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Old Mice, Hooked to Young Mice, Grow Younger

Wed, 11/06/2013 - 1:31pm
Cynthia Fox

This fall, Harvard University regenerative biologist Amy Wagers hooked up the circulatory systems of mice with multiple sclerosis (MS) to those of young healthy mice. She and a global team found that factors in the young blood prompted anti-inflammatory immune cell formation. This, in turn, actually regenerated the dying myelin sheaths wrapped around neuronal axons that are the very signature of MS.

A commentary in Nature Reviews Neurology said a new MS drug may come from the work. “Hope is on the horizon,” the title said.

But Wagers’ tiny armies of “heterochronic parabiotic mice” are lightyears more talented than that. In a 2005 Nature, with her former mentor, Stanford University stem cell pioneer Irving Weissman, she reported hooking up young to old mice and rejuvenating the old mouse livers. A factor in the young blood prompted liver stem cell proliferation in the oldsters.

Then there was the 2012 Cell Stem Cell parabiosis paper she wrote with stem cell biologist Robin Franklin of the University of Cambridge, in which Wagers reported that monocytes from young mice, pumping through the bloodstream of older mice, rejuvenated axon myelination—for a lifetime.

And this May, in Cell, she, Richard Lee, and others from Harvard reported that, after four weeks of parabiotic exposure to young mouse blood, cardiac hypertrophy in old mice “dramatically regressed.” They discovered a growth factor in young mice called GDF11 declines with age, and prompted the rejuvenation. Later, treatment of old mice with externally administered GDF11 “recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.”

“Amy Wagers is a leader in stem cell biology—full out,” Wagers’ Harvard Stem Cell Institute colleague Kevin Eggan told a recent New York Stem Cell Foundation (NYSCF) conference, giving her the NYSCF-Robertson award.

Amy Wagers, PhDWagers first turned to heterochronic parabiosis—the coupling of two blood systems—for a different purpose while in Weissman’s lab in the early 2000’s. At that time, many researchers were claiming adult stem cells were so plastic they could form different tissues; that is, that blood stem cells could form skin, skin stem cells could form blood, etc.  But when she hooked up the blood systems of two mice, after “labeling” one mouse’s cells, she found blood stem cells from one mouse only formed blood in that second mouse—it formed no other tissues. That work helped “settled the score once and for all,” Eggan said. “Blood stays blood.”

Because the plasticity approach had many fans, her stand took “resiliency,” said Eggan. “She’s a role model.”

Ever since, in her own Harvard lab, she has focused on the ways aging affects “stem cell potential throughout life,” she told the NYSCF. “Aging perturbs ability of tissues to maintain themselves. It perturbs homeostasis (the balance of body systems), repair after injury, the function of many tissues.” It does all this, she surmised at the outset, by affecting “resident progenitor cells.”

It was thus possible, she thought, “global regulators, maybe in the bloodstream,” may be involved. Blood, after all, “has access to all tissues of the body.”

So far, she has been proving her hunches correct.

“Our lab, with labs at Berkeley, UCSF and Stanford, have used heterochronic parabiosis to demonstrate, in a series of papers, that exposure to a youthful circulatory system can enhance, in older mice, their satellite muscle cells, their progenitors for remyelination, and neural stem cells. This has led us to conclude that age influences progenitor stem cells.”

It has also led the labs to start identifying possible drug candidates, like activin-A, which prompted the remyelination in the MS mice, and the GDF11 that reduced cardiac hypertrophy.

The latter, she said, “accounts for more than 50 percent of heart failure patients over 75.” The “reversion” her group saw in the thickened walls of her old mice after exposure to four weeks of young blood was “remarkable.”

To show that it was not a behavioral change, a case of the older mice getting exercise being dragged out on the town by their young friends, her team conducted “sham parabioses.” There was no reversion of cardiac hypertrophy in such cases.

She and others have also found heterochronic parabiosis improves skin healing in diabetic mice.

Heterochronic parabiosis has been around for almost 100 years, leading to advances in immunology, among other fields. Wagers is the first to aggressively use it to explore stem cell aging.

In upcoming months, Wagers says, her team will use heterochronic parabiosis “to look at changes in blood and immune function, as well as changes in the nervous system.”

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