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Wednesday, January 13, 2016

REVERSING AGING WITH ONE PROTEIN: GDF11


The pioneering discovery that young blood—and in particular, a single blood protein called GDF11—can regenerate many organs, including your Heart and your Brain
This research is truly the future finding its way back to us right now. The effects they show with GDF11 are remarkable, but in a sense inevitble once one realizes the nature of the incredible system of life and death of cells in which that one protein works.
The fact of which we have been speaking here for a while, that we are being reborn every day from stem cells nursing in niches in different tissues and just waiting to be allowed to "graduate" from state to stage of differentiation before they can go "on stage" to perform is dependent on a complex interaction among various elements.
Growth differentiation factor 11 (GDF11) also known as bone morphogenetic protein 11 (BMP-11) is a protein that in humans is encoded by the GDF11 gene GDF11 belongs to the transforming growth factor beta superfamily. It operates in the brain as well as in the heart and muscles. Various different TGFBeta Family Growth factors operate in different tissues of the body.
GDF11 is of interest to us here because it already is known to play a similar role in the brain as a regulator of neurogenesis. We shall be dealing with the "system" of which GDF11 is a part in the brain extensively. If you wish to look ahead, here is one recent study of a more technical nature:
Transcriptional basis for the inhibition of neural stem cell proliferation and migration by the TGFβ-family member GDF11.
http://www.ncbi.nlm.nih.gov/pubmed/24244313
But we mention this neurogenesis research because we truly wish the reader to appreciate how relevant and imminent the knowledge being uncovered in this area of "anti-aging" is to our understanding of neuroscience and the Brain.
Whether this protein GDF11, which was found by sheer technological force s to be the likeliest canddiate through the analysis of differencebetween the blood of the young organism and the blood of the older organism which shared their circulation, is the ultimately optimal messenger that we needed to utilize while it was signalling in that complex over all system is not yet clear.
What is clear however is that these researchers have regenerated hearts in mice by interceding in this process of progression from stem cell to final functioning heart cells. And it also clear that since muscle and nerve are similarly myeloid in origins, very much of what works for muscle tissues works for nerves and neurogenesis in the brain.
Indeed research has already been done where young blood has renewed and revitalized the brains of aged mice (we'll be posting on that shortly)
The Wagers study at Harvard is described below
Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy
http://www.cell.com/abstract/S0092-8674(13)00456-X
And this is an interview with Wagers from which most of this post is drawn
It was a series of “oh my moments,” Wagers said, when her group, and that of Harvard neurologist Lee Rubin, found that GDF11 can rejuvenate stem and differentiated cells in muscles and brains of old mice—in many ways, including via DNA repair. “On the other hand, all that occurred only because we had been looking for a long time for something that could recapitulate the effects of heterochronic parabiosis,” she said
The latter involves hooking old mice to young via the blood system, which Wagers and others used a decade ago to prove muscles in old mice can rejuvenate. Similar Stanford University work, which Wagers called “exciting,” was also named a 2014 Science breakthrough. It boosted cognition in old mice by giving them infusions of young blood, and led to a clinical trial.
Heterochronic parabiosis was first described in 1864 by Paul Bert, a French zoologist. When Cornell University’s Clive McKay tried it in the 1950s, he noted that it appeared to rejuvenate old mice, but he lacked the tools to prove it.
Then in 2005 Wagers, in collaboration with her former mentor, Stanford stem cell scientist Irv Weissman, along with Stanford biologist Thomas Rando and post doc Irina Conboy, published a paper in Nature, which found that parabiosis revives aging mouse muscle.
Wagers began analyzing young blood, trying to find a driving molecule behind the stunning effects they had all seen.
In 2013, Wagers and Lee showed that GDF11 tightened hypertrophic mouse hearts, restoring efficiency. This year, Wagers and Rubin published two separate Science papers finding GDF11, in the equivalent of “70-year-old” mice, rejuvenated muscles enough to improve exercise capacity, and rejuvenated brain neurons and blood vessels well enough to improve sense of smell.
As noted, a Stanford group—led by neurologist Tony Wyss-Coray—has launched a clinical trial for Alzheimer’s based on a similar approach detailed in a 2014 Nature Medicine study. In the study, old mice performed better cognitively after receiving several infusions of young blood. More synaptic connections formed in their hippocampi. The related Phase 1 clinical trial is giving 18 patients with mild-to-moderate Alzheimer’s many transfusions of young blood.
Her group has narrowed the source of GDF11 to three different cell types, for which they have animal models. “We are working very hard on that. The mRNA transcript is present in many cell types, so the key question is where the majority of the production happening.
Our own impression here is that the particular cell of origin is of less interest than understanding the complex system dynamics of the various components in this progression of from stem cells through pluripotent cells to differentiation to various cell types and then when they are "ready for prime time" to performing with their predecessors.
It seems to us that the microglial cells are at the very top of the list of likely suspects for being the most important regulators. but that, of course, astrocytes are involved as are T-cells...as well as the older cells already "on stage"
Most likely the GDF11 is providing a quintessential "butterfly" effect when a complex system can be sent into another pattern by intervention at one moment in the overall harmony of the whole system. But that still is all the more remarkable if that is the case.
Wagers asks, "If you deplete it from a particular cell source, do you cause a decline in blood levels? We should know shortly. This is a big deal because we still don’t know why GDF levels decline with age. One possibility is that the cells that make it, make less. The other possibility is that the cells that normally make it are lost with age. If it’s the latter, another therapeutic avenue is to boost the number of those cells.”
Cells affected are sometimes multipotent stem cells, sometimes not. “The heart remodeling involved no stem cells,” Wagers said. “Adult cardiomyocytes changed their size. Terminally differentiated satellite muscle cells underwent a remodeling of their structural integrity. In the brain, neural stem cells expanded. But we don’t think stem cells were involved in remodeling the blood vasculature.”
A really important question is `Do you need to continuously supply the factor, or does it re-set the system?’ So far there is some evidence it re-sets.” The Stanford transfusion work is encouraging as “it says whatever activity is causing the changes persists in plasma for a period of time.” Aging may be about “imbalance of signals.”