Itaconate prolongs the healthy lifespan by activating UPR^mt in Caenorhabditis elegans

Itaconate (ItA), a byproduct of the Krebs cycle, has recently emerged as an anti-inflammatory metabolite for inhibiting the overactive immune response. In addition to its immunomodulatory and antimicrobial effects, ItA may have other therapeutic avenues. Herein, the effect of ItA on aging was explored in order to better establish the therapeutic potential of this promising metabolite. ItA extended the lifespan and enhanced the stress resistance of Caenorhabditis elegans (C. elegans), even at the doses of 0.01 and 0.1 μM. Moreover, the lifespan extension effect of ItA was pronounced even for the aged worms (days 7 and 9 post adult stage). Furthermore, ItA was found to extend the healthy longevity of C. elegans in a mitochondria-dependent manner. ItA protected the mitochondrial integrity, increased ATP content, and decreased the reactive oxygen species (ROS) in C. elegans. Mechanistic investigations showed that ItA specifically activated the mitochondrial unfolded protein response (UPR^mt) in worms and significantly increased the expression of activating transcription factor associated with stress-1 (ATFS-1) that senses mitochondrial stress and communicates with the nucleus during the UPR^mt. ItA extended the lifespan of C. elegans in an ATFS-1-dependent manner. In summary, this study elucidates the molecular mechanism by which ItA extends the healthy lifespan and highlights the importance of mitochondrial integrity in the intervention of aging.