Search

Cognitive decline frequently occurs with increasing age, but mechanisms contributing to age-associated cognitive decline (ACD) are not well understood and solutions are lacking. Understanding and reversing mechanisms contributing to ACD are important because increased age is identified as the single most important risk factor for dementia. We reported earlier that ACD in older humans is associated with glutathione (GSH) deficiency, oxidative stress (OxS), mitochondrial dysfunction, glucose dysmetabolism and inflammation, and that supplementing GlyNAC (glycine and N-acetylcysteine) improved these defects. To test whether these defects occur in the brain in association with ACD, and could be improved/reversed with GlyNAC supplementation, we studied young (20-week) and old (90-week) C57BL/6J mice. Old mice received either regular or GlyNAC supplemented diets for 8 weeks, while young mice received the regular diet. Cognition and brain outcomes (GSH, OxS, mitochondrial energetics, autophagy/mitophagy, glucose transporters, inflammation, genomic damage and neurotrophic factors) were measured. Compared to young mice, the old-control mice had significant cognitive impairment and multiple brain defects. GlyNAC supplementation improved/corrected the brain defects and reversed ACD. This study finds that naturally-occurring ACD is associated with multiple abnormalities in the brain, and provides proof-of-concept that GlyNAC supplementation corrects these defects and improves cognitive function in aging.

Abstract Background Oxidative stress (OxS) and mitochondrial dysfunction are implicated as causative factors for aging. Older adults (OAs) have an increased prevalence of elevated OxS, impaired mitochondrial fuel‐oxidation (MFO), elevated inflammation, endothelial dysfunction, insulin resistance, cognitive decline, muscle weakness, and sarcopenia, but contributing mechanisms are unknown, and interventions are limited/lacking. We previously reported that inducing deficiency of the antioxidant tripeptide glutathione (GSH) in young mice results in mitochondrial dysfunction, and that supplementing GlyNAC (combination of glycine and N‐acetylcysteine [NAC]) in aged mice improves naturally‐occurring GSH deficiency, mitochondrial impairment, OxS, and insulin resistance. This pilot trial in OA was conducted to test the effect of GlyNAC supplementation and withdrawal on intracellular GSH concentrations, OxS, MFO, inflammation, endothelial function, genotoxicity, muscle and glucose metabolism, body composition, strength, and cognition. Methods A 36‐week open‐label clinical trial was conducted in eight OAs and eight young adults (YAs). After all the participants underwent an initial (pre‐supplementation) study, the YAs were released from the study. OAs were studied again after GlyNAC supplementation for 24 weeks, and GlyNAC withdrawal for 12 weeks. Measurements included red‐blood cell (RBC) GSH, MFO; plasma biomarkers of OxS, inflammation, endothelial function, glucose, and insulin; gait‐speed, grip‐strength, 6‐min walk test; cognitive tests; genomic‐damage; glucose‐production and muscle‐protein breakdown rates; and body‐composition. Results GlyNAC supplementation for 24 weeks in OA corrected RBC‐GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin‐resistance, genomic‐damage, cognition, strength, gait‐speed, and exercise capacity; and lowered body‐fat and waist‐circumference. However, benefits declined after stopping GlyNAC supplementation for 12 weeks. Conclusions GlyNAC supplementation for 24‐weeks in OA was well tolerated and lowered OxS, corrected intracellular GSH deficiency and mitochondrial dysfunction, decreased inflammation, insulin‐resistance and endothelial dysfunction, and genomic‐damage, and improved strength, gait‐speed, cognition, and body composition. Supplementing GlyNAC in aging humans could be a simple and viable method to promote health and warrants additional investigation.

Determinants of length of life are not well understood, and therefore increasing lifespan is a challenge. Cardinal theories of aging suggest that oxidative stress (OxS) and mitochondrial dysfunction contribute to the aging process, but it is unclear if they could also impact lifespan. Glutathione (GSH), the most abundant intracellular antioxidant, protects cells from OxS and is necessary for maintaining mitochondrial health, but GSH levels decline with aging. Based on published human studies where we found that supplementing glycine and N-acetylcysteine (GlyNAC) improved/corrected GSH deficiency, OxS and mitochondrial dysfunction, we hypothesized that GlyNAC supplementation could increase longevity. We tested our hypothesis by evaluating the effect of supplementing GlyNAC vs. placebo in C57BL/6J mice on (a) length of life; and (b) age-associated GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage in the heart, liver and kidneys. Results showed that mice receiving GlyNAC supplementation (1) lived 24% longer than control mice; (2) improved/corrected impaired GSH synthesis, GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage. These studies provide proof-of-concept that GlyNAC supplementation can increase lifespan and improve multiple age-associated defects. GlyNAC could be a novel and simple nutritional supplement to improve lifespan and healthspan, and warrants additional investigation.

Diabetes is the leading global cause for blindness, kidney failure and amputations. Preventing these complications requires optimal glycemic control, and it is imperative that diabetic patients understand the fundamental concepts of diabetes care. Although patients attend formal diabetes education classes, many do not comprehend basic concepts of diabetes, and are often noncompliant with diet, exercise and medications. A novel approach termed ‘analogy-based comprehensive diabetes education’ (ABCDE) was developed to educate HIV-patients with diabetes about basic concepts of diabetes care. The object of this manuscript is to report the results of a retrospective chart review on the impact of ABCDE on glycemic outcomes in 24 patients who had failed usual care (including formal diabetes education, physician visits, and diabetic medications), and were non-adherent with diet and medications. They received only the ABCDE without any changes in pharmacotherapy. The impact on glycosylated hemoglobin (HbA1c) and fasting blood glucose (FBG) was assessed at subsequent visits. HbA1c was found to decline by 22% and 33% after 3 and 6 months, respectively, with corresponding declines in FBG by 53% and 59%, respectively. These results suggest that ABCDE in outpatient diabetes clinics could be effective in behavior modification toward improving glycemic control, and warrants additional investigation.

Patients with type 2 diabetes (T2D) are known to have mitochondrial dysfunction and increased insulin resistance (IR), but the underlying mechanisms are not well understood. We reported previously that (a) adequacy of the antioxidant glutathione (GSH) is necessary for optimal mitochondrial fatty-acid oxidation (MFO); (b) supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC) in mice corrected GSH deficiency, reversed impaired MFO, and lowered oxidative stress (OxS) and IR; and (c) supplementing GlyNAC in patients with T2D improved GSH synthesis and concentrations, and lowered OxS. However, the effect of GlyNAC on MFO, MGO (mitochondrial glucose oxidation), IR and plasma FFA (free-fatty acid) concentrations in humans with T2D remains unknown. This manuscript reports the effect of supplementing GlyNAC for 14-days on MFO, MGO, IR and FFA in 10 adults with T2D and 10 unsupplemented non-diabetic controls. Fasted T2D participants had 36% lower MFO (p < 0.001), 106% higher MGO (p < 0.01), 425% higher IR (p < 0.001) and 76% higher plasma FFA (p < 0.05). GlyNAC supplementation significantly improved fasted MFO by 30% (p < 0.001), lowered MGO by 47% (p < 0.01), decreased IR by 22% (p < 0.01) and lowered FFA by 25% (p < 0.01). These results provide proof-of-concept that GlyNAC supplementation could improve mitochondrial dysfunction and IR in patients with T2D, and warrant additional research.

Humanity is battling a respiratory pandemic pneumonia named COVID-19 which has resulted in millions of hospitalizations and deaths. COVID-19 exacerbations occur in waves that continually challenge healthcare systems globally. Therefore, there is an urgent need to understand all mechanisms by which COVID-19 results in health deterioration to facilitate the development of protective strategies. Oxidative stress (OxS) is a harmful condition caused by excess reactive-oxygen species (ROS) and is normally neutralized by antioxidants among which Glutathione (GSH) is the most abundant. GSH deficiency results in amplified OxS due to compromised antioxidant defenses. Because little is known about GSH or OxS in COVID-19 infection, we measured GSH, TBARS (a marker of OxS) and F2-isoprostane (marker of oxidant damage) concentrations in 60 adult patients hospitalized with COVID-19. Compared to uninfected controls, COVID-19 patients of all age groups had severe GSH deficiency, increased OxS and elevated oxidant damage which worsened with advancing age. These defects were also present in younger age groups, where they do not normally occur. Because GlyNAC (combination of glycine and N-acetylcysteine) supplementation has been shown in clinical trials to rapidly improve GSH deficiency, OxS and oxidant damage, GlyNAC supplementation has implications for combating these defects in COVID-19 infected patients and warrants urgent investigation.

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.

This paper explains about control of VSC using uni-polar switching based Static Compensator (STATCOM) using Peak Detection Control Strategy for elimination of PQ Problems. The proposed STATCOM are operated in PFC (Power Factor Correction) mode and ZVR (Zero Voltage Regulation) mode. Under these operation modes of STATCOM is able to suppression of harmonics, PFC at source, reactive power compensation, load balancing and compensation of neutral current. A non-isolated star/three individual single- phase transformers are connected at PCC (Point of Common Coupling) to mitigate neutral current. The Peak Detection Control Strategy is simple to implement for estimating switching pulses for VSC. This peak detection control strategy based STATCOM is modelled, simulated results are validated using MATLAB R2013b.

The present study aims to identify whether the delineation of potential groundwater potential zones (GWPZs) is essential for monitoring surface and conserving underground water resources. This study analysed the morphology of earth surface characteristics such as geomorphology, lineament density, lithology, slope, soil types, land use and land cover, drainage density, land surface temperature, normalized difference vegetation index, rainfall, and topographic wetness index parameters to delineate the potential groundwater zones. This article applies the analytical hierarchy process (AHP) and multi-influence factor (MIF) methods to identify potential groundwater zones in the Tirunelveli and Tenkasi districts of Tamil Nadu, India. In the AHP method, individual parameter's geometric mean and normalized weights were determined using the pair-wise matrix analytical method. Remote sensing-geographic information system (RS-GIS) techniques were used to generate thematic map layers from normalized weights to delineate GWPZs. The GWPZs were classified as Very Low, Low, Medium, High, and Very High. The result shows that the GWPZs were identified as 3.57, 0.55, 6.62, 58.09, and 31.21% in the study area for the five classes, respectively. In this study, the thematic maps were also prepared by assigning fixed scores and weights from the MIF approach. In the MIF approach, GWPZs were classified into five classes and identified as 3.16, 0.33, 2.14, 61.21, and 33.16% in the study area, respectively. GWPZ maps were evaluated for both MIF and AHP techniques using the Kappa statistics method with agreement values of 0.77 and 0.72%, respectively. This study's GIS-RS method is more proficient and efficient in delineating the GWPZs.