In an attempt to understand secrets of longevity, researchers are focusing on the peculiar lifespan of ants, specifically queen ants. Along with their close relatives bees, ants are eusocial insects characterized by highly organized social systems comprised of castes. In this cooperative system, each caste (i.e., worker, soldier, and queen) carries out specific functions in support of the colony. As much as the social functions in castes are varied and strictly regulated, so too are lifespans between castes. The typical lifespan of a worker ant is a modest 1 to 2 years; queen ants, however, can live up to 30 times longer. As a result, a significant amount of research has been devoted to unraveling the mechanisms driving this feature. Yan, et al.,  report in Science that modulation of the insulin/IGF-1 signaling (IIS) pathway, shown to be crucial to many pro-longevity interventions, is responsible for extreme lifespan extension in queen ants.

Interventions that extend lifespan are numerous, utilizing dietary models (e.g., calorie and methionine restriction), genetic modifications (e.g., the Ames dwarf mouse), and pharmaceutical therapies (e.g., metformin) to achieve these benefits. Central to these approaches is the targeting of the ancient and highly conserved IIS pathway, which promotes survival when conditions are less than ideal for successful reproduction. IIS is acutely responsive to environmental nutrient status, and during periods of abundance, insulin and IGF-1 levels are elevated, initiating a cascade of changes allowing for maximal growth and reproduction. However, in the event an organism finds itself in an environment where nutrients are limited, IGF-1 is decreased and pro-growth pathways are inactivated in favor of mechanisms for maintenance and survival, e.g. autophagy, lipolysis, and ketosis. Consequently, animals that grow quickly and reproduce abundantly tend to have shorter lifespans; conversely, animals with impaired growth and reproductive faculties tend to have longer lifespans. As a result, many IGF-1 lowering, pro-longevity interventions have the added effects of reduced organism size and impaired reproduction.

Queen ants grow twice as large as workers and are solely responsible for colony reproduction, committing them to a perpetual state of egg production. To maintain this reproductive state, queens must consume an abundant amount of food. As a result, insulin and IGF-1 levels are chronically high and the IIS pathway activates a continual pro-growth signaling cascade, inhibiting pro-longevity maintenance processes. In most organisms, such a state would lead to a significantly reduced lifespan; however, queen ants live around thirty times longer than worker caste ants, despite nearly identical genetic backgrounds.

In order to understand the mechanisms underlying the paradoxical nature of this phenomenon, researchers examined the fat bodies of these long-lived queens. Fat bodies in ants are equivalent to mammalian livers, which are subject to the many changes instigated by insulin and IGF-1 signaling. Their findings revealed a surprising change in the pro-longevity protein FOXO. Typically, increased nutrient consumption results in elevated levels of insulin and the activation of the protein AKT. AKT in turn acts on FOXO by preventing its translocation into the nucleus; however, long-lived ants in this study were shown to have increased levels of FOXO localized to the nucleus, despite high levels of insulin. Upon localization to the nucleus, FOXO is then responsible for regulating genes that promote cellular maintenance and increased longevity. It was shown that elevated levels of the protein Imp-L2 allowed AKT levels to remain low regardless of high insulin levels. In the presence of increased insulin, Imp-L2 secreted from the ovaries is thought to block insulin receptors on the surface of cells in fat bodies, preventing the activation of AKT and allowing FOXO to activate pro-longevity genes within the nucleus.

This unorthodox control of the IIS pathway in queen ants could potentially lead to the development of novel therapies to treat age-related diseases in a manner that avoids the typical trade-offs of impaired growth and reproduction. Therapies capable of simultaneously promoting growth and maintenance could prove to be invaluable in aging populations, which are more prone to increased frailty and diseases of wasting.

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