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Saturday, 14 June 2014

Discovery: How To Reverse Old Age

Discovery: How To Reverse Old Age

Harvard researchers find protein that could reverse the aging process

A protein that's more abundant in young mice appears to reverse the aging process in older...
A protein that's more abundant in young mice appears to reverse the aging process in older animals (Photo: Rama)


Researchers from the Harvard Stem Cell Institute (HSCI) have shown that injections of a protein dubbed GDF11, when administered to older mice, appear to cause a reversal of many signs of aging. Analysis showed that every major organ system tested displayed signs of improvement, with the protein even appearing to reverse some of the DNA damage which is synonymous with the aging process itself.

The protein GDF11 is found in humans as well as mice, and is now being considered for possible human testing due to its surprising and apparently regenerative properties.

A previous study had focused on examining the hearts of mice the equivalent of 70 human years old. The mice were regularly exposed to the blood of younger mice whose blood carried a higher concentration of GDF11. Ordinarily the hearts of older mice are enlarged and weakened, however results from the previous study displayed that, thanks to the GDF11 protein present in the blood of the younger mice, the hearts of the elderly mice reduced in size, making them appear younger and healthier. The changes were not purely aesthetic however, with the mice displaying an increased ability to exercise for prolonged periods of time.

The most recent set of experiments tested the protein in two ways. The first stage of the testing involved linking the circulatory systems of an older and a younger mouse through what is known as a parabiotic system. This allowed the protein-rich blood from the younger mouse to flow through the elder's system continuously, maximizing the effect of the protein. The second method involved injecting the older mice with a concentrated dose of GDF11.

Results from the second study showed that the protein had positive effects reaching far beyond the heart. It was found that, having been exposed to increased levels of the protein, all organs examined by the researchers displayed a heightened level of function. Furthermore, whilst previous studies on the protein had focused on regenerating damaged muscle in mice, the most recent study focused on the repair of cells damaged by the aging process. The GDF11 protein was found to reverse some of this damage, allowing muscle to function as effectively as that of a much younger mouse.

Analysis of the brains of the older mice via MRI imaging displayed an increase in neural stem cells along with the development of blood cells in the brain. “There seems to be little question that, at least in animals, GDF11 has an amazing capacity to restore aging muscle and brain function,” states Dr. Doug Melton, co-chair of HSCI. The team believes that due to the increased blood flow exhibited in the brain of the elderly mice, it may be possible to reverse some of the cognitive effects of aging. The protein was also found to improve the olfactory system of older mice, greatly heightening their sense of smell.

In terms of human applications, it is hoped that a drug derived from GDF11 will lead to a cure for conditions such as diastolic heart failure. This condition is a defect which eventually causes one or more of the ventricles of the heart to deteriorate while attempting to fill the heart with blood, in order to pump it around the body. There is also a possibility that a GDF11-inspired drug could be used to combat Alzheimer's, a condition synonymous with the aging process.

Looking to the future, the team will continue studies of the GDF11 protein, with a view to begin human medical trials within three to five years.

The research papers regarding the discoveries surrounding GDF11 are available in the journal Science.

From Gizmag @ http://www.gizmag.com/gdf11-protein-aging-mice-harvard/31929/

Functioning of aged brains and muscles in mice made younger


Lee Rubin Harvard Stem Cell GDF11Lee Rubin, PhD, and Amy Wagers, PhD, (below) of the Harvard Stem Cell Institute provide more evidence that a protein known as GDF11 reverses signs of aging in mice. (Credit: B.D. Colen/Harvard University)


Harvard stem cell researchers advance understanding of aging


Harvard Stem Cell Institute (HSCI) researchers have shown that a protein they previously demonstrated can make the failing hearts in aging mice appear more like those of young health mice, similarly improves brain and skeletal muscle function in aging mice.

In two separate papers given early online release today by the journal Science—which is publishing the papers this coming Friday, Professors Amy Wagers, PhD, and Lee Rubin, PhD, of Harvard’s Department of Stem Cell and Regenerative Biology (HSCRB), report that injections of a protein known as GDF11, which is found in humans as well as mice, improved the exercise capability of mice equivalent in age to that of about a 70-year-old human, and also improved the function of the olfactory region of the brains of the older mice—they could detect smell as younger mice do.

Rubin, and Wagers, who also has a laboratory at the Joslin Diabetes Center, each said that, baring unexpected developments, they expect to have GDF11 in initial human clinical trials within three to five years.

Postdoctoral fellow Lida Katsimpardi, PhD, is the lead author on the Rubin group’s paper, and postdocs Manisha Sinha, PhD, and Young Jang, PhD, are the lead authors on the paper from the Wagers group.

Both studies examined the effect of GDF11 in two ways. First, by using what is called a parabiotic system, in which two mice are surgically joined and the blood of the younger mouse circulates through the older mouse. And second, by injecting the older mice with GDF11, which in an earlier study by Wagers and Richard Lee, MD, of Brigham and Women’s Hospital who is also an author on the two papers released today, was shown to be sufficient to reverse characteristics of aging in the heart.

Doug Melton, PhD, co-chair of HSCRB and co-director of HSCI, reacted to the two papers by saying that he couldn’t “recall a more exciting finding to come from stem cell science and clever experiments. This should give us all hope for a healthier future. We all wonder why we were stronger and mentally more agile when young, and these two unusually exciting papers actually point to a possible answer: the higher levels of the protein GDF11 we have when young. There seems to be little question that, at least in animals, GDF11 has an amazing capacity to restore aging muscle and brain function,” he said.

Melton, Harvard’s Xander University Professor, continued, saying that the ongoing collaboration between Wagers, a stem cell biologist whose focus has been on muscle, Rubin, whose focus is on neurodegenerative diseases and using patient generated stem cells as targets for drug discovery, and Lee, a practicing cardiologist and researcher, “is a perfect example of the power of the Harvard Stem Cell Institute as an engine of truly collaborative efforts and discovery, bringing together people with big, unique ideas and expertise in different biological areas.”

As Melton noted, GDF11 is naturally found in much higher concentrations in young mice than in older mice, and raising its levels in the older mice has improved the function of every organ system thus far studied.

Amy Wagers HarvardWagers first began using the parabiotic system in mice 14 years ago as a postdoctoral fellow at Stanford University, when she and colleagues Thomas Rando, MD, PhD, of Stanford, Irina Conboy, PhD, of the University of California, Berkley, and Irving Weissman, MD, of Stanford, observed that the blood of young mice circulating in old mice seemed to have some rejuvenating effects on muscle repair after injury.

Last year, she and Richard Lee published a paper in which they reported that when exposed to the blood of young mice, the enlarged, weakened hearts of older mice returned to a more youthful size, and their function improved. And then working with a Colorado firm, the pair reported that GDF11 was the factor in the blood apparently responsible for the rejuvenating effect. That finding has raised hopes that GDF11 may prove, in some form, to be a possible treatment for diastolic heart failure, a fatal condition in the elderly that now is irreversible, and fatal.

“From the previous work it could have seemed that GD11 was heart specific,” said Wagers, “but this shows that it is active in multiple organs and cell types. Prior studies of skeletal muscle and the parabiotic effect really focused on regenerative biology. Muscle was damaged and assayed on how well it could recover,” Wagers explained.

She continued: “The additional piece is that while prior studies of young blood factors have shown that we achieve restoration of muscle stem cell function and they repair the muscle better, in this study, we also saw repair of DNA damage associated with aging, and we got it in association with recovery of function, and we saw improvements in unmanipulated muscle. Based on other studies, we think that the accumulation of DNA damage in muscle stem cells might reflect an inability of the cells to properly differentiate to make mature muscle cells, which is needed for adequate muscle repair."

Wagers noted that there is still a great deal to be learned about the mechanics of aging in muscle, and its repair. “I don’t think we fully understand how this happening or why. We might say that the damage is modification to the genetic material; the genome does have breaks in it. But whether it’s damaging, or a necessary part of repair, we don’t know yet.”

Rubin, whose primary research focus is on developing treatment for neurodegenerative diseases, particularly in children, said that when his group began its GDF11 experiments, “we knew that in the old mouse things were bad in the brain, there is a reduced amount of neurogenesis (the development of neurons), and it’s well known that cognition goes down. It wasn't obvious to me that those things that can be repaired in peripheral tissue could be fixed in the brain.”

Rubin said that postdoctoral fellow Lida Katsimpardi, the lead author on his group’s paper, was taught the parabiotic experimental technique by Wagers, but conducted the Rubin group’s experiments independently of the Wagers group, and “she saw an increase in neural stem cells, and increased development of blood vessels in the brain.” Rubin said that 3D reconstruction of the brain, and magnetic resonance imaging (MRI) of the mouse brain showed “more new blood vessels and more blood flow,” both of which are normally associated with younger, healthier brain tissue.”

Younger mice, Rubin said, “have a keen sense of olfactory discrimination,” they can sense fine differences in odor. “When we tested the young mice, they avoided the smell of mint; the old mice didn’t. But the old mice exposed to the blood of the young mice, and those treated with GDF11 did."

“We think an effect of GDF11 is the improved vascularity and blood flow, which is associated with increased neurogenesis,” Rubin said. “However, the increased blood flow should have more widespread effects on brain function. We do think that, at least in principle, there will be a way to reverse some of the cognitive decline that takes place during aging, perhaps even with a single protein. It could be that a molecule like GDF11, or GDF11 itself, could” reverse the damage of aging.

“It isn’t out of question that GDF11,” or a drug developed from it, “might be capable of slowing some of the cognitive defects associated with Alzheimer’s disease, a disorder whose main risk factor is aging itself,” Rubin said. It is even possible that this could occur without directly changing the “plaque and tangle burden” that are the pathological hallmarks of Alzheimer’s. Thus, a future treatment for this disease might be a combination of a therapeutic that reduces plaques and tangles, such as an antibody directed against the β-amyloid peptide, with a potential cognition enhancer like GDF11.

Wagers said that the two research groups are in discussions with a venture capital group to obtain funding to “be able to do the additional preclinical work” necessary before moving GDF11 into human trials.

“I would wager that the results of this work, together with the other work, will translate into a clinical trial and a treatment,” said the stem cell biologist. “But of course that’s just a wager.”

From the Harvard Stem Cell Institute @ http://hsci.harvard.edu/news/functioning-aged-brains-and-muscles-mice-made-younger

For more information about longevity see http://nexusilluminati.blogspot.com/search/label/immortalism
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