GDF11 Levels Correlate with Mouse Strain Life Spans and are Strongly Heritable
Growth differentiation factor 11 (GDF11) is a protein that appears connected to regulation of stem cell activity in response to rising levels of cell and tissue damage that occur with aging. GDF11 levels fall with aging, as does stem cell activity, and increased GDF11 has been shown to increase stem cell activity in aged mice, producing benefits to health and organ function. There is still some debate over exactly what is going on under the hood in the GDF11 studies carried out to date, and whether researchers are correctly interpreting the results, however. A number of groups are presently exploring the molecular and genetic mechanisms that determine variations in GDF11 levels, with an eye towards the goal of therapies that can compensate for falling levels in aged individuals, and here is news of recent research on this topic:
Previous studies have found that blood levels of this hormone, growth differentiation factor 11, decrease over time. Restoration of GDF11 reverses cardiovascular aging in old mice and leads to muscle and brain rejuvenation. Scientists have now discovered that levels of this hormone are determined by genetics, representing another potential mechanism by which aging is encoded in the genome. Future studies will seek to reveal why GDF11 levels decrease later in life and whether they can be sustained to prevent disease. "Finding that GDF11 levels are under genetic control is of significant interest. Since it is under genetic control, we can find the genes responsible for GDF11 levels and its changes with age."The study confirmed results from previous experiments showing that GDF11 levels decrease over time and also showed that most of the depletion occurs by middle age. In addition, the study examined the relationship between GDF11 levels and markers of aging such as lifespan in 22 genetically diverse inbred mice strains. Of note, the strains with the highest GDF11 levels tended to live the longest. Using gene mapping, the researchers then identified seven candidate genes that may determine blood GDF11 concentrations at middle age, demonstrating for the first time that GDF11 levels are highly heritable. "Essentially, we found a missing piece of the aging/genetics puzzle. Very generally, we've made an important step toward learning about aging and why we age and what are the pathways that drive it. It's the first step down a long road, but it's an important step."
Link: http://news.uga.edu/releases/article/link-between-genetics-aging-0216/
Reason: I think you're right that downregulation of GDF11 and other signaling changes correlated with aging are responses to accumulating cellular damage of various sorts (with the aim of lowering stem cell activity in order to lower likelihood of cancer, probably). However, it also seems that GDF11 and other similar things might be important targets in a package of robust rejuvenation therapies--if your body, for some reason, lacks the ability to re-upregulate these stem cell controlling signals even after damage has been cleared, then some therapy would be useful to force the upregulation. Or is there evidence that upregulation would automatically occur once damage is cleared? If so, then I guess research on GDF11 isn't directly useful to the SENS project, but I doubt the evidence points conclusively one way or the other yet.
TGF-beta interacts with the same ALK5 receptor as GDF-11 but is significantly available in much greater quantity and rises with age leading to stem cell decline. One of the main contributors to this increase is Glucosepane and I think this is really where we should be focusing all efforts, remove AGE we should see results. I think GDF-11 is a distraction from fixing the real problem AGE!
One only has to look at the Conboy work to see evidence of this and their explanation:
GDF11 abdicates the throne of systemic rejuvenation
As recently revealed, the key findings on diminished levels of GDF11 with age and of the positive effects of this protein on myogenesis are not reproduced [36, 40–42]. Very importantly, this would not come as a shock if one would read the relevant papers. Based on the science, GDF11 is 90% identical to myostatin, which inhibits (not activates) myogenesis. GDF11 in neurogenesis serves to limit the numbers of neural stem cells [43, 44] and this discrepancy was not cited or discussed in the pro-rejuvenation papers. GDF11 signals through the same receptor as TGF-beta1 and myostatin (more efficiently than myostatin [40] and inhibition (not activation) of this ALK5 receptor has been shown to enhance and rejuvenate myogenesis and also, neurogenesis [6, 37]. The bulk of data questions the anti-aging effects of GDF11, and makes the Cell Metabolism paper important for avoiding years of unproductive research in the wrong directions.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637204/
When I was reading the Irina Conboy's paper earlier a couple of days ago, I found this cited paper :
http://www.ncbi.nlm.nih.gov/pubmed/26372181
And it made me think of something.
They can't measure GDF11 separately from myostatin in vivo (in normal mice anyway).
So when they ran the tests "supplementing" the mice with GDF11 which they thought failed with age, what they actually did was superdose the mice with GDF11 far beyond the normal range of that protein. So what I think happened is - they simply found a cost inefficient way to inhibit myostatin. And we already know myostatin inhibition leads to muscle growth.
It's just a theory.
Not only do you have the GDF11/GDF8 Level issue, but now immunoglobulin also is messing up the results.
The problem with testing for GDF11 levels are even worse, according to a paper
by Wagers etc..
"Furthermore, we showed by Western analysis that the apparent age-dependent increase in GDF11 levels, as reported by Egerman et al, is attributable to cross-reactivity of the anti-GDF11 antibody with immunoglobulin, which is known to increase with age." http://www.ncbi.nlm.nih.gov/pubmed/26489925
I wonder how many of the papers already published were dependent on this anti-GDF11 antibody?