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  • 1
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2019
    In:  Innovation in Aging Vol. 3, No. Supplement_1 ( 2019-11-08), p. S416-S416
    In: Innovation in Aging, Oxford University Press (OUP), Vol. 3, No. Supplement_1 ( 2019-11-08), p. S416-S416
    Abstract: Aging is associated with impaired mitochondrial fatty-acid oxidation (MFO) due to unknown mechanisms, and interventions are lacking. We hypothesized that impaired MFO in aging occurs due to Glutathione-deficiency and tested this in a randomized, placebo-controlled double-blind clinical-trial in 24 older-humans (71.1y) and 12 young-controls (25.5y) using calorimetry, muscle-biopsy and tracer-protocols. Older-humans received either GlyNAC (Glycine 1.33mmol/kg/d and N-acetylcysteine 0.83mmol/kg/d as Glutathione precursors) or isonitrogenous-placebo for 16-weeks; young-controls received GlyNAC for 2-weeks. Compared to young-controls, older humans had significantly lower Glutathione, impaired MFO, lower gait-speed and physical-function, and higher oxidative-stress, inflammation and insulin-resistance. GlyNAC supplementation in older-humans significantly improved and restored MFO; increased gait-speed (19%,) and physical-function; and decreased oxidative-stress (TBARS 80%), inflammation (IL-6 83%; TNF-alpha 58%), and insulin-resistance (HOMA-IR 68%), but young-controls were unaffected. These data provide proof-of-concept that GlyNAC supplementation could improve the health of older-humans by correcting Glutathione-deficiency and mitochondrial-defects to improve gait-speed, oxidative-stress, inflammation and insulin-resistance.
    Type of Medium: Online Resource
    ISSN: 2399-5300
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2905697-4
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  • 2
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2019
    In:  Innovation in Aging Vol. 3, No. Supplement_1 ( 2019-11-08), p. S256-S256
    In: Innovation in Aging, Oxford University Press (OUP), Vol. 3, No. Supplement_1 ( 2019-11-08), p. S256-S256
    Abstract: Sarcopenia in aging leads to decreased muscle mass and physical-function (muscle strength and exercise capacity), but underlying mechanisms are not well understood and effective interventions are limited. We hypothesized that deficiency of the intracellular antioxidant protein Glutathione initiates a unique self-perpetuating metabolic cycle linking impaired fasted mitochondrial fuel-oxidation (fMFO) to protein catabolism and contributes to sarcopenia. We also hypothesized that supplementing the Glutathione precursor amino-acids glycine and N-acetylcysteine (GlyNAC) to correct Glutathione deficiency in older humans could reverse these defects. We tested our hypothesis in a 24-week open-label clinical-trial in 8 older-humans (74y) studied before and 24-weeks after GlyNAC supplementation, compared to 8 gender-matched unsupplemented young-controls (25y), and measured intracellular Glutathione concentrations, fMFO, physical-function, muscle-protein breakdown-rate (MPBR), gluconeogenesis, and urine nitrogen-excretion (UNE). GlyNAC supplementation in older humans corrected Glutathione deficiency and restored impaired fMFO (to levels in young controls), lowered MPBR and UNE, and increased physical-function, but did not affect gluconeogenesis or increase lean-mass, and suggest that muscle amino-acids are utilized for energy needs rather than glucose production. The absence of an increase in lean-mass suggests that GlyNAC should be combined with anabolic agents for potential benefits in combating sarcopenia. Overall, these results indicate the presence of a unique reversible metabolic cycle in older humans initiated by Glutathione deficiency which results in impaired mitochondrial fatty-acid and glucose oxidation, muscle-protein breakdown, UNE, and leads to deficiency of glycine and cysteine which re-initiate the cycle. These data have implications for improving physical-function and muscle mass in age-associated sarcopenia, and warrants further investigation.
    Type of Medium: Online Resource
    ISSN: 2399-5300
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2905697-4
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  • 3
    In: Journal of Applied Physiology, American Physiological Society, Vol. 105, No. 6 ( 2008-12), p. 1959-1966
    Abstract: During the neonatal period, high protein breakdown rate is a metabolic process inherent to elevated rates of protein accretion in skeletal muscle. To determine the relationship between hindlimb net movements of essential and nonessential amino acids in the regulation of hindlimb protein breakdown during an overnight fasting-feeding cycle, we infused overnight-food-deprived 10- and 28-day-old piglets with [1- 13 C]phenylalanine and [ ring- 2 H 4 ]tyrosine over 7 h (during 3 h of fasting and then during 4 h of feeding). Extraction rates for aspartate and glutamate after an overnight fast were 15% and 51% in the 10-day-old compared with 6% and 25% in the 28-day-old ( P 〈 0.05) piglets, suggesting an altered requirement for precursors of amino acids to shuttle nitrogen to the liver as early life progresses. This occurred simultaneously with marginal positive hindlimb net balance of essential amino acids after an overnight fast, with negative net release of many nonessential amino acids, such as alanine, asparagine, glutamine, glycine, and proline. This suggests that newborn muscle does not undergo significant protein mobilization after a short period of fasting in support of an elevated rate of protein accretion. Furthermore, tyrosine efflux from hindlimb breakdown between overnight fasting and feeding periods was not different in the 10-day-old piglets, for which tyrosine was limiting, but when tyrosine supply balanced requirements in the 28-day-old piglet, hindlimb efflux was increased ( P = 0.01). The results of the present study indicate that proteolysis and net movements of amino acids are coordinated mechanisms that sustain the elevated rate of net protein accretion during overnight feeding-fasting cycles in the neonate.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    RVK:
    RVK:
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 4
    Online Resource
    Online Resource
    American Physiological Society ; 1999
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 276, No. 1 ( 1999-01-01), p. G49-G57
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 276, No. 1 ( 1999-01-01), p. G49-G57
    Abstract: The objective of this study was to quantify the utilization of dietary and systemic phenylalanine for mucosal and hepatic constitutive protein synthesis in piglets. Seven female piglets (7.6 kg) bearing arterial, portal, peripheral venous, and gastric catheters were fed a high-protein diet and infused intragastrically with U- 13 C-labeled protein and intravenously with [ 2 H( phenyl) 5 ]phenylalanine ([ 2 H 5 ]phenylalanine) for 6 h. The isotopic enrichment of the two phenylalanine tracers was measured in arterial and portal blood, in mucosal and hepatic-free and protein-bound phenylalanine, and in very low-density apolipoprotein B-100, albumin, and fibrinogen. The relative isotopic enrichments of the tracers in mucosal-free (ratio of 2 H 5 - to U- 13 C-labeled = 0.20 ± 0.05) and protein-bound (0.32 ± 0.08) phenylalanine differed significantly ( P 〈 0.01). Although this suggests preferential use of arterial phenylalanine for mucosal protein synthesis, on a molar basis, 59 ± 6% of the mucosal protein was derived from dietary phenylalanine. There were significant differences ( P 〈 0.025) between the relative labeling of the two tracers in arterial (ratio of 2 H 5 - to U- 13 C-labeled = 1.25 ± 0.48) and portal (ratio of 2 H 5 - to U- 13 C-labeled = 0.72 ± 0.18) phenylalanine. The mean ratio of the two tracers in all proteins of hepatic origin that were analyzed (0.69 ± 0.18) was similar to that of portal phenylalanine. We conclude that in the fed state portal phenylalanine is preferentially used for constitutive as well as secreted hepatic protein synthesis.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1999
    detail.hit.zdb_id: 1477329-6
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    American Physiological Society ; 2004
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 287, No. 2 ( 2004-08), p. E327-E330
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 287, No. 2 ( 2004-08), p. E327-E330
    Abstract: The plasma concentrations of albumin, HDL apolipoprotein A1 (apoA1), retinol-binding protein (RBP), transthyretin (TTR), haptoglobulin, and fibrinogen were measured, and a stable isotope infusion protocol was used to determine the fractional and absolute synthesis rates of RBP, TTR, and fibrinogen in 12 young adults on three occasions during a reduction of their habitual protein intake from 1.13 to 0.75 g·kg −1 ·day −1 for 10 days. This study was performed to determine whether healthy adults could maintain the rates of synthesis of selected nutrient transport and positive acute-phase proteins when consuming a protein intake of 0.75 g·kg −1 ·day −1 . During the lower protein intake, the plasma concentration of all the proteins, other than HDL-apoA1, remained unchanged. HDL-apoA1 concentration was significantly reduced ( P 〈 0.05) after 3 days of the lower protein intake, but not at 10 days. The rates of synthesis of RBP and TTR declined significantly ( P 〈 0.05), whereas the rate of synthesis of fibrinogen remained unchanged. The results indicate that, when normal adults consume the recommended safe level of protein, 0.75 g·kg −1 ·day −1 , there is a slower rate of turnover of nutrient transport proteins than on their habitual diet. Hence, healthy individuals consuming this amount of protein may be less able to mount an adequate metabolic response to a stressful stimulus.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2004
    detail.hit.zdb_id: 1477331-4
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    American Physiological Society ; 1999
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 276, No. 6 ( 1999-06-01), p. E1092-E1098
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 276, No. 6 ( 1999-06-01), p. E1092-E1098
    Abstract: Although several studies have shown that asymptomatic human immunodeficiency virus infection elicits an increase in whole body protein turnover, it is not known whether this increased protein turnover includes changes in the kinetics of acute-phase proteins (APPs). To answer this question, we measured 1) the plasma concentrations of four positive (C-reactive protein, α 1 -antitrypsin, haptoglobin, and fibrinogen) and four negative APPs [albumin, high-density lipoprotein (HDL)-apolipoprotein (apo) A1, transthyretin, and retinol-binding protein] and 2) the fractional (FSR) and absolute (ASRs) synthesis rates of three positive and three negative APPs using a constant intravenous infusion of [ 2 H 5 ]phenylalanine in five subjects with symptom-free acquired immunodeficiency syndrome (AIDS) and five noninfected control subjects. Compared with the values of the controls, the plasma concentrations, FSRs, and ASRs of most positive APPs were higher in the AIDS group. The negative APPs had faster FSRs in the AIDS group, there was no difference between the ASRs of the two groups, and only HDL-apoA1 had a lower plasma concentration. These results suggest that symptom-free AIDS elicits an APP response that is different from bacterial infections, as the higher concentrations and faster rates of synthesis of the positive APPs are not accompanied by lower concentrations and slower rates of synthesis of most of the negative APPs.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1999
    detail.hit.zdb_id: 1477331-4
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Cambridge University Press (CUP) ; 2010
    In:  British Journal of Nutrition Vol. 104, No. 4 ( 2010-08-28), p. 498-502
    In: British Journal of Nutrition, Cambridge University Press (CUP), Vol. 104, No. 4 ( 2010-08-28), p. 498-502
    Abstract: During pregnancy, growth of the foetus depends on an adequate glycine supply because it is needed for synthesis of fetal DNA, collagen and serine. Since pregnant adolescent girls give birth to lower birth weight babies, it is possible that they do not produce sufficient glycine to meet overall demands as their adult counterparts, especially after an overnight fast. The objective of the study was to measure and compare the flux of glycine among adolescents and adult women in the first and third trimesters of pregnancy. Glycine flux was measured by continuous intravenous infusion of 2 H 2 -glycine in eight overnight fasted adolescents and in eight adult women in the first and third trimesters of pregnancy. There was a significant interaction between subject's age and time of pregnancy ( P  = 0·02), as weight-specific glycine flux decreased by 39 % from trimesters 1 to 3 in the adolescents but increased by approximately 5 % in the adults. Whole body glycine flux also decreased significantly in the adolescent group ( P   〈  0·05) from trimesters 1 to 3, and this was associated with a significant reduction in plasma glycine concentration. In trimester 3, there was a positive correlation between glycine flux and the subject's age indicating that younger subjects had slower fluxes. These findings suggest that after a brief period of food deprivation, the pregnant adolescent cannot maintain glycine production as her adult counterpart in late pregnancy. It is possible that this inability to maintain endogenous glycine production makes her foetus more vulnerable to impaired growth if food deprivation becomes more frequent or is prolonged.
    Type of Medium: Online Resource
    ISSN: 0007-1145 , 1475-2662
    Language: English
    Publisher: Cambridge University Press (CUP)
    Publication Date: 2010
    detail.hit.zdb_id: 2016047-1
    SSG: 12
    SSG: 21
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  • 8
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 1999
    In:  Pediatric Research Vol. 45, No. 4, Part 2 of 2 ( 1999-4), p. 290A-290A
    In: Pediatric Research, Springer Science and Business Media LLC, Vol. 45, No. 4, Part 2 of 2 ( 1999-4), p. 290A-290A
    Type of Medium: Online Resource
    ISSN: 0031-3998 , 1530-0447
    Language: Unknown
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1999
    detail.hit.zdb_id: 2031217-9
    SSG: 12
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  • 9
    In: Reproductive Biology and Endocrinology, Springer Science and Business Media LLC, Vol. 17, No. 1 ( 2019-12)
    Type of Medium: Online Resource
    ISSN: 1477-7827
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2119215-7
    SSG: 12
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  • 10
    Online Resource
    Online Resource
    Portland Press Ltd. ; 1989
    In:  Clinical Science Vol. 77, No. 1 ( 1989-07-01), p. 93-97
    In: Clinical Science, Portland Press Ltd., Vol. 77, No. 1 ( 1989-07-01), p. 93-97
    Abstract: 1. Whole body protein turnover and resting metabolic rate were measured in six adults with homozygous sickle cell disease (genotype HbSS) and in six normal adults (genotype HbAA) of similar age. 2. Turnover was measured with prime/intermittent oral doses of [15N]glycine over 18 h and resting energy expenditure was measured by indirect calorimetry. 3. In HbSS, nitrogen flux (0.9 ± 0.08 g day−1 kg−1), protein synthesis (6.0 ± 0.5 g day−1 kg−1) and protein degradation (5.6 ± 0.5 g day−1 kg−1) were significantly increased compared with HbAA nitrogen (flux 0.5 ± 0.02 g day−1 kg−1, protein synthesis 3.2 ± 0.2 g day−1 kg−1 and protein degradation 2.8 ± 0.2 g day−1 kg−1). 4. Resting energy expenditure was significantly higher in HbSS compared with HbAA when expressed per unit of body weight (115 ± 3 and 94 ± 4 kJ day−1 kg−1, respectively) or weight 0.75 (317 ± 6 and 269 ± 8 kJ day−1 kg−0.75, respectively). 5. The increase in protein turnover and energy expenditure suggest that patients with HbSS exist in a hypermetabolic state that requires greater dietary energy compared with HbAA.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 1989
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