NF-κB Immunity in the Brain Determines Fly Lifespan in Healthy Aging and Age-Related Neurodegeneration

Summary

During aging, innate immunity progresses to a chronically active state. However, what distinguishes those that “age well” from those developing age-related neurological conditions is unclear. We used Drosophila to explore the cost of immunity in the aging brain. We show that mutations in intracellular negative regulators of the IMD/NF-κB pathway predisposed flies to toxic levels of antimicrobial peptides, resulting in early locomotor defects, extensive neurodegeneration, and reduced lifespan. These phenotypes were rescued when immunity was suppressed in glia. In healthy flies, suppressing immunity in glial cells resulted in increased adipokinetic hormonal signaling with high nutrient levels in later life and an extension of active lifespan. Thus, when levels of IMD/NF-κB deviate from normal, two mechanisms are at play: lower levels derepress an immune-endocrine axis, which mobilizes nutrients, leading to lifespan extension, whereas higher levels increase antimicrobial peptides, causing neurodegeneration. Immunity in the fly brain is therefore a key lifespan determinant.

Graphical Abstract

Highlights

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  Constitutive immunity predisposes to short lifespan with severe neurodegeneration

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  Blocking constitutive immunity in glia rescues predisposed flies

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  Suppression of immunity in glia of healthy flies triggers adipokinetic signaling

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  This immune-endocrine axis mobilizes nutrients and extends active lifespan

Abstract

In humans, both healthy aging and age-dependent neurodegeneration are accompanied by an upregulation of innate immunity. What is the cause and what is the consequence remain unclear. Kounatidis et al. show that, in flies, NF-κB immune signaling controls lifespan in healthy flies, as well as in those predisposed to early neurodegeneration.