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Parabiosis Points to GDF-11 as a Means to Reverse Age-Related Cardiac Hypertrophy

Posted: May 12, 2013 at 3:05 am

Parabiosis involves joining the circulatory systems of two animals. This is of interest for a number of studies in which old mice and young mice are linked together, known as heterochronic parabiosis. The young mice acquire a little of the metabolic, cellular, and gene expression changes characteristic of old mice, while in the the old mice some of these measures reverse towards more youthful levels. In stem cell activity in particular, the environment of signals present in the blood seems to dictate age-related decline as much as does any inherent damage to stem cells or their niches. This reinforces the view of stem cell aging as an evolved reaction to the cellular damage of aging that acts to extend life by reducing cancer risk, but at the cost of a slow decline into death due to ever more poorly maintained tissues and organs.

Heterochronic parabiosis studies in mice have been taking place for some years now, and researchers are beginning to link differences in gene expression and protein levels in old tissues versus young tissues to specific age-related conditions. The next logical step is to see if age-related dysfunction can be reversed by changing these protein levels in old animals:

Young blood reverses heart decline in old mice

Pumping young blood around old bodies - at least in mice - can reverse cardiac hypertrophy - the thickening and swelling of the heart muscle that comes with age and is a major cause of heart failure. After just four weeks, the older mouse's heart had reverted to almost the same size as that of its younger counterpart. The hearts of the young mice were unaffected, even though they were pumping some blood from the older mice.

After ruling out the effect of reduced blood pressure on the older mice, the team identified a potential candidate: a protein called GDF11, which was present in much higher quantities in the blood of the young mice. To test the effect of GDF11, the researchers gave old mice with cardiac hypertrophy daily injections of it for 30 days. At the end of the treatment, their hearts were significantly smaller than those in a second group of mice of the same age and with the same condition, but that had been injected with saline.

Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy

The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation.

Using modified aptamer-based proteomics, we identified the TGF-? superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.

Overriding declines in stem cell activity and forms of tissue degeneration by changing the levels of protein signals present in aged tissues is clearly going to be an important field of medicine in the near future. It may ultimately even take over from stem cell transplants as the principle mode of treatment for many age-related conditions. Some of those transplant therapies are most likely working through the same mechanisms, after all. Regeneration happens because the introduced stem cells are altering the signaling environment and waking up native stem cells, not because they are building new cells and patching up tissue structures.

However, one caveat is that this sort of work doesn't address any of the cellular and molecular damage that initiated the evolved response to reduce stem cell activity. That damage is still there: mitochondrial DNA mutations, high levels of oxidative damage, harmful build up of various forms of metabolic byproducts in and around cells, and so on. At the very least one would expect a growing risk of cancer to accompany a resurgence in stem call activity in an old person - which may be an entirely acceptable risk as cancer therapies improve past chemotherapy and towards targeted cell killers with no side effects.

Even if short term benefits can be obtained via altered signaling protein levels in old tissue, it is still the case that the underlying damage of aging must be repaired. Boosting stem cell activity so far appears to be a better class of potential treatment for many conditions than the best of what can be found in the clinic today, but it is still a form of patching over the underlying causes rather than fixing them.


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