(1) Background: Polyphenols (PP) play an important role in the prevention of non-communicable diseases and may contribute to healthy aging. To investigate the molecular and cellular aspects of PP metabolites on longevity with a focus on mitochondrial function, we applied a pre-fermented mixture of polyphenols (Rechtsregulat^®, RR) to rodents and nematodes. (2) Methods: The lifespans of Navar Medical Research Institute (NMRI) mice and C. elegans were recorded. The heat-stress resistance (37 °C) of C. elegans N2 was measured using nucleic staining. Respiration and membrane potential (ΔΨm) were measured in isolated mitochondria. The energetic metabolites adenosine triphosphate (ATP), lactate, and pyruvate were determined in lysates. Expression levels of longevity related genes were determined using quantitative real time polymerase chain reaction (qRT-PCR). Phenolic compounds were identified using ultra high performance liquid chromatography-diode array detection-Iontrap-multiple stage mass spectrometry (UHPLC-DAD-Iontrap-MSⁿ). (3) Results: Several phenolic metabolites including protocatechuic acid (PCA) were identified in RR. Feeding of mice with RR resulted in a significantly increased lifespan. Heat-stress resistance (RR *** p = 0.0006; PCA **** p < 0.0001), median lifespan (NMRI: RR ** p = 0.0035; C. elegans RR * p = 0.0279; PCA **** p < 0.0001), and activity of mitochondrial respiratory chain complexes (RR *⁻** p = 0.0237 − 0.0052; PCA * p = 0.019 − 0.0208) of C. elegans were significantly increased after incubation with RR (10%) or PCA (780 µM). PCA significantly improved nematodes ΔΨm (* p = 0.02058) and ATP levels (* p = 0.029). RR significantly up-regulated lactate levels, indicating enhanced glycolysis. The expression levels of longevity related genes daf-16, sir-2.1, and skn-1 were significantly upregulated after PCA, and partially after RR administration. (4) Conclusion: Phenolic metabolites such as PCA have the potential to enhance health and lifespan and mitochondrial function, and thus may contribute to healthy aging.

Introduction: Aging represents one of the major risk factors for metabolic diseases, such as diabetes and obesity, or neurodegeneration. Polyphenols and its metabolites, especially simple phenolic acids, have gained more and more attention as a preventive strategy for age-related, non-communicable diseases, due to their hormetic potential. Using the nematode Caenorhabditis elegans ( C. elegans ) we investigate the effect of protocatechuic, gallic and vanillic acid to improve mitochondrial function and health associated parameters as a preventive measure. Methods: Lifespan, heat-stress resistance and chemotaxis of C. elegans strain PX627, as a specific model for aging, were assessed in 2-day and 10-day old nematodes. Mitochondrial membrane potential (ΔΨm) and ATP generation of young and aged nematodes were measured. mRNA expression levels of longevity and energy metabolism-related genes were determined using qRT-PCR. Results: All phenolic acids were able to significantly increase the nematodes lifespan, heat-stress resistance and chemotaxis at micromolar concentrations. While ΔΨm was only affected by age, vanillic acid significantly decreased ATP concentrations in aged nematodes. Genetic analysis revealed increased glycolytic activity mediated through vanillic acid, suggesting improved thermogenesis. Conclusion: While life- and health-span parameters are positively affected by the investigated phenolic acids, the concentrations applied were unable to impact mitochondrial performance, suggesting hormesis. In contrast to the other phenolic acids, vanillic acid showed potential in regulating glucose homeostasis, making it a prime candidate for future diabetes and obesity focused approaches.