This open access paper takes a brief tour of the dominant themes in the aging of heart tissue, viewed structurally and biochemically. These are some of the changes that have yet to be assembled into a coherent and generally agreed upon chain of events, starting with fundamental cellular damage, and proceeding through successive layers of cause and consequence in reaction to that damage. Most of the research community begins a line of inquiry with an investigation of one facet of the aged, diseased state. Researchers then attempt to work backwards to identify and address proximate causes of the observed problems, one by one, producing marginal improvements. The alternative approach of starting with fundamental damage and attempting to fix it in order to observe a resulting sweeping improvement all the way down the chain of consequences has far too little support. Note the links to the list of fundamental damage from the SENS rejuvenation research portfolio in the items below: mitochondrial damage and amyloid are mentioned directly; senescent cells and cross-linking drive harmful extracellular matrix changes; cross-linking also stiffens arteries, which produces hypertension, which in turn drives remodeling of heart structure.
The average lifespan of the human population is increasing worldwide, mostly because of declining fertility and increasing longevity. It has been predicted that, in 2035, nearly one in four individuals will be 65 years or older. With age being the dominant risk factor for the development of cardiovascular diseases, their prevalence increases dramatically with increasing age. At the end of the twentieth century, researchers announced the emergence of two new epidemics of cardiovascular disease: heart failure and atrial fibrillation. The prevalence of heart failure in the adult population in developed countries is 1-2%, which rises to more than 10% among persons 70 years or older. The same trend is seen for atrial fibrillation, with a prevalence rising from 0.12 - 0.16% in persons younger than 49 years, to 3.7-4.2% in persons aged 60-70 years, to 10-17% in persons aged 80 years or older. Since there is a clear association between aging of the population and increasing prevalence of cardiovascular disease, cardiovascular aging most likely affects pathophysiological pathways also implicated in the development of cardiovascular disease. Therefore, a better insight into cardiac aging may unravel factors implicated in cardiac pathophysiology and help towards improved prevention of human cardiovascular disease.
On a structural level, the most striking phenomenon seen with age is an increase in the thickness of the left ventricle (LV) wall as a result of increased cardiomyocyte size. This hypertrophy affects the LV in an asymmetrical way, leading to a redistribution of cardiac muscle. In the elderly, atrial contraction plays a much greater role in LV filling during diastole than in the young population. This change in function is associated with the development of atrial hypertrophy and dilation. Left atrial size has been associated with the presence of atrial fibrillation, indicating that atrial remodeling favors the development of this arrhythmia.
Remodeling at the cellular level includes a loss of cardiomyocytes and sinoatrial node pacemaker cells with age, and may contribute to the compensatory development of hypertrophy. This compensatory remodeling process may also involve changes in the composition of the extracellular matrix. The function of the extracellular matrix is to maintain the myocardial structure throughout the cardiac cycle. Hereby it plays an important role in the elastic and viscous properties of the LV. Changes in both the quantity of fibrosis and in the type of collagen fibers have been associated with old age in human hearts. It is easy to imagine that changes in the elastic properties of the LV caused by fibrosis may eventually lead to diastolic dysfunction. Indeed, in hypertensive heart disease patients, more severe diastolic dysfunction has been associated with a more active fibrotic process.
Another histopathological change found in cardiac tissue of old people is amyloid deposition. An autopsy study on a Finnish population aged 85 or over showed the presence of amyloid deposits in 25%, with a strong correlation between the presence of amyloid and the age at time of death. Amyloid found in heart of the elderly is derived from the transthyretin molecule. With age, this molecule may become structurally unstable and result in the development of misfolded intermediates that aggregate and precipitate as amyloid, mainly in the heart. In some cases, amyloid deposition in the heart occurs at a level that will lead to the progressive development of heart failure. This infiltrative cardiomyopathy is defined as systemic senile amyloidosis (SSA).
Cardiac function requires an enormous amount of energy and mitochondria are critical for the required ATP production in the myocardium. They also play a fundamental role in the survival and function of cardiomyocytes. Cardiac senescence is accompanied by a general decline in mitochondrial function, clonal expansion of dysfunctional mitochondria, increased production of reactive oxygen species (ROS), suppressed mitophagy and dysregulation of mitochondrial quality processes such as fusion and fission. Of these processes, the development of oxidative stress as a consequence of excessive ROS generation is the most frequently described phenomenon. The mitochondrial free radical theory of aging is debated, but in the context of cardiac disease, ample evidence exists for the existence of a pathogenic link between enhanced ROS production, mitochondrial dysfunction and the development of heart failure.