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<p>Transcription factors DAF-16/FOXO and HLH-30/TFEB have been linked to aging regulation, but how they synergize to promote longevity is not fully understood. Here, we reveal a functional interaction between these two transcription factors that supports healthier aging in <i>Caenorhabditis elegans</i>. Namely, DAF-16 and HLH-30 cooperate to trigger robust lysosomal tubulation under various contexts, which contributes to systemic health benefits in late age. Remarkably, lysosome tubulation can be artificially induced via overexpression of a small lysosomal gene, <i>dSVIP</i>, in the absence of one transcription factor, but not both. Mechanistically, intestinal overexpression of <i>dSVIP</i> leads to nuclear accumulation of DAF-16 and HLH-30 in gut and non-gut tissues and triggers global gene expression changes, including induction of <i>vps-34</i> and related lipid-metabolism genes, that promote tubular-lysosome activity. Collectively, our work reveals a cellular process under control of DAF-16 and HLH-30 that elicits pro-health effects in aging.</p>

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DAF-16/FOXO and HLH-30/TFEB comprise a cooperative regulatory axis controlling tubular lysosome induction in C. elegans

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月10日

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  • Cristian Ricaurte-Perez,
  • Joshua P. Gill,
  • P. Kerr Wall,
  • Olga Dubuisson,
  • Kathryn R. DeLeo,
  • K. Adam Bohnert,
  • Alyssa E. Johnson

摘要

Transcription factors DAF-16/FOXO and HLH-30/TFEB have been linked to aging regulation, but how they synergize to promote longevity is not fully understood. Here, we reveal a functional interaction between these two transcription factors that supports healthier aging in Caenorhabditis elegans. Namely, DAF-16 and HLH-30 cooperate to trigger robust lysosomal tubulation under various contexts, which contributes to systemic health benefits in late age. Remarkably, lysosome tubulation can be artificially induced via overexpression of a small lysosomal gene, dSVIP, in the absence of one transcription factor, but not both. Mechanistically, intestinal overexpression of dSVIP leads to nuclear accumulation of DAF-16 and HLH-30 in gut and non-gut tissues and triggers global gene expression changes, including induction of vps-34 and related lipid-metabolism genes, that promote tubular-lysosome activity. Collectively, our work reveals a cellular process under control of DAF-16 and HLH-30 that elicits pro-health effects in aging.