Mild mitochondrial impairment enhances innate immunity and longevity through ATFS‐1 and p38 signaling.

While mitochondrial function is essential for life in all multicellular organisms, a mild impairment of mitochondrial function can extend longevity in model organisms. By understanding the molecular mechanisms involved, these pathways might be targeted to promote healthy aging. In studying two long‐lived mitochondrial mutants in C. elegans, we found that disrupting subunits of the mitochondrial electron transport chain results in upregulation of genes involved in innate immunity, which is driven by the mitochondrial unfolded protein response (mitoUPR) but also dependent on the canonical p38‐mediated innate immune signaling pathway. Both of these pathways are required for the increased resistance to bacterial pathogens and extended longevity of the long‐lived mitochondrial mutants, as is the FOXO transcription factor DAF‐16. This work demonstrates that both the p38‐mediated innate immune signaling pathway and the mitoUPR act in concert on the same innate immunity genes to promote pathogen resistance and longevity and that input from the mitochondria can extend longevity by signaling through these pathways. This indicates that multiple evolutionarily conserved genetic pathways controlling innate immunity also function to modulate lifespan. SYNOPSIS: Mild impairment of mitochondrial function results in enhanced innate immunity and lifespan extension. Both phenotypes are driven by activation of the mitochondrial unfolded protein response but are also dependent on p38‐mediated innate immune signaling. Mild impairment of mitochondrial function enhances innate immunity in a p38‐dependent manner through activation of ATFS‐1.The mitochondrial unfolded protein response and p38‐mediated innate immune signaling pathway act in concert to promote resistance to bacterial pathogens and extend lifespan.The p38‐mediated innate immune signaling pathway plays a key role in determining longevity.Different levels of p38‐mediated innate immune signaling are optimal for different contexts of lifespan extension. [ABSTRACT FROM AUTHOR]