Researchers have recently discovered that administering young blood to older mice causes their hearts to beat faster, muscles to strengthen more quickly and thinking to sharpen. Now scientists are researching specific components in young blood which appear to halt brain aging.
Heterochronic parabiosis and administration of pro-youthful factors such as GDF11, clusterin, GPLD1, and a-klotho have been shown to effectively reverse functional hallmarks of brain aging by multiple pathways.
1. It thickens the heart
Scientists have begun unraveling the secret behind why blood from young mice seems to rejuvenate older ones. Two teams, from Cambridge and California, have published three papers using heterochronic parabiosis – connecting two mice (one old, one young) so their circulatory systems share blood. They found this trick delayed muscle, organ, and brain aging, with treated mice running longer on treadmills with more branching blood vessels than untreated ones and experiencing slower cognitive decline than untreated ones. Furthermore, scientists injected plasma from young mice directly into aged brains of aged mice who experienced cognitive decline reversing its key measure of cognitive decline by injecting plasma from young mice into aged ones to reverse key measures of cognitive decline by one measure or another measure.
Heterochronic parabiosis (HCP) is an established technique of surgically connecting two animals’ circulatory systems – usually aged and young animals – together to increase circulation between them. Previous research conducted with this approach has demonstrated how administering young blood to older mice counteracted age-related dysfunctions such as reduced hippocampal neurogenesis and impaired long-term potentiation; suggesting factors in an animal’s systemic environment contribute to pro-aging processes which negatively impact brains and organs alike.
Recently, large-scale proteomic comparisons of blood and cerebrospinal fluid have revealed dramatic shifts in the composition of proteins present both old and young blood, providing researchers with an opportunity to pinpoint specific proteins which accelerate aging as well as determine whether parabiosis could restore them.
Studies suggest that aging of hematopoietic stem cells (HSCs) in bone marrow contributes to pro-aging processes that impair brain function. Indeed, recent data from heterochronic HSC transplantation demonstrate this link; pro-ageing factors released by an aging hematopoietic system – such as CyPA – have been linked with cognitive dysfunction among recipient mice.
Numerous studies have demonstrated the therapeutic effect of administering young blood to rejuvenate an aging brain. Studies have uncovered numerous beneficial outcomes from such therapy, such as improved cognition, enhanced adult hippocampal neurogenesis, increased SVZ long-term potentiation, etc. Most of these effects are mediated by GDF11 present in young blood.
2. It boosts the brain’s plasticity
Scientists used heterochronic parabiosis, or stitching the circulatory systems of old and young mice together, to discover that younger blood was beneficial in many organs – including heart, liver, muscles and brain – though how exactly this happened remains unknown.
Villeda’s research team set out to identify which of the substances present in young blood could be to blame. They used three-month old mice as subjects and administered plasma injections followed by tracking effects on neurons using ribonucleic acid sequencing and immunostaining of their hippocampus region – crucial for memory and learning processes.
What they found was surprising: adding young blood to old mice caused their stem cells to activate, producing new brain cells and strengthening connections among neurons – giving the hippocampus its capacity for learning from new experiences again, similar to what might happen with teenagers’ minds.
Villeda’s team noted similar effects across different regions of the brain. But their research into hippocampus was particularly remarkable: Villeda discovered that young plasma contains CREB proteins which act as master switches to turn on various genes simultaneously; when old plasma had lower concentrations of this particular molecule, so too were its effects seen within its various areas of influence: such as in hippocampus or other brain regions.
Next, CyPA (a protein found in platelets from young blood) was fed to old mice as part of an intervention strategy to increase CREB’s activity and prevent its decline with age, improving neurogenesis, CBF, cognition and other brain functions. This proved extremely successful at keeping hippocampal neurogenesis going while simultaneously increasing cognitive performance.
The lab’s research indicates that factors found in young blood may help protect against age-related neurodegeneration. They could activate stem cells that produce neurons and boost their connections, and reduce inflammation linked to Alzheimer’s and other conditions – thus giving us hope that infusions of young blood might eventually slow or reverse Alzheimer’s.
3. It reverses memory problems
Infusions of young blood are becoming an increasingly popular research tool as blood vessel lining cells respond particularly favorably to rejuvenating chemicals found in plasma. Furthermore, blood is easily transported throughout the circulatory system to reach every cell in your body – giving researchers an excellent opportunity to investigate molecular mechanisms of aging and how they might be reversed. Studies have already shown how infusions of young blood rejuvenate aging muscles and organs but now scientists are beginning to take notice of its potential impacts on brain tissue as well.
Saul Villeda of Stanford Graduate School reported back in 2011 that blood from young mice had an effect on older ones, similar to what can be observed with healthy volunteers’ plasma (the clear, yellow liquid part of blood with all proteins and antibodies but no blood cells). Now in a paper published by Nature Medicine, Villeda’s team demonstrated how when old mice received plasma from young mice their brains experienced bursts of activity related to synaptic plasticity similar to what young mice experience when exposed to young blood plasma.
The team conducted further analysis on protein levels within the hippocampus – an essential region for memory formation – using old mice with young blood. Their hippocampuses displayed greater activity of Creb, a gene known to promote nerve growth during development; when aged mice received plasma injections into young mice however, there was significantly less Creb activity present within their hippocampus.
These findings indicate that one component of young blood plasma PF4 is essential to the beneficial effects of heterochronic parabiosis on hippocampal neurogenesis and cognitive function in aged mice brain8. Furthermore, depletion of PF4 in aged mice completely eliminates all cognitive benefits derived from young blood plasma; suggesting targeting specific pro-aging factors or pathways using combination therapeutic approaches could potentially prevent age-related memory decline9.
Villeda’s laboratory continues to explore how various cells in the body–in particular adipose mesenchymal stem cells and hematopoietic stem cells–react to young blood. He uses single cell RNA sequencing technology to identify any active components found in young blood that help regenerate aging tissue, as well as how these ingredients could potentially be replicated using human umbilical cord plasma to provide life-extending therapies to humans.
4. It makes the brain more flexible
Since the mid 2000s, researchers have been using parabiosis to demonstrate that young blood is rejuvenating old animal’s muscles and brains. Their results showed that older mice given young blood ran faster on treadmills, learned quicker how to avoid an electrical shock while swimming through water mazes, produced new neurons in their hippocampus memory center more quickly, produced new neurons more frequently while swimming through water mazes as well as producing more. Furthermore, infusions of younger mouse plasma–the clear liquid part of blood containing soluble factors and platelets–also helped rejuvenate old brains while improving cognitive performance significantly
Researchers have been fascinated with these results and have embarked on an investigation of young blood’s anti-aging properties. One protein they’ve focused on is called PF4. Studies conducted earlier have demonstrated that when two mice connected at the hip share a circulatory system, their cells produce PF4 to help nerves form new pathways more easily and connect. When given to older mice it makes them more flexible in both thinking and behavior than ever before–less likely to fall into patterns leading to depression or alcoholism.
Scientists suspect PF4 and GDF11, two proteins associated with anti-aging blood, might be key players. Both proteins appear to promote nerve stem cell proliferation in the brain – encouraging new neurons and improving cognition – through stimulating nerve growth factor expression. The team from UCSF and Stanford isolated these proteins by taking plasma samples from young and old mice separated into groups and tested how these factors affected hippocampuses as well as behavioral tests on these animals.
Young blood enabled old mice to receive more of the brain-enhancing protein Creb, a master regulator of gene activity that facilitates new neuron connections essential for learning and memory formation. With age comes decreased Creb activation levels which may contribute to decreased cognitive function.
Plasma containing PF4 and GDF11 rejuvenated old mice’s brains, increasing their ability to process complex information and solve problems more quickly and more easily. They had more branching blood vessels in their hippocampus, were able to run longer on treadmills, swim longer through water mazes, as well as maintain good cardiovascular health in adulthood. These findings indicate that these proteins could act as natural neural regenerative medicines to keep adult minds healthy and flexible throughout adulthood.
