3-phenyllactic acid promotes healthspan through SKN-1/ATFS-1-mediated mitochondrial activation and stress resilience

Abstract

The mechanisms underlying the impact of probiotic supplementation on health remain largely elusive. While previous studies have primarily focused on the discovery of novel bioactive bacteria and alterations in the microbiome environment to explain potential probiotic effects, our research delves into the role of living lactic acid bacteria (LAB) and their conditioned media, highlighting that only the former, not dead bacteria, enhance the healthspan of Caenorhabditis elegans. To elucidate the underlying mechanisms, we conducted transcriptomic profiling through RNA-seq analysis in C. elegans exposed to LAB or 3-phenyllactic acid (PLA), mimicking the presence of key candidate metabolites of LAB and evaluating healthspan. Our findings reveal that PLA treatment significantly extends the healthspan of C. elegans by promoting energy metabolism and stress resilience in a SKN-1/ATFS-1-dependent manner. Moreover, PLA-mediated longevity is associated with a novel age-related parameter, the Healthy Aging Index (HAI), introduced in this study, which comprises healthspan-related factors such as motility, oxygen consumption rate (OCR), and ATP levels. Extending the relevance of our work to humans, we observed an inverse correlation between blood PLA levels and physical performance in patients with sarcopenia, when compared to age-matched non-sarcopenic controls. Our investigation thus sheds light on the pivotal role of the metabolite PLA in probiotics-mediated enhancement of organismal healthspan, and also hints at its potential involvement in age-related sarcopenia. These findings warrant further investigation to delineate PLAs role in mitigating age-related declines in healthspan and resilience to external stressors. HighlightsO_LIMetabolites Produced by Lactic Acid Bacteria Function as Mediators of Longevity in C. elegans C_LIO_LI3-Phenyllactic Acid (PLA) Augmented Lifespan Extension and Elevated the Healthy Aging Index (HAI) C_LIO_LIPLA Facilitated Healthy Aging by Inducing Mitochondrial Activation and Stress Resistance Dependent on SKN-1/ATFS-1 C_LIO_LIPatients with Sarcopenia and Symptoms of Frailty Exhibited Reduced Blood PLA Levels. C_LI