Glycine and N‐acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial

Abstract Aging is the biggest risk factor for cognitive-decline and Alzheimer’s disease (AD), but underlying mechanisms are not well-understood and interventions are lacking. Cognitive-decline in AD has been associated with deficiency of glutathione, (the most abundant, intracellular, antioxidant protein), elevated oxidative-stress, insulin-resistance and increased inflammation. We identified and reported that glutathione-deficiency and oxidative-stress in older-adults occur due to decreased availability of precursor amino-acids glycine and cysteine, and can be corrected with GlyNAC (a combination of glycine and the cysteine precursor N-acetylcysteine). We hypothesized that cognitive decline in older-adults is linked to glutathione-deficiency, mitochondrial-dysfunction, oxidative-stress, insulin-resistance, and inflammation. The first abstract discusses the rationale and findings of an open-label clinical trial: compared to young-humans, older-adults had cognitive-decline, glutathione-deficiency, mitochondrial-dysfunction, abnormal glucose-metabolism and insulin-resistance, oxidative-stress, endothelial-dysfunction and inflammation. These defects were improved/reversed by supplementing GlyNAC for 24-weeks, but benefits receded on stopping GlyNAC for 12-weeks. The second abstract presents a study in 8 young (20-weeks old) and 16 aged (90-weeks old) wild-type male C57BL/6J mice where we found that aged-mice had naturally-occurring cognitive-impairment, and brain defects in glutathione-deficiency, oxidative-stress, glucose-transport, mitochondrial glucose-oxidation, insulin-resistance, endoplasmic-reticulum stress, autophagy, mitophagy, inflammation, senescence, genomic and telomere damage. Aged-mice received either GlyNAC or isonitrogenous-placebo supplementation for 8-weeks, and only GlyNAC-fed mice improved cognition and brain defects. Collectively these data highlights the discovery of novel and reversible mechanistic defects in older-adults and aged-mice with naturally-occurring cognitive-decline, and identifies that supplementing GlyNAC can improve brain-health and cognition. These findings could have important implications for reversing cognitive-decline in older-adults, and AD.

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CORRECTING GLUTATHIONE DEFICIENCY IN AGING: IMPACT ON MITOCHONDRIA, STRENGTH, INFLAMMATION AND METABOLIC DEFECTS

Innovation in Aging ◽

10.1093/geroni/igz038.1550 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S415-S416

Author(s):

Rajagopal Sekhar ◽

George E Taffet ◽

Roger Fielding

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Insulin Resistance ◽

Clinical Trial ◽

Diastolic Heart Failure ◽

Nutritional Intervention ◽

Primary Objective ◽

Double Blind ◽

Glutathione Deficiency ◽

The Impact

Abstract Aging is associated with deficiency of Glutathione, the most abundant, intracellular, antioxidant protein, but underlying mechanisms are unknown and interventions limited. This symposium is primarily focused on the results of placebo-controlled, double-blind randomized clinical-trial (RCT) on the impact of correcting Glutathione deficiency in older humans on mitochondrial impairment, oxidative stress, strength, inflammation, and insulin resistance. Dr. Jahoor’s presentation will serve as an introduction by discussing mechanisms underlying Glutathione deficiency and validation of a novel nutritional intervention based on supplementing glycine and N-acetylcysteine (GlyNAC) to correct Glutathione deficiency in older-humans. Dr. Sekhar will present the results of a pilot 16-week pilot randomized, placebo-controlled, double-blind clinical trial in older humans investigating the effect of supplementing GlyNAC (vs. placebo) to improve Glutathione levels and oxidative-stress in 24 older-humans and 12 young-humans on impaired mitochondrial fuel-oxidation (MFO) and other defects. The trial met its primary objective that that GlyNAC supplementation (and not placebo) significantly improved Glutathione deficiency and corrected impaired MFO (and defects in its molecular regulation), and also significantly improved gait-speed (increased 19% increase to match young-humans), muscle-strength, exercise-capacity, and lowered oxidative-stress (80%) inflammation (IL-6 83%, TNF-alpha 58%), and insulin-resistance (68%). Dr. Taffet will discuss age-induced diastolic heart failure, and the effect of supplementing GlyNAC (vs. NAC alone) in aged 24-month old mice with diastolic heart-failure, impaired myocardial MFO and cardiac-inflammation. Collectively this symposium on Glutathione and Aging will highlight the discovery that supplementing GlyNAC to correct Glutathione deficiency in older-humans has significant health benefits, and could be a novel nutritional-intervention in aging.

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CORRECTING GLUTATHIONE DEFICIENCY AND MITOCHONDRIAL DYSFUNCTION IN OLDER HUMANS: A RANDOMIZED CLINICAL TRIAL

Innovation in Aging ◽

10.1093/geroni/igz038.1552 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S416-S416

Author(s):

Rajagopal V Sekhar ◽

Premranjan Kumar ◽

Jean W Hsu ◽

James Suliburk ◽

George E Taffet ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Clinical Trial ◽

Physical Function ◽

Gait Speed ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Double Blind ◽

Mitochondrial Fatty Acid ◽

Glutathione Deficiency

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.

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Effect of Aerobic Exercise Training and Essential Amino Acid Supplementation for 24 Weeks on Physical Function, Body Composition, and Muscle Metabolism in Healthy, Independent Older Adults: A Randomized Clinical Trial

The Journals of Gerontology Series A ◽

10.1093/gerona/gly109 ◽

2018 ◽

Vol 74 (10) ◽

pp. 1598-1604 ◽

Cited By ~ 11

Author(s):

Melissa M Markofski ◽

Kristofer Jennings ◽

Kyle L Timmerman ◽

Jared M Dickinson ◽

Christopher S Fry ◽

...

Keyword(s):

Older Adults ◽

Clinical Trial ◽

Body Composition ◽

Protein Synthesis ◽

Muscle Strength ◽

Randomized Clinical Trial ◽

Walking Speed ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Before And After

Abstract Background Essential amino acids (EAA) and aerobic exercise (AE) acutely and independently stimulate skeletal muscle protein anabolism in older adults. Objective In this Phase 1, double-blind, placebo-controlled, randomized clinical trial, we determined if chronic EAA supplementation, AE training, or a combination of the two interventions could improve muscle mass and function by stimulating muscle protein synthesis. Methods We phone-screened 971, enrolled 109, and randomized 50 independent, low-active, nonfrail, and nondiabetic older adults (age 72 ± 1 years). We used a 2 × 2 factorial design. The interventions were: daily nutritional supplementation (15 g EAA or placebo) and physical activity (supervised AE training 3 days/week or monitored habitual activity) for 24 weeks. Muscle strength, physical function, body composition, and muscle protein synthesis were measured before and after the 24-week intervention. Results Forty-five subjects completed the 24-week intervention. VO2peak and walking speed increased (p < .05) in both AE groups, irrespective of supplementation type, but muscle strength increased only in the EAA + AE group (p < .05). EAA supplementation acutely increased (p < .05) muscle protein synthesis from basal both before and after the intervention, with a larger increase in the EAA + AE group after the intervention. Total and regional lean body mass did not change significantly with any intervention. Conclusions In nonfrail, independent, healthy older adults AE training increased walking speed and aerobic fitness, and, when combined with EAA supplementation, it also increased muscle strength and EAA-stimulated muscle protein synthesis. These increases occurred without improvements in muscle mass.

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Abstract 357: Hepatic ERK2 Suppresses Endoplasmic Reticulum Stress, Leading to Protection from Oxidative Stress and Endothelial Dysfunction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a357 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Takehiko Kujiraoka ◽

Yasushi Satoh ◽

Makoto Ayaori ◽

Yasunaga Shiraishi ◽

Yuko Arai-Nakaya ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Fatty Acid ◽

Endothelial Dysfunction ◽

Er Stress ◽

Vascular Complications ◽

Metabolic Remodeling ◽

And Oxidative Stress

Background Insulin signaling comprises 2 major cascades, the IRS/PI3K/Akt and Ras/Raf/MEK/ERK pathways. Many studies on the tissue-specific effects of the former pathway had been conducted, however, the role of the latter cascade in tissue-specific insulin resistance had not been investigated. High glucose/fatty acid toxicity, inflammation and oxidative stress, all of which are associated with insulin resistance, can activate ERK. Liver plays a central role of metabolism and hepatosteatosis (HST) is associated with vascular diseases. The aim of this study is to elucidate the role of hepatic ERK2 in HST, metabolic remodeling and endothelial dysfunction. Methods Serum biomarkers of vascular complications in human were compared between subjects with and without HST diagnosed by echography for regular medical checkup. Next, we created liver-specific ERK2 knockout mice (LE2KO) and fed them with a high-fat/high-sucrose diet (HFHSD) for 20 weeks. The histological analysis, the expression of hepatic sarco/endoplasmic reticulum (ER) Ca 2+ -ATPase 2 (SERCA2) and glucose-tolerance/insulin-sensitivity (GT/IS) were tested. Vascular superoxide production and endothelial function were evaluated with dihydroethidium staining and isometric tension measurement of aorta. Results The presence of HST significantly increased HOMA-IR, an indicator of insulin resistance or atherosclerotic index in human. HFHSD-fed LE2KO revealed a marked exacerbation in HST and metabolic remodeling represented by the impairment of GT/IS, elevated serum free fatty acid and hyperhomocysteinemia without changes in body weight, blood pressure and serum cholesterol/triglyceride levels. In the HFHSD-fed LE2KO, mRNA and protein expressions of hepatic SERCA2 were significantly decreased, which resulted in hepatic ER stress. Induction of vascular superoxide production and remarkable endothelial dysfunction were also observed in them. Conclusions Hepatic ERK2 revealed the suppression of hepatic ER stress and HST in vivo , which resulted in protection from vascular oxidative stress and endothelial dysfunction. HST with hepatic ER stress can be a prominent risk of vascular complications by metabolic remodeling and oxidative stress in obese-related diseases.

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Lower limb muscle mass is associated with insulin resistance more than lower limb muscle strength in non‐diabetic older adults

Geriatrics and Gerontology International ◽

10.1111/ggi.13805 ◽

2019 ◽

Vol 19 (12) ◽

pp. 1254-1259

Author(s):

Toshiaki Seko ◽

Hiroshi Akasaka ◽

Masayuki Koyama ◽

Nobuaki Himuro ◽

Shigeyuki Saitoh ◽

...

Keyword(s):

Insulin Resistance ◽

Older Adults ◽

Muscle Strength ◽

Muscle Mass ◽

Lower Limb ◽

Lower Limb Muscle ◽

Limb Muscle

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Relationship Between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues

Journal of Clinical Medicine ◽

10.3390/jcm8091385 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1385 ◽

Cited By ~ 48

Author(s):

Burgos-Morón ◽

Abad-Jiménez ◽

Marañón ◽

Iannantuoni ◽

Escribano-López ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Current Knowledge ◽

Β Cells ◽

The Relationship ◽

And Oxidative Stress

Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia and insulin resistance in which oxidative stress is thought to be a primary cause. Considering that mitochondria are the main source of ROS, we have set out to provide a general overview on how oxidative stress is generated and related to T2D. Enhanced generation of reactive oxygen species (ROS) and oxidative stress occurs in mitochondria as a consequence of an overload of glucose and oxidative phosphorylation. Endoplasmic reticulum (ER) stress plays an important role in oxidative stress, as it is also a source of ROS. The tight interconnection between both organelles through mitochondrial-associated membranes (MAMs) means that the ROS generated in mitochondria promote ER stress. Therefore, a state of stress and mitochondrial dysfunction are consequences of this vicious cycle. The implication of mitochondria in insulin release and the exposure of pancreatic β-cells to hyperglycemia make them especially susceptible to oxidative stress and mitochondrial dysfunction. In fact, crosstalk between both mechanisms is related with alterations in glucose homeostasis and can lead to the diabetes-associated insulin-resistance status. In the present review, we discuss the current knowledge of the relationship between oxidative stress, mitochondria, ER stress, inflammation, and lipotoxicity in T2D.

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Daily Treatment with Sildenafil Reverses Endothelial Dysfunction and Oxidative Stress in an Animal Model of Insulin Resistance

European Urology ◽

10.1016/j.eururo.2007.11.018 ◽

2008 ◽

Vol 53 (6) ◽

pp. 1272-1281 ◽

Cited By ~ 34

Author(s):

Delphine Behr-Roussel ◽

Alexandra Oudot ◽

Stéphanie Caisey ◽

Olivier L.E. Coz ◽

Diane Gorny ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Animal Model ◽

Endothelial Dysfunction ◽

Daily Treatment ◽

And Oxidative Stress

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Supplementing Glycine and N-acetylcysteine (GlyNAC) in Aging HIV Patients Improves Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Endothelial Dysfunction, Insulin Resistance, Genotoxicity, Strength, and Cognition: Results of an Open-Label Clinical Trial

Biomedicines ◽

10.3390/biomedicines8100390 ◽

2020 ◽

Vol 8 (10) ◽

pp. 390

Author(s):

Premranjan Kumar ◽

Chun Liu ◽

James W. Suliburk ◽

Charles G. Minard ◽

Raja Muthupillai ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Clinical Trial ◽

Cognitive Decline ◽

Muscle Protein ◽

Glucose Production ◽

Premature Aging ◽

Open Label ◽

Breakdown Rates ◽

Genomic Damage

Background: Patients with HIV (PWH) develop geriatric comorbidities, including functional and cognitive decline at a younger age. However, contributing mechanisms are unclear and interventions are lacking. We hypothesized that deficiency of the antioxidant protein glutathione (GSH) contributes to multiple defects representing premature aging in PWH, and that these defects could be improved by supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC). Methods: We conducted an open label clinical trial where eight PWH and eight matched uninfected-controls were studied at baseline. PWH were studied again 12-weeks after receiving GlyNAC, and 8-weeks after stopping GlyNAC. Controls did not receive supplementation. Outcome measures included red-blood cell and muscle GSH concentrations, mitochondrial function, mitophagy and autophagy, oxidative stress, inflammation, endothelial function, genomic damage, insulin resistance, glucose production, muscle-protein breakdown rates, body composition, physical function and cognition. Results: PWH had significant defects in measured outcomes, which improved with GlyNAC supplementation. However, benefits receded after stopping GlyNAC. Conclusions: This open label trial finds that PWH have premature aging based on multiple biological and functional defects, and identifies novel mechanistic explanations for cognitive and physical decline. Nutritional supplementation with GlyNAC improves comorbidities suggestive of premature aging in PWH including functional and cognitive decline, and warrants additional investigation.

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