Polyphenols and Metabolites Enhance Survival in Rodents and Nematodes—Impact of Mitochondria

Abstract

(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.

IMPACT OF PHENOLIC ACIDS ON THE ENERGY METABOLISM AND LONGEVITY IN C. ELEGANS

“…This is in accordance with Saul et al, who reported gallic acid to prolong the nematodes lifespan and to protect against thermal stress [45]. While PCA has been extensively investigated and its health promoting capacities are well described [24,47], analysis of VA on the nematodes health (and mitochondrial function) is novel to the literature. To further strengthen these findings we analysed key genetic marker genes for longevity and stress-resistance daf-16 and sir-2.1 [50,51].…”

“…In fact, the antioxidant capacities of some phenolic acids were found to exceed that of well-known antioxidant vitamins [22]. In a previous study we demonstrated beneficial effects for the phenolic acid PCA on mitochondrial function and longevity in the nematode model C. elegans [24]. Here we follow up on the health promoting capacities of PCA using a recently described nematode model enabling the comparison of young and aged nematodes without the use of 5-fluoro-2'-deoxyuridine, which heavily affects mitochondrial function, to maintain synchronous populations [26].…”

“…A heat-stress resistance assay was used to determine a target concentration for each phenolic acid in young nematodes. The effect of three concentrations (namely 100 µM, 250 µM and 500 µM), covering a range commonly used for phenolic investigations in C. elegans [24,47,48], was assessed and the lowest concentration reaching a level of significance (p* < 0.05) chosen for further investigation.…”

“…In fact, all substances significantly increased the nematodes median survival, with vanillic acid being the most potent. A lifespan extension for all three phenolic acids is well documented [24,45,47,49]. Protection against thermal stress has already been demonstrated during determination of target concentrations in young, but not in aged 10-day old, nematodes.…”

“…In a recent study, we found the phenolic acid protocatechuic acid (PCA) to be a powerful agent to improve mitochondrial functions and induce longevity [24]. Using the nematode Caenorhabditis elegans, we further elucidate the hormetic potential of phenolic acids, metabolites of polyphenolic fermentation, on mitochondrial functions, as well as life-and health-span parameters.…”