Taurine deficiency as a driver of aging.

Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.

Taurine linked with healthy aging.

Reversing age-associated taurine loss improves mouse longevity and monkey health.

Hyperreflexia and enhanced ripple oscillations in the taurine-deficient mice.

In this study, we examined neuronal excitability and skeletal muscle physiology and histology in homozygous knockout mice lacking cysteine sulfonic acid decarboxylase (CSAD-KO). Neuronal excitability was measured by intracerebral recording from the prefrontal cortex. Skeletal muscle response was measured through stretch reflex in the ankle muscles. Specifically, we measured the muscle tension, amplitude of electromyogram and velocity of muscle response. Stretch reflex responses were evoked using a specialized stretching device designed for mice. The triceps surae muscle was stretched at various speeds ranging from 18 to 18,000° s-1. A transducer recorded the muscle resistance at each velocity and the corresponding EMG. We also measured the same parameter in anesthetized mice. We found that at each velocity, the CSAD-KO mice generated more tension and exhibited higher EMG responses. To evaluate if the enhanced response was due to neuronal excitability or changes in the passive properties of muscles, we anesthetize mice to eliminate the central component of the reflex. Under these conditions, CSAD-KO mice still exhibited an enhanced stretch reflex response, indicating ultrastructural alterations in muscle histology. Consistent with this, we found that sarcomeres from CSAD-KO muscles were shorter and thinner when compared to control sarcomeres. Neuronal excitability was further investigated using intracerebral recordings of brain waves from the prefrontal cortex. We found that extracellular field potentials in CSAD-KO mice were characterized by reduced amplitude of low-frequency brain waves (delta, theta, alpha, beta and gamma) and increased in the high low-frequency brain waves (slow and fast ripples). Increased slow and fast ripple rates serve as a biomarker of epileptogenic brain. We have previously shown that taurine interacts with GABAA receptors and induces biochemical changes in the GABAergic system. We suggest that taurine deficiency leads to alterations in the GABAergic system that contribute to the enhanced stretch reflex in CSAD-KO mice through biochemical mechanisms that involve alterations not only at the spinal level but also at the cortical level.

A plasma metabolomic signature of Leber hereditary optic neuropathy showing taurine and nicotinamide deficiencies.

Leber's hereditary optic neuropathy (LHON) is the most common disorder due to mitochondrial DNA mutations and complex I deficiency. It is characterized by an acute vision loss, generally in young adults, with a higher penetrance in males. How complex I dysfunction induces the peculiar LHON clinical presentation remains an unanswered question. To gain an insight into this question, we carried out a non-targeted metabolomic investigation using the plasma of 18 LHON patients, during the chronic phase of the disease, comparing them to 18 healthy controls. A total of 500 metabolites were screened of which 156 were accurately detected. A supervised Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) highlighted a robust model for disease prediction with a Q2 (cum) of 55.5%, with a reliable performance during the permutation test (cross-validation analysis of variance, P-value = 5.02284e-05) and a good prediction of a test set (P = 0.05). This model highlighted 10 metabolites with variable importance in the projection (VIP) > 0.8. Univariate analyses revealed nine discriminating metabolites, six of which were the same as those found in the Orthogonal Projections to Latent Structures Discriminant Analysis model. In total, the 13 discriminating metabolites identified underlining dietary metabolites (nicotinamide, taurine, choline, 1-methylhistidine and hippurate), mitochondrial energetic substrates (acetoacetate, glutamate and fumarate) and purine metabolism (inosine). The decreased concentration of taurine and nicotinamide (vitamin B3) suggest interesting therapeutic targets, given their neuroprotective roles that have already been demonstrated for retinal ganglion cells. Our results show a reliable predictive metabolomic signature in the plasma of LHON patients and highlighted taurine and nicotinamide deficiencies.

The Anti-Inflammatory Effect of Taurine on Cardiovascular Disease.

Taurine is a non-protein amino acid that is expressed in the majority of animal tissues. With its unique sulfonic acid makeup, taurine influences cellular functions, including osmoregulation, antioxidation, ion movement modulation, and conjugation of bile acids. Taurine exerts anti-inflammatory effects that improve diabetes and has shown benefits to the cardiovascular system, possibly by inhibition of the renin angiotensin system. The beneficial effects of taurine are reviewed.

Development of plasma and whole blood taurine reference ranges and identification of dietary features associated with taurine deficiency and dilated cardiomyopathy in golden retrievers: A prospective, observational study.

INTRODUCTION: A surge in Food and Drug Administration (FDA) consumer complaints identified concerns that legume-rich, grain-free diets were associated with nutritionally-mediated dilated cardiomyopathy (DCM). Golden retrievers represent the most reported breed affected by this condition and previous studies documented the disease is responsive to dietary change and taurine supplementation. Although dietary findings across cases are compelling, prospective studies with control groups are lacking. The role of diet in developing taurine deficiency and echocardiographic changes consistent with DCM in healthy dogs is unknown. OBJECTIVES: We hypothesized that golden retrievers eating non-traditional diets are at a higher risk of having taurine deficiency and nutritionally-mediated DCM compared with those eating traditional commercial diets. We aimed to compare taurine concentrations and echocardiographic indices of systolic function between golden retrievers in each diet group and elucidate associations between diet and these variables. Additionally, we aimed to generate breed-specific reference intervals for whole blood and plasma taurine concentrations. ANIMALS: 86 golden retrievers. METHODS: Golden retrievers eating traditional or non-traditional diets were evaluated and diet history, taurine concentrations and echocardiographic data were collected. Dietary features, taurine concentrations and echocardiographic findings were compared between diet groups. Relative risks were calculated for the likelihood of echocardiographic abnormalities and taurine deficiency in each diet group. Breed-specific reference intervals were constructed for taurine concentrations in dogs from the traditional diet group. RESULTS: Golden retrievers eating non-traditional diets had significantly lower taurine concentrations and more frequent systolic dysfunction. Breed specific reference intervals are higher than previously reported across breeds. CONCLUSIONS: Non-traditional diets, which were typically grain-free and contained legumes in this study, were significantly associated with and have increased relative risk for the identification of taurine deficiency and echocardiographic abnormalities consistent with nutritionally-mediated DCM. These findings were identifiable in the absence of clinical signs and support the findings of multiple previous studies and the ongoing FDA investigation.

Differential Metabolomic Analysis of Liver Tissues from Rat Models of Parenteral Nutrition-Associated Liver Disease.

Parenteral nutrition (PN) is a life-saving therapy for patients with intestinal failure, but parenteral nutrition-associated liver disease (PNALD) limits its long-term use. The present study is aimed at determining which pathways are altered most notably in a rat model of PNALD. We randomly assigned male Sprague-Dawley (SD) rats into two different groups, whereby they received either enteral nutrition (EN) or PN. Liver tissues were harvested from all rats 7 days later for metabolomic profiling. The composition of primary conjugated bile acids was altered, the synthesis of polyunsaturated fatty acids was reduced, the conversion of pyruvate to acetyl-CoA was blocked, and the synthesis of phosphatidylcholine was inhibited in rats with PNALD. Riboflavin, which is involved in the electron transfer process in the mitochondrial electron transport chain, was remarkably decreased in PNALD rats. A deficiency of polyunsaturated fatty acids, riboflavin, choline, and taurine might be involved in the progression of PNALD. The implications of these findings for the field of medicine are that supplementation with polyunsaturated fatty acids, riboflavin, choline, and taurine might have potential as therapeutic strategies for PNALD and also shed light on the mechanisms of PNALD.

ß-alanine supplementation induces taurine depletion and causes alterations of the retinal nerve fiber layer and axonal transport by retinal ganglion cells.

To study the effect of taurine depletion induced by ß-alanine supplementation in the retinal nerve fiber layer (RNFL), and retinal ganglion cell (RGC) survival and axonal transport. Albino Sprague-Dawley rats were divided into two groups: one group received ß-alanine supplementation (3%) in the drinking water during 2 months to induce taurine depletion, and the other group received regular water. After one month, half of the rats from each group were exposed to light. Retinas were analyzed in-vivo using Spectral-Domain Optical Coherence Tomography (SD-OCT). Prior to processing, RGCs were retrogradely traced with fluorogold (FG) applied to both superior colliculi, to assess the state of their retrograde axonal transport. Retinas were dissected as wholemounts, surviving RGCs were immunoidentified with Brn3a, and the RNFL with phosphorylated high-molecular-weight subunit of the neurofilament triplet (pNFH) antibodies. ß-alanine supplementation decreases significantly taurine plasma levels and causes a significant reduction of the RNFL thickness that is increased after light exposure. An abnormal pNFH immunoreactivity in some RGC bodies, their proximal dendrites and axons, and a further diminution of the mean number of FG-traced RGCs compared with Brn3a+RGCs, indicate that their retrograde axonal transport is affected. In conclusion, taurine depletion causes RGC loss and axonal transport impairment. Finally, our results suggest that care should be taken when ingesting ß-alanine supplements due to the limited understanding of their potential adverse effects.

Influences of Taurine Deficiency on Bile Acids of the Bile in the Cat Model.

Taurine content in the body is maintained by both biosynthesis from sulfur-contained amino acids in the liver and ingestion from usual foods, mainly seafoods and meat. Contrary to the rodents, the maintenance of taurine content in the body depends on the oral taurine ingestion in cats as well as humans because of the low ability of the biosynthesis. Therefore, insufficient of dietary taurine intake increases the risks of various diseases such as blind and expanded cardiomyopathy in the cats. One of the most established physiological roles of taurine is the conjugation with bile acid in the liver. In addition, taurine has effect to increase the expression and activity of bile acid synthesis rate-limiting enzyme CYP7A1. Present study purposed to evaluate the influence of taurine deficiency on bile acids in the cats fed taurine-lacking diet. Adult cats were fed the soybean protein-based diet with 0.15% taurine or without taurine for 30 weeks. Taurine concentration in serum and liver was undetectable, and bile acids in the bile were significantly decreased in the taurine-deficient cats. Taurine-conjugated bile acids in the bile were significantly decreased, and instead, unconjugated bile acids were significantly increased in the taurine-deficient cats. Present results suggested that the taurine may play an important role in the synthesis of bile acids in the liver.

Taurine Supplementation Inhibits Cardiac and Systemic Renin-Angiotensin System Overactivity After Cardiac Ischemia/Reperfusion in Adult Female Rats Perinatally Depleted of Taurine Followed by High Sugar Intake.

Perinatal taurine depletion and high sugar intake from weaning onward worsen cardiac damage and arterial pressure control after ischemia/reperfusion (IR) in adult male and female rats, which can be ameliorated by high taurine diets or inhibition of renin-angiotensin system. This study tests if taurine supplementation ameliorates cardiac damage and arterial pressure control in adult female rats via alterations of both cardiac and systemic renin-angiotensin system. Female Sprague-Dawley rats were fed normal rat chow and drank water alone (control, C) or water containing 3% beta-alanine (taurine depletion, TD) from conception to weaning, and female offspring were subjected to high sugar intake (normal rat chow and 5% glucose in water; CG and TDG) or the normal rat diet (CW and TDW). At 7 weeks of age, half of the rats in each group received 3% taurine in water (CW+T, CG+T, TDW+T, and TDG+T). One week later, rats were subjected to IR or Sham procedures followed by renal nerve recording, plasma and cardiac angiotensin II measurements. Cardiac angiotensin II levels significantly elevated in CG, TDW, and TDG. Further, plasma angiotensin II concentrations were significantly elevated only in the TDG, in consistent with a significant increase in renal nerve activity to juxtaglomerular cells, but not renal vessels and tubules. These abnormalities were ameliorated by short-term taurine supplementation. Thus, in adult female rats that are perinatally depleted of taurine followed by high sugar intake after weaning, taurine supplementation decreases the adverse effects of cardiac IR via inhibition of both cardiac and systemic renin-angiotensin system overactivity.

The Relationship between Plasma Taurine Levels and Diabetic Complications in Patients with Type 2 Diabetes Mellitus.

Background: Taurine has an active role in providing glucose homeostasis and diabetes causes a decline in taurine levels. This paper investigates the relationship between taurine and diabetic complications, patients' demographic features, and biochemical parameters. Methods: Fifty-nine patients with type 2 diabetes mellitus (T2DM), and 28 healthy control subjects between the ages of 32 and 82 were included in the study. The mean age of subjects was 55.6 ± 10.3 and mean diabetes duration was 10.2 ± 6.0 years. The most commonly accompanying comorbidity was hypertension (HT) (64.5%, n = 38), and the most frequent diabetic complication was neuropathy (50.8%, n = 30). Plasma taurine concentrations were measured by an enzyme-linked immunoassay (ELISA) kit. Results: Plasma taurine concentrations were significantly lower in diabetic patients (0.6 ± 0.1 mmol/L) than controls (0.8 ± 0.2 mmol/L) and in hypertensive (0. 6 ± 0.1 mmol/L) patients (p = 0.000, p = 0.027 respectively). Conclusion: Plasma taurine levels were decreased in patients with T2DM and this was not related to FBG, HbA1c, and microalbuminuria. With regard to complications, we only found a correlation with neuropathy. We suggest that taurine levels may be more important in the development of diabetes; however, it may also have importance for the progression of the disease and the subsequent complications. We further assert that taurine measurement at different times may highlight whether there is a causal relationship in the development of complications.

Metabolomic Profiling of Aqueous Humor in Glaucoma Points to Taurine and Spermine Deficiency: Findings from the Eye-D Study.

We compared the metabolomic profile of aqueous humor from patients with primary open-angle glaucoma (POAG; n = 26) with that of a group of age- and sex-matched non-POAG controls (n = 26), all participants undergoing cataract surgery. Supervised paired partial least-squares discriminant analysis showed good predictive performance for test sets with a median area under the receiver operating characteristic of 0.89 and a p-value of 0.0087. Twenty-three metabolites allowed discrimination between the two groups. Univariate analysis after the Benjamini-Hochberg correction showed significant differences for 13 of these metabolites. The POAG metabolomic signature indicated reduced concentrations of taurine and spermine and increased concentrations of creatinine, carnitine, three short-chain acylcarnitines, 7 amino acids (glutamine, glycine, alanine, leucine, isoleucine, hydroxyl-proline, and acetyl-ornithine), 7 phosphatidylcholines, one lysophosphatidylcholine, and one sphingomyelin. This suggests an alteration of metabolites involved in osmoprotection (taurine and creatinine), neuroprotection (spermine, taurine, and carnitine), amino acid metabolism (7 amino acids and three acylcarnitines), and the remodeling of cell membranes drained by the aqueous humor (hydroxyproline and phospholipids). Five of these metabolic alterations, already reported in POAG plasma, concern spermine, C3 and C4 acylcarnitines, PC aa 34:2, and PC aa 36:4, thus highlighting their importance in the pathogenesis of glaucoma.

Special topic: The association between pulse ingredients and canine dilated cardiomyopathy: addressing the knowledge gaps before establishing causation.

In July 2018, the Food and Drug Administration warned about a possible relationship between dilated cardiomyopathy (DCM) in dogs and the consumption of dog food formulated with potatoes and pulse ingredients. This issue may impede utilization of pulse ingredients in dog food or consideration of alternative proteins. Pulse ingredients have been used in the pet food industry for over 2 decades and represent a valuable source of protein to compliment animal-based ingredients. Moreover, individual ingredients used in commercial foods do not represent the final nutrient concentration of the complete diet. Thus, nutritionists formulating dog food must balance complementary ingredients to fulfill the animal's nutrient needs in the final diet. There are multiple factors that should be considered, including differences in nutrient digestibility and overall bioavailability, the fermentability and quantity of fiber, and interactions among food constituents that can increase the risk of DCM development. Taurine is a dispensable amino acid that has been linked to DCM in dogs. As such, adequate supply of taurine and/or precursors for taurine synthesis plays an important role in preventing DCM. However, requirements of amino acids in dogs are not well investigated and are presented in total dietary content basis which does not account for bioavailability or digestibility. Similarly, any nutrient (e.g., soluble and fermentable fiber) or physiological condition (e.g., size of the dog, sex, and age) that increases the requirement for taurine will also augment the possibility for DCM development. Dog food formulators should have a deep knowledge of processing methodologies and nutrient interactions beyond meeting the Association of American Feed Control Officials nutrient profiles and should not carelessly follow unsubstantiated market trends. Vegetable ingredients, including pulses, are nutritious and can be used in combination with complementary ingredients to meet the nutritional needs of the dog.

Is vegetarianism healthy for children?

According to the Academy of Nutrition and Dietetics' influential position statement on vegetarianism, meat and seafood can be replaced with milk, soy/legumes, and eggs without any negative effects in children. The United States Department of Agriculture endorses a similar view. The present paper argues that the Academy of Nutrition and Dietetics ignores or gives short shrift to direct and indirect evidence that vegetarianism may be associated with serious risks for brain and body development in fetuses and children. Regular supplementation with iron, zinc, and B12 will not mitigate all of these risks. Consequently, we cannot say decisively that vegetarianism or veganism is safe for children.

Taurine is Involved in Energy Metabolism in Muscles, Adipose Tissue, and the Liver.

Energy metabolism is a basic and general process, by which the body acquires and uses energy to maintain normal function, and taurine plays a vital role in energy metabolism. Taurine deficiency may cause a weak energy metabolism and energy metabolism dysfunction. Taurine biosynthetic ability is limited, and its supplementation in the diet can strengthen energy metabolism in muscle performance, cardiac function, liver activity, and adipose tissue. Combining taurine with other drugs may have a superior effect in energy metabolism. In many metabolic disorders, taurine, or the combination of taurine with other drugs, also functions as a repair treatment for damaged tissues, and acts as a promoter for the balance of energy metabolism. The present study discusses the potential roles of taurine in energy metabolism.

Taurine: A Regulator of Cellular Redox Homeostasis and Skeletal Muscle Function.

Taurine is a nonproteinogenic ß-aminosulfonic acid. Important dietary sources of taurine are fish and seafood. Taurine interacts with ion channels, stabilizes membranes, and regulates the cell volume. These actions confirm its high concentrations in excitable tissues like retina, neurons, and muscles. Retinal degeneration, cardiomyopathy, as well as skeletal muscle malfunction are evident in taurine-deficient phenotypes. There is evidence that taurine counteracts lipid peroxidation and increases cellular antioxidant defense in response to inflammation. In activated neutrophils, taurine reacts with hypochloric acid to form taurine chloramine, which triggers the Kelch-like ECH-associated protein 1-nuclear factor E2-related factor 1 (Keap1-Nrf2) pathway. Consequently, Nrf2 target genes, such as heme oxygenase-1 and catalase, are induced. Furthermore, taurine may prevent an overload of reactive oxygen species (ROS) directly by an inhibition of ROS generation within the respiratory chain. Taurine affects mitochondrial bioenergetics and taurine-deficient mice exhibit an impaired exercise performance. Moreover, some studies demonstrate that taurine enhances the glycogen repletion in the postexercise recovery phase. In the case of taurine deficiency, many studies observed a phenotype known in muscle senescence and skeletal muscle disorders. Overall, taurine plays an important role in cellular redox homeostasis and skeletal muscle function.

Taurine deficiency and dilated cardiomyopathy in golden retrievers fed commercial diets.

INTRODUCTION: Golden retrievers are over-represented in cases of taurine-deficient dilated cardiomyopathy and recently a surge in cases has prompted further investigation. OBJECTIVE: To describe the clinical, dietary, and echocardiographic features in golden retrievers diagnosed with taurine deficiency and dilated cardiomyopathy, and to determine specific dietary associations. A second aim was to determine the whole blood taurine concentrations in a representative sample of healthy golden retrievers. ANIMALS: Twenty-four client-owned golden retrievers with documented taurine deficiency and dilated cardiomyopathy and 52 healthy client-owned golden retrievers. METHODS: In this multicenter prospective observational study, baseline and follow-up echocardiographic data, complete diet and medical histories, and whole blood, plasma, or serum taurine concentrations were obtained. Baseline and follow-up echocardiographic data were compared. Associations were evaluated between specific diets and taurine deficiency or congestive heart failure. The prevalence of low whole blood taurine concentrations in the healthy golden retrievers was calculated. RESULTS: Twenty-three of 24 dogs diagnosed with taurine deficiency and dilated cardiomyopathy were fed diets that were either grain-free, legume-rich, or a combination of these factors. None of these diets were feeding trial tested using Association of American Feed Control Officials (AAFCO) procedures. Twenty-three of 24 dogs had significant improvement in their echocardiographic parameters and normalization of taurine concentrations following diet change and taurine supplementation. Nine of 11 dogs diagnosed with congestive heart failure (CHF) had resolution of their congestion at follow-up with five no longer requiring diuretic therapy and four tolerating diuretic dose reduction by >50%. CONCLUSIONS: Certain diets and diet characteristics were associated with the development of taurine deficiency. Taurine deficiency and dilated cardiomyopathy in golden retrievers is likely multifactorial, including a combination of dietary, metabolic, and genetic factors.

Tissue Taurine Depletion Induces Profibrotic Pattern of Gene Expression and Causes Aging-Related Cardiac Fibrosis in Heart in Mice.

Dietary taurine deficiency results in dilated cardiomyopathy in cats while in mice taurine deficiency produced by knocking out the taurine transporter (TauT) gene leads to a reduction in cardiac function with advancing age. The present study elucidated the involvement of cardiac fibrosis in the aging-dependent cardiac disorder of the TauT-knockout (TauTKO) mouse. Old (18-24-month-old) TauTKO mice, but not young (3-5-month-old) mice, exhibit cardiac fibrosis. Transcriptome microarray analysis revealed an increase in pro-fibrotic genes, such as S100A4, ACTA2 and CTGF, in both young and old TauTKO hearts. Based on transcriptome-pathway analysis the genes involved in "organization of extracellular matrix," such as LGALS3, are enriched in old TauTKO hearts compared to old wild-type hearts, suggesting the contribution of these genes to fibrosis. In conclusion, taurine depletion predisposes the heart to fibrosis, which leads to cardiac fibrosis upon aging.

Taurine Depletion Causes ipRGC Loss and Increases Light-Induced Photoreceptor Degeneration.

Purpose: To examine if light exposure exacerbates retinal neuronal loss induced by taurine depletion. Methods: Albino rats received ß-alanine in the drinking water to induce taurine depletion. One month later, half of the animals were exposed to white light (3000 lux) continuously for 48 hours and the rest remained in normal environmental conditions. A control group of animals nontreated with ß-alanine also was prepared, and half of them were exposed to light using the same protocol. All the animals were processed 2 months after the beginning of the experiment. Retinas were dissected as wholemounts and immunodetected with antibodies against Brn3a, melanopsin, S-opsin, and L-opsin to label different retinal populations: Brn3a+ retinal ganglion cells (RGCs) (image-forming RGCs), m+RGCs (non-image-forming RGCs), and S- and L/M-cones, respectively. Results: Light exposure did not affect the numbers of Brn3a+RGCs or m+RGCs but diminished the numbers of S- and L/M-cones and caused the appearance of rings devoid of cones, mainly in an "arciform" area in the superotemporal retina. Taurine depletion caused a diminution of all the studied populations, with m+RGCs the most affected, followed by S-cones. Light exposure under taurine depletion increased photoreceptor degeneration but did not seem to increase Brn3a+RGCs or m+RGCs loss. Conclusions: Our results document that taurine is necessary for cell survival in the rat retina and even more under light-induced photoreceptor degeneration. Thus, taurine supplementation may help to prevent retinal degenerations, especially those that commence with S-cone degeneration or in which light may be an etiologic factor, such as inherited retinal degenerations, AMD, or glaucoma.