Many genetic and environmental factors that affect aging and lifespan have been identified over the last several decades. Unfortunately, interventions that increase lifespan and delay aging are frequently associated with a decrease in reproduction and growth (Kirkwood, 2005). This has been presumed to be a tradeoff for the allocation of limited biological resources for longevity versus reproduction and growth. Dietary restriction or reduced insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS), for instance, promotes longevity while generally decreasing reproduction in multiple species ranging from Caenorhabditis elegans to mammals (Lee and Lee, 2022; Lee et al., 2021a). Conversely, upregulation of IIS decreases lifespan and increases reproduction in model organisms (Templeman and Murphy, 2018). Interestingly, in eusocial insects, such as ants and bees, reproductive and large queens in colonies exhibit extreme longevity compared with sterile workers, indicating that the tradeoff is not inevitable. If the molecular basis of this fascinating phenomenon is identified and applied to humans, we could live exceptionally long and healthy lives. However, the underlying mechanisms remained poorly understood.

A recent breakthrough study provides biological evidence for how queen ants exhibit a long lifespan and active reproduction simultaneously (Yan et al., 2022). When the queen in a colony of Indian jumping ants, Harpegnathos saltator, dies or is removed, a worker becomes a reproductive pseudoqueen known as gamergate. Importantly, pseudoqueens have a lifespan that is more than five times that of workers; the lifespans of pseudoqueens and workers are 3 years and 7 months, respectively. Moreover, when pseudoqueens are placed in a colony with an established reproductive caste, they can be reverted to nonreproductive workers known as revertants, which have a short lifespan. Therefore, the authors utilized pseudoqueens (and revertants) as excellent tools for conducting controllable experiments to study the longevity and fecundity of queen ants because of their similar size with workers, reversibility, and relatively easy manipulation.

The authors first determined gene expression changes in pseudoqueen ants by performing RNA sequencing using tissues crucial for reproduction, metabolism, and aging, including the brain, ovary, and fat body (an organ equivalent to mammalian liver and adipose tissue). They found that the mRNA level of insulin is increased in the brains of pseudoqueen ants. In addition, injecting synthetic insulin into the abdomens of worker ants promotes oogenesis. These data suggest a positive role of circulating insulin hormone in active reproduction, which is consistent with a previous study using various ant species (Chandra et al., 2018).

However, the results with insulin described above raise a conundrum, because insulin upregulation often decreases lifespan while promoting reproduction. How do pseudoqueens display longevity with increased insulin levels? The authors tested the possibility that additional regulation downstream of IIS may differentially affect longevity and reproduction. IIS involves two downstream branches: the IIS–AKT (also known as protein kinase B) and IIS–mitogen-activated protein kinase (MAPK) pathways. The authors found that the IIS–MAPK branch is activated in the fat body and ovary. Treatment with U0126, a MAPK kinase inhibitor, decreases the number of yolky oocytes in pseudoqueens. Thus, insulin produced from the brain appears to activate the IIS–MAPK branch in the ovary and fat body, resulting in the production of mature egg chambers. Interestingly, even with upregulated insulin, pseudoqueen ants exhibit decreased IIS–AKT activity in the fat body and some parts of the ovary. As the inhibition of the IIS–AKT branch increases the nuclear localization of forkhead box O (FOXO), subsequently promoting longevity in various organisms (Lee and Lee, 2022; Lee et al., 2021a), this is consistent with longevity in pseudoqueens.

The authors then determined how insulin upregulation in the brain differentially regulates the two different downstream branches of the IIS. In the ovaries of pseudoqueens, the expression of imaginal morphogenesis protein-late 2 (Imp-L2), which encodes a secretory protein that inhibits the IIS pathway, is elevated. Furthermore, treatment with synthetic Imp-L2 inhibits the activation of IIS–AKT caused by the injection of insulin in fat bodies while having no effect on the IIS–MAPK branch. Thus, Imp-L2 produced by the ovary of pseudoqueens appears to specifically inhibit IIS–AKT, very likely increasing lifespan and fecundity.

In summary, the authors demonstrated that communication among multiple tissues, including the brain, fat body, and ovary, through nuanced regulation of IIS via insulin can promote longevity and active reproduction in eusocial insects. The present work is also consistent with a study showing that a proper modulation of DAF-18/phosphatase and tensin homolog (PTEN) in IIS can restore reproduction and growth in long-lived C. elegans (Park et al., 2021). In addition, temporal inhibition of IIS can delay and even reverse aging without affecting reproduction and growth in C. elegans (Dillin et al., 2002; Lee et al., 2021b). Therefore, these studies clearly indicate that longevity does not have to be associated with impaired reproduction and growth.

The present work, like numerous other important studies, raises many intriguing questions. What causes insulin induction in the brains of pseudoqueens? Which factors contribute directly to the longevity conferred by reduced IIS–AKT branch in pseudoqueen ants? Does the regulation of two downstream branches of IIS (IIS–AKT and IIS–MAPK) also affect reproduction and longevity in queen ants, as well as other eusocial insects such as bees and termites? Most importantly, can mammals enjoy longevity and active reproduction by properly modulating IIS in distinct tissues? The last question is not far-fetched, as changes in IIS have been associated with the prevention of age-associated diseases such as cancer and diabetes in humans (Guevara-Aguirre et al., 2011). Addressing all of these questions will help in the development of anti-aging drugs for humans without adverse side effects, and perhaps our children or grandchildren will be able to live 400 years of healthy and reproductive lives.

We thank all Lee lab members for their helpful comments and discussions. This research was supported by the KAIST Key Research Institutes Project (Interdisciplinary Research Group) to S.J.V.L.

H.L. and S.J.V.L. wrote the paper.

The authors have no potential conflicts of interest to disclose.