Phosphatidylinositol Transfer Protein-1 Integrates Insulin/IGF-1 and TOR Signaling to Negatively Regulate Lifespan and Healthspan in Caenorhabditis elegans

Lin, Y.-H.; Liao, Y.-H.; Liao, S.-B.; Lin, T.-Y.; Shanmugam, M. M.; Hsu, P.-J.; Chen, C.-S.; Ching, T.-T.; Wagner, O. I.; Yuh, C.-H.; Wang, H.-D.

doi:10.1101/2025.11.28.691094

bioRxiv · 10.1101/2025.11.28.691094

Phosphatidylinositol Transfer Protein-1 Integrates Insulin/IGF-1 and TOR Signaling to Negatively Regulate Lifespan and Healthspan in Caenorhabditis elegans

Lin, Y.-H.·Liao, Y.-H.·Liao, S.-B.·Lin, T.-Y.·Shanmugam, M. M.·Hsu, P.-J.·Chen, C.-S.·Ching, T.-T.·Wagner, O. I.·Yuh, C.-H.·Wang, H.-D.

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Abstract

BackgroundPhosphatidylinositol transfer protein-1 (pitp-1) is involved in phosphoinositide turnover. The role of pitp-1 in promoting healthy longevity remains unknown. Our previous work showed that the phosphoinositide turnover genes dagl-1 and dgk-5 regulates lifespan, as overexpression of dagl-1 or knockdown of dgk-5 prolongs lifespan and enhances oxidative stress resistance through 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. MethodsC. elegans mutants, RNAi-mediated knockdown, and transgenic overexpression were applied to assess lifespan, motility, stress resistance. Temporal and tissue-specific RNAi were applied to identify the critical time window and tissue for pitp-1-mediated lifespan regulation. TOR signaling was measured by phosphorylated S6 kinase and puromycin incorporation, and transcriptomic analysis identified affected pathways. Resultspitp-1 negatively regulates lifespan and healthspan in Caenorhabditis elegans. Genetic deletion or RNAi-mediated knockdown of pitp-1 extends lifespan, attenuates age-related motility decline, and increases oxidative stress resistance. Temporal and spatial analyses reveal that suppression of pitp-1 in neurons during early adulthood is sufficient to promote healthy longevity. Mechanistically, these beneficial effects upon pitp-1 reduction are mediated by suppressing TOR signaling. Conversely, pitp-1 overexpression shortens lifespan and impairs healthspan via TOR activation. Moreover, pitp-1 is transcriptionally repressed by DAF-16 downstream of insulin/IGF-1 signaling (IIS), and contributes to IIS-mediated lifespan extension. ConclusionThese findings identify pitp-1 as a novel regulator of healthy aging that integrates IIS and TOR pathways, providing new insights into conserved mechanisms for promoting healthy longevity.

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Lin, Y.-H., Liao, Y.-H., Liao, S.-B., Lin, T.-Y., Shanmugam, M. M., Hsu, P.-J., Chen, C.-S., Ching, T.-T., Wagner, O. I., Yuh, C.-H., Wang, H.-D.. 2025-12-02. Phosphatidylinositol Transfer Protein-1 Integrates Insulin/IGF-1 and TOR Signaling to Negatively Regulate Lifespan and Healthspan in Caenorhabditis elegans. https://doi.org/10.1101/2025.11.28.691094

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