Can we rejuvenate aging brains?

Summary: The researchers review current studies on cognitive rejuvenation and discuss steps we can take to help protect our brains as we age.

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Neuroscientist Tony Wyss-Coray, Ph.D., spent 20 years unearthing and examining various molecules with neuroprotective and neurodegenerative properties. These molecules are found in or on different types of cells in the brain and in the blood vessels that surround them, or floating in the blood and cerebrospinal fluid that bathes it. And they become increasingly important as we age.

Wyss-Coray and her colleagues have discovered substances in the blood that can speed up or slow down the brain’s aging clock. They have identified proteins on the surface of blood vessels through which some of these molecules can act on the brain, despite the existence of the blood-brain barrier. It has even shown that older mice that obtain cerebrospinal fluid from young mice look and act younger.

I asked Wyss-Coray, the DH Chen Distinguished Professor of Neurology and Neurological Sciences and director of the Phil and Penny Knight Initiative for Brain Resilience, to put together his findings in the field of cognitive rejuvenation.

Tell us about age-related cognitive loss.

The problems of aging begin to be tangible for most of us over the age of 50 or 60, when we realize that remembering 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 gray hair. These memory lapses become more frequent and we begin to speak more slowly so that we can replace the missing words with others.

While it’s not clear how this normal age-related decline relates to more severe cognitive decline and dementia, one-third of Americans over the age of 85 have symptoms of Alzheimer’s disease, and that number is doubling in the next 10 years of life. Unfortunately, we have no tools to predict who will go from forgetfulness to dementia.

However, not everyone is destined to experience this downward trajectory. One in three centenarians appears to be resistant to cognitive decline. This provides hope and a springboard to study brain aging and cognitive decline.

How did you come to investigate ‘young fluids’ as a means of cognitive rejuvenation?

Brain tissue is rarely available in living subjects, so we focused our research on cerebrospinal fluid and blood. These early studies, now more than 15 years ago, of fluids from cognitively normal older people and Alzheimer’s patients were hampered by unreliable assays, but they did show us one thing: general age-related changes in the protein composition of the blood were deep.

We confirmed that the levels of a large number of proteins changed significantly between the ages of 20 and 90 people. Because age is by far the most important risk factor for Alzheimer’s disease and other neurodegenerative diseases, the question was whether the changes we observed were a cause of brain aging or a consequence.

To find out, we turned to a method that former Stanford Medicine neurology professor Tom Rando, MD, Ph.D. (now at UCLA), whose lab was right next door to mine, was using to study muscle stem cell aging: surgically joining the circulatory systems of a young and an old mouse, so that the animals shared their blood.

What we observed was surprising: Old mice exposed to their young partner’s blood showed multiple signs of rejuvenation, including increased numbers of certain types of neurons, increased neuronal activity, and reduced brain inflammation.

When we treated old mice with repeated intravenous infusions of young plasma (the liquid fraction of blood), these mice became smarter and behaved more like young mice on multiple cognitive tests. In contrast, young mice exposed to aged blood or treated with aged plasma experienced accelerated brain aging and loss of cognitive function.

Are these findings applicable to humans?

The findings, in part, have been translated to humans. In clinical trials, young plasma infusions have produced significant benefits in Alzheimer’s patients. In a double-blind, placebo-controlled clinical trial (performed by others), plasma withdrawal and replacement with albumin-rich plasma from young donors resulted in significant functional improvements in Alzheimer’s patients.

This implies that experiments with blood-swapping mice may be relevant to people, and that blood plasma may hold the secret to rejuvenation.

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You and your colleagues have identified numerous substances and proteins found in various body fluids and tissues, all acting at different sites to enhance the youth 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 a complicated web of interconnected systems. There are several hundred thousand nodes in this network that we call a biological organism, which includes proteins, sugars, lipids, and metabolites. Each of these components fulfills a function fine-tuned by evolution; sometimes it is essential and irreplaceable, but often it is redundant.

Imagine a flight map over the US that includes all airlines and consists of hundreds of connection points, some more important than others. The network helps the economy to function by moving goods and people from one place to another. Removing some nodes could cause the system to crash, while others may be taken out of service with little impact.

This shows a brain in a light bulb.
Brain tissue is rarely available in living subjects, so we focused our research on cerebrospinal fluid and blood. The image is in the public domain

Some of the most successful drugs, like the workhorse anti-inflammatory aspirin, have targeted multiple biological pathways through many different cell types and tissues. Young plasma or cerebrospinal fluid (nature’s cocktails) appears to contain dozens of beneficial proteins and probably other types of molecules, and may well remain the most powerful elixir.

In mice, at least, it seems possible to achieve therapeutic benefits using individual protein factors that we have identified. One protein may be particularly helpful in slowing muscle loss, while another may boost brain function.

What can we all do here and now to keep our brains in shape?

Stress seems to be the biggest source of damage we can inflict on our bodies. It not only leads to physical symptoms like high blood pressure, chest pain, digestive problems, and sleep disturbances; it also weakens the immune system and contributes to inflammation, possibly accelerating the aging process. Chronic stress is a key source of psychiatric manifestations and unhappiness.

A recent large study suggests that up to 40% of dementia in the US is due to modifiable risk factors such as high blood pressure, obesity, and physical inactivity. At this time, there are no good pharmacological treatments for cognitive decline and neurodegeneration. In its absence, some of the strongest scientifically documented benefits for brain function come from physical exercise.

About this research news on aging and neuroscience

Author: brucegoldman
Font: Stanford
Contact: Bruce Goldman–Stanford
Image: The image is in the public domain.

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