For decades, the story of Alzheimer's research has been dominated by a battle between A-beta and tau amyloids, both of which can kill neurons and impact the brain's ability to function. A new study suggests, however, that these sticky brain plaques may not be operating alone.

Johns Hopkins University researchers have identified more than 200 types of misfolded proteins in rats that could be associated with age-related cognitive decline.

The findings could lead the way to finding new therapeutic targets and treatments in humans that could provide relief for the millions of people over 65 who suffer from Alzheimer's, dementia, or other diseases that rob them of their memories and independence as they age.

"Amyloids are the buildup of misshapen proteins. They're big and ugly and easy to see under the microscope, so it makes sense that they catch our attention. But we're seeing hundreds of proteins misfolding in ways that don't clump together in an amyloid and yet still seem to impact how the brain functions," said Stephen Fried, an assistant professor of chemistry and protein scientist who studies how molecules in the brain change during aging. "Our research is showing that amyloids are just the tip of the iceberg."

The results were published on July 11 in Science Advances.

To understand the molecular differences between older brains that are mentally sharp and those that are experiencing decline, Fried and his team studied 17 2-year-old rats that grew up in the same colony. Seven rats performed poorly on memory and problem-solving tests and were considered cognitively impaired, while 10 performed as well as 6-month-old rats.

The researchers then measured more than 2,500 types of protein in the hippocampus, the part of the brain associated with spatial learning and memory. For the first time, scientists were able to determine for a large number of proteins whether individual proteins were misshapen or folded incorrectly, allowing the researchers to work out which proteins misfold for all the rats and are associated with aging in general versus which proteins specifically misfold in cognitively impaired rats.

More than 200 proteins were misfolded in the cognitively impaired rats yet maintained their shapes in the cognitively healthy rats. The findings suggest that some of those proteins are contributing to cognitive decline, the researchers said.

Misfolded proteins are unable to carry out tasks necessary for a cell to function properly, so cells have a natural surveillance system that identifies and destroys these misbehaving proteins. Previously, researchers thought misfolded proteins -- specifically A-beta and tau proteins -- were only disruptive when they clumped into amyloids.

"We think there are a lot of proteins that can be misfolded, not form amyloids, and still be problematic," Fried said. "And that suggests these misfolded proteins have ways of escaping this surveillance system in the cell."

But exactly how those misfolded proteins slip past a cell's security system remains a mystery.

Next, the team plans to look at misfolded proteins under high-resolution microscopes to get a more detailed picture of what their deformities look like at the molecular level.

"A lot of us have experienced a loved one or a relative who has become less capable of doing those everyday tasks that require cognitive abilities," Fried said. "Understanding what's physically going on in the brain could lead to better treatments and preventive measures."

Read more …Scientists just found 200+ hidden proteins that may drive Alzheimer’s

Being consistently physically active in adulthood is linked to a 30–40% lower risk of death from any cause in later life, while upping levels from below those recommended for health is still associated with a 20–25% lower risk, finds a pooled data analysis of the available evidence, published online in the British Journal of Sports Medicine.

The findings prompt the researchers to conclude that switching to a more active lifestyle at any point in adult life may extend the lifespan, and that it’s never too late to start.

Currently, it’s recommended that adults should aim for 150-300 weekly minutes of moderate intensity physical activity, or 75-150 weekly minutes of vigorous intensity physical activity, or a combination of the two, note the researchers.

But while these recommendations were based on the best evidence available, most of it captured measurements of physical activity at only one point in time, which might hide the potential impact of changing patterns during adulthood, they add.

The researchers therefore wanted to find out if differing patterns of physical activity, as well as its cumulative impact during adulthood, might be associated with a lower risk of death from all causes, and specifically from cardiovascular disease and cancer. 

They scoured research databases for relevant studies that assessed physical activity at two or more points in time, and included in their review 85 studies published in English up to April 2024, with sample sizes ranging from 357 to 6,572,984 participants. 

Fifty nine of the studies looked at long term patterns of physical activity across adulthood; 16 looked at the average benefits of different physical activity levels; and 11 explored the potential impact of cumulative physical activity on risk of death.

To overcome the challenges posed by different analytical methods used, the researchers carried out separate analyses for each of them.

Pooled data analysis of the study results showed that, overall, a higher level of physical activity was associated with lower risks of all the included outcomes. 

Consistently active people (32 studies) had around a 30–40% lower risk of dying from any cause, while those who increased their levels of physical activity (21 studies) from below those recommended had a 20-25% lower risk of death from any cause. 

Specifically, participants who switched from being physically inactive to being active were 22% less likely to die from any cause than those who remained inactive, while those who increased their leisure time physical activity levels were 27% less likely to do so.

On the other hand, swapping an active lifestyle for an inactive one wasn’t associated with a lower risk of death from any cause.

Generally, the associations observed between a high level of physical activity and a lower risk of death were more evident for cardiovascular disease than for cancer. 

Compared with participants who were consistently inactive over time, those who were consistently active, overall, or only in their leisure time, were around 40% and 25% less likely to die from cardiovascular disease and cancer, respectively. 

But in general, the evidence for the associations between physical activity patterns and death from a specific cause remained inconclusive, especially for death from cancer.

The pooled data suggested that people who were consistently active or who became active had lower risks of death from any cause, and specifically from cardiovascular disease, when meeting the recommended weekly physical activity levels.

But being consistently physically active and clocking up more than the recommended maximum weekly amount of moderate to vigorous intensity exercise was associated with only a small additional reduction in risk.

Maintaining or increasing physical activity at levels below the recommended weekly amount, however, was associated with appreciable health benefits, indicating that some physical activity is always better than none, say the researchers.  

And an average volume of physical activity that met the recommended weekly amount was also associated with a 30–40% lower risk of death from all causes. But more research is needed to confirm this, they add.

The researchers acknowledge some limitations to their findings, including that most of the studies included in the pooled data analyses relied on subjective assessments of physical activity, which may not always have been accurate. 

And there were only a few studies that looked at cumulative amounts of physical activity, or cancer deaths.

Nevertheless, the findings have important public health implications, insist the researchers.

“First, our results emphasized the importance of [physical activity] across adulthood, indicating that initiating [it] at any point in adulthood may provide survival benefits.” 

They add: “As being consistently active provides greater health benefits than being previously active (ie, no longer maintaining activity), this highlights the importance of sustained [physical activity] over time. 

“Future [physical activity] interventions may not only target inactive people, but also support active people to maintain their activity.”

Read more …It’s never too late: Just moving more could add years to your life

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