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Summary 1: for Scientific Audience

Cognitive impairment is one of the difficulties that most humans face when they are aged.
This impairment is due to the degeneration in structure and function of the brains. Finding a
mean to reverse this degeneration by age will help to improve lives of many aged people. In
recent research by Villeda and colleagues has found that blood from young mice improve
cognitive function and neuron plasticity of aged mice. The improvements were shown at
molecular, structural functional and cognitive levels. The study also discovered that Creb is
involved in the mechanism of how young blood positively reverses aged related cognition
impairment.
The study was focusing on hippocampus of the brains because hippocampus, which is
important for learning and memory, is vulnerable when humans aged. Three and eighteen monthold mice were used as 3 and 18 month-old mice as young and aged models respectively.
Administration of blood to aged mice was obtained by plasma injection or parabiosis, in which
two mice share vascular system. Aged heterochronic parabionts are aged mice getting young
blood, and age isoparabionts are aged mice getting aged blood. Various experiments were
performed to discover the effect of young blood on aged brains at different levels.
At the molecular level, data from genome-wide microarray analysis,
immunohistochemistry, and transcriptional analysis shown that exposure to young blood changed
the expression of a group of genes involved in the pathway of regulating the plasticity of
hippocampus. Creb is the critical gene in the pathway being identified. Creb encodes a
transcription factor that regulate the expression of many genes important to many physiological
functions including neuron function. Immunohistochemistry results shown that Creb is more
active in the dendate gyrus and CA1 regions of the hippocampus of mice getting young blood.
The study also identified the increasing expression of two early immediate genes, Egr1 and c-fos,
corresponding to Creb transcription factor. These early immediate genes encode for transcription
factors that are essential for neural plasticity.
At the structural level, the results from Golgi stain shown increasing number of dendrite
spines in dendate gyrus but not CA1 region of hippocampus of the mice exposing to young
blood. Dendrite spines, which contain neuron transmitter receptors and signaling systems
essential for synaptic plasticity, are important in memory and learning.
At functional level, extracellular eclectrophysiological recordings on hippocampus slices
shown that long-term potentiation remain above the baseline in the mice getting young blood

while quickly reach baseline level in mice getting aged blood. Long term potentiation is known
to positively correlate with learning and memory.
At the cognitive level, contextual fear condition and radial arm water maze (RAWM)
were used to test difference in cognitive level, including learning and memory, of two groups of
mice. The results shown that young blood did not affect the spatial learning ability. However, the
mice with young blood increase freezing contextual fear condition experiment, which implied
improved ability of learning and memory. Aged mice given young blood plasma also had
learning and memory for hidden location enhanced comparing to aged mice getting aged blood
and aged not getting any blood. Interestingly, corroborated experiments shown that the heated
young blood did not remain the cognitive improving effect on aged mice as non-heated young
blood. Therefore the key factor in young blood lose it rejuvenating effect with heat.
Expanded transcriptional analysis was used to examine the involvement of Creb in the
biological mechanism of inversing aged cognitive impairment by young blood. The Creb
signaling was inhibited by either the dominant-negative DNA binding-incompetent form of Creb
(K-Creb) or shRNAs. The aged mice having inhibited Creb did not show improvement in
cognition in structural and cognitive levels comparing to mice without young blood. Specifically,
the aged mice with treated with K-Creb or shRNAs then young blood did not increase number of
dendrite spines comparing to the aged group without young blood. The mice treated with K-Creb
before young blood did not show enhanced memory and learning comparing to group without
young blood. However, the group with K-Creb and aged blood reduce spatial learning comparing
to group of mice with active Creb and aged blood. Immunohistochemistry also shown increased
level of phosphorylated Creb in aged mice treated with young blood. These results together
confirmed that young blood enhance cognition in aged mice involve mediation of Creb.
Data from the study demonstrate that molecule from young blood enhance the cognition
of aged mice at cognitive, functional, structure and molecular levels. The reversing effect of
young blood is mediated by Creb. The results suggest two possible ways to reverse cognitive
degradation by age, whether by adding factor from young blood or removing a factor from aged
blood. It needs further studies to investigate and isolate these factors.
Summary 2: for Non-scientific Audience
Cognitive impairment is what most people face when they age even if they are healthy.
Having a mean to reverse this aging effect is important since it can improve lives of many aged
people, especially at this period of time, when baby boomer generation enter their old age. In

recent study by scientists of University of California San Francisco and Stanford University has
found that blood from young animals can enhance memory and learning ability in old animals.
The scientists have done initial investigations to understand how young blood rejuvenates the
aged brains.
They found that the young blood positively change the structure of the aged mice brains
so that the neurons communicate more effectively. Imagine that the neurons is like net of city
streets. Where the neurons meet each other is like where the streets each other. What the young
blood did to the neurons structure is like expanding the street so they have more lanes where they
meet so traffic goes faster. When the neurons communicate faster or more effectively, learning
and memory is improved.
One might ask how the scientists know mice learn and memory better because they
cannot talk. The scientists used different scientific tests to examine and compare the behavior of
mice getting young blood and aged blood. The tests show that mice with young blood learn to
fear better than the mice with aged blood. Mice with young blood are also better in learning and
finding way and hidden places.
Understand how the young blood works on reversing the cognition impairment in aged
animals will help the scientists to find the mean to do the same thing. They found that exposure
to young blood changed the gene, which is very important to how neurons response and
communicate with each other. This gene is like the manager in a factory. When the manager is
more active, he makes the leaders of the small groups of more active, which leads to the workers
in the groups more active and produced more required products. These products support the
neurons communication therefore enhance learning and memory. When the scientists made the
manager gene inactive, they found that even being given with young blood, the aged mice did
not have improved cognition as well as brain structure. So the young blood reverses cognitive
impairment in the aged mice through the manager gene, which was identified in the study.
The results above are very promising but it is not practical to inject the whole blood into
aged patients to cure cognitive impairment. So it suggests that some key factors inside the young
blood have the rejuvenating effect on aged brains. When aged mice got injected with heated
young blood, they did not improve learning and memory as they did if they were injected with
non-heated young blood. Combining with the above results of how young blood rejuvenate aged
brains, the scientists suggested that the solution for improving cognition in aged mice was either

to add some factors from young blood or to inactivate some factors from aged blood of aged
animals.
Before applying on humans, it needs more studies to identify and isolate the factors from
young blood and in-depth investigations of the effects of these factors. However, the results from
this study promised the ways to find the means to reverse age-related cognitive impairment in
humans.
References
Villeda, S. A., Plambeck, K. E., Middeldorp, J., Castellano, J. M., Mosher, K. I., Luo, J., Smith,
L. K., Bieri, G., Lin, K., Berdnik, D., Wabl, R., Udeochu, J., Wheatley, E. G., Zou, B.,
Simmons, D. A., Xie, X. S., Longo, F. M., Wyss-Coray, T. 2014. Young blood reverses
age-related impairments in cognitive function and synaptic plasticity in mice. Nature
medicine. 20:659-663