A novel immune modulator IM33 mediates a glia-microbiota-neuronal axis that controls lifespan

Aging is a complex biological process that involves multiple systems and is accompanied by behavioral changes. Two common features of aging are altered immune regulation and sleep decline, but the link between them is unknown. Using Drosophila, we found that a novel immune modulator, immune induced molecule 33 (IM33), and its mammalian homolog, secretory leukocyte protease inhibitor (SLPI), are upregulated in old flies and in old mice respectively. Knockdown of IM33 in glia results in significant changes in gut microbiota composition, including an increased abundance of Lactiplantibacillus plantarum. Enrichment of these bacteria in the gut overproduces DAP-type peptidoglycan, which triggers the activation of insulin-producing cells in the brain by binding to the peptidoglycan recognition protein LE (PGRP-LE) receptor. This results in sleep fragmentation, thus leading to a reduction in lifespan. Therefore, IM33 acts on the glia- microbiota-neuronal axis, linking neuroinflammation with sleep decline during aging.