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REVERSING AGING BY IMPROVING ENERGETICS, STRENGTH, COGNITION AND INFLAMMATION IN OLDER HUMANS: ROLE OF GLUTATHIONE

ABSTRACT: Abstract Aging in older humans is associated with impaired mitochondrial fatty-acid oxidation (MFO), muscle weakness, cognitive decline and inflammation, but contributing mechanisms are not well understood and effective interventions are lacking. We proposed a unifying hypothesis that deficiency of the endogenous antioxidant protein Glutathione predisposes to all of these defects which are reversible on correcting Glutathione deficiency. To test our hypothesis, we conducted a 36-week open label clinical trial (NCT02348762) in 8 older humans (73.8 ± 1y) studied before and after 24-weeks of supplementation with N-acetylcysteine and Glycine (NAC-Gly, as Glutathione precursor amino-acids), and again 12-weeks after stopping supplements to determine washout changes. 8 young humans (25.8 ± 1y) served as controls, and were not supplemented. Study measures were intracellular Glutathione, fasted MFO (calorimetry), physical function (gait-speed, grip-strength, chair-rise and 6-minute walk tests), cognition (MoCA, Montreal Cognitive-Assessment; trail-making tests; verbal-fluency test; symbol-digital modalities test), plasma oxidative-stress (F2-isoprostanes), inflammation (Interleukein-6; Tumor Necrosis Factor alpha; C-reactive Protein) and body composition (DEXA-scan). Compared to young-controls, older humans had significantly (P<0.05 to P<0.01) impaired MFO, physical and cognitive decline, and higher inflammation and body fat. After 24-weeks of supplementation outcome measures improved significantly (P<0.05 to P<0.01), with complete normalization of fMFO (P<0.001), gait-speed (strength, P<0.001) and MoCA (cognition, P<0.01) to young controls. Accrued benefits declined on stopping supplementation. These novel discoveries provide a proof-of-concept for the exciting possibility that supplementing NAC-Gly in older humans could offer a novel nutritional approach to reverse age-related abnormalities in mitochondrial energetics, physical function, cognition, inflammation and body composition, and thereby ‘reverse aging’.

SUBMITTER: Sekhar R

PROVIDER: S-EPMC6239379 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Project description:BackgroundOxidative 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.MethodsA 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.ResultsGlyNAC 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.ConclusionsGlyNAC 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.

Project description:IntroductionMaintaining older adults' health and well-being can be achieved through the optimization of physical and mental health, while preserving independence, social participation, and quality of life. Cognitive change has been described as a normal process of aging and it involves domains such as processing speed, attention, memory, language, visuospatial abilities, and executive functioning, among others.ObjectiveTo describe cognitive changes in older adults with healthy aging.MethodsThis is a study that involved data from 14,893 and 14,154 individuals aged >60 years or older from the 2012 and 2015 waves, respectively, who participated in the Mexican Health and Aging Study (MHAS). Participants with healthy aging were identified and described in the MHAS-2012 wave and followed to 2015. Eight cognitive domains evaluated in the Cross-Cultural Cognitive Evaluation (CCCE,) as well as sociodemographic and health characteristics, were described. Criteria for healthy aging involved the following: CCCE ≥ -1.5 standard deviations above the mean on reference norms, independence on basic and instrumental activities of daily living, self-reported "life close to ideal," and preserved functional and social performance.ResultsFrom a total of n = 9,160 older adults from the MHAS-2012 wave, n = 1,080 (11.8%) had healthy aging. In the healthy aging group, the median age was 67 years (IQR: 63-73), 58.1% were female and the median for education was 6 (IQR: 3-8) years. The mean CCCE score was 57 (SD: 16.9) points. In the MHAS-2012 cross-sectional analysis, except for orientation, visuospatial abilities, and verbal fluency, all cognitive domain scores were lower with passing age. When comparing cognitive domain scores in the 225 older adults identified with healthy aging between the 2012 and 2015 MHAS waves, there were almost no observable differences.ConclusionIn the cross-sectional analysis, Mexican adults with healthy aging had lower scores in the verbal learning memory, visual scanning, numeracy, visual memory, and verbal recall domains', as well as lower global cognitive scores in the higher age groups. There were no cognitive changes in the 3 year follow-up, except for a lower gradient of scores in the verbal recall memory domain. Longer prospective studies are needed to characterize greater cognitive changes.

Project description:ObjectivesResistance training (RT) is a promising strategy to slow or prevent fluid cognitive decline during aging. However, the effects of strength-specific RT programs have received little attention. The purpose of this single-group proof of concept clinical trial was to determine whether a 12-week strength training (ST) program could improve fluid cognition in healthy older adults 60 to 80 years of age, and to explore concomitant physiological and psychological changes.MethodsTwenty participants (69.1 ± 5.8 years, 14 women) completed this study with no drop-outs or severe adverse events. Baseline assessments were completed before an initial 12-week control period, then participants were re-tested at pre-intervention and after the 12-week ST intervention. The NIH Toolbox Cognition Battery and standard physical and psychological measures were administered at all three time points. During the 36 sessions of periodized ST (3 sessions per week), participants were supervised by an exercise specialist and challenged via autoregulatory load progression.ResultsTest-retest reliability over the control period was good for fluid cognition and excellent for crystallized cognition. Fluid composite scores significantly increased from pre- to post-intervention (8.2 ± 6.1%, p < 0.01, d = 1.27), while crystallized composite scores did not (-0.5 ± 2.8%, p = 0.46, d = -0.34). Performance on individual fluid instruments, including executive function, attention, working memory, and processing speed, also significantly improved. Surprisingly, changes in fluid composite scores had small negative correlations with changes in muscular strength and sleep quality, but a small positive correlation with changes in muscular power.ConclusionsThus, improvements in fluid cognition can be safely achieved in older adults using a 12-week high-intensity ST program, but further controlled studies are needed to confirm these findings. Furthermore, the relationship with other widespread physiological and psychological benefits remains unclear.

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REVERSING AGING BY IMPROVING ENERGETICS, STRENGTH, COGNITION AND INFLAMMATION IN OLDER HUMANS: ROLE OF GLUTATHIONE

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