Cardiac aging in mice and humans: the role of mitochondrial oxidative stress

Abstract

Age is a major risk factor for cardiovascular diseases, not only because it prolongs exposure to several other cardiovascular risks, but also owing to intrinsic cardiac aging, which reduces cardiac functional reserve, predisposes the heart to stress, and contributes to increased cardiovascular mortality in the elderly. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans, including left ventricular hypertrophy, fibrosis, and diastolic dysfunction. Cardiac aging in mice is accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations, increased mitochondrial biogenesis, as well as decreased cardiac SERCA2 protein. All of these age-related changes are significantly attenuated in mice overexpressing catalase targeted to mitochondria. These findings demonstrate the critical role of mitochondrial reactive oxygen species in cardiac aging and support the potential application of mitochondrial antioxidants to cardiac aging and age-related cardiovascular diseases.

Figure 1

Echocardiography of 170 WT and mCAT C57Bl/6 mice in a longevity cohort. (A) Left ventricular mass index (LVMI=LVM/body weight), (B) systolic function measured by percentage of fractional shortening (FS), (C) diastolic function measured by tissue Doppler imaging Ea/Aa, (D) the proportion of mice with diastolic dysfunction, defined as Ea/Aa<1, (E) left atrial dimension and (F) the myocardial performance index were analyzed. The linear trends across ages in WT mice were significant for all parameters (P<0.05 for all). The beneficial effect of mCAT vs. WT was analyzed by the interaction term between genotype and the age trend, and was significant in all cases (P <0.01 for all except fractional shortening, P =0.03). Data reanalyzed from (Dai et al. 2009)

Figure 2. Mitochondrial DNA mutations, oxidative damage and biogenesis in aged heart and the protective effect of mCAT

(A, B) Mitochondrial DNA point mutation and deletion frequencies (both per million base pairs) increased significantly with age and were attenuated in old mCAT mouse hearts. (C) Protein carbonyls content (nmol/mg) from cardiac mitochondrial extracts increased significantly with age, while mCAT attenuated age-dependent oxidative damage to mitochondrial proteins. (D) Mitochondrial DNA copy number (normalized to young WT) increased significantly with age, and old mCAT mice had significantly less increase in mitochondrial DNA copy number. (E) Electron micrographs displayed disruption of cristae and vacuolation of mitochondria (loss of electron density) in old WT mouse hearts, which was better protected in old mCAT heart mitochondria. (F) Upregulation of genes involved in mitochondrial biogenesis in the aged heart, including PGC-1a, TFAM, NRF-1 and NRF-2, and changes in PGC-1a and TFAM were attenuated in old mCAT mice (*P <0.025 between young vs. old WT, # P <0.025 between old WT vs. mCAT; n=9–12 each group; old: 26–28 months, young:4–5 months old).