[An Attempt toward the Discovery of Compounds for Extending (Healthy) Lifespan]

Over the past decade, the author has established a highly original screening system (T-cell activation-inhibitory assay: TAIN assay) and has conducted a search for compounds that extend (healthy) lifespan. In the early phase, the screening focused on plant-derived natural compounds (PDNC). Through this process, several candidate compounds were identified, and many of them were demonstrated to exert significant anti-inflammatory and/or metabolic improvement effects. However, it later became clear that, when proposing these PDNC to society as (healthy) lifespan-extending agents and promoting their widespread use, it is crucial to ensure large-scale supply and guaranteed safety. In particular, the author came to recognize the importance of focusing on substances for which safety can reasonably be assured. Accordingly, the screening strategy was revised: PDNC were excluded, and the focus was narrowed to approved pharmaceutical drugs whose safety has already been established to a certain extent. As a result of TAIN assay followed by the second screening assessing anti-inflammatory and/or metabolism-improving effects, anti-inflammatory effects of ibudilast, benproperine, and cloperastine were confirmed at both the cellular and animal levels, while tipepidine demonstrated beneficial effects on lipid and glucose metabolism. Among these drugs, only tipepidine exhibited a lifespan-extending effect in nematodes. Furthermore, this effect was suggested to be mediated through the AMP-activated protein kinase signaling pathway. The author believes that further advancement of screening using the TAIN assay will lead to the identification of additional pharmaceutical drugs that extend lifespan in nematodes, and ultimately to the discovery of compounds that can truly extend human (healthy) lifespan.