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Background <p>Phosphatidylinositol transfer protein-1 (<i>pitp-1</i>) is involved in the phosphoinositide (PIP) cycle. The role of <i>pitp-1</i> in promoting healthy longevity remains unknown. Our previous work showed that the PIP cycle–related genes <i>diacylglycerol lipase-1</i> (<i>dagl-1)</i> and <i>diacylglycerol kinase-5</i> (<i>dgk-5)</i> regulate lifespan, as overexpression of <i>dagl-1</i> or knockdown of <i>dgk-5</i> prolongs lifespan and enhances oxidative stress resistance through target of rapamycin (TOR) signaling. As <i>pitp-1</i> is a key component of this pathway, we investigated its role in lifespan regulation and the underlying mechanisms, aiming to clarify whether it represents a critical regulator of healthy longevity and how it coordinates conserved signaling pathways to regulate aging.</p> Methods <p><i>Caenorhabditis elegans</i> (<i>C. elegans</i>) mutants, RNAi-mediated knockdown, and transgenic overexpression were applied to assess lifespan, motility, and stress resistance. Temporal and tissue-specific RNAi were applied to identify critical time window and tissue for <i>pitp-1</i>-mediated lifespan regulation. TOR signaling was measured by phosphorylated S6 kinase (p-S6K) and puromycin incorporation, and transcriptomic analysis identified affected pathways.</p> Results <p><i>pitp-1</i> negatively regulated lifespan and healthspan in <i>C. elegans</i>. Genetic deletion or RNAi-mediated knockdown of <i>pitp-1</i> extended lifespan, attenuated age-related motility decline, and increased oxidative stress resistance. Temporal and spatial analyses revealed that suppression of <i>pitp-1</i> in neurons during early adulthood was sufficient to promote healthy longevity. Mechanistically, these beneficial effects upon <i>pitp-1</i> reduction were associated with suppression of TOR signaling. Conversely, <i>pitp-1</i> overexpression shortened lifespan and impaired healthspan via TOR activation. Moreover, <i>pitp-1</i> was transcriptionally repressed by DAF-16 downstream of insulin/IGF-1 signaling (IIS), and contributed to IIS-mediated longevity regulation. Furthermore, <i>pitp-1</i> reduction also improved organismal proteostasis, as evidenced by decreased polyglutamine (polyQ) aggregation and enhanced motility in a neuronal proteotoxicity model.</p> Conclusions <p>These findings identify <i>pitp-1</i> as a novel regulator of healthy aging, suggesting a role in coordinating IIS and TOR signaling and providing new insights into conserved mechanisms of longevity regulation.</p>

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Phosphatidylinositol transfer protein-1 integrates insulin/IGF-1 and TOR signaling to negatively regulate lifespan and healthspan in Caenorhabditis elegans

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月27日

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  • Yen-Hung Lin,
  • Yun-Hsun Liao,
  • Sin-Bo Liao,
  • Tzu-Yu Lin,
  • Muniesh Muthaiyan Shanmugam,
  • Pei-Jia Hsu,
  • Chang-Shi Chen,
  • Tsiu-Ting Ching,
  • Oliver Ingvar Wagner,
  • Chiou-Hwa Yuh,
  • Horng-Dar Wang

摘要

Background

Phosphatidylinositol transfer protein-1 (pitp-1) is involved in the phosphoinositide (PIP) cycle. The role of pitp-1 in promoting healthy longevity remains unknown. Our previous work showed that the PIP cycle–related genes diacylglycerol lipase-1 (dagl-1) and diacylglycerol kinase-5 (dgk-5) regulate lifespan, as overexpression of dagl-1 or knockdown of dgk-5 prolongs lifespan and enhances oxidative stress resistance through target of rapamycin (TOR) signaling. As pitp-1 is a key component of this pathway, we investigated its role in lifespan regulation and the underlying mechanisms, aiming to clarify whether it represents a critical regulator of healthy longevity and how it coordinates conserved signaling pathways to regulate aging.

Methods

Caenorhabditis elegans (C. elegans) mutants, RNAi-mediated knockdown, and transgenic overexpression were applied to assess lifespan, motility, and stress resistance. Temporal and tissue-specific RNAi were applied to identify critical time window and tissue for pitp-1-mediated lifespan regulation. TOR signaling was measured by phosphorylated S6 kinase (p-S6K) and puromycin incorporation, and transcriptomic analysis identified affected pathways.

Results

pitp-1 negatively regulated lifespan and healthspan in C. elegans. Genetic deletion or RNAi-mediated knockdown of pitp-1 extended lifespan, attenuated age-related motility decline, and increased oxidative stress resistance. Temporal and spatial analyses revealed that suppression of pitp-1 in neurons during early adulthood was sufficient to promote healthy longevity. Mechanistically, these beneficial effects upon pitp-1 reduction were associated with suppression of TOR signaling. Conversely, pitp-1 overexpression shortened lifespan and impaired healthspan via TOR activation. Moreover, pitp-1 was transcriptionally repressed by DAF-16 downstream of insulin/IGF-1 signaling (IIS), and contributed to IIS-mediated longevity regulation. Furthermore, pitp-1 reduction also improved organismal proteostasis, as evidenced by decreased polyglutamine (polyQ) aggregation and enhanced motility in a neuronal proteotoxicity model.

Conclusions

These findings identify pitp-1 as a novel regulator of healthy aging, suggesting a role in coordinating IIS and TOR signaling and providing new insights into conserved mechanisms of longevity regulation.