Fight Aging!

The heart is one of the least regenerative of tissues in mammals, and we might well stop for a moment to ask why this is the case. Species capable of exception regeneration, such as salamanders and zebrafish, can regrow entire sections of the heart when injured. But even restricting ourselves to a consideration of mammals, why is it that the heart cannot regenerate as well as, say, the liver, the most regenerative of adult mammalian organs? Asking why the heart cannot regenerate goes hand in hand with asking how to change this state of affairs. There are a fair number of research groups involved in various different approaches to the questions above and the consequent development of treatments. It is a busy corner of the field. Even putting aside work on the comparative biology of salamanders, zebrafish, and other proficient regenerators, in just the last few months there have been papers on the manipulation of PORCN and activation of STAT3 as ways to enhance heart regeneration, bringing it more in line with other tissues.

What would we gain with a more regenerative heart? Probably a lower mortality rate for cardiovascular disease, though it is hard to say just how most of these manipulations would interact with the disruption of regenerative processes and reduced tissue maintenance that is present in older individuals. Any improvement in healing would reduce mortality following a heart attack, but this is a poor second best to preventing such injuries from happening in the first place. I think the most likely place for this sort of thing in the future roadmap for applied rejuvenation biotechnology is to help remediate the structural damage done to heart tissue over the course of aging. The first old people to undergo repair therapies that remove the low-level cell and tissue damage that causes aging will still be left with hearts that have remodeled and weakened as a consequence of decades of an increasing load of that damage. You might read around the topic of ventricular hypertrophy in this context, for example. These structural changes will not fix themselves, as things stand in the normal operation of even youthful human biology, and thus some form of enhanced and guided regeneration will be required to set matters to rights.

Here, I'll point out a couple more examples of recent research into heart regeneration: why it is suppressed, and how it might be improved. They are quite different from one another, and from the examples noted above, which is encouraging. When there are numerous diverse approaches to a problem in biotechnology or medicine, it is that much more likely that at least one of the approaches will, in the end, prove both useful and practical.

New insight into why the heart does not repair itself

Heart muscle is one of the least renewable tissues in the body, which is one of the reasons that heart disease is the leading cause of death. Researchers have studied pathways known to be involved in heart cell functions and discovered a previously unknown connection between processes that keep the heart from repairing itself. "We are investigating the question of why the heart muscle doesn't renew. In this study, we focused on two pathways of cardiomyocytes or heart cells: the Hippo pathway, which is involved in stopping renewal of adult cardiomyocytes, and the dystrophin glycoprotein complex (DGC) pathway, essential for cardiomyocyte normal functions."

Previous work had hinted that components of the DGC pathway may somehow interact with members of the Hippo pathway. The researchers genetically engineered mice to lack genes involved in one or both pathways, and then determined the ability of the heart to repair an injury. These studies showed for the first time that dystroglycan 1, a component of the DGC pathway, directly binds to Yap, part of the Hippo pathway, and that this interaction inhibited cardiomyocyte proliferation. "The discovery that the Hippo and the DGC pathways connect in the cardiomyocyte and that together they act as 'brakes,' or stop signals to cell proliferation, opens the possibility that by disrupting this interaction one day it might be possible to help adult cardiomyocytes proliferate and heal injuries caused by a heart attack, for example."

Young at Heart: Restoring Cardiac Function with a Matrix Molecule

Heart disease remains the leading cause of death worldwide, yet the few available treatments are still mostly unsuccessful once the heart tissue has suffered damage. Mammalian hearts are actually able to regenerate and repair damage - but only up to around the time of birth. Afterward, that ability disappears, seemingly forever. Research at has uncovered a molecule in newborn hearts that appears to control the renewal process. When injected into adult mouse hearts injured by heart attacks, this molecule, called Agrin, seems to "unlock" that renewal process and enable heart muscle repair.

Following a heart attack in humans, the healing process is long and inefficient. Once damaged, muscle cells called cardiomyocytes are replaced by scar tissue, which is incapable of contracting and thus cannot participate in pumping. This, in turn, leads to further stress on the remaining muscle and eventual heart failure. Heart regeneration into adulthood does exist in some of our fellow vertebrates. Fish, for example, can efficiently regenerate damaged hearts. Closer relatives on the evolutionary tree - mice - are born with this ability but lose it after a week of life. That week gives researchers a time window in which to explore the cues that promote heart regeneration.

Researchers believed that part of the secret might lay outside of the heart cells themselves - in the surrounding supportive tissue known as the extracellular matrix, or ECM. Many cell-to-cell messages are passed through this matrix, while others are stored within its fibrous structure. So the team began to experiment with ECM from both newborn and week-old mice, clearing away the cells until only the surrounding material was left, and then observing what happened when bits of the ECM were added to cardiac cells in culture. The researchers found that the younger ECM, in contrast to the older, elicited cardiomyocyte proliferation.

A screening of ECM proteins identified several candidate molecules for regulating this response, among them Agrin. Agrin was already known for its effects on other tissues - particularly in the neuromuscular junction, where it helps regulate the signals passed from nerves to muscles. In mouse hearts, levels of this molecule drop over the first seven days of life, suggesting a possible role in heart regeneration. The researchers then added Agrin to cell cultures and noted that it caused the cells to divide.

Next, the researchers tested Agrin on mouse models of heart injury, asking whether it could reverse the damage. Indeed, they found that following a single injection of Agrin mouse hearts were almost completely healed and fully functional, although the scientists were surprised to find that it took over a month for the treatment to impart its full impact on cardiac function and regeneration. At the end of the recovery period, however, the scar tissue was dramatically reduced, replaced by living heart tissue that restored the heart's pumping function. The researchers speculate that in addition to causing a certain amount of direct cardiomyocyte renewal, Agrin somehow affects the body's inflammatory and immune responses to a heart attack, as well as the pathways involved in suppressing the fibrosis, or scarring, which leads to heart failure. The length of the recovery process, however, is still a mystery, as the Agrin itself disappears from the body within a few days of the injection.

If in a speculative mood, you might revisit research published last year in which the authors demonstrated that extracellular matrix taken from zebrafish, a species capable of regenerating heart tissue, produced enhanced regeneration in mouse hearts following transplant. It would be interesting to see whether or not agrin is the mediator of that effect as well.