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

Abstract

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. 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. 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. 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.