Ketone bodies: from enemy to friend and guardian angel

During starvation, fasting, or a diet containing little digestible carbohydrates, the circulating insulin levels are decreased. This promotes lipolysis, and the breakdown of fat becomes the major source of energy. The hepatic energy metabolism is regulated so that under these circumstances, ketone bodies are generated from β-oxidation of fatty acids and secreted as ancillary fuel, in addition to gluconeogenesis. Increased plasma levels of ketone bodies thus indicate a dietary shortage of carbohydrates. Ketone bodies not only serve as fuel but also promote resistance to oxidative and inflammatory stress, and there is a decrease in anabolic insulin-dependent energy expenditure. It has been suggested that the beneficial non-metabolic actions of ketone bodies on organ functions are mediated by them acting as a ligand to specific cellular targets. We propose here a major role of a different pathway initiated by the induction of oxidative stress in the mitochondria during increased ketolysis. Oxidative stress induced by ketone body metabolism is beneficial in the long term because it initiates an adaptive (hormetic) response characterized by the activation of the master regulators of cell-protective mechanism, nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuins, and AMP-activated kinase. This results in resolving oxidative stress, by the upregulation of anti-oxidative and anti-inflammatory activities, improved mitochondrial function and growth, DNA repair, and autophagy. In the heart, the adaptive response to enhanced ketolysis improves resistance to damage after ischemic insults or to cardiotoxic actions of doxorubicin. Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors may also exert their cardioprotective action via increasing ketone body levels and ketolysis. We conclude that the increased synthesis and use of ketone bodies as ancillary fuel during periods of deficient food supply and low insulin levels causes oxidative stress in the mitochondria and that the latter initiates a protective (hormetic) response which allows cells to cope with increased oxidative stress and lower energy availability. Keywords Ketogenic diet, Ketone bodies, Beta hydroxybutyrate, Insulin, Obesity, Type 2 diabetes, Inflammation, Oxidative stress, Cardiovascular disease, SGLT2, Hormesis

An Environmental Contributor to Parkinson’s Disease Causes a Hormetic Lifespan Effect in C. elegans

Only 5-10% of Parkinson’s Disease (PD) cases have a direct genetic origin; however, exposure to herbicides, pesticides, and interactions with soil are potential risk factors. PD is characterized by the loss of dopaminergic (DA) neurons and the formation of protein inclusions that contain α-synuclein (α-syn). Conversely, a soil bacterium, Streptomyces venezuelae (S. ven), produces a secondary metabolite that causes age- and dose- dependent DA neurodegeneration in C. elegans; it also exacerbates α-syn-induced DA neurodegeneration. Previous studies from our lab determined that exposure to the S. ven metabolite caused oxidative stress, mitochondrial fragmentation and enhanced reactive oxygen species (ROS). Here we report that exposure to S. ven metabolite causes a hormetic effect on C. elegans lifespan, where low concentrations (5X) extend lifespan in N2 animals, but at higher concentrations (20X) lifespan is decreased. To further examine this hormetic response, we examined daf-16 mutants in this assay. daf-16 mutants displayed no significant differences between solvent and metabolite at both high and low concentrations, suggesting the hormetic response is daf-16 dependent. We also studied S. ven metabolite on C. elegans aging mutants. We investigated mutants in the AMPK signaling pathway and found when exposed to the 20X concentration of S. ven metabolite, aak-2 mutants displayed no significant difference between solvent and metabolite over lifespan. However, when aak-2 mutants were exposed to solvent control and the 5X concentration, mutants displayed a decreased lifespan. This suggests that functional aak-2 might be important for increased lifespan when combating toxicants following chronic exposure.

Hormetic response and transcriptome profiling reveal the mechanism underlying metabolic and cuticular resistance to host-specific terpenoid defences in an emerging insect pest, Pagiophloeus tsushimanus (Coleoptera: Curculionidae)

The resistance mechanisms evolved by insects to overcome host-plant allelochemicals are a key consideration in pest management. Camphor oil (EO) and its main component (i.e., D-camphor) form a specific terpenoid-defensive system in camphor trees, Cinnamomum camphora. However, an emerging insect pest, Pagiophloeus tsushimanus, has recently caused serious damage to this intractable plant species and is largely elusive. Here, we used feeding bioassays and RNA-seq to investigate the mechanism underlying the resistance of the beetle to host-specific terpenoid defences. First, a hormetic response in both larval weight and developmental time, which is a highly generalized dose-response phenomenon in toxicology but occurs infrequently in the context of insect-plant interactions, was observed in terpenoid-feeding individuals. Then, comparative transcriptome analysis between terpenoid-feeding and control groups indicated that both CYP450-mediated metabolic resistance and CP-mediated cuticular resistance were jointly employed to cope with terpenoid-induced stress. In addition, a small portion of genes involved in the glucose transport pathway were upregulated at the low D-camphor dose, suggesting that an extra intake of glucose used for larval growth may contribute to a hormetic response. These findings suggested that the dual terpenoid resistance mechanisms in this specialist are an essential precondition for the hormetic response in larval growth, ultimately contributing to the widespread successful colonization of host camphor trees. Overall, our study will open new avenues for understanding insect-plant coevolutionary adaptation and developing durable pest control strategies.

Differential root and shoot magnetoresponses in Arabidopsis thaliana

The geomagnetic field (GMF) is one of the environmental stimuli that plants experience continuously on Earth; however, the actions of the GMF on plants are poorly understood. Here, we carried out a time-course microarray experiment to identify genes that are differentially regulated by the GMF in shoot and roots. We also used qPCR to validate the activity of some genes selected from the microarray analysis in a dose-dependent magnetic field experiment. We found that the GMF regulated genes in both shoot and roots, suggesting that both organs can sense the GMF. However, 49% of the genes were regulated in a reverse direction in these organs, meaning that the resident signaling networks define the up- or downregulation of specific genes. The set of GMF-regulated genes strongly overlapped with various stress-responsive genes, implicating the involvement of one or more common signals, such as reactive oxygen species, in these responses. The biphasic dose response of GMF-responsive genes indicates a hormetic response of plants to the GMF. At present, no evidence exists to indicate any evolutionary advantage of plant adaptation to the GMF; however, plants can sense and respond to the GMF using the signaling networks involved in stress responses.

Enzymatic Responses to Low-Intensity Radiation of Tritium

The present study considers a possible role of enzymatic reactions in the adaptive response of cells to the beta-emitting radionuclide tritium under conditions of low-dose exposures. Effects of tritiated water (HTO) on the reactions of bacterial luciferase and NAD(P)H:FMN-oxidoreductase, as well as a coupled system of these two reactions, were studied at radioactivity concentrations ≤ 200 MBq/L. Additionally, one of the simplest enzymatic reactions, photobiochemical proton transfer in Coelenteramide-containing Fluorescent Protein (CLM-FP), was also investigated. We found that HTO increased the activity of NAD(P)H:FMN-oxidoreductase at the initial stage of its reaction (by up to 230%); however, a rise of luciferase activity was moderate (<20%). The CLM-FP samples did not show any increase in the rate of the photobiochemical proton transfer under the exposure to HTO. The responses of the enzyme systems were compared to the ‘hormetic’ response of luminous marine bacterial cells studied earlier. We conclude that (1) the oxidoreductase reaction contributes significantly to the activation of the coupled enzyme system and bacterial cells by tritium, and (2) an increase in the organization level of biological systems promotes the hormesis phenomenon.