Effects of glycine and n-acetylcysteine on glutathione levels and mitochondrial energy metabolism in healthy aging

Abstract Glutathione is an intracellular antioxidant that neutralizes reactive oxygen species and prevents tissue damage. Dietary supplementation with the glutathione precursors glycine and n-acetylcysteine supports the maintenance of normal glutathione levels in several age-related diseases, but the optimal doses and their efficacy in healthy elderly are not established. We report results from a randomized controlled clinical trial in 114 healthy volunteers (mean age = 65 years) receiving glycine and n-acetylcysteine (GlyNAC) at three different doses for two weeks (1.2g/1.2, 2.4g/2.4g, 3.6g/.3.6g of each amino acid). Older subjects showed increased oxidative damage and a lower reduced-to-oxidized glutathione ratio (GSH:GSSG) compared to young subjects, but unchanged total glutathione levels. GlyNAC did not increase levels of circulating glutathione compared to placebo treatment, the primary study endpoint. However, stratification analyses suggest that subjects with high oxidative stress and low glutathione status responded with glutathione generation. We find that unrelated to glutathione status, healthy aging was associated with lower levels of fasting glycine that can be increased towards those observed in young subjects with supplementation. Using preclinical models, we find that tissue glycine depletion is a common feature of healthy aging. Supplementation of old mice with glycine efficiently improved age-related decline of mitochondrial respiratory function in skeletal muscle and prevented a gene program associated with protein catabolism observed in control-treated animals. In conclusion, GlyNAC is safe and well-tolerated and may selectively increase glutathione levels in older subjects with oxidative stress and glutathione demand. Our data further suggest that glycine may support mitochondrial function independently of NAC.

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Age-related changes in the control of finger force vectors

Journal of Applied Physiology ◽

10.1152/japplphysiol.00430.2010 ◽

2010 ◽

Vol 109 (6) ◽

pp. 1827-1841 ◽

Cited By ~ 56

Author(s):

Shweta Kapur ◽

Vladimir M. Zatsiorsky ◽

Mark L. Latash

Keyword(s):

Neural Control ◽

Healthy Aging ◽

Force Production ◽

Uncontrolled Manifold ◽

Total Force ◽

Finger Force ◽

Healthy Elderly ◽

Age Related ◽

Young Subjects ◽

Force Vectors

We explored changes in finger interaction in the process of healthy aging as a window into neural control strategies of natural movements. In particular, we quantified the amount of force produced by noninstructed fingers in different directions, the amount of force produced by the instructed finger orthogonally to the task direction, and the strength of multifinger synergies stabilizing the total force magnitude and direction during accurate force production. Healthy elderly participants performed accurate isometric force production tasks in five directions by individual fingers and by all four fingers acting together. Their data were compared with a dataset obtained in a similar earlier study of young subjects. Finger force vectors were measured using six-component force/torque sensors. Multifinger synergies were quantified using the framework of the uncontrolled manifold hypothesis. The elderly participants produced lower force magnitudes by noninstructed fingers and higher force magnitudes by instructed fingers in nontask directions. They showed strong synergies stabilizing the magnitude and direction of the total force vector. However, the synergy indexes were significantly lower than those observed in the earlier study of young subjects. The results are consistent with an earlier hypothesis of preferential weakening of intrinsic hand muscles with age. We interpret the findings as a shift in motor control from synergic to element-based, which may be causally linked to the documented progressive neuronal death at different levels of the neural axis.

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Altered Brain Mitochondrial Metabolism in Healthy Aging as Assessed by in vivo Magnetic Resonance Spectroscopy

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.197 ◽

2009 ◽

Vol 30 (1) ◽

pp. 211-221 ◽

Cited By ~ 147

Author(s):

Fawzi Boumezbeur ◽

Graeme F Mason ◽

Robin A de Graaf ◽

Kevin L Behar ◽

Gary W Cline ◽

...

Keyword(s):

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Brain Function ◽

Healthy Aging ◽

Mitochondrial Metabolism ◽

Elderly Subjects ◽

Resonance Spectroscopy ◽

Healthy Elderly ◽

Age Related ◽

Young Subjects

A decline in brain function is a characteristic feature of healthy aging; however, little is known about the biologic basis of this phenomenon. To determine whether there are alterations in brain mitochondrial metabolism associated with healthy aging, we combined 13C/1H magnetic resonance spectroscopy with infusions of [1-13C]glucose and [2-13C]acetate to quantitatively characterize rates of neuronal and astroglial tricarboxylic acid cycles, as well as neuroglial glutamate–glutamine cycling, in healthy elderly and young volunteers. Compared with young subjects, neuronal mitochondrial metabolism and glutamate–glutamine cycle flux was ∼30% lower in elderly subjects. The reduction in individual subjects correlated strongly with reductions in N-acetylaspartate and glutamate concentrations consistent with chronic reductions in brain mitochondrial function. In elderly subjects infused with [2-13C]acetate labeling of glutamine, C4 and C3 differed from that of the young subjects, indicating age-related changes in glial mitochondrial metabolism. Taken together, these studies show that healthy aging is associated with reduced neuronal mitochondrial metabolism and altered glial mitochondrial metabolism, which may in part be responsible for declines in brain function.

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Carotenoids: How Effective Are They to Prevent Age-Related Diseases?

Molecules ◽

10.3390/molecules24091801 ◽

2019 ◽

Vol 24 (9) ◽

pp. 1801 ◽

Cited By ~ 14

Author(s):

Bee Ling Tan ◽

Mohd Esa Norhaizan

Keyword(s):

Oxidative Stress ◽

Healthy Aging ◽

The Elderly ◽

Antioxidant Systems ◽

Potential Intervention ◽

Healthy Longevity ◽

Age Related ◽

Underlying Mechanisms ◽

Endogenous Antioxidant

Despite an increase in life expectancy that indicates positive human development, a new challenge is arising. Aging is positively associated with biological and cognitive degeneration, for instance cognitive decline, psychological impairment, and physical frailty. The elderly population is prone to oxidative stress due to the inefficiency of their endogenous antioxidant systems. As many studies showed an inverse relationship between carotenoids and age-related diseases (ARD) by reducing oxidative stress through interrupting the propagation of free radicals, carotenoid has been foreseen as a potential intervention for age-associated pathologies. Therefore, the role of carotenoids that counteract oxidative stress and promote healthy aging is worthy of further discussion. In this review, we discussed the underlying mechanisms of carotenoids involved in the prevention of ARD. Collectively, understanding the role of carotenoids in ARD would provide insights into a potential intervention that may affect the aging process, and subsequently promote healthy longevity.

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Effect of ‘Autonomic Blockade’ on Cardiac β-Adrenergic Chronotropic Responsiveness in Healthy Young, Healthy Elderly and Endurance-Trained Elderly Subjects

Clinical Science ◽

10.1042/cs0870297 ◽

1994 ◽

Vol 87 (3) ◽

pp. 297-302 ◽

Cited By ~ 15

Author(s):

G. A. Ford ◽

O. F. W. James

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Geometric Mean ◽

Cardiovascular Responses ◽

The Elderly ◽

Elderly Subjects ◽

Healthy Elderly ◽

Age Related ◽

Autonomic Blockade ◽

Young Subjects

1. Cardiac chronotropic responses to isoprenaline are reduced with ageing in man. It is unclear whether this is due to reduced cardiac β-adrenergic sensitivity or to age-associated differences in reflex cardiovascular responses to the vasodilatory effects of isoprenaline. Age-associated changes in physical activity are also reported to influence β-adrenergic sensitivity. 2. The aim of the present study was to determine the contribution of alterations in reflex changes in parasympathetic and sympathetic influences and physical fitness to the age-associated reduction in cardiac chronotropic responses to β-adrenergic agonists. 3. The effect of ‘autonomic blockade’ with atropine (40 μg/kg intravenously) and clonidine (4 μg/kg intravenously) on blood pressure, heart rate and chronotropic responses to intravenous bolus isoprenaline doses was determined in eight healthy young (mean age 21 years), nine healthy elderly (72 years) and 10 endurance-trained elderly (69 years) subjects. 4. Elderly subjects had a reduced increase in heart rate after atropine (young, 49 ± 9 beats/min; elderly, 36 ± 5 beats/min; endurance-trained elderly, 34 ± 12 beats/min; P < 0.01) and did not demonstrate the transient increase in systolic blood pressure after clonidine observed in young subjects (young, 11 ± 10 mmHg; elderly, −12 ± 16 mmHg; endurance-trained elderly, −18 ± 11 mmHg; P < 0.01). 5. Cardiac chronotropic sensitivity to isoprenaline after ‘autonomic blockade’ increased in the young but decreased in the elderly subjects. The isoprenaline dose that increased heart rate by 25 beats/min before and after autonomic blockade' was: young, before 1.6 μg, after 2.8 μg, P < 0.01 (geometric mean, paired test); elderly, before 6.9 μg, after 3.6 μg, P < 0.05; endurance-trained elderly, before 5.9 μg, after 4.0 μg, P < 0.05. Cardiac chronotropic sensitivity to isoprenaline was significantly reduced in elderly compared with young subjects before (P < 0.01) but was similar after (P = 0.09) ‘autonomic blockade’. Chronotropic sensitivity did not differ between healthy and endurance-trained elderly subjects before or after ‘autonomic blockade’. 6. The age-associated reduction in cardiac chronotropic responses to bolus isoprenaline is primarily due to an age-related reduction in the influence of reflex cardiovascular responses on heart rate and not to an age-related reduction in cardiac β-adrenergic sensitivity. Endurance training is not associated with altered β-adrenergic chronotropic sensitivity in the elderly. The transient pressor response to intravenously administered clonidine may be lost in ageing man.

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Gastrointestinal Microbiota and Their Contribution to Healthy Aging

Digestive Diseases ◽

10.1159/000443350 ◽

2016 ◽

Vol 34 (3) ◽

pp. 194-201 ◽

Cited By ~ 21

Author(s):

Anna Maria Mello ◽

Giulia Paroni ◽

Julia Daragjati ◽

Alberto Pilotto

Keyword(s):

Old Age ◽

Healthy Aging ◽

Adverse Outcomes ◽

Microbiota Composition ◽

Older Individuals ◽

Gastrointestinal Microbiota ◽

Targeted Interventions ◽

Age Related ◽

Increased Risk ◽

Older Subjects

Studies on populations at different ages have shown that after birth, the gastrointestinal (GI) microbiota composition keeps evolving, and this seems to occur especially in old age. Significant changes in GI microbiota composition in older subjects have been reported in relation to diet, drug use and the settings where the older subjects are living, that is, in community nursing homes or in a hospital. Moreover, changes in microbiota composition in the old age have been related to immunosenescence and inflammatory processes that are pathophysiological mechanisms involved in the pathways of frailty. Frailty is an age-related condition of increased vulnerability to stresses due to the impairment in multiple inter-related physiologic systems that are associated with an increased risk of adverse outcomes, such as falls, delirium, institutionalization, hospitalization and death. Preliminary data suggest that changes in microbiota composition may contribute to the variations in the biological, clinical, functional and psycho-social domains that occur in the frail older subjects. Multidimensional evaluation tools based on a Comprehensive Geriatric Assessment (CGA) have demonstrated to be useful in identifying and measuring the severity of frailty in older subjects. Thus, a CGA approach should be used more widely in clinical practice to evaluate the multidimensional effects potentially related to GI microbiota composition of the older subjects. Probiotics have been shown to be effective in restoring the microbiota changes of older subjects, promoting different aspects of health in elderly people as improving immune function and reducing inflammation. Whether modulation of GI microbiota composition, with multi-targeted interventions, could have an effect on the prevention of frailty remains to be further investigated in the perspective of improving the health status of frail ‘high risk' older individuals.

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Is there evidence for an age-related reduction in metabolic rate?

Journal of Applied Physiology ◽

10.1152/jappl.1998.85.6.2196 ◽

1998 ◽

Vol 85 (6) ◽

pp. 2196-2204 ◽

Cited By ~ 104

Author(s):

Leonard S. Piers ◽

Mario J. Soares ◽

Leanne M. McCormack ◽

Kerin O’Dea

Keyword(s):

Metabolic Rate ◽

Qualitative Change ◽

Cross Sectional Study ◽

Lean Tissue ◽

Tissue Mass ◽

Cross Sectional ◽

Lean Tissue Mass ◽

Age Related ◽

Older Subjects ◽

Young Subjects

To determine whether the age-related reduction in basal metabolic rate (BMR) is explained by a quantitative and/or qualitative change in the components of lean tissue, we conducted a cross-sectional study in groups of young ( n = 38, 18–35 yr) and older ( n = 24, 50–77 yr) healthy individuals. BMR was measured by indirect calorimetry. Body composition was obtained by using dual-energy X-ray absorptiometry (DEXA), which permitted four compartments to be quantified [bone mineral mass, fat mass (FM), appendicular lean tissue mass (ALTM), and nonappendicular lean tissue mass (NALTM)]. Absolute BMR and ALTM were lower, whereas FM was significantly higher in the older, compared with young, subjects. BMR, adjusted for differences in FM, ALTM, and NALTM, was significantly lower in the older subjects by 644 kJ/day. In separate regression analyses of BMR on body compartments, older subjects had significantly lower regression coefficients for ALTMand NALTM, compared with young subjects. Hence, the age-related decline in BMR is partly explained by a reduction in the quantity, as well as the metabolic activity, of DEXA-derived lean tissue components.

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Hypothalamus-Pituitary-Adrenal Hyperactivity in Human Aging Is Partially Refractory to Stimulation by Mineralocorticoid Receptor Blockade

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2005-0105 ◽

2005 ◽

Vol 90 (10) ◽

pp. 5656-5662 ◽

Cited By ~ 39

Author(s):

Roberta Giordano ◽

Mario Bo ◽

Micaela Pellegrino ◽

Marco Vezzari ◽

Matteo Baldi ◽

...

Keyword(s):

Hpa Axis ◽

Mineralocorticoid Receptor ◽

Elderly Subjects ◽

Cortisol Secretion ◽

Mineralocorticoid Receptors ◽

Placebo Administration ◽

Healthy Elderly ◽

Age Related ◽

Young Subjects ◽

Mineralocorticoid Antagonists

Context: The hypothalamus-pituitary-adrenal (HPA) axis is mainly regulated by CRH, arginine vasopressin, and glucocorticoid feedback. Hippocampal mineralocorticoid receptors mediate proactive glucocorticoid feedback and mineralocorticoid antagonists, accordingly, stimulate HPA axis. Age-related HPA hyperactivity reflects impaired glucocorticoid feedback at the suprapituitary level. Design: ACTH, cortisol, and dehydroepiandrosterone (DHEA) secretion were studied in eight healthy elderly (75.1 ± 3.2 yr) and eight young (25.0 ± 4.6 yr) subjects during placebo or canrenoate (CAN) administration (200 mg iv bolus followed by 200 mg infused over 4 h). Results: During placebo administration, ACTH and cortisol areas under the curve (AUCs) in elderly subjects were higher than in young subjects (P ≤ 0.01); conversely, DHEA AUCs in elderly subjects were lower than in young subjects (P = 0.002). CAN increased ACTH, cortisol, and DHEA levels in both groups. In young subjects, ACTH, cortisol, and DHEA levels at the end of CAN infusion were higher (P ≤ 0.05) than after placebo. In elderly subjects, at the end of CAN infusion, ACTH, cortisol, and DHEA levels were higher (P = 0.01) than after placebo. Under CAN, ACTH and cortisol AUCs were persistently higher (P ≤ 0.01) and DHEA AUCs lower (P = 0.006) in elderly than in young subjects. Cortisol AUCs after CAN in young subjects did not become significantly different from those in elderly subjects after placebo. Conclusions: 1) Evening-time ACTH and cortisol secretion in elderly subjects is higher than in young subjects; 2) ACTH and cortisol secretion in elderly subjects is enhanced by CAN but less than that in young subjects; and 3) DHEA hyposecretion in elderly subjects is partially restored by mineralocorticoid antagonism. Age-related variations of HPA activity may be determined by some derangement in mineralocorticoid receptors function at the hippocampal level.

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Plant-Derived Bioactives and Oxidative Stress-Related Disorders: A Key Trend towards Healthy Aging and Longevity Promotion

Applied Sciences ◽

10.3390/app10030947 ◽

2020 ◽

Vol 10 (3) ◽

pp. 947 ◽

Cited By ~ 7

Author(s):

Bahare Salehi ◽

Elena Azzini ◽

Paolo Zucca ◽

Elena Maria Varoni ◽

Nanjangud V. Anil Kumar ◽

...

Keyword(s):

Oxidative Stress ◽

Healthy Aging ◽

Biological Effects ◽

Biologically Active ◽

Bioactive Molecules ◽

Human Beings ◽

Aging Effects ◽

Treatment And Prevention ◽

Age Related ◽

And Oxidative Stress

Plants and their corresponding botanical preparations have been used for centuries due to their remarkable potential in both the treatment and prevention of oxidative stress-related disorders. Aging and aging-related diseases, like cardiovascular disease, cancer, diabetes, and neurodegenerative disorders, which have increased exponentially, are intrinsically related with redox imbalance and oxidative stress. Hundreds of biologically active constituents are present in each whole plant matrix, providing promissory bioactive effects for human beings. Indeed, the worldwide population has devoted increased attention and preference for the use of medicinal plants for healthy aging and longevity promotion. In fact, plant-derived bioactives present a broad spectrum of biological effects, and their antioxidant, anti-inflammatory, and, more recently, anti-aging effects, are considered to be a hot topic among the medical and scientific communities. Nonetheless, despite the numerous biological effects, it should not be forgotten that some bioactive molecules are prone to oxidation and can even exert pro-oxidant effects. In this sense, the objective of the present review is to provide a detailed overview of plant-derived bioactives in age-related disorders. Specifically, the role of phytochemicals as antioxidants and pro-oxidant agents is carefully addressed, as is their therapeutic relevance in longevity, aging-related disorders, and healthy-aging promotion. Finally, an eye-opening look into the overall evidence of plant compounds related to longevity is presented.

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Effect of age and posture on human lymphocyte adenylate cyclase activity

Clinical Science ◽

10.1042/cs0740331 ◽

1988 ◽

Vol 74 (3) ◽

pp. 331-334 ◽

Cited By ~ 4

Author(s):

Scott L. Mader ◽

Alan S. Robbins ◽

Laurence Z. Rubenstein ◽

Michael L. Tuck ◽

Philip J. Scarpace

Keyword(s):

Adenylate Cyclase ◽

Acute Stress ◽

Cyclase Activity ◽

Adenylate Cyclase Activity ◽

Elderly Subjects ◽

Upright Posture ◽

Adenylate Cyclase System ◽

Healthy Elderly ◽

Age Related ◽

Young Subjects

1. A number of age-related changes have been reported in the catecholamine–adrenoceptor–adenylate cyclase system. Most of the data available on these alterations come from resting subjects; the response to acute stress may provide additional insights into the age effect on these responses. 2. We measured supine and 10 min upright plasma noradrenaline and lymphocyte adenylate cyclase activity in ten healthy elderly subjects (age 66–80 years) and seven healthy young subjects (age 27–34 years). 3. Isoprenaline stimulation of lymphocyte adenylate cyclase activity was not significantly different between supine and upright positions or between elderly and young subjects. There was a marked increase in forskolin-stimulated adenylate cyclase activity in the upright posture in both elderly and young subjects. The increment over supine levels was 70% in the elderly (P < 0.025) and 73% in the young (P < 0.05). This enhanced forskolin activity was not seen in two young subjects who became syncopal. 4. These data suggest that enhanced forskolin-stimulated adenylate cyclase activity occurs after 10 min of upright posture in both elderly and young subjects, and may be relevant to immediate blood pressure regulation. We were unable to demonstrate any age-related differences in these acute adrenergic responses.

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Effect of Exogenous Cholecystokinin (CCK)-8 on Food Intake and Plasma CCK, Leptin, and Insulin Concentrations in Older and Young Adults: Evidence for Increased CCK Activity as a Cause of the Anorexia of Aging

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.12.8107 ◽

2001 ◽

Vol 86 (12) ◽

pp. 5830-5837 ◽

Cited By ~ 109

Author(s):

Caroline G. MacIntosh ◽

John E. Morley ◽

Judith Wishart ◽

Howard Morris ◽

Jan B. M. J. Jansen ◽

...

Keyword(s):

Food Intake ◽

Older People ◽

Healthy Aging ◽

Protein Energy Malnutrition ◽

Age Groups ◽

Postprandial Glucose ◽

Saline Control ◽

Older Subjects ◽

Young Subjects ◽

The Impact

Healthy aging is associated with reductions in appetite and food intake—the so-called anorexia of aging, which may predispose to protein-energy malnutrition. One possible cause of the anorexia of aging is an increased satiating effect of cholecystokinin (CCK). To investigate the impact of aging on the satiating effects of CCK, 12 young and 12 older healthy subjects received 25-min iv infusions of saline (control) and CCK-8, 1 ng/kg per min or 3 ng/k per min, on 3 separate days before a test meal. Older subjects ate less than young subjects, and food intake was suppressed 21.6% by CCK-8, compared with the control day (P < 0.05). The suppression of energy intake by CCK-8 in older subjects was twice that in young subjects (32 ± 6% vs. 16 ± 6% sem, P < 0.05) and was related to plasma CCK-8 concentrations, which were higher at baseline (P < 0.05) and increased more during CCK-8 infusions in older than young subjects (P < 0.01). The extent of suppression of food intake per given rise in plasma CCK-8 concentrations did not differ between the two age groups (P = 0.35). Endogenous CCK concentrations were higher at baseline in older subjects (P < 0.001) and decreased during the CCK-8 but not control infusions (P < 0.01), suggesting that CCK suppresses its own release. Plasma leptin concentrations were not affected by CCK infusion, whereas postprandial insulin concentrations were lowered and the peak postprandial glucose concentration was delayed but not affected by CCK-8 infusion. Because older people retain their sensitivity to the satiating effects of exogenous CCK and plasma endogenous CCK concentrations are higher in older people, increased CCK activity may contribute to the anorexia of aging.

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