Immune Molecule IM33 Sheds Light on Lifespan Regulation

Aging, a universal biological process, manifests as a series of gradual changes affecting the behaviour and capabilities of living organisms. Past studies have spotlighted various physiological factors contributing to aging, such as immune responses, imbalances in reactive oxygen production, and sleep disturbances.

However, the intricate interplay between these factors and their role in the aging process remains inadequately understood. In a groundbreaking study, researchers at Washington University in St. Louis have identified an immune molecule with the potential to play a pivotal role in modulating aging and the lifespan of living organisms. 

The study, published in Neuron, was inspired by two independent research efforts at the university. A previous investigation had identified the gene Slpi as highly upregulated in the meninges of aging mice. Recognizing the evolutionary conservation of Slpi and its ortholog IM33 in Drosophila, the researchers turned to fruit flies to leverage their genetic advantages and shorter lifespan for studying the gene’s role in aging.

Simultaneously, other findings in the lab suggested that cytokines, proteins supporting the immune system and managing inflammation, could influence animal behaviour. This led the researchers to explore the potential connection between cytokines, immune modulation, and aging. 

To unravel the complexities of aging and the potential role of the immune molecule IM33, the researchers employed a multidisciplinary approach encompassing genetics, neuroscience, immunology, and microbiology. This involved genetic perturbation, behavioural assessments, microbiota manipulation, neuronal activity imaging, and molecular sequencing to investigate IM33’s role in various aspects of aging. 

The study utilized fruit flies (Drosophila) and mice to understand the role of IM33 and its analogue SLPI in controlling the aging process. When the researchers knocked down the IM33 gene in the immune cells of fruit flies, they observed an increase in reactive oxygen species and alterations in gut microbiota composition.

This resulted in oxidative stress, dysbiosis, and a reduction in the flies’ lifespan. Notably, the knockdown of IM33 also induced sleep disturbances, a phenomenon associated with aging and shortened lifespan. The researchers proposed a brain-gut-brain axis mediated by IM33, controlling the physiology of flies.

Knocking down IM33 in immune cells triggered oxidative stress and dysbiosis, affecting the gut-brain communication and subsequently influencing aging-related processes. This finding suggests that IM33 serves as a messenger conveying information between the brain and gut to regulate aging and lifespan beyond its traditional immune role. 

Describing their work as a proof-of-concept study, lead researcher Wangchao Xu emphasized that an evolutionarily conserved immune molecule can act as a messenger, influencing aging processes. This expands our understanding of neuroimmune interactions in aging and highlights the potential significance of immune molecules in regulating lifespan. 

The study suggests that peptidoglycan signaling, a conserved immune pathway, in neurons could be a novel target to slow down aging. The researchers emphasize the need for further investigation into the mechanisms through which brain secreted IM33 shapes the gut immune environment.

Additionally, testing the role of meningeal Slpi in mice could provide crucial insights into the shared mechanisms of aging evolutionarily. The research conducted by Xu and his colleagues at Washington University in St. Louis represents a significant contribution to the ongoing efforts to unravel the neural and genetic underpinnings of aging.

By identifying IM33 as a potential key player in regulating aging and lifespan, this study opens avenues for future research aimed at understanding the intricacies of immune modulation in the aging process. The findings hold promise for potential therapeutic targets to mitigate the effects of aging, paving the way for translational studies and advancements in aging-related research. 

Journal Reference  

Wangchao Xu et al, A novel immune modulator IM33 mediates a glia-gut-neuronal axis that controls lifespan, Neuron (2023). DOI: 10.1016/j.neuron.2023.07.010.