How To Reverse Aging in the Brain

The aging global population is the greatest challenge faced by 21st-century healthcare systems. Even COVID-19 is, in a sense, a disease of aging. The risk of death from the virus roughly doubles for every nine years of life, a pattern that is almost identical to a host of other illnesses. But why are old people vulnerable to so many different things?

It turns out that a major hallmark of the aging process in many mammals is inflammation. By that, I don’t mean intense local response we typically associate with an infected wound, but a low grade, grinding, inflammatory background noise that grows louder the longer we live. This “inflammaging” has been shown to contribute to the development of atherosclerosis (the buildup of fat in arteries), diabetes, high blood pressure , frailty, cancer and cognitive decline.

Now a new study published in Nature reveals that microglia — a type of white blood cells found in the brain — are extremely vulnerable to changes in the levels of a major inflammatory molecule called prostaglandin E2 (PGE2). The team found that exposure to this molecule badly affected the ability of microglia and related cells to generate energy and carry out normal cellular processes.

Fortunately, the researchers found that these effects occurred only because of PGE2’s interaction with one specific receptor on the microglia. By disrupting it, they were able to normalize cellular energy production and reduce brain inflammation. The result was improved cognition in aged mice. This offers hope that the cognitive impairment associated with growing older is a transient state we can potentially fix, rather than the inevitable consequence of aging of the brain. Levels of PGE2 increase as mammals age for a variety of reasons — one of which is probably the increasing number of cells in different tissues entering a state termed cellular senescence. This means they become dysfunctional and can cause damage to tissue by releasing PGE2 and other inflammatory molecules.

But the researchers also found that macrophages — another type of white blood cells related to microglia — from people over the age of 65 made significantly more PGE2 than those from young people. Intriguingly, exposing these white blood cells to PGE2 suppressed the ability of their mitochondria — the nearest thing a cell has to batteries — to function. This meant that the entire pattern of energy generation and cellular behavior was disrupted.

Although PGE2 exerts its effects on cells through a range of receptors, the team were able to narrow down the effect to interaction with just one type (the “EP2 receptor” on the macrophages). They showed this by treating white blood cells, grown in the lab, with drugs that either turned this receptor on or off. When the receptor was turned on, cells acted as if they had been exposed to PGE2. But when they were treated with the drugs that turned it off, they recovered. That’s all fine, but it was done in a petri dish. What would happen in an intact body?

The researchers took genetically modified animals in which the EP2 receptor had been removed and allowed them to grow old. They then tested their learning and memory by looking at their ability to navigate mazes (something of a cliche for researchers) and their behavior in an “object location test.” This test is a bit like someone secretly entering your house, swapping your ornaments around on the mantelpiece and then sneaking out again. The better the memory, the longer the subject will spend looking suspiciously at the new arrangement, wondering why it has changed.

It turned out that the old genetically modified mice learned and remembered just as well as their young counterparts. These effects could be duplicated in normal old mice by giving them one of the drugs that could turn the EP2 receptor off for one month. So it seems possible that inhibiting the interaction of PGE2 with this particular receptor may represent a new approach to treating late-life cognitive disorders.

Source: https://www.theconversation.com/

A Simple Blood Test To Find Early Signs Of Alzheimer’s

A new study found that a simple blood test can detect beta-amyloid protein buildup in a person’s brain years before Alzheimer’s disease symptoms appearHigh amounts of beta-amyloid can clump together and form plaques on the brain, which is strongly associated with Alzheimer’s disease. Other research has found that amyloid plaques can appear as early as 20 years before the first sign of Alzheimer’s symptoms, such as cognitive decline and memory loss.

In the study, 158 adults in their 60s and 70s — most of whom had normal cognitive function — underwent a PET scan to spot amyloid plaque in the brain, and a blood test to measure beta-amyloid in the body. The blood test looked for two forms of beta-amyloid protein: beta-amyloid 42 and beta-amyloid 40. When beta-amyloid begins to build up, the ratio between the two proteins changes, and the blood test detects this.

The researchers labeled each blood test result as either amyloid positive or negative. They then compared them with the PET scans. They found that the PET scans confirmed the blood test results  88% of the time. When other risk factors were included, such as age and the appearance of the gene variant ApoE4 (which also is linked to a higher risk for Alzheimer’s), the test’s accuracy rose to 94%.

While there is some debate as to whether amyloid plaque actually causes Alzheimer’s, a simple blood test that indicates you may be at a higher risk of the disease would be one more reason to adopt lifestyle changes. The researchers added that they expect the blood test to be available within a few years.

The results were published online Aug. 1, 2019, by the journal Neurology.

Source: https://www.health.harvard.edu/

Exercise Is The Most Powerful Technique To Keep Our Brain Sharp

Unfortunately, we can’t go hard forever. But in the future, that might not be a problem: New research has revealed how to harness the cognitive benefits of a workout — without the actual workout. Scientists think this help slow aging in the brain. A study published Thursday in Science suggests the benefits of exercise run in the blood and may be able to be transferred from one swoll organism to another, less-swoll one.

Researchers report that unexercised, aged mice who received blood plasma donations from exercised mice improved their performance on spatial memory tests and showed fewer markers of inflammation related to aging. The authors suggest that these improvements occurred because exercise releases a series of circulating factors (like proteins) into the bloodstream. Saul Villeda, the study’s senior author and an assistant professor of anatomy at The University of California San Francisco, said that one specific protein abundant in the liver appears to be especially important. It’s called Glpd and it sends a crucial message to the body.

I think it’s sort of signaling to your body: repair yourself or restore yourself,” Villeda explains.

The study builds upon the larger idea that aging in the brain isn’t inevitable, and that the basic lifestyle tools we have to stave it off can be further honed to keep brains sharp into old age. It’s possibly a step towards an exercise pill that’s intended to keep the brain swole, not the body — though Villeda cautions that this is far in the future.

Numerous studies have suggested that exercise can help slow cognitive decline. The mechanisms for that differ, but a working idea is that exercise triggers a series of changes in the body, including the release of certain blood factors that may confer benefits, the study notes. Villeda calls the blood a “conduit” for all the organs in the body to communicate with one another, which suggests that might help transfer exercise-related benefits from one creature to another. In the study, a group of aged mice (18 months old) was given access to a running wheel all the time. Another group of sedentary mice was provided with nesting materials (to promote more chilling and less running). Then, blood plasma (which is the white-ish part of blood that contains all the circulating cells and proteins) was taken from each group and injected into two additional groups over three weeks.

The mice with their fresh runner-blood injections then performed a water-based maze test — they had to find a platform to get to safety — and a fear conditioning test. These tests are designed to test spatial learning memory. If you’ve ever had a moment when you realize that you can’t find your car in the parking lot anymore, you’ve experienced a lapse in that type of memory, Villeda explains.

All of a sudden, you might see this older individual using their car alarm to try and find their car because they can’t quite remember where their car was,” he says. “Those are the types of impairments that already are occurring with just normal age before you get dementia or disease.

The mice who received blood plasma transfusions from the exercised mice were faster to learn the location of the dry platforms in the maze compared to those that got plasma from sedentary mice. In the fear-based test, the mice were quicker to freeze in response to a context clue – suggesting that they were faster to learn what might cause them harm. In mouse-years, you might think of these aged mice as 70-year-olds, Villeda says. The improvements seen in the mice who received plasma donation were the equivalent of turning back the clock decades, he explains:

We’re reversing it probably back to the late 30s, early 40s. But that’s a significant improvement for these animals.”

This study suggests that these transfusions may help to preserve memory functions that once existed in younger animals, Villeda says — his team found that they were able to reverse some of the animal’s cognitive impairments. What these transfusions can not do is boost memory — the goal is to prevent decline, not add benefits.

Source: https://science.sciencemag.org/
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