Cysteine protease cathepsin B promotes lysosome integrity to extend the lifespan of alternative day fasting worms.

Alternative day fasting (ADF) has been shown to enhance the lifespan of animals. However, human trials evaluating the efficacy of ADF have only recently emerged, presenting challenges due to the extreme nature of this dietary regimen. To better understand the effects of ADF, we investigated its impact using Caenorhabditis elegans as a model organism. Our findings reveal that ADF extends the lifespan of worms nourished on animal-based protein source, while those fed with plant-based protein as the primary protein source do not experience such benefits. Remarkably, initiating ADF during midlife is sufficient to prolong lifespan, whereas implementation during youth results in developmental damage, and in older age, fails to provide additional extension effects. Furthermore, we discovered that midlife ADF up-regulates the expression of two cysteine protease cathepsin B genes, cpr-2 and cpr-5, which preserve lysosomal integrity and enhance its function in digesting aggregated proteins, as well as enhancing lipid metabolism and ameliorating neurodegenerative disease markers and phenomena during aging. This suggests that midlife ADF has long lasting anti-aging effects and may delay the onset of related diseases, specifically in animals consuming animal-based protein source. These findings offer valuable insights into the effects of ADF and provide guidance for future research and potential applications in individuals.

Inhibiting HSD17B8 suppresses the cell proliferation caused by PTEN failure.

Loss of the tumor suppressor PTEN homolog daf-18 in Caenorhabditis elegans (C. elegans) triggers diapause cell division during L1 arrest. While prior studies have delved into established pathways, our investigation takes an innovative route. Through forward genetic screening in C. elegans, we pinpoint a new player, F12E12.11, regulated by daf-18, impacting cell proliferation independently of PTEN's typical phosphatase activity. F12E12.11 is an ortholog of human estradiol 17-beta-dehydrogenase 8 (HSD17B8), which converts estradiol to estrone through its NAD-dependent 17-beta-hydroxysteroid dehydrogenase activity. We found that PTEN engages in a physical interplay with HSD17B8, introducing a distinctive suppression mechanism. The reduction in estrone levels and accumulation of estradiol may arrest tumor cells in the G2/M phase of the cell cycle through MAPK/ERK. Our study illuminates an unconventional protein interplay, providing insights into how PTEN modulates tumor suppression by restraining cell division through intricate molecular interactions.