Neuronal MML-1/MXL-2 regulates systemic aging via glutamate transporter and cell non-autonomous autophagic and peroxidase activity
Journal | Proc. Natl. Acad. Sci. U. S. A. 120(39):e2221553120. (2023) |
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Title | Neuronal MML-1/MXL-2 regulates systemic aging via glutamate transporter and cell non-autonomous autophagic and peroxidase activity |
Laboratory | Laboratory of Intracellular Membrane Dynamics |
Abstract
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.
Authors | Tatsuya Shioda (1), Ittetsu Takahashi (1), Kensuke Ikenaka (2), Naonobu Fujita (3, 4), Tomotake Kanki (5), Toshihiko Oka (6), Hideki Mochizuki (2), Adam Antebi (7, 8), Tamotsu Yoshimori (1, 9, 10), Shuhei Nakamura (1, 9, 11)
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PubMed | 37722055 |