Improved Cardiovascular Function in Old Mice After N-Acetyl Cysteine and Glycine Supplemented Diet: Inflammation and Mitochondrial Factors

Cieslik, Katarzyna A.; Sekhar, Rajagopal V.; Granillo, Alejandro; Reddy, Anilkumar K.; Medrano, Guillermo; Heredia, Celia Pena; Entman, Mark L.; Hamilton, Dale J.; Li, Shumin; Reineke, Erin L.; Gupte, Anisha A.; Zhang, Aijun; Taffet, George E.

doi:10.1093/gerona/gly034

Cited by 29 publications

(21 citation statements)

References 53 publications

(64 reference statements)

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“…A recent study by Cieslik and colleagues showed that combined treatment with glutathione precursors, N-Acetyl Cysteine (NAC) and Glycine, but not NAC alone, can reverse age-related diastolic dysfunction ( Cieslik et al, 2018 ). While the study suggests that aged mice may benefit from increased glutathione content, the effects of the combined treatment on in vivo cardiac glutathione contents and S-glutathionylation remain to be established.…”

Section: Discussionmentioning

confidence: 99%

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Chiao

Zhang

Sweetwyne

et al. 2020

eLife

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Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. Improved diastolic function was concordant with increased phosphorylation of cMyBP-C Ser282 but was independent of titin isoform shift. Late-life viral expression of mitochondrial-targeted catalase (mCAT) produced similar functional benefits in old mice and SS-31 did not improve cardiac function of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. These results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and implicate mitochondrial energetics and redox signaling as therapeutic targets for cardiac aging.

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Section: Discussionmentioning

confidence: 99%

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Chiao

Zhang

Sweetwyne

et al. 2020

eLife

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“…A recent study by Cieslik and colleagues showed that combined treatment with glutathione precursors, N-Acetyl Cysteine (NAC) and Glycine, but not NAC alone, can reverse age-related diastolic dysfunction 35 . While the study suggests that aged mice may benefit from increased glutathione content, the effects of the combined treatment on in vivo cardiac glutathione contents and S-glutathionylation remain to be established.…”

Section: Targeting Mitochondrial Oxidative Stress In Late-life Reversmentioning

confidence: 99%

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Chiao

Zhang

Sweetwyne

et al. 2020

Preprint

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Mitochondrial dysfunction is a hallmark of aging but whether restoration of mitochondrial function can reverse pre-existing age-related diseases is not well-established. Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans, and we show here that 8-week treatment with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit in old mice. Mechanistically, SS-31 treatment normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice; these cellular changes were accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. The improvement in diastolic function was associated with increased phosphorylation at Ser282 of cMyBP-C but was independent of titin isoform shift. SS-31 treatment cannot further improve cardiac function of old mice that express mitochondrial-targeted catalase (mCAT), implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. Late-life viral expression of mCAT produced similar functional benefits in old mice, further indicating that reduction of mitochondrial ROS as a critical mechanism. Despite their similar functional benefits, SS-31 and mCAT differentially regulated cMyBP-C and cTnI phosphorylation, suggesting divergence of mechanisms downstream of mitochondrial ROS reduction. Overall, these results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and implicate mitochondrial energetics and redox signaling as therapeutic targets of cardiac aging.

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“…The effects of NAC were greatest, achieving an almost two-fold increase in plasma GSH levels [38]. In addition, NAC supplementation was found to benefit individuals with low resting GSH levels [74], and may be even more effective when supplemented with glycine [75].…”

Section: Effect Of Individual Amino Acid Supplementationmentioning

confidence: 99%

Impact of Supplementary Amino Acids, Micronutrients, and Overall Diet on Glutathione Homeostasis

Gould

Pazdro

2019

Nutrients

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Glutathione (GSH) is a critical endogenous antioxidant found in all eukaryotic cells. Higher GSH concentrations protect against cellular damage, tissue degeneration, and disease progression in various models, so there is considerable interest in developing interventions that augment GSH biosynthesis. Oral GSH supplementation is not the most efficient option due to the enzymatic degradation of ingested GSH within the intestine by γ-glutamyltransferase, but supplementation of its component amino acids—cysteine, glycine, and glutamate—enhances tissue GSH synthesis. Furthermore, supplementation with some non-precursor amino acids and micronutrients appears to influence the redox status of GSH and related antioxidants, such as vitamins C and E, lowering systemic oxidative stress and slowing the rate of tissue deterioration. In this review, the effects of oral supplementation of amino acids and micronutrients on GSH metabolism are evaluated. And since specific dietary patterns and diets are being prescribed as first-line therapeutics for conditions such as hypertension and diabetes, the impact of overall diets on GSH homeostasis is also assessed.

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Improved Cardiovascular Function in Old Mice After N-Acetyl Cysteine and Glycine Supplemented Diet: Inflammation and Mitochondrial Factors

Cited by 29 publications

References 53 publications

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Impact of Supplementary Amino Acids, Micronutrients, and Overall Diet on Glutathione Homeostasis

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