Cerebral deficiency of vitamin B5 (d-pantothenic acid; pantothenate) as a potentially-reversible cause of neurodegeneration and dementia in sporadic Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of age-related neurodegeneration and dementia, and there are no available treatments with proven disease-modifying actions. It is therefore appropriate to study hitherto-unknown aspects of brain structure/function in AD to seek alternative disease-related mechanisms that might be targeted by new therapeutic interventions with disease-modifying actions. During hypothesis-generating metabolomic studies of brain, we identified apparent differences in levels of vitamin B5 between AD cases and controls. We therefore developed a method based on gas chromatography-mass spectrometry by which we quantitated vitamin B5 concentrations in seven brain regions from nine AD cases and nine controls. We found that widespread, severe cerebral deficiency of vitamin B5 occurs in AD. This deficiency was worse in those regions known to undergo severe damage, including the hippocampus, entorhinal cortex, and middle temporal gyrus. Vitamin B5 is the obligate precursor of CoA/acetyl-CoA (acetyl-coenzyme A), which plays myriad key roles in the metabolism of all organs, including the brain. In brain, acetyl-CoA is the obligate precursor of the neurotransmitter acetylcholine, and the complex fatty-acyl groups that mediate the essential insulator role of myelin, both processes being defective in AD; moreover, the large cerebral vitamin B5 concentrations co-localize almost entirely to white matter. Vitamin B5 is well tolerated when administered orally to humans and other mammals. We conclude that cerebral vitamin B5 deficiency may well cause neurodegeneration and dementia in AD, which might be preventable or even reversible in its early stages, by treatment with suitable oral doses of vitamin B5.

Transient vitamin B5 starving improves mammalian cell homeostasis and protein production.

Maintaining a metabolic steady state is essential for an organism's fitness and survival when confronted with environmental stress, and metabolic imbalance can be reversed by exposing the organism to fasting. Here, we attempted to apply this physiological principle to mammalian cell cultures to improve cellular fitness and consequently their ability to express recombinant proteins. We showed that transient vitamin B5 deprivation, an essential cofactor of central cellular metabolism, can quickly and irreversibly affect mammalian cell growth and division. A selection method was designed that relies on mammalian cell dependence on vitamin B5 for energy production, using the co-expression of the B5 transporter SLC5A6 and a gene of interest. We demonstrated that vitamin B5 selection persistently activates peroxisome proliferator-activated receptors (PPAR), a family of transcription factors involved in energy homeostasis, thereby altering lipid metabolism, improving cell fitness and therapeutic protein production. Thus, stable PPAR activation may constitute a cellular memory of past deprivation state, providing increased resistance to further potential fasting events. In other words, our results imply that cultured cells, once exposed to metabolic starvation, may display an improved metabolic fitness as compared to non-exposed cells, allowing increased resistance to cellular stress.

Pantothenate auxotrophy in Zymomonas mobilis ZM4 is due to a lack of aspartate decarboxylase activity.

The bacterium Zymomonas mobilis naturally produces ethanol at near theoretical maximum yields, making it of interest for industrial ethanol production. Zymomonas mobilis requires the vitamin pantothenate for growth. Here we characterized the genetic basis for the Z. mobilis pantothenate auxotrophy. We found that this auxotrophy is due to the absence of a single gene, panD, encoding aspartate-decarboxylase. Heterologous expression of Escherichia coli PanD in Z. mobilis or supplementation of the growth medium with the product of PanD activity, ß-alanine, eliminated the need for exogenous pantothenate. We also determined that Z. mobilis IlvC, an enzyme better known for branched-chain amino acid synthesis, is required for pantothenate synthesis in Z. mobilis, as it compensates for the absence of PanE, another pantothenate synthesis pathway enzyme. In addition to contributing to an understanding of the nutritional requirements of Z. mobilis, our results have led to the design of a more cost-effective growth medium.

Vitamin D deficiency changes the intestinal microbiome reducing B vitamin production in the gut. The resulting lack of pantothenic acid adversely affects the immune system, producing a "pro-inflammatory" state associated with atherosclerosis and autoimmunity.

STUDY OBJECTIVES: Vitamin D blood levels of 60-80ng/ml promote normal sleep. The present study was undertaken to explore why this beneficial effect waned after 2years as arthritic pain increased. Pantothenic acid becomes coenzyme A, a cofactor necessary for cortisol and acetylcholine production. 1950s experiments suggested a connection between pantothenic acid deficiency, autoimmune arthritis and insomnia. The B vitamins have been shown to have an intestinal bacterial source and a food source, suggesting that the normal intestinal microbiome may have always been the primary source of B vitamins. Review of the scientific literature shows that pantothenic acid does not have a natural food source, it is supplied by the normal intestinal bacteria. In order to test the hypothesis that vitamin D replacement slowly induced a secondary pantothenic acid deficiency, B100 (100mg of all B vitamins except 100mcg of B12 and biotin and 400mcg of folate) was added to vitamin D supplementation. METHODS: Vitamin D and B100 were recommended to over 1000 neurology patients. Sleep characteristics, pain levels, neurologic symptoms, and bowel complaints were recorded by the author at routine appointments. RESULTS: Three months of vitamin D plus B100 resulted in improved sleep, reduced pain and unexpected resolution of bowel symptoms. These results suggest that the combination of vitamin D plus B100 creates an intestinal environment that favors the return of the four specific species, Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria that make up the normal human microbiome. HYPOTHESES: 1) Seasonal fluctuations in vitamin D levels have normally produced changes in the intestinal microbiome that promoted weight gain in winter. Years of vitamin D deficiency, however, results in a permanently altered intestinal environment that no longer favors the "healthy foursome". 2) Humans have always had a commensal relationship with their intestinal microbiome. We supplied them vitamin D, they supplied us B vitamins. 3) The four species that make up the normal microbiome are also commensal, each excretes at least one B vitamin that the other three need but cannot make. 4) Improved sleep and more cellular repairs eventually depletes body stores of pantothenic acid, causing reduced cortisol production, increased arthritic pain and widespread "pro-inflammatory" effects on the immune system. 5) Pantothenic acid deficiency also decreases available acetylcholine, the neurotransmitter used by the parasympathetic nervous system. Unopposed, increased sympathetic tone then produces hypertension, tachycardia, atrial arrhythmias and a "hyper-adrenergic" state known to predispose to heart disease and stroke.

High-performance liquid chromatographic method for profiling 2-oxo acids in urine and its application in evaluating vitamin status in rats.

B-group vitamins are involved in the catabolism of 2-oxo acids. To identify the functional biomarkers of B-group vitamins, we developed a high-performance liquid chromatographic method for profiling 2-oxo acids in urine and applied this method to urine samples from rats deficient in vitamins B1 and B6 and pantothenic acid. 2-Oxo acids were reacted with 1,2-diamino-4,5-methylenebenzene to produce fluorescent derivatives, which were then separated using a TSKgel ODS-80Ts column with 30 mmol/L of KH2PO4 (pH 3.0):acetonitrile (7:3) at a flow rate of 1.0 mL/min. Vitamin B1 deficiency increased urinary levels of all 2-oxo acids, while vitamin B6 deficiency only increased levels of sum of 2-oxaloacetic acid and pyruvic acid, and pantothenic acid deficiency only increased levels of 2-oxoisovaleric acid. Profiles of 2-oxo acids in urine samples might be a non-invasive way of clarifying the functional biomarker of B-group vitamins.

Dietary pantothenic acid depressed the gill immune and physical barrier function via NF-κB, TOR, Nrf2, p38MAPK and MLCK signaling pathways in grass carp (Ctenopharyngodon idella).

This study explored the effects of pantothenic acid (PA) on the immune and physical barrier function, and relative mRNA levels of signaling molecules in the gill of grass carp (Ctenopharyngodon idella). The results indicated that compared with optimal PA supplementation, PA deficiency (1.31 mg/kg diet) decreased gill interleukin 10, transforming growth factor ß1, inhibitor of κBα (IκBα), eIF4E-binding protein 2, Claudin b and ZO-1 mRNA levels; anti-superoxide anion activity, and activities and mRNA levels of copper/zinc superoxide dismutase, manganese superoxide dismutase, glutathione peroxidase, glutathione reductase and NF-E2-related factor (P < 0.05). Additionally, PA deficiency and excess (75.08 mg/kg diet) decreased gill complement 3 and glutathione contents, lysozyme and acid phosphatase, anti-hydroxy radical, catalase and glutathione S-transferases activities, and liver-expression antimicrobial peptide 2, hepcidin, Claudin 3, Claudin c and Occludin mRNA levels (P < 0.05). Conversely, PA deficiency increased gill reactive oxygen species and protein carbonyl contents, and interferon γ2, interleukin 8, nuclear factor kappa B P65, Claudin 15a, Kelch-like ECH-associating protein 1a and Kelch-like ECH-associating protein 1b mRNA levels (P<0.05). Moreover, PA deficiency and excess increased gill malondialdehyde content, and tumor necrosis factor α, interleukin 1ß, IκB kinase α, IκB kinase ß, IκB kinase γ, target of rapamycin and ribosomal S6 protein kinase1 p38 mitogen-activated protein kinases and myosin light-chain kinase mRNA levels (P<0.05). In conclusion, PA deficiency decreased immune and physical barrier function, and regulated relative mRNA levels of signaling molecules in fish gill. Based on the quadratic regression analysis of gill lysozyme activity, the optimal PA levels in grass carp (253.44-745.25 g) were estimated to be 36.97 mg/kg diet.

Dietary pantothenic acid deficiency and excess depress the growth, intestinal mucosal immune and physical functions by regulating NF-κB, TOR, Nrf2 and MLCK signaling pathways in grass carp (Ctenopharyngodon idella).

This study investigated the effects of dietary pantothenic acid (PA) on the growth, intestinal mucosal immune and physical barrier, and relative mRNA levels of signaling molecules in the intestine of grass carp (Ctenopharyngodon idella). A total of 540 grass carp (253.44 ± 0.69 g) were fed six diets with graded levels of PA (PA1, PA15, PA30, PA45, PA60 and PA75 diets) for 8 weeks. The results indicated that compared with PA deficiency (PA1 diet) and excess (PA75 diet) groups, optimal PA supplementation increased (P < 0.05): (1) percent weight gain (PWG), feed intake and feed efficiency; (2) lysozyme activity, complement 3 content, liver-expressed antimicrobial peptide 2 and hepcidin, interleukin 10, transforming growth factor ß1 and inhibitor of κBα mRNA levels in some intestinal segments; (3) activities and mRNA levels of copper/zinc superoxide dismutase, manganese superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferases and glutathione reductase, and NF-E2-related factor 2 (Nrf2) mRNA level in the whole intestine; (4) Claudin b, Claudin 3, Claudin c, Occludin and ZO-1 mRNA levels in some intestinal segments of grass carp. Conversely, optimal PA supplementation decreased (P < 0.05): (1) tumor necrosis factor α, interleukin 1ß, interferon γ2, interleukin 8, nuclear factor κB P65 (NF-κB P65), IκB kinase α, IκB kinase ß, IκB kinase γ and target of rapamycin (TOR) mRNA expression levels in some intestinal segments; (2) reactive oxygen species, malondialdehyde and protein carbonyl contents, and Kelch-like ECH-associating protein 1a, Kelch-like ECH-associating protein 1b in the intestine; (3) Claudin 12, Claudin 15a and myosin light-chain kinase (MLCK) mRNA levels in some intestinal segments of grass carp. In conclusion, optimum PA promoted growth, intestinal mucosal immune and physical function, as well as regulated mRNA levels of signaling molecules NF-κB P65, TOR, Nrf2 and MLCK in grass carp intestine. Based on the quadratic regression analysis of PWG and intestinal lysozyme activity, the optimal PA levels in grass carp (253.44-745.25 g) were estimated to be 37.73 mg/kg and 41.38 mg/kg diet, respectively.

D-pantethine has vitamin activity equivalent to d-pantothenic acids for recovering from a deficiency of D-pantothenic acid in rats.

D-Pantethine is a compound in which two molecules of D-pantetheine bind through an S-S linkage. D-Pantethine is available from commercial sources as well as from D-pantothenic acid. We investigated if D-pantethine has the same vitamin activity as D-pantothenic acid by comparing the recovery from a deficiency of D-pantothenic acid in rats. D-Pantothenic acid-deficient rats were developed by weaning rats on a diet lacking D-pantothenic acid for 47 d. At that time, the urinary excretion of D-pantothenic acid was almost zero, and the body weight extremely low, compared with the control (p<0.05); the contents of free D-pantothenic acid were also significantly reduced in comparison with those of controls (p<0.05). D-Pantothenic acid-deficient rats were administered a diet containing D-pantothenic acid or D-pantethine for 7 d. D-Pantethine and D-pantothenic acid contents of the diets were equimolar in forms of D-pantothenic acid. We compared various parameters concerning nutritional status between rats fed D-pantothenic acid- and D-pantethine-containing diets. The recoveries of body weight, tissue weights, and tissue concentrations of free D-pantothenic acid, dephospho-CoA, CoA, and acetyl-CoA were identical between rats fed diets containing D-pantothenic acid and D-pantethine. Thus, the biological efficiency for recovering from a deficiency of D-pantothenic acid in rats was equivalent between D-pantothenic acid and D-pantethine.

Increased physical activity not decreased energy intake is associated with inpatient medical treatment for anorexia nervosa in adolescent females.

There is a dearth of data regarding changes in dietary intake and physical activity over time that lead to inpatient medical treatment for anorexia nervosa (AN). Without such data, more effective nutritional therapies for patients cannot be devised. This study was undertaken to describe changes in diet and physical activity that precede inpatient medical hospitalization for AN in female adolescents. This data can be used to understand factors contributing to medical instability in AN, and may advance rodent models of AN to investigate novel weight restoration strategies. It was hypothesized that hospitalization for AN would be associated with progressive energy restriction and increased physical activity over time. 20 females, 11-19 years (14.3±1.8 years), with restricting type AN, completed retrospective, self-report questionnaires to assess dietary intake and physical activity over the 6 month period prior to inpatient admission (food frequency questionnaire, Pediatric physical activity recall) and 1 week prior (24 hour food recall, modifiable activity questionnaire). Physical activity increased acutely prior to inpatient admission without any change in energy or macronutrient intake. However, there were significant changes in reported micronutrient intake causing inadequate intake of Vitamin A, Vitamin D, and pantothenic acid at 1 week versus high, potentially harmful, intake of Vitamin A over 6 months prior to admission. Subject report of significantly increased physical activity, not decreased energy intake, were associated with medical hospitalization for AN. Physical activity and Vitamin A and D intake should be carefully monitored following initial AN diagnosis, as markers of disease progression as to potentially minimize the risk of medical instability.

Pantothenic acid refeeding diminishes the liver, perinephrical fats, and plasma fats accumulated by pantothenic acid deficiency and/or ethanol consumption.

OBJECTIVE: Pantothenic acid (PaA) is a vitamin that is an integral part of coenzyme A (CoA). CoA is an essential coenzyme in fat metabolism. The aim of this study was to determine whether PaA deficiency causes the accumulation of tissue fats and, if so, can refeeding of PaA decrease such accumulated fat. METHODS: Weaning rats were fed the PaA-free diet for 30 d. Rats were then divided into two groups. One group was continuously fed the PaA-free diet, and the other was fed the PaA-containing diet for an additional 13 d. At the end of the experiment, liver fat and perinephric fat were weighed, and plasma triglyceride levels measured. An additional similar experiment was conducted in which rats consumed 15% ethanol instead of water. RESULTS: Fat that accumulated by consuming the PaA-free diet for 30 d was decreased by consuming the PaA-containing diet for an additional 13 d. Ethanol feeding elicited much greater accumulation of liver, perinephric, and plasma fats if rats were fed the PaA-free diet. In such cases, administration of PaA could decrease the accumulated fat. CONCLUSION: PaA deficiency causes fat accumulation, and readministration of PaA decreases the tissue fat in rats fed the pantothenic acid-free diet. Ethanol accelerated the accumulation of fat in rats fed the PaA-free diet. PaA could be beneficial for decreasing accumulated tissue fat.

Pantothenic acid deficiency may increase the urinary excretion of 2-oxo acids and nicotinamide catabolites in rats.

Pantothenic acid (PaA) is involved in the metabolism of amino acids as well as fatty acid. We investigated the systemic metabolism of amino acids in PaA-deficient rats. For this purpose, urine samples were collected and 2-oxo acids and L-tryptophan (L-Trp) and its metabolites including nicotinamide were measured. Group 1 was freely fed a conventional chemically-defined complete diet and used as an ad lib-fed control, which group was used for showing reference values. Group 2 was freely fed the complete diet without PaA (PaA-free diet) and used as a PaA-deficient group. Group 3 was fed the complete diet, but the daily food amount was equal to the amount of the PaA-deficient group and used as a pair-fed control group. All rats were orally administered 100 mg of L-Trp/kg body weight at 09:00 on day 34 of the experiment and the following 24-h urine samples were collected. The urinary excretion of the sum of pyruvic acid and oxaloacetic acid was higher in rats fed the PaA-free diets than in the rats fed pair-fed the complete diet. PaA deficiency elicited the increased urinary excretion of anthranilic acid and kynurenic acid, while the urinary excretion of xanthurenic acid decreased. The urinary excretion of L-Trp itself, 3-hydroxyanthranilic acid, and quinolinic acid revealed no differences between the rats fed the PaA-free and pair-fed the complete diets. PaA deficiency elicited the increased excretion of N(1)-methylnicotinamide, N(1)-methyl-2-pyridone-5-carboxamide, and N(1)-methyl-4-pyridone-3-carboxamide. These findings suggest that PaA deficiency disturbs the amino acid catabolism.

Preparation of a γ-glutamylcysteine-enriched yeast extract from a newly developed GSH2-deficient strain.

Gamma-glutamylcysteine (γ-GC), the precursor of glutathione (GSH), may have significant health benefits as a dietary supplement, but there are few cost-effective methods available for its large-scale production. We developed an efficient method for producing γ-GC in a mutant yeast strain using a three-step breeding procedure and a unique cultivation process. In the first breeding step, we prepared a glutathione synthetase (GSH2)-deficient yeast mutant. In the second step, selenate (SeO(4)(2-)) sensitivity was introduced by crossing the GSH2-deficient mutant with a strain harboring the met30 mutation. In the final step, pantothenic acid auxotrophy was introduced by ethyl methanesulfonate mutagenesis. The isolated strain displayed significantly enhanced cellular γ-GC when cultivated in synthetic medium without pantothenic acid, reaching a maximum level of 4.39% of dry cell weight. Using this strain, we were able to prepare a yeast extract containing approximately 13% γ-GC (w/w), which is markedly higher than the reported value (0.3%) of commercially available yeast extracts. The present method may facilitate large-scale γ-GC production for investigating the nutritive value and other benefits of dietary γ-GC.

The discovery of niacin, biotin, and pantothenic acid.

The aim was to describe the discovery of niacin, biotin, and pantothenic acid. By the 1920s, it became apparent that 'water-soluble B' (vitamin B) is not a single substance. In particular, fresh yeast could prevent both beriberi and pellagra, but the 'antipolyneuritis factor' in yeast is thermolabile, while the antipellagra factor is heat stable, suggesting that there are at least two water-soluble vitamins. Various terms were proposed for these water-soluble factors, but vitamins B(1) and B(2) were most widely used to refer to the thermolabile and heat-stable factors, respectively. Although vitamin B(1) proved to be a single chemical substance (thiamin), vitamin B(2) was ultimately found to be a complex of several chemically unrelated heat-stable factors, including niacin, biotin, and pantothenic acid. Recognition that niacin is a vitamin in the early 20th century resulted from efforts to understand and treat a widespread human disease - pellagra. American epidemiologist and US Public Health Service officer Joseph Goldberger (1874-1929) had been instrumental to elucidating the nutritional basis for pellagra. Goldberger conducted a classic series of observational and experimental studies in humans, combined with an extensive series of experiments with an animal model of the condition (black tongue in dogs). In contrast, recognition that biotin and pantothenic acid are vitamins occurred somewhat later as a result of efforts to understand microbial growth factors. The metabolic roles in humans of these latter substances were ultimately elucidated by human experiments using particular toxins and by studies of rare inborn errors of metabolism. Symptomatic nutritional deficiencies of biotin and pantothenic acid were, and continue to be, rare.

Simultaneous high-performance liquid chromatography determination of coenzyme A, dephospho-coenzyme A, and acetyl-coenzyme A in normal and pantothenic acid-deficient rats.

We describe here a simultaneous high-performance liquid chromatography method for practical and rapid determination of coenzyme A (CoA), dephospho-CoA, and acetyl-CoA in tissues. These coenzymes are biosynthesized from the vitamin pantothenic acid (PaA), which is involved in the metabolism of fatty acids, amino acid catabolism, and several other nutrients. The method employed a Tosoh TSK-GEL ODS-100 V column (250×4.6mm i.d., particle size 5µm) eluted with 100mmol/L NaH(2)PO(4) and 75mmol/L CH(3)COONa (pH was adjusted to 4.6 by the addition of concentrated H(3)PO(4))-acetonitrile (94:6, v/v) at a flow rate of 1.0ml/min. The ultraviolet detector was set at 259nm. The limits of detection for CoA, dephospho-CoA, and acetyl-CoA all were 10pmol. The method was applied to the analysis of several tissues of rats fed normal and PaA-free diets. The results clearly showed that the method was suitable for the simultaneous determination of CoA, dephospho-CoA, and acetyl-CoA in the liver, heart, kidney, spleen, testis, large colon, and muscle, but not for the small intestine, of rats.

[The separate and combined effects of calcium pantothenate deficiency and cadmium intoxication on rat reproductive function].

The publication presents investigation evaluated of separate and combined effects of calcium pantothenate deficiency and cadmium (Cd2+) intoxication on rat reproductive function. The experi-ments were performed on 280 adult and 890 offspring of Wistar rats. Reproductive function was estimated by fertility study, prenatal and postnatal development of offspring. The separate and combined effects of and cadmium intoxication during the mating period and pregnancy had no effect on fertility and fecundity of rats, pre-and postimplantation loss, the survival of offspring, and not caused the abnormal development of skeleton and internal organs. However, in prenatal ontogeny of this effect was manifested by lower body weight and fetal growth, postnatal - underdevelopment of rat pups in all morphological and functional studied parameters and increasing number of stillbirths in the offspring.

The effect of pantothenic acid deficiency on keratinocyte proliferation and the synthesis of keratinocyte growth factor and collagen in fibroblasts.

It has been reported that pantothenic acid (vitamin B5) and panthenol, an alcohol derivative of pantothenic acid, have beneficial moisturizing effects on the skin. However, few studies have investigated the mechanism of action of pantothenic acid on skin tissues. We tried to clarify the role of pantothenic acid on skin function by using keratinocytes and fibroblasts. The depletion of pantothenic acid from the culture medium suppressed keratinocyte proliferation and promoted differentiation. Moreover, pantothenic acid depletion decreased the synthesis of keratinocyte growth factor and procollagen 4a2 in fibroblasts. These results suggest that pantothenic acid is essential for maintaining keratinocyte proliferation and differentiation.

Effects of pantothenic acid on testicular function in male rats.

Pantothenic acid (PaA) is a water-soluble vitamin required to sustain various physiological functions in animals. The physiological roles of PaA on testicular function, in particular, testicular endocrinology and sperm mortility, were investigated in rats. Male rats at 3 weeks of age were fed a PaA-free diet or a 0.0016% PaA diet (control) for 7 weeks. Total body weight, as well as the weights of the liver, kidney, pituitary, testis, epididymis, seminal vesicle and prostate; sperm motility; and the plasma concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and corticosterone were measured in rats at 10 weeks of age. Body weight gain decreased from 5 weeks of age in rats fed the PaA-free diet compared with the control. The relative weights of the testes were significantly higher in the PaA-deficient group compared with the control group. Several parameters of sperm motility were significantly reduced in the PaA-deficient group compared with the control group. In addition, the plasma concentrations of testosterone and corticosterone were significantly lower in the PaA-deficient group compared with the control group, whereas the plasma concentrations of FSH and LH showed no change. These results clearly demonstrate that PaA is an essential factor in testicular endocrinology and sperm motility in male rats.

Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase-associated neurodegeneration.

We asked whether a movement disorder could be elicited by deprivation of pantothenic acid (PA; vitamin B5), the substrate for the enzyme pantothenate kinase 2 (PANK2), which is deficient in the inherited neurological disorder PKAN (pantothenate kinase-associated neurodegeneration formerly called Hallervorden-Spatz syndrome). This study was undertaken because mice made null for Pank2 failed to show the neurological manifestations of the human disease. Wild-type and Pank2 mutant mice were fed pantothenic acid-deficient diets and were monitored for general health, fertility and movement compared with animals on control diets over time. Mice of both genotypes on PA-deficient diets exhibited poor grooming, greying of fur and decreased body weight. With PA deprivation, wild-type mice manifested azoospermia (a phenotype also seen in Pank2 mice) as well as a movement disorder with a low-lying pelvis and slow steps. Rear limbs appeared to drag and occasionally extended into unnatural postures for 16-17 s duration, possibly indicative of dystonia. Movement disruption probably also occurs in PA-deprived Pank2 mutant mice, but they died precipitously before undergoing detailed analysis. Remarkably, restoration of dietary PA led to recovery of general health and grooming, weight gain, reversal of the movement disorder, and reappearance of mature sperm within 4 weeks. This study confirms the primacy of PA metabolism in the mechanism of disease in PKAN. PA deprivation provides a useful phenocopy for PKAN and allows us to test pharmacological and other interventional strategies in the treatment of this devastating disease.

Delaying the mitochondrial decay of aging.

Mitochondrial dysfunction may be a principal underlying event in aging, including the degenerative diseases of aging such as brain degeneration. Mitochondria provide energy for basic metabolic processes, and their decay with age impairs cellular metabolism and leads to cellular decline. Progress over the last decade in delaying the mitochondrial decay of aging is reviewed.