Cardiac aging: from molecular mechanisms to significance in human health and disease

Abstract

Cardiovascular diseases (CVDs) are the major causes of death in the western world. The incidence of cardiovascular disease as well as the rate of cardiovascular mortality and morbidity increase exponentially in the elderly population, suggesting that age per se is a major risk factor of CVDs. The physiologic changes of human cardiac aging mainly include left ventricular hypertrophy, diastolic dysfunction, valvular degeneration, increased cardiac fibrosis, increased prevalence of atrial fibrillation, and decreased maximal exercise capacity. Many of these changes are closely recapitulated in animal models commonly used in an aging study, including rodents, flies, and monkeys. The application of genetically modified aged mice has provided direct evidence of several critical molecular mechanisms involved in cardiac aging, such as mitochondrial oxidative stress, insulin/insulin-like growth factor/PI3K pathway, adrenergic and renin angiotensin II signaling, and nutrient signaling pathways. This article also reviews the central role of mitochondrial oxidative stress in CVDs and the plausible mechanisms underlying the progression toward heart failure in the susceptible aging hearts. Finally, the understanding of the molecular mechanisms of cardiac aging may support the potential clinical application of several "anti-aging" strategies that treat CVDs and improve healthy cardiac aging.

FIG. 1.

The prevalence of various CVDS with age. The prevalence of high blood pressure (A), stroke (B), coronary heart diseases (C), and heart failure (D) significantly increase with age in both men and women. There is an exponential increase in CVD mortality in the elderly population (E). Data source: NCHS and NHLBI (273). CVD, cardiovascular disease; NCHS, National Center for Health Statistics; NHLBI, National Heart Lung and Blood Institute.

FIG. 2.

Age-dependent changes in cardiac structure and function. (A). Posterior wall thickness (cm/m²) by M-mode echocardiography significantly increases with age in both men and women, (B). Peak E wave (early diastolic filling) declines with age. (C). Doppler E/A ratio of mitral inflow, an indicator of diastolic function, decreased with age in apparently healthy participants in both the Baltimore Longitudinal Study on Aging and the Framingham Heart Study. Ejection fraction (D) and heart rate (E) after maximal exercise decrease with age in both genders. (F). Cardiac index (Cardiac output normalized to body surface area) decreases with age. [Reproduced with permission from Lakatta and Levy (2003)].

FIG. 3.

Echocardiographic changes in aging and mitochondrial mutator mice. Echocardiographic analysis of WT and mCAT C57Bl/6 mice in a longevity cohort (A–D) and Polg^m/m in the presence or absence of mCAT `(E–H). (A, E) Left ventricular mass index (LVMI=calculated LVM/body weight), (B, F) systolic function measured by percentage of fractional shortening (FS), (C, G) diastolic function measured by tissue Doppler imaging Ea/Aa, (D, H) the myocardial performance index (MPI) were analyzed. The linear trends across ages in WT mice were significant for all parameters (p<0.05 for all, left panels). The beneficial effect of mCAT versus WT was analyzed by the interaction between genotype and the linear age trend, and was significant in all cases (p<0.01 for all except fractional shortening, p=0.03). *p<0.05 versus Polg^m/m at 4–6 months old, ^#p<0.05 versus Polg^m/m at 13–14 months old (right panels). Data reanalyzed from Dai, et al. (67,71). LVMI, Left ventricular mass index; mCAT, catalase targeted to mitochondria.

FIG. 4.

Mitochondrial ROS theory of aging: ROS vicious cycle. Mitochondria are primary producers and targets of ROS. ROS production as a byproduct of escape of electrons from the electron transport chain (ETC) can directly damage ETC components or damage to mitochondrial DNA, which, in turn, results in altered levels or function of ETC components (complexes I-V are shown). In either case, the compromised ETC produces increased ROS, resulting in increased damage and a vicious cycle of mitochondrial ROS induced ROS. The end results are decreased ETC efficiency, damage to cellular macromolecules, and activation of cellular ROS and redox signaling. ROS, reactive oxygen species.

FIG. 5.

Mitochondrial-lysosomal axis theory of aging. Damaged mitochondria accumulate when normal autophagy/mitophagy or mitochondrial fission/fusion are disrupted. According to the mitochondrial-lysosomal axis theory of aging, this accumulation of damaged mitochondria is a key step in the progression of aging and mitochondria-associated disease.

FIG. 6.

Increased production of ROS in mitochondria of old mouse cardiac tissue. Ex-vivo live staining of cardiac tissue from 4 month (top row) and 20 month (bottom row) old male mice. MitoSOX has unique excitation/emission spectra for superoxide specific products (405 wavelength, shown in yellow) and nonspecific products of oxidation (514, shown in red). White arrows point to focal high-superoxide producing mitochondria. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 7.

Mitochondrial oxidative damage in cardiac aging. (A). Mitochondrial protein carbonyl (nmol/mg) significantly increased in old WT (OWT,>24 months) and even more in middle-aged Polg (MPolg, 13.5 months) mouse hearts when compared with young WT mouse hearts. mCAT significantly reduced these age-dependent mitochondrial protein carbonylation. (B). Mitochondrial DNA deletion frequency significantly increased in old WT (>24 months) and young Polg (4 months) when compared with young WT, and this is dramatically increased in middle-aged Polg (13.5 months). mCAT overexpression significantly reduced the deletion frequency for both. *p<0.05 compared with YWT.

FIG. 8.

mTOR pathway in aging. A simplified diagram of key nutrient signaling inputs to mTOR and key targets of TORC1 phosphorylation (4EBP1 and S6K1 (also known as p70S6K). mTOR, mammalian target of rapamycin; TORC, target of rapamycin complex.

FIG. 9.

Mitochondrial oxidative damage after Ang II. Ang II delivered for 4 weeks in an osmotic ominipump (1.1 mg/kg/d) significantly increased (A) mitochondrial protein carbonyl (nmol/mg) and (B) mitochondrial DNA deletion frequency in WT hearts, both of which are significantly ameliorated in mCAT hearts. (C). Electron micrographs demonstrate damaged/vacuolated mitochondria (arrowheads) and autophagosomes (arrow) after Ang II in WT hearts. (D) Western blots of LC-3 showed that LC-3 II/I ratio, an indicator of autophagosomes, significantly increased in WT after Ang II, and this was attenuated by mCAT. (E) NADPH oxidase isoform 4 (NOX4) significantly increased after Ang II for 4 weeks. *p<0.05, **p<0.01 compared with saline-treated WT controls, ^#p<0.05 compared with Ang II-treated WT. Ang, Angiotensin II; NADPH, nicotineamide adenine dinucleotide phosphate.

FIG. 10.

Mitochondrial oxidative stress in Ang II-induced cardiac hypertrophy. (A) Normalized heart weight, (B) Echocardiography at baseline and after 4-week Ang II. *p<0.05, compared with saline-treated WT controls, ^#p<0.05 compared with Ang II-treated WT.

FIG. 11.

Mitochondria amplify ROS signaling in cardiac hypertrophy and failure. Ang II binds to ATR1, a Gαq coupled-receptor, then activates NADPH oxidases (NOX2 and NOX4). ROS from NOXs may contribute to mitochondrial ROS, which will then be amplified within mitochondria through ROS-induced ROS release and an ROS-mitochondrial DNA damage-increased ROS vicious cycles. Primary mtDNA damage in mice with homozygous mutation of polymerase gamma induces cardiac hypertrophy and failure through increase in mitochondrial ROS secondary to these vicious cycles. Breaking the ROS vicious cycles within mitochondria by mCAT or mitochondrial targeted SS-31 antioxidant is effective in attenuating both cardiac hypertrophy and failure. ATR1, Angiotensin II receptor 1.

FIG. 12.

Mitochondrial-targeted antioxidants SS-31 in Ang II-treated mice. (A). Left ventricular mass index (LVMI), (B). Diastolic function measured by Ea/Aa at baseline and after a 4 week exposure to Ang II. SS-31, but not NAC is protective of cardiac hypertrophy (LVMI) and diastolic function (Ea/Aa). NAC, N-acetyl cysteine.