Reduced Ribose-5-Phosphate Isomerase A-1 Expression in Specific Neurons and Time Points Promotes Longevity in Caenorhabditis elegans

Deregulation of redox homeostasis is often associated with an accelerated aging process. Ribose-5-phosphate isomerase A (RPIA) mediates redox homeostasis in the pentose phosphate pathway (PPP). Our previous study demonstrated that Rpi knockdown boosts the healthspan in Drosophila. However, whether the knockdown of rpia-1, the Rpi ortholog in Caenorhabditis elegans, can improve the healthspan in C. elegans remains unknown. Here, we report that spatially and temporally limited knockdown of rpia-1 prolongs lifespan and improves the healthspan in C. elegans, reflecting the evolutionarily conserved phenotypes observed in Drosophila. Ubiquitous and pan-neuronal knockdown of rpia-1 both enhance tolerance to oxidative stress, reduce polyglutamine aggregation, and improve the deteriorated body bending rate caused by polyglutamine aggregation. Additionally, rpia-1 knockdown temporally in the post-developmental stage and spatially in the neuron display enhanced lifespan. Specifically, rpia-1 knockdown in glutamatergic or cholinergic neurons is sufficient to increase lifespan. Importantly, the lifespan extension by rpia-1 knockdown requires the activation of autophagy and AMPK pathways and reduced TOR signaling. Moreover, the RNA-seq data support our experimental findings and reveal potential novel downstream targets. Together, our data disclose the specific spatial and temporal conditions and the molecular mechanisms for rpia-1 knockdown-mediated longevity in C. elegans. These findings may help the understanding and improvement of longevity in humans.