Anti-Insulin Signals Help Queen Ants Live Long and Prosper

Researchers have discovered that modified insulin signaling pathways in ant queens may be responsible for their astounding longevity and reproductive ability. The findings are published in the journal Science.

Balancing reproduction and longevity

In many species across the animal kingdom, there is a compromise between reproduction and longevity. Higher rates of reproduction and more offspring are associated with decreased life expectancy – i.e., the genes that encourage reproduction also result in increased nutritional and metabolic requirements, at the expense of longevity. For example, organisms like yeast and mice adapt to live longer and reproduce less when their diets are restricted.

This phenomenon is thought to be regulated by changes in insulin signaling, the hormone that regulates glucose metabolism. Mutations in the insulin/insulin-like growth factor (IGF) signaling pathway lead to a longer lifespan in a range of species including nematode worms, fruit flies and mice. Raised energy demands, as a result of reproduction, require increased food consumption that in turn raises insulin levels.

The insulin signaling pathway is comprised of many branches – the MAPK pathway and the AKT pathway are two major examples. Activation of the MAPK pathway aids egg production, while the AKT pathway can result in aging and shortened lifespan, creating a trade-off between reproduction and longevity.

However, Harpagnathos saltator, also known as the Indian jumping ant, is an interesting exception to the rule. These ants live in colonies with one reproductive female, the queen, responsible for all the colony’s egg-laying duties. She typically lives for five years, while her worker neighbors live for just seven months. When the queen dies, workers attempt to switch their “caste” by dueling other workers with their antennae until one remains, becoming a “pseudo-queen” – also known as a gamergate. Gamergates acquire the ability to lay eggs as well as a considerably longer lifespan. When placed in a new colony with an established queen, gamergates transition into “revertants”, losing their queen-like characteristics and changing back to a worker role. Interestingly, the loss of their reproductive abilities also occurs with reduced longevity, in which their lifespan reverts back to worker-like levels.

To understand more about the relationship between reproduction and longevity during caste switching in H. saltator, researchers at New York University investigated how gene expression changes during this process and how various cellular signaling pathways are affected.

Anti-insulin protein selectively blocks AKT signals

The researchers first measured the longevity of the various castes within H. saltator colonies. Regular worker ants had a median lifespan of 217 days, while gamergate lifespan was fivefold at ~1100 days. Revertants, meanwhile, had a decreased lifespan of 188 days, which the authors hypothesize is caused by stress during the reversion process.

Next, using RNA sequencing – a technique that measures the transcriptome, indicating which of the genes encoded in our DNA are turned on or off and to what extent – the researchers investigated how the expression of various genes was altered between workers, gamergates and revertants. This reveals which genes have significantly altered expression between these groups, known as differentially expressed genes (DEGs). They analyzed tissue taken from the brain, ovaries and fat body – an insect organ similar to the liver. This showed that over 60% of DEGs in the fat body and ovary of gamergates returned to levels similar to normal workers after the transition to revertants.

Insulin expression increased in the brains of gamergates, consistent with the need to increase metabolism and facilitate egg production. However, the researchers still wanted to discover how the observed increase in insulin signaling in reproductive castes does not result in a reduced lifespan.

The researchers examined the two cell signaling pathways that are activated by insulin signaling – the MAPK and AKT pathways. The AKT branch inactivates the forkhead box O (FOXO) transcription factor, which results in decreased longevity, whereas the MAPK branch promotes cell proliferation and egg development. They found that AKT was active in the fat body of workers, but MAPK was only mildly activated. As expected, they observed that MAPK was activated in the fat bodies of gamergates to facilitate egg production. However, AKT activity was significantly lower in the fat bodies and ovaries of gamergates.

Additionally, expression of the insulin-suppressing protein Imp-L2 – which specifically blocks AKT activity, and not MAPK activity – was increased in the fat body and ovary of gamergates. The authors propose that inhibition of the AKT pathway by Imp-L2 in gamergates may explain how this reproductive caste maintains reproductive ability while significantly increasing lifespan. 

Could there be a similar effect in vertebrates?

Technology Networks spoke to Professor Claude Desplan, silver professor of biology and neural science at New York University and one of the study’s senior authors, about the results. “Insulin is well known to affect aging, and one particular branch of the insulin signaling pathway (AKT/FOXO) has been implicated in aging. Our work shows that ants can use insulin to produce metabolites (lipids) for egg formation through activation of the other branch of the insulin pathway (MAPK) while blocking the AKT branch. We have identified the molecule Imp-L2 that is responsible for this anti-AKT-insulin. This might serve as a potent repressor of aging while preserving much of insulin function,” he summarized.

Desplan also elaborated on the future plans for the project. He explained, “We do not understand how a secreted molecule, Imp-L2, can block only one of the intracellular branches of the insulin signaling pathway.” He stated that the team is switching to studying this mechanism in fruit flies (Drosophila melanogaster) as many of the tools and techniques used in this study are more powerful when used in flies than in ants. “We are also generating mutations in Imp-L2 in ants to test whether it prevents the extended longevity of queens. We hope to expand this work to vertebrates, where the role of the homolog of Imp-L2 (IGFBP7) is poorly understood,” Desplan concluded.

Professor Claude Desplan was speaking to Sarah Whelan, Science Writer for Technology Networks.

Reference: Yan H, Opachaloemphan C, Carmona-Aldana F, et al. Insulin signaling in the long-lived reproductive caste of ants. Science. 2022;377(6610):1092-1099. doi: 10.1126/science.abm8767