Researchers have in recent years found a number of ways to enhance regeneration in specific tissues in various laboratory species. In this one the focus is on cardiotrophin 1, and is particularly interesting when held up in comparison to what is known of the roles and relationships in heart aging from other studies of this gene. Here, researchers temporarily increase cardiotrophin 1 levels in rodents in order to produce improved regeneration of damaged heart tissue in a scenario of heart failure. Yet in the past, it was demonstrated that cardiotrophin 1 knockout mice, lacking this protein throughout their lives, live longer than their unmodified peers. This is thought to be the case because this protein spurs greater arterial stiffness and fibrosis of heart tissue, as well as greater hypertrophy as heart muscle enlarges in response to rising blood pressure and other changes that accompany aging. This hypertrophy isn't beneficial: it is a form of dysfunction, a structural alteration that weakens the heart and disarrays normal processes in ways that can lead to heart failure.
How to reconcile these opposing observations? Perhaps by looking at the way in which regeneration runs awry in old age: regenerative processes are disrupted by inflammation resulting from senescent cells and immune system failure. Fibrosis is one of the consequences, the generation of scar-like structures in place of correctly functioning tissue. Everything else being equal, more active regeneration in the heart over the long term will mean more fibrosis and consequent tissue dysfunction in this scenario, just as too little regeneration heads to a different bad end. Yet greater regeneration applied only in the short term might prove capable of more positive outcomes. Similarly for cardiac hypertrophy, if heart tissue has a greater capacity for regeneration and growth, then the possible extent of hypertrophy is correspondingly larger when it takes place over years of later life. For a short term boost in regenerative capacity that risk is diminished. This is probably an overly simplistic view; as the paper makes notes there is no clear-cut line to draw between the regulatory controls of beneficial growth and pathological growth of heart tissue.
What we might take away from this is that the rules can be very different for changes in any of the controlling mechanisms of metabolism depending on whether the long term or the short term is considered. Cellular biochemistry is complicated, and that makes it hard to find ways to manipulate it into better states that are not found normally in nature. Not that having examples in nature makes it all that much easier - look at the lack of progress towards practical calorie restriction mimetics, for example, despite this being a very easily induced and well-studied altered state of metabolism. I take this as an argument in support of the cost-effectiveness of repair-based approaches to aging and age-related disease: try to depart from the known, good biochemistry as little as possible, precisely because that is expensive and time-consuming. Instead of attempting to improve human metabolism, focus instead on repair, meaning removal of the differences between old and young tissues with the goal of restoring the known normal biochemistry of youthful individuals.
Researchers have discovered that a protein called cardiotrophin 1 (CT1) can trick the heart into growing in a healthy way and pumping more blood. They show that this good kind of heart growth is very different from the harmful enlargement of the heart that occurs during heart failure. They also show that CT1 can repair heart damage and improve blood flow in animal models of heart failure. "When part of the heart dies, the remaining muscles try to adapt by getting bigger, but this happens in a dysfunctional way and it doesn't actually help the heart pump more blood. We found that CT1 causes heart muscles to grow in a more healthy way and it also stimulates blood vessel growth in the heart. This actually increases the heart's ability to pump blood, just like what you would see with exercise and pregnancy."
Heart muscle cells treated with CT-1 become longer, healthier fibres. CT-1 causes blood vessels to grow alongside the new heart muscle tissue and increases the heart's ability to pump blood. When CT-1 treatment stops, the heart goes back to its original condition, just like it does when exercise or pregnancy end. CT-1 dramatically improves heart function in two animal models of heart failure - one caused by a heart attack (affecting the left side of the heart) and one caused by high blood pressure in the lungs (pulmonary hypertension, affecting the right side of the heart). CT-1 stimulates heart muscle growth through a molecular pathway that has traditionally been associated with promoting cell suicide (apoptosis), but CT-1 has a better ability to control this pathway.
The researchers note that while exercise could theoretically have the same benefits as CT-1, people with heart failure are usually limited in their ability to exercise. The researchers have patents pending for the use of CT-1 to treat heart conditions and they hope to develop partnerships to test this protein in patients. If this testing is successful it will take a number of years for the treatment to become widely available.
Heart muscle growth, commonly referred to as cardiac hypertrophy, is a compensatory response that matches organ size to the systemic demands of the body. Hypertrophy can be a detrimental or beneficial adaptation, depending on the type of growth that occurs. In pathologic hypertrophy, heart muscle mass increases (wall thickness) without a corresponding improvement in function. Pathologic hypertrophy is generally irreversible and readily transitions to heart failure (HF), making this maladaptive process a leading cause of morbidity and mortality. Given the prominence in disease etiology, the biochemical and molecular characteristics of pathologic hypertrophy have been intensely studied and documented.
Physiologic cardiac hypertrophy is a form of beneficial remodeling, characterized by a modest increase in heart mass with improved contractile function that is reversible. Both pregnancy and endurance exercise provide well-documented means to engage this form of organ growth, a response that can also directly antagonize pathologic hypertrophy and the progression to heart failure. Akt- and MAPK-mediated signaling cascades appear to be consistent molecular signatures of physiologic hypertrophy, yet there is a paucity of definitive information regarding systemic factors that may initiate or propagate this healthy remodeling event. Insulin-like growth factor has been examined as a probable physiologic hypertrophy agonist, yet the pleiotrophic effects of this hormone may preclude its use as a bona fide cardiac restoration agent.
Cardiotrophin 1 (CT1) was originally identified as a promising hypertrophic agonist in vitro, however its expression has been more recently linked to myocardial pathology, systemic elevated blood pressure, and cardiac failure in both animals and humans. Despite these observational data implicating CT1 in certain cardiovascular diseases, this cytokine is known to bind and engage gp130 receptor complexes, a known pro-survival signal for cardiomyocytes. Therefore, we reasoned that elevated expression of CT1 in human cardiac pathologies may simply reflect a compensatory response, which attempts to curtail disease progression through the biologic remodeling activity of CT1.
Here, we demonstrate that human CT1 protein (hCT1) engages a fully reversible form of myocardial growth, and that hCT1 attenuates the ongoing pathology and loss-of-function in an aggressive and unremitting model of right heart failure (RHF). hCT1 promotes cardiomyocyte growth in part by inducing a limited activation of an otherwise pathologic hypertrophy signal, as mediated by the caspase 3 protease. In addition, hCT1 engages a cardiomyocyte-derived vascular growth signal to ensure that the modest heart muscle growth is temporally matched with a supporting angiogenic response. Moreover, two weeks administration of hCT1 in vivo produced cardiac remodeling that was similar to that induced by exercise and, in a model of progressive RHF due to severe pulmonary arterial hypertension, improved cardiac function and reversed right ventricle (RV) dilatation. These data suggest that hCT1 fulfills the criteria as a beneficial remodeling agent, with a capacity to curtail or limit an intractable form of HF.