Parabiosis Points to GDF-11 as a Means to Reverse Age-Related Cardiac Hypertrophy
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.
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-β 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.
What's the basis for these comments about "youngblood" type treatments increasing the risk of cancer? Is there some empirical evidence that this will happen? Did the old mice in the studies develop cancer? Or is it just pure speculation?
@Chris: Speculation based on what is theorized about the evolutionary reasons for stem cell decline.
Well some empirical evidence would be more convincing. Actually, there are some natural experiments that could yield some empirical data because we have transplanted organs from older donors to younger recipients. I haven't studied this in detail, but the reports I've read have the organs functioning well and no reported problems with cancers. The mice studies could be extended to investigate cancer risk if this hasn't been done already.
"(...) 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," as in SENS 7 categories of damage. But shouldn't this change in the signaling be one of the categories of damage (and repair)? I would imagine that the change in signaling is directly related to the epigenomic changes (and to a small extent to the genetic changes). So, does any of the 7 categories of damage created by de Grey cover recovery of the epigenetic changes? Oncogenic nuclear mutations and epimutations are related only to the cancer, but not necessarily to the changes in an organ like heart, right? So maybe junk inside and outside of a cell causes these type of epigenetic changes and if one clears the junk, this type of heart-restoring signaling will occur?
@nanotech.republika.pl: essentially yes, my take is that the forms of damage outlined in SENS (such as amyloid, lipfuscin, and mitochondrial DNA damage) are the upstream cause of these epigenetic changes. One of the markers of success that should result from early attempts at implementing SENS technologies is some degree of reversal of these age-related epigenetic alterations.
I wonder whether getting this sort of treatment would be regarded as taking a drug or a supplement. The way I understand it is that GDF11 is a protein circulating in everybody's blood and the envisaged treatment would supplement the amount for older people to match the levels in younger people.
So what sort of testing or clinical trials would be needed if any?
There doesn't seem to anything to patent or to make outrageous profits from, so I wonder how the drug companies view this discovery?
There was also the CCL11 story from Stanford using 24 month and 3 month mice in 2011.
So, the 1990s rumor about a Greek politician who traveled to a specific European country to get massive blood transfusions of young blood in order to reverse some of his aging might be true? :)