Neuronal MML-1/MXL-2 Regulates Systemic Aging Via Glutamate Transporter and Cell Nonautonomous Autophagic and Peroxidase Activity.

Accumulating evidence has demonstrated the presence of intertissue- communication regulating systemic aging, but the underlying molecular network has not been fully explored. We and others previously showed that two basic helix-loop-helix transcription factors, MML-1 and HLH-30, are required for lifespan extension in several longevity paradigms, including germlineless Caenorhabditis elegans. However, it is unknown what tissues these factors target to promote longevity. Here, using tissue- specific knockdown experiments, we found that MML-1 and its heterodimer partners MXL-2 and HLH-30 act primarily in neurons to extend longevity in germlineless animals. Interestingly, however, the downstream cascades of MML-1 in neurons were distinct from those of HLH-30. Neuronal RNA interference (RNAi)-based transcriptome analysis revealed that the glutamate transporter GLT-5 is a downstream target of MML-1 but not HLH-30. Furthermore, the MML- 1-GTL-5 axis in neurons is critical to prevent an age- dependent collapse of proteostasis and increased oxidative stress through autophagy and peroxidase MLT-7, respectively, in long-lived animals. Collectively, our study revealed that systemic aging is regulated by a molecular network involving neuronal MML-1 function in both neural and peripheral tissues.SignificanceThe Mondo complex (MML- 1/ MXL- 2) is required for multiple longevity-promoting pathways in Caenorhabditis elegans. However, the tissues involved in this function of MML- 1/MXL- 2 have remained elusive. Here, we found that neuronal MML- 1/MXL- 2 was preferentially involved in the longevity and maintenance of tissue integrity conferred by germline deficiency. Neuronal MML- 1/MXL- 2 activated transcription of the glutamate transporterglt-5, which modulated autophagic activity and redox homeostasis by increasing expression of the peroxidase mlt-7 in nonneuronal tissues of long- lived animals. Our study provides evidence that intertissue-communications by neuronal MML- 1/MXL- 2 result in systemic regulation that is crucial for controlling organismal aging.