Abstract Body: Common features of the aging heart include dysregulated metabolism, inflammation, and fibrosis, which can all contribute to diastolic dysfunction. Imbalanced oxidative stress can exacerbate each of these conditions, worsening the age-related cardiac defects.
Therefore, we hypothesized that increasing natural antioxidant defenses (glutathione) may favor a healthier cardiac aging phenotype. Twenty-one month-old mice were fed for 12 weeks with a diet supplemented in two glutathione precursors, Glycine and N-Acetyl Cysteine (GlyNAC) or with a control diet. Heart function was measured noninvasively and longitudinally at baseline and then every 6 weeks.
We found that GlyNAC reduced the age-associated increase in left atrial volume in old male, but not in old female mice ( 12% ± 3% in GlyNAC vs 20% ± 2% in control males (*); 11% ± 3% in GlyNAC vs 16% ± 3% in control females; * P=0.03). It also improved exercise performance in males. Subsequent unbiased cardiac proteome analysis identified that GlyNAC modestly changed global protein expression in males and pointed to the significant changes in two pathways: mitochondria-metabolism and extracellular matrix. Further analysis performed on mitochondrial extracts determined that GlyNAC diet led to an increase in Ndufb8, a subunit of the mitochondrial respiratory chain complex (1.76±0.3 in GlyNAC males vs 0.7±0.1 in control males, P=0.02). In the GlyNAC old male mitochondria, we found an improved catalytic activity for CPT1b (7.51±0.79 vs 3.74±0.32 in control males; P=0.002) and an increased CrAT activity (1.99±0.23 vs 1.06±0.08 in control males; P=0.005). Both enzymes are involved in fatty acid metabolism. Hearts from GlyNAC-fed old males exhibited enrichment in Fmod, a protein that can inhibit collagen fibril formation (1.08±0.03 vs 0.89±0.05, P=0.01), possibly reducing extracellular matrix stiffness. In females, the expression or enzymatic activities of these proteins were not affected by the GlyNAC-supplemented diet.
In summary, our study supports the concept that aged male and female hearts exhibit basic phenotypical differences that may affect the response to interventions. These observations may have direct relevance in cardiac gerontology.