Summary taken from http://m.pnas.org/content/early/2016/08/24/1607571113.long
Study: 45 CFS patients and 39 controls from a Northern California clinic were studied, equally divided between males and females. Ave. KPS was 62 for males and 54 for females. Males were ave age 53, females were ave age 52. 612 metabolites from 63 biochemical pathways were measured using advanced liquid chromatography on plasma. 60 metabolites in both males and females out of 612 were abnormal compared to controls. CFS cases showed abnormalities in 20 metabolic pathways (9 common to both and 11 with gender differences). 80% of the diagnostic metabolites (8 in men and 13 in females) were decreased and consistent with a hypometabolic state with low mitochondrial function, low peroxisomal function and low NADPH. An average of 10 metabolite abnormalities contributed to the diagnosis of CFS and an average of 30 metabolite abnormalities were unique to the individual.
What is CFS?
Many of the pathways and metabolites that were abnormal in CFS are also known to be features of dauer, a well-studied, long-lived survival and persistence state triggered by environmental stress. Interestingly, the direction of CFS abnormalities was opposite to metabolic syndrome and opposite to the metabolic response to infection, inflammation, or environmental stress that has been called the CDR (Cell Defense Response). For example, cholesterol, phospholipid, sphingolipid, and purine metabolism are all decreased in CFS and dauer but are increased in metabolic syndrome and the stereotyped CDR. These facts suggest that CFS is an evolutionarily conserved, genetically regulated, hypometabolic state similar to dauer that permits survival and persistence under conditions of environmental stress but at the cost of severely curtailed function and quality of life.
What is Dauer?
Dr Naviuax’s results show that the metabolic features of CFS are consistent with a hypometabolic state. Sphingolipids, glycosphingolipids, phospholipids, purines, microbiome aromatic amino acid and branch chain amino acid metabolites, FAD, and lathosterol were decreased. The decreases in these metabolites correlated with disease severity as measured by Karnofsky scores. Much research has been done on the hypometabolic phenotype in other biologic systems, including dauer, diapause, hibernation, estivation, torpor, ischemic preconditioning, ER stress, the unfolded protein response (? NanoVi responsive), autophagy, and caloric restriction. Dauer, which means persistence or long-lived in German, is an example of one well-studied system. The developmental stage of dauer is a hypometabolic state capable of living efficiently by altering a number of basic mitochondrial functions, fuel preferences, behavior, and physical features. Dauer is comprised of an evolutionarily conserved and synergistic suite of metabolic and structural changes that are triggered by exposure to adverse environmental conditions. Entry into dauer confers a survival advantage in harsh conditions. When the dauer response is blocked by certain mutations (dauer defectives), animals are short-lived when exposed to environmental stress. These mutations show that the latent ability to enter into a hypometabolic state during times of environmental threat is adaptive, even though it comes at the cost of decreasing the optimal functional capacity. Similar to dauer, CFS appears to represent a hypometabolic survival state that is triggered by environmental stress. The metabolic features of CFS and dauer correspond to the same pathways that characterize the acute CDR and metabolic syndrome but are regulated in the opposite direction. For example, cholesterol, phospholipids, and uric acid are often elevated in the acute CDR and metabolic syndrome, but these metabolites were decreased in CFS patients. A prediction based on these findings is that patients with CFS would be more resistant to the constellation of hypertension, dyslipidemia, central obesity, and insulin resistance that increase all-cause mortality associated with metabolic syndrome, but at the cost of significant long-term disability, pain, and suffering.
The Importance of Mitochondria, Redox, and NADPH Metabolism in Chronic Fatigue.
All of the metabolic abnormalities that Dr Naviaux identified in CFS were either directly regulated by redox or the availability of NADPH. About 60% of NADPH is produced by the pentose phosphate pathway under baseline conditions (Glucose to D-Ribose). The other 40% is produced by the combined flux through five NADP+ dependent enzymes: (i) malic enzyme (ME), (ii) isocitrate dehydrogenase (IDH), (iii) glutamate dehydrogenase (GDH), (iv) nicotinamide nucleotide transhydrogenase (NNT), and (v) methylene tetrahydrofolate dehydrogenase 2-like protein (MTHFD2L). Each of these enzymes has at least one mitochondrial isoform and is known to be up-regulated under conditions of environmental or developmental stress. It has recently been shown that mitochondrial MTHFD2L is responsible for producing 20–40% of cellular NADPH by the oxidation of methylene tetrahydrofolic acid to 10-formyl tetrahydrofolate. These data show that folates are important not only in methylation reactions but also in regulating intracellular redox and NADPH levels. A number of single nucleotide polymorphisms (SNPs) have been identified in the MTHFD2L gene that correlate with the CDR and interleukin 1β (IL1β) production triggered by smallpox vaccination. Mitochondrial pools of NADPH are in continuous communication with NADH levels through the enzyme NNT. Therefore, NADPH acts as a global barometer of cellular fuel status by interrogating both mitochondrial electron (NADH) consumption and the availability of cytoplasmic reducing equivalents as NADPH. When mitochondrial electron transport decreases for any reason, fewer molecules of oxygen are converted to water (H2O) by cytochrome c oxidase. If capillary delivery of oxygen to the cell is unchanged, the concentration of dissolved oxygen rises in the cell like water in a bowl in response to instantaneous decreases in mitochondrial oxygen consumption. This activates scores of enzymes that are kinetically regulated by the availability of dissolved oxygen and can act as oxygen sensors. Some of these include NADPH oxidases like Nox4 that make hydrogen peroxide (H2O2) from the excess diatomic oxygen (O2) to initiate the oxidative shielding response (? Oxygen toxicity by IVRT criteria). When reduced (NADPH) and total (NADPH plus NADP+) pools are low, sterol, fatty acid, protein, and nucleotide synthesis fall to baseline survival levels. When NADPH levels are higher (anabolic stimulation), metabolism is shifted from persistence to normal cell function and growth, anabolic pathways are stimulated, biomass is created, and carbons and electrons are stored as biopolymers for cell growth and repair in the form of lipids, protein, glycogen, glycans, and nucleic acids.