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

Overview

1. Institute of Biotechnology, National Tsing Hua University,Hsinchu, 300044 Taiwan
2. Institute of Molecular and Cellular Biology, National Tsing Hua University,Hsinchu, 300044 Taiwan
3. Present Address: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland,70211 Kuopio, Finland
4. Department of Life Science, National Tsing Hua University,Hsinchu, 300044 Taiwan
5. Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University,Tainan, Taiwan
6. Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University,Taipei, 112304 Taiwan
7. Institute of Bioinformatics and Structural Biology, National Tsing Hua University,Hsinchu, 300044 Taiwan
8. Institute of Molecular and Genomic Medicine, National Health Research Institutes,Zhunan, Miaoli 35053 Taiwan

Abstract

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.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12929-026-01246-x.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• figshare:32109957, at figshare; found in DataCite
• figshare:32109960, at figshare; found in DataCite
• figshare:32109963, at figshare; found in DataCite
• figshare:32109966, at figshare; found in DataCite
• figshare:32109969, at figshare; found in DataCite

Other data links

• ncbi.nlm.nih.gov/geo, NCBI; found in the text, “Gene Expression Omnibus (GEO) analysis”

Data availability

All the RNAseq raw data can be accessed by the GEO accession number GSE309580.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 7 keywords, 9 MeSH terms, 2 funders, 67 references.

Cite

This paper

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. (2026). Phosphatidylinositol transfer protein-1 integrates insulin/IGF-1 and TOR signaling to negatively regulate lifespan and healthspan in Caenorhabditis elegans. Journal of biomedical science, 33(1), 42. https://doi.org/10.1186/s12929-026-01246-x

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