C. elegans worms that lack calcineurin (right) have bloated and distended intestines (green) compared to worms in which the enzyme is present (left). Image credit: Das et al. 2024 (CC BY 4.0)
Many research efforts currently focus on identifying the dietary, pharmacological or genetic interventions that could help to prolong life. In the process, these investigations often uncover complex or even unexpected relationships between a range of physiological processes. The link between longevity and the immune system, for example, is yet to be fully understood.
To explore these dynamics, Das et al. focused on calcineurin, an enzyme present in organisms across the tree of life. In humans, calcineurin is known to regulate a set of proteins essential for the immune response; these proteins are absent in the microscopic worm Caenorhabditis elegans, in which inhibiting calcineurin extends lifespan. Investigating how calcineurin inhibition impacts the immune system of C. elegans therefore presents a unique opportunity to better understand the complex links between immunity and longevity.
Experiments conducted on worms genetically modified to lack calcineurin showed that these animals lived longer than their ‘normal’ counterparts, but that they were also more susceptible to infection when exposed to a harmful species of bacteria. Further experiments showed that the enzyme was crucial for regulating defecation in C. elegans. Without calcineurin, the worms became bloated and constipated; they could not properly eliminate bacteria, which could then proliferate in the digestive system and cause issues. However, intestinal bloating also activated signalling pathways normally triggered by calorie restriction – an intervention well-known for extending the lifespan of various species.
Taken together, the findings by Das et al. help explain why calcineurin inhibition in C. elegans leads to opposite effects on longevity and resistance to infection. They also align with a recent body of work showing the profound effect of gut bloating on food-seeking behaviors, immunity and lifespan. Further investigations into these mechanisms may one day uncover new ways to improve human health.
