NIH. US: Youth serum for real? Spanish
explorer Ponce de Leon may have never discovered the Fountain of Youth,
but researchers have engineered an exciting new lead. Researchers fused
the circulatory systems of young and old mice to create a shared blood
supply. In the old mice, the young blood triggered new muscle and more
neural connections, and follow-up studies revealed that their memory
formation improved. The researchers discovered that a gene called Creb prompts the rejuvenation. Block the protein produced by Creb,
and the young blood loses its anti-aging magic. Another team
discovered that a factor called GDF11 increased the number of neural
stem cells and stimulated the growth of new blood vessels in the brains
of older animals.
Infusing blood from younger creatures into older ones in hopes of
halting—or even reversing—the aging process may sound like a macabre
scene straight out of “Game of Thrones.” However, several scientific
studies have shown that when older animals receive blood from younger
counterparts, it improves the function of stem cells throughout the
body, boosting tissue regeneration and healing. What’s not been clear is
whether this activity can also rejuvenate the brain’s cognitive powers.
Let’s face it: aging is tough on the brain. The number of neural stem
cells shrinks, producing fewer neurons; and many of the genes that
promote brain development and neural connections become less active. To
find out if young blood might hold some of the answers to this complex
problem, two teams of NIH-funded researchers—one in Massachusetts and
the other in California—recently turned to mice as a model system.
For the West Coast team, led by Saul
Villeda of the University of California, San Francisco and Tony
Wyss-Coray of Stanford University, the effort began a few years ago with
the discovery that when old mice are exposed to blood from young mice,
their neural stem cells increase. The opposite was also found to be
true: blood from old mice inhibited stem cell proliferation in young
brains and hindered certain types of memory and learning [1].
In their new work, the researchers fused the circulatory systems of
young mice (3 months old) with that of old mice (18 months old). The
procedure, called parabiosis, created a shared blood supply. As a
control, the researchers connected the circulatory systems of old mice.
After 35 days, the researchers examined the animals’ brains, focusing on
the hippocampus—the area essential to learning and memory.
In the young-old mouse pairs, exposure to young blood reactivated
genes in the older animal’s brain that encouraged neurons to make new
connections, which are key to forming memories and learning new skills.
Of particular interest was the increased activity of the Creb
gene and other plasticity genes known to be very active in developing
brains. Through confocal microscopy, researchers observed an increased
number of dendritic spines, which are connection points for neurons to
chat with each other. And, by measuring the brain’s electrical activity,
they found indications of improved communication in the dentate gyrus,
which is the input region of the hippocampus [2]. In contrast, no
significant changes were detected in the brains of the old-old mouse
pairs.
Building on those findings, Wyss-Coray, winner of a 2013 NIH
Director’s Transformative Research Award, and Villeda, winner of a 2012
NIH Director’s Early Independence Award, set out to see what the
biological changes might mean for behavior. First, they injected blood
plasma from young mice into old mice every week for eight weeks. Serving
as controls were old mice that received either plasma derived from
other old mice or young plasma that had been heated (destroying any
proteins that might be involved in the blood’s regenerative properties).
Then, the animals’ cognitive abilities were put to the test. It turns
out that old mice that received young plasma were better than controls
at remembering spatial tasks and recalling frightening experiences,
showing that their spatial and contextual memory skills had improved.
These researchers suspected that the CREB protein, a master regulator
of neuronal plasticity, orchestrated a significant number of
rejuvenating effects and that something in young blood was ramping up
its production. To explore the idea, Villeda came up with a strategy to
prevent CREB from responding; sure enough, young blood was then unable
to trigger changes in neural architecture or memory in older mice.
Meanwhile, the East Coast team, led by Lee Rubin and Amy Wagers of
the Harvard Stem Cell Institute, Cambridge, MA, was busy using mouse
parabiosis, as well as injections of a protein called growth
differentiation factor 11 (GDF11), in their quest to improve their
understanding of the rejuvenative powers of young blood. This group had
previously isolated GDF11 from young blood and shown that GDF11
injections reduced age-related thickening of the heart in mice. In a new
study focused on the brain, Wagers, winner of a 2008 NIH Director’s New
Innovator Award, and her colleagues found that either exposure to young
blood or daily injections of GDF11 could boost the number of neural
stem cells and stimulate the growth of new blood vessels in the
subventricular zone of older animals’ brains. The cognitive upside
observed in such mice was improved sense of smell [3].
Taken together, these findings from two independent groups raise the
tantalizing possibility of protecting, or even restoring, the cognitive
powers that tend to slip as people grow older. With more basic,
translational, and clinical research, scientists may someday be able to
develop treatments—replacing or mimicking the beneficial proteins found
in young blood, or blocking the detrimental ones found in old blood—that
will allow more and more individuals to experience healthy aging.
References:
[1] The ageing systemic milieu negatively regulates neurogenesis and cognitive function.
Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM,
Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS,
Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF,
Galasko DR, Xie XS, Rando TA, Wyss-Coray T. Nature. 2011 Aug 31;477(7362):90-4.
[2] Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.
Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J,
Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG,
Zou B, Simmons DA, Xie XS, Longo FM, Wyss-Coray T. Nat Med. 2014 May 4.
[3] Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors.Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL. Science. 2014 May 9;344(6184):630-4.