Abstract
Target of rapamycin complex 1 (TORC1) and AMP-activated protein kinase (AMPK) antagonistically modulate metabolism and aging. However, how they coordinate to determine longevity and if they act via separable mechanisms is unclear. Here, we show that neuronal AMPK is essential for lifespan extension from TORC1 inhibition, and that TORC1 suppression increases lifespan cell non autonomously via distinct mechanisms from global AMPK activation. Lifespan extension by null mutations in genes encoding raga-1 (RagA) or rsks-1 (S6K) is fully suppressed by neuronal-specific rescues. Loss of RAGA-1 increases lifespan via maintaining mitochondrial fusion. Neuronal RAGA-1 abrogation of raga-1 mutant longevity requires UNC-64/syntaxin, and promotes mitochondrial fission cell nonautonomously. Finally, deleting the mitochondrial fission factor DRP-1 renders the animal refractory to the pro-aging effects of neuronal RAGA-1. Our results highlight a new role for neuronal TORC1 in cell nonautonomous regulation of longevity, and suggest TORC1 in the central nervous system might be targeted to promote healthy aging.
Highlights
Aging is the single biggest risk factor for the majority of non-communicable complex diseases, including some of those with the greatest negative impact on human health outcomes worldwide (Escoubas, Silva-Garcia, & Mair, 2017)
Expression of raga-1 in the nervous system, did not rescue other phenotypes resulting from loss of RAGA-1 function, including reduced body size (Fig 2f) and developmental delay (Figure 2—figure supplement 3). These results show that Target of rapamycin complex 1 (TORC1) activity in neurons modulates systemic aging, and this activity can be uncoupled from its regulation of growth and development. 211 Neuronal RAGA-1 modulates aging via neuropeptide signaling To identify mechanisms coupled to neuronal RAGA-1 regulation of lifespan, we examined the transcriptomes of wild type (“WT”), raga-1 mutant (“mutant”) and raga214 1 mutant with neuronal raga-1 expression (“rescue”) C. elegans by RNA-Seq
The longevity effects by unc-64 mutation on raga-1 neuronal rescue animals, combined with the RNA seq results, strongly suggest that neuronal TORC1 actively causes the release of neuropeptide signals to limit longevity cell nonautonomously. 260 Neuronal RAGA-1 drives peripheral mitochondrial fragmentation in aging animals Since genes linked to organelle organization were upregulated in the raga-1 mutant but not in rescue, we explored whether this might be causal to longevity of the raga-1 mutants
Summary
Aging is the single biggest risk factor for the majority of non-communicable complex diseases, including some of those with the greatest negative impact on human health outcomes worldwide (Escoubas, Silva-Garcia, & Mair, 2017). We saw similar rescue using neuronal expression of full-length wild type aak-2 (Figure 1—figure supplement 1g) These data demonstrate that activity of AMPK in neurons is a critical mediator of TORC1 longevity, and suggest that neuronal TORC1 activity itself may impact healthy aging. 283 To test whether mitochondria in peripheral tissues might be affected by signals generated by neuronal TORC1 activity cell nonautonomously, we examined mitochondrial morphology in body wall muscle in wild type, raga-1 mutant and raga-1 neuronal rescue animals (Figure 4a, b). Driving mitochondrial fusion by drp-1 fully restores longevity in neuronal raga-1 rescue animals to that of single raga-1 mutants (Figure 5f) These data suggest that neuronal TORC1 modulates lifespan via cell nonautonomous effects on mitochondrial dynamics. Our results highlight a critical role of neuronal TORC1 activity on healthy aging, and suggest that lifespan extension by reduced TORC1 signaling requires a fused mitochondrial network which itself can be modulated via TORC1 activity in neurons
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
