If at the bottom of aging are root causes, and at the top of aging are end results, meaning organ and tissue failure and age-related disease, then the majority of aging research is focused on the middle layer of the problem in between. This middle layer is made up of the exceptionally complex changes in cellular biochemistry that take place over the course of aging, a snake-pit of long chains of cause and effect, with many feedback loops and interactions. All of this is incompletely investigated, and the links to top and bottom tiers of aging are in many places only tenuously understood or proven. Making progress towards a grand map of cellular metabolism and aging is very slow and very expensive.
The research here is an example of this type of work, illustrating that even the better-studied portions of the cellular biochemistry of aging include collections of contradictory observations and clashing evidence, yet to be explained, and that there is all too little consideration given as to why the observed changes take place. Until more attention to root causes appears on a regular basis in everyday papers such as this one, then the research community will continue to give little attention to those root causes. As a consequence little progress will be made in the matter of preventing and reversing aging. Researchers will remain in the wilderness of the middle layer, eternally cataloging, and never intervening in any effective way.
Heart failure, which is a complex pathophysiological syndrome, is one of the leading causes of mortality in the world. In the cardiovascular area, there is an age-dependent increase in the prevalence of left ventricular hypertrophy, diastolic dysfunction, and atrial fibrillation, which are not necessarily associated with classical risk factors for cardiovascular diseases. There is also an aging-related increase in vascular intimal thickening and vessel stiffness. In addition, maladaptation and/or abnormal response to stress (e,g,. pathological hypertrophy, apoptosis, replacement fibrosis, progression to heart failure) can be aging-related.
Here, we will review the contribution of Wnt/β-catenin signaling and p53 pathway, both of which play an important role in aging, to the progression of cardiac remodeling and dysfunction in the failing heart. Wnt/β-catenin signaling plays critical roles in stem cell self-renewal, development as well as adult homeostasis, and augmented Wnt/β-catenin signaling is also implicated in aging, aging-related phenotypes, and various diseases. Wnt/β-catenin signaling is activated in the failing heart. Circulating C1q was identified as a potent activator of Wnt/β-catenin signaling, promoting systemic aging-related phenotypes including sarcopenia and heart failure.
In a previous report, cardiac-specific overexpression of a positive regulator of Wnt/β-catenin signaling was found to cause extensive hypertrophy, heart failure, and premature death in mice. On the other hand, it was reported that stabilization of β-catenin attenuates adaptive cardiac hypertrophy and leads to impaired cardiac function under angiotensin II treatment. The Wnt1/β-catenin injury response activated cardiac fibroblasts to promote cardiac repair after acute ischemic cardiac injury, preserving cardiac function. In other reports, blocking of Wnt/β-catenin signaling was shown to avert adverse remodeling or improve cardiac function in animal models of myocardial infarction. In spite of such a context-dependency, Wnt/β-catenin signaling is thought to play a pivotal role in the progression of cardiac dysfunction/heart failure.
The p53 pathway also plays an important role in the pathophysiology of heart failure through the induction of aging-related phenotypes. Replicative senescence induced by telomere dysfunction and stress-induced premature senescence are mediated by p53. p53 activates a cellular response to stress signals (e,g,. DNA damage) that leads to a halt in proliferation via apoptosis or senescence. Such a depletion of cells could compromise the structure and function of tissues, which are the processes towards aging-related phenotypes and tumor suppression. In particular, because cardiomyocytes do not proliferate after birth, p53 exerts a pathogenic effect on cardiomyocytes through the induction of apoptosis.
Further investigations with multidisciplinary approaches will be required to fully clarify the molecular mechanisms underlying heart failure.