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

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 PLA’s role in mitigating age-related declines in healthspan and resilience to external stressors. Highlights ### Competing Interest Statement The authors have declared no competing interest.