a predictor of lifespan.

The precise mechanism by which ES-62 acts to promote male gut health remains to be defined. Future studies may elucidate how exactly ES-62 promotes gut health, why its effects are male-specific, and whether humans can use it for health and lifespan extension. Clinical trials will need to begin to find whether ES-62 holds any benefits to humans, and as yet none are underway.