Aging is associated with many changes in the human brain. We may notice, for example, that short-term memory is not as robust as we get older. One reason for this is that the hippocampus, the area of the brain that deals with the formation of short-term memory and learning, is affected by normal aging. The reason is complicated, but the more-or-less short version of the story has to do in part with genes. Genes are the individual instructions for function in your genetic library, the DNA. Your DNA contains over 20,000 genes and these may be turned on (upregulated), or turned off (downregulated). Those on/off gene switches are often influenced by chemical messages from other cells. Selection of which genes work is one way humans can start out as a single cell (a fertilized egg), and wind up trillions of cells in the collective that is an adult.
Every living cell in your body contains the full DNA library that makes you who and what you are. The key is that each type of cell needs different instructions from the DNA to form and carry out basic functions that make them unique cell types of the brain, liver, skin, and so on. Even within the brain, there are many different types of cells that make up different parts and have very different functions. The cells of the hippocampus don’t appear or function in a way similar to the cells of the basal ganglia, for example. And, as we age, the functions of cells change for better or worse in response to needs at the time and the dictates of our genes.
Brain cells communicate with each other at points called synapses. Imagine a cell having many branches that connect with the branches of other cells. You have over 80 billion brain cells (neurons), and each forms up to 10,000 synapses with other neurons – though the average is probably closer to 7,000. When you learn something, it is because you are able to form new connections between neurons through a process called synaptic plasticity. In medicine, if something is plastic, it is able to change. Synaptic plasticity allows a set of new connections that makes a new synaptic pathway, and through that pattern of connected neurons, you have learned something. This new learning is stored as a memory that can be called upon again.
In the older person, synapses of the hippocampus may have trouble with one of the functions of memory formation called long-term potentiation (1). The process is influenced by genes that control synaptic plasticity. Those genes may be downregulated, and one culprit is thought to be a tiny chemical messenger in the tissue around the cell (2).
It turns out that in younger people there are proteins in the blood plasma that upregulate the same genes. This might be why younger people have better memory.
Multiple times over the last several years researchers have shown that exposing older cells to young blood can improve function (3), and even reverse age-related changes to brain cells (4) and cognitive function (5), though these studies were in mice, not humans.
Researchers at Stanford University have been on the cutting edge of this investigative work, and a paper published in April 2017 in the journal Nature (6) hypothesized that plasma from human umbilical cord blood would contain “a reservoir of such plasticity-promoting proteins.” They showed that human cord plasma treatment revitalized the hippocampus and improved cognitive function in older mice, who were better able to learn mazes and avoid unpleasant situations. Researchers did not just test wholesale injection of plasma however. Over 60 compounds found in the umbilical plasma were tested, and a molecule was identified that by itself made positive changes. TIMP2, known to be present in human cord plasma, young mouse plasma, and young mouse hippocampus, was found to increase synaptic plasticity at the level of the hippocampus in older mice, and it was shown that blocking TIMP2 prevented long-term potentiation (memory formation).
In the PLasma for Alzheimer SymptoM Amelioration Study (PLASMA) (NCT02256306), Stanford researchers next trialed intravenously-administered plasma from young donors to 18 patients with mild-moderate Alzheimer disease (AD) (7). Participants were given one unit of plasma weekly over four weeks. The primary endpoint was a measure of safety and tolerability. Secondary outcome measures included changes over a nine-week period in cognitive tests, functional activities, activities of daily living, and depression. Other lab and imaging studies were also included. No results are posted on ClinicalTrials.gov. However, Stanford Medicine News Center quoted investigator Dr. Sharon Sha, who noted the trial showed good tolerability, but “no significant changes in participants’ mood or their performance on tests of cognition … these kinds of changes are typically observed only in clinical trials whose durations exceed one year” (8). Thus, larger, longer studies are needed to see if these improvements would occur. Stage of disease may be another key factor. Still, it is encouraging that the therapy was tolerated, and the door is open to new trials.
An ongoing study at Stanford is the The Stanford Parkinson’s Disease Plasma Study (SPDP) (NCT02968433) (9), which proposes to show that “young plasma infusions can be performed safely in patients with Parkinson’s Disease (PD).” In the study, secondary outcomes include “behavioral and laboratory data that will support the next study that will inquire whether young plasma infusions improve or slow the progression of cognitive, mood and/or motor impairment and rate markers of the disease.” All 15 participants will undergo neuropsychological, neuropsychiatric, and motor assessment prior to receiving infusions of one unit of young plasma, twice a week over a four week duration. Following that period, participants will undergo reassessments. There will be no placebo arm, or as investigators put it, “no deception will be used.” The primary outcome measure will be an assessment of safety and adverse events. Secondary outcome measurements will include change in motor function up to eight weeks out. Finally, there will be a measure of potential change in cognitive ability.
If compounds in young blood are helpful in PD, the goal might be to isolate them and form new therapies. This work in PD is in the early stages of development, though it is very helpful that so much of the groundwork has been done in mice and in Alzheimer disease.
REFERENCES
- Burke, S. N. & Barnes, C. A. Neural plasticity in the ageing brain. Nature Rev. Neurosci. 7. 2006;30–40
- Lee, et al. Gene-expression profile of the ageing brain in mice. Nature Genet.2000;25:294–297
- Conboy, et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature.2005;433:760–764
- Katsimpardi, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014;344:630–634
- Villeda, S. A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Med. 2014;20:659–663
- Castellano, et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 2017; 544:488–492
- https://clinicaltrials.gov/ct2/show/NCT02256306?term=NCT02256306&rank=1
- https://med.stanford.edu/news/all-news/2017/11/clinical-trial-finds-blood-plasma-infusions-for-alzheimers-safe.html
- https://clinicaltrials.gov/ct2/show/NCT02968433?term=nct02968433&rank=1
