Although the heart is commonly thought of as something that causes us emotional joy and pain, while also providing us with the urge to make reckless decisions, we have to give it more credit. In actuality, this incredible organ will beat more than 2.5 billion times in an average adult lifetime, pumping 5-6 quarts of blood throughout the body every minute [2]. This vital function provides oxygenated blood to the entire body, ensuring that our other organs can do their jobs. As with any machine, however, constant use and degrading maintenance mechanisms can lead to decreased function. Debilitating disorders like heart disease and heart failure are on the rise in an aging population; this has given researchers powerful motivation to study these disorders with the hope of finding potential therapies.

Heart Regeneration and Aging

Many of our organs, including the skin, skeletal muscle, intestines, blood, and even the liver, can naturally regenerate. In some cases, this regeneration ability is due to resident adult stem cell populations which have two main properties: they are able to self-renew, ensuring that we don’t lose them, and they have the ability to become any of the cell types found within their respective tissues. For instance, the most well characterized adult stem cell, the hematopoietic (blood) stem cell, is able to differentiate, or become more specialized, into all the cell types of the blood, including red cells, white cells, and platelets.

Scientists have been searching for resident adult stem cell or progenitor cell populations in the heart, but the majority of the evidence indicates that these populations are either very rare or do not exist. Whether these cell populations exist or not, research has made it clear that our hearts do regenerate, albeit at an extremely slow pace, most likely due to the division of existing, mature cardiomyocytes (heart muscle cells). In a fascinating study, researchers cleverly used the historical nuclear bomb tests of the 1950’s to look at human heart regeneration. These nuclear tests released many radioactive isotopes into the atmosphere, including carbon-14. This carbon was incorporated into the tissues of people living at the time. By observing the levels of carbon-14 in these individuals over time, the researchers were able to demonstrate that the heart does indeed replace itself very slowly [3].

Whether new cardiomyocytes are generated throughout our lifetimes remains an area of intense research. Interestingly, studies in animal models, including zebrafish and salamanders, have demonstrated that these creatures are able to robustly regenerate heart tissue. For instance, you can simply cut away 20% of a zebrafish’s heart, and, within a few weeks, it will completely regenerate [4]. In mammals, the situation is entirely different. After injury to a mouse or human heart, the natural response is to generate permanent fibrous scar tissue that may impede heart function. It is important and promising to note, however, that zebrafish also produce scar tissue during heart regeneration, but for some unknown reason, this scar tissue is eventually degraded and replaced with healthy heart tissue. This suggests that sometime during our evolution, we either lost the ability to regenerate the heart, or the ability still exists but is repressed.

These results are exciting because they suggest that we may be able to enhance heart regeneration through some type of therapy, which is desperately needed. Heart failure, or the inability of the heart to pump enough blood to support other organs, is the primary cause of more than 55,000 deaths per year in the U.S., and it is estimated that this disorder costs the U.S. $34.4 billion dollars per year [5]. One of the main causes of heart failure is cardiac hypertrophy, or the growth in size of individual cardiomyocytes. Due to the enlargement of individual cells, the heart has to work harder to pump less blood, which ultimately leads to the inability to properly support other organs. Unfortunately for us, cardiac hypertrophy naturally increases with age, but therein lies the potential for discovery. By comparing old and young individuals, scientists have been trying to identify factors that can return the heart to a youthful state, with the ultimate hope of identifying factors that promote natural regeneration.

Parabiosis

One can imagine that the simplest way to rejuvenate an aging heart would be through treatment with some type of drug or protein that could easily travel through the blood. Although cell therapies, including reprogramming cells from other parts of the body into heart muscle, have gained significant research interest, they have considerable technical and regulatory hurdles to overcome. To help identify factors that could promote rejuvenation or regeneration of an aging heart, some researchers have turned to a centuries old technique known as parabiosis, or the surgical joining of two animals to develop a single, shared circulatory system (Figure 1 top). By physically joining old and young mice together, parabiosis allows researchers to expose the old heart to a youthful blood environment, or conversely, a young heart to an old environment. The beauty of this technique is two-fold. First, it does not require that you know exactly what is in the blood to see an effect, and second, any factor that you may find is already natural to the system, increasing the likelihood that it may be safe to use.

Parabiosis experiments have already been used to show that exposure to a youthful blood environment can greatly enhance muscle and neural regeneration in old mice. Recently, Richard Lee, Amy Wagers, and their colleagues at the Harvard Stem Cell Institute extended this technique to look at cardiac hypertrophy in aging mice, a study that gained considerable media attention [1]. Remarkably, they found that, when exposed to a youthful blood environment, cardiac hypertrophy was reversed in old mice. The entire heart in the old mouse significantly decreased in size after one month. Importantly, they showed that this was not due to changes in blood pressure or behavior due to the parabiosis surgical procedure. It is also interesting to note that the young mouse hearts did not increase in size during this procedure. This suggests that the old mouse blood is simply lacking the factors that cause this effect rather than containing factors that actively increase heart size.

Of course, it would not be practical to start joining the circulatory systems of children and teens to aging adults, therefore the researchers set out to find the factors responsible for this remarkable change in heart size. Initially, they did not find any differences in metabolic factors; however, when they compared the protein composition of young blood to old blood, they found 13 factors that were significantly different. One factor, which they decided to follow up on, was the protein, growth differentiation factor 11 (GDF-11).

What is Growth Differentiation Factor 11?

GDF-11, also known as bone morphogenetic protein 11 (BMP-11), is a protein that belongs to a family of cell signaling molecules known as the transforming growth factor beta (TGF-b) superfamily. This family of proteins is important for regulating embryonic development and adult tissue. GDF-11 is similar in structure to myostatin, a protein well known to regulate skeletal muscle size.

Using purified protein, the researchers in this study treated old mice with GDF-11 and were able to reproduce the findings of the parabiosis experiments, namely the reduction of cardiac hypertrophy (Figure 1 bottom). The cardiomyocytes themselves, when treated with GDF-11, had reduced expression of proteins that lead to increased cell growth, and interestingly, GDF-11 only had an effect on age-related cardiac hypertrophy. When hypertrophy was induced in young mice, this protein had no effect.

Caveats and Limitations

These remarkable findings suggest that purified GDF-11 could be used in older individuals to help reduce age-related cardiac hypertrophy. Treatment with this protein could potentially reduce the incidence of heart failure; however, we also must be aware of certain caveats and limitations in this study.

Since this study was conducted in mice, it is not guaranteed that this protein will work similarly in humans. Significant testing will need to be done before there are broad human clinical trials. The study also only considered naturally aging hearts with no indication of whether this protein could help with any heart-related diseases, which are common causes of heart failure. Moreover, it is not clear from the study whether heart function was actually improved after treatment with GDF-11. The researchers did not test heart rate, blood pressure, or the ejection fraction, a measure of how much blood volume the heart pumps in one contraction, in mice only treated with GDF-11. Although cardiac hypertrophy was significantly reduced, this is not the only significant factor regulating heart function. For instance, it is known that as we age, our heart muscle cells increase their ploidy, or the number of copies of the genome that they each contain. Although the majority of the cells in our body contain two copies of the genome, as the heart gets older and cardiac hypertrophy takes place, many of the cardiomyocytes contain anywhere from 8 to 16 copies of the genome, which may significantly alter their biology. This study did not investigate the ploidy of the cells, so it is unclear how well GDF-11 returns the heart to a ‘youthful’ state. With respect to GDF-11, it is also clear that this is not the only factor having an effect, indeed, the researchers found 12 other potential factors that could be interesting to study. Finally, GDF-11 is highly produced in the spleen, and it is possible that treatment with this protein in older mice could affect other organ systems.

The exciting finding that GDF-11 can reduce age-related cardiac hypertrophy will certainly lead to a host of additional studies down the road. This study highlights the fact that scientists can discover rejuvenation or regenerative factors through interesting techniques like parabiosis. Investigating differences between old and young animals could potentially lead to a variety of therapies that may ultimately help our aging population.

Figure 1: This figure shows an overview of the paper published in the journal Cell by researchers from the Harvard Stem Cell Institute. At the top, a young and old mouse are surgically joined by parabiosis, and after 4 weeks time, researchers found that the old mouse heart had decreased in size. When they examined the blood of old and young mice, they found a protein, GDF-11, that when injected into old mice had the same effect on heart size (bottom). [1]

Video: The lead researchers on the project, Richard Lee and Amy Wagers, discuss their experiment and findings.


Jonathan Henninger is a graduate student in the Biological and Biomedical Sciences Program at Harvard University.

References:

[1] Loffredo, F.S., et al., Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell, 2013. 153(4): p. 828-39.http://www.cell.com/abstract/S0092-8674(13)00456-X

[2] Cleveland Clinic “Heart Facts” http://my.clevelandclinic.org/heart/heart-blood-vessels/heart-facts.aspx

[3] U.S. News and World Report, “Cells Renew in the Human Heart” http://www.usnews.com/science/articles/2009/04/03/cells-renew-the-human-heart

[4] “Zebra fish may hold clues to human cardiac regeneration” http://www.theheart.org/article/263615.do

[5] Centers for Disease Control and Prevention “Heart Failure Fact Sheet” http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm

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