Overview: Researchers review current studies on cognitive rejuvenation and discuss steps we can take to protect our brains as we age.
Neuroscientist Tony Wyss-Coray, Ph.D., has spent 20 years excavating and investigating various molecules with neuroprotective and neurodegenerative properties. These molecules are found in or on various cell types in the brain and on the blood vessels that adjoin them, or float in the blood and cerebrospinal fluid that surrounds them. And they become more and more important as we get older.
Wyss-Coray and his colleagues have found substances in the blood that can speed up or slow down the brain’s aging clock. They have identified proteins on blood vessel surfaces that allow some of these molecules to act on the brain, despite the existence of the blood-brain barrier. He has even shown that older mice given young cerebrospinal fluid look and behave younger.
I asked Wyss-Coray, the DH Chen Distinguished Professor of Neurology and Neurological Sciences and the director of the Phil and Penny Knight Initiative for Brain Resilience, to piece together his findings on cognitive rejuvenation.
Tell us about aging-related cognitive loss.
Age issues begin to become tangible for most people over the age of 50 or 60 when we realize that picking up a person’s name or a word on the tip of the tongue is not just the result of a bad day, but a manifestation of aging, such as wrinkles or graying hair. This memory loss is more common and we begin to speak more slowly in order to replace missing words with others.
While it’s unclear how this normal age-related decline is linked to more severe cognitive impairment and dementia, a third of Americans over the age of 85 have symptoms of Alzheimer’s disease, and that number doubles in the next 10 years of their lives. Unfortunately, we have no tools to predict who will progress from forgetfulness to dementia.
However, not everyone is destined to experience this downward trajectory. One in three centenarians appears to be resilient to cognitive decline. This offers hope and a springboard for studying brain aging and cognitive decline.
How did you come to research ‘young fluids’ as a means of cognitive rejuvenation?
Brain tissue is rarely available in living subjects, so we focused our research on spinal fluid and blood. These early studies, now more than 15 years ago, of fluids from older people with normal cognition and patients with Alzheimer’s disease were hampered by unreliable tests, but they showed us one thing: The overall age-related changes in blood protein composition were drastic.
We confirmed that the levels of large numbers of proteins changed significantly between the 20th and 90th year of life in humans. Because age is by far the most important risk factor for Alzheimer’s disease and other neurodegenerative diseases, the question became whether the changes we observed were a cause of brain aging or a consequence.
To find out, we resorted to a method that former Stanford Medicine professor of neurology Tom Rando, MD, Ph.D. (now at UCLA), whose lab was right next door to mine, used to study muscle stem cell aging: surgically joining the circulatory systems of a young and an old mouse so that the animals share their blood.
What we saw was striking: Old mice exposed to their young partner’s blood showed multiple signs of rejuvenation, including an increase in the number of certain types of neurons, increased neuronal activity and a decrease in brain inflammation.
When we treated old mice with repeated intravenous infusions of young plasma (the liquid fraction of blood), these mice became smarter and performed more like young mice on multiple cognitive tests. Conversely, young mice exposed to aged blood or treated with aged plasma experienced accelerated brain aging and a loss of cognitive function.
Do these findings apply to humans?
The findings have been partially translated to humans. In clinical trials, infusions of young plasma have shown significant benefits in patients with Alzheimer’s disease. In a placebo-controlled, double-blind clinical trial (conducted by others), removing plasma and replacing it with albumin-rich plasma from young donors resulted in significant functional improvements in patients with Alzheimer’s disease.
This implies that the experiments with blood exchange mice may be relevant to humans and that blood plasma may hold the secret of rejuvenation.
You and your colleagues have identified numerous substances and proteins found in various body fluids and tissues, all of which act in different places to improve the youthfulness of different types of cells in the brain. Can you explain how so many different substances, cell types and processes seem to produce similar results?
Biology is an intricate web of interconnected systems. There are several hundred thousand nodes in this network that we call a biological organism, including proteins, sugars, lipids and metabolites. Each of these components performs a function that has been honed by evolution; sometimes it is essential and irreplaceable, but often it is superfluous.
Imagine a flight map over the US, including all airlines and made up of hundreds of connection points, some more important than others. The network helps keep the economy going by moving goods and people from one place to another. Removing some nodes can cause the system to collapse, while others can be taken out of service with little impact.
Some of the most successful drugs — like that anti-inflammatory workhorse, aspirin — have been shown to target multiple biological pathways in many different cell types and tissues. Young plasma or spinal fluid – nature’s cocktails – seem to contain dozens of beneficial proteins and probably other kinds of molecules, and may well remain the most potent elixir.
In mice, at least, it seems possible to achieve therapeutic benefits using individual protein factors that we identified. One protein may be particularly helpful for slowing muscle loss, while another may boost brain function.
What can we all do in the here and now to keep our brains in shape?
Stress appears to be the greatest source of damage we can do to our bodies. It not only leads to physical symptoms such as high blood pressure, chest pain, digestive problems and sleep disturbances; it also weakens the immune system and contributes to inflammation, potentially speeding up the aging process. Chronic stress is a major source of psychiatric manifestations and unhappiness.
A recent large study suggests that up to 40% of dementia in the US is caused by modifiable risk factors, including hypertension, obesity and physical inactivity. At present, there are no effective pharmacological treatments for cognitive decline and neurodegeneration. In their absence, some of the strongest scientifically documented benefits to brain function come from exercise.
About this news about aging and neuroscience research
Author: Bruce Goldman
Contact: Bruce Goldman – Stanford
Image: The image is in the public domain