Reversing Aging Processes with One Protein: A 2014 Breakthrough

The pioneering discovery that young blood—and in particular, a single blood protein called GDF11—can regenerate many organs, was named by Science as one of the ten top breakthroughs of 2014.

Furthermore, a key group behind the work—Amy Wagers’ Harvard University stem cell team—expects to “shortly” identify the human cells that generate GDF11, she told Bioscience Technology in a recent interview.

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.

“So way back when the data from the heterochronic parabiosis studies first came in…that was a wow moment, too,” said the 41-year-old Wagers. “It is surprising that this works with parabiosis. It is surprising that this works with whole blood. And it is surprising that it works with just one protein.”

Science said the work has “profound implications for aging.”

From whole systems to one protein

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.

“We’ve been looking at young blood for a long time, using many different strategies. It has been more than a decade-long process,” Wagers told Bioscience Technology. The pursuit of GDF11 “was pushed forward by two observations. First, we did some transcriptional profiling of cells that were targets of this rejuvenation, muscle satellite cells from old mice, and rejuvenated cells from old mice that had been joined to young mice. We found that one of the key transcriptional pathways that was deregulated in the old cells, but restored to a more youthful pattern after heterochronic parabiosis, was the TGF signaling pathway (of which GDF is a part). So we were interested in that pathway.”

She continued: “Then, through cardiologist Rich Lee of Harvard, we had a collaboration with Somalogics, a biotech that does aptamer-based screening of proteins in circulation. They analyzed for us the blood of young and old mice and found 13 analytes that reliably distinguished young versus old. Number two on that list was GDF11. So we got excited about GDF11. It was pulled out of the screen, and it was in the signaling pathway that we knew was deregulated and restored after heterochronic parabiosis.”

A last consideration, she said, was “practical. The recombinant GDF11 protein is available commercially so we could quickly test impact of changing levels.”

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.

Clinical trials

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.

Wagers is headed for clinical trial as well, but wants to answer many questions first. Her group has finished the first of three studies gauging how long effects of GDF11 last. The above 2005 paper showed effects of parabiosis lasted three weeks, the time span studied. “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.”

All kinds of cells affected

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.”

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. 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.”

The group sees no tumors—but it is looking. “After treatment with GDF11 we see cells no longer carry DNA damage. So it is unlikely we are causing a proliferation of DNA-damaged cells. But to make sure nothing in the DNA repair process goes awry, we have treated mice for 60 days with GDF11. There is no increased incidence of tumors. But we are gearing up to go longer and use more sensitive models.”

That the protein prompts some DNA repair is a huge advantage, as there are worries with other techniques that DNA can be damaged. “And it is really exciting that GDF doesn’t select for certain cells. It looks like this happens to every cell.”

The group seeks to modify GDF, however, as in its protein state, too much of it may be needed per patient. They are also looking at mimetics, smaller molecules that could engage receptors and prompt cells to produce GDF11 themselves.

“GDF is unique in that it has the potential to be a biomarker for aging. It has the potential to be a therapeutic. And it has the potential to explain mechanistically both the process of degeneration, and regeneration,” Wagers concluded.