Just 3,000 Steps a Day May Help Protect the Brain From Alzheimer’s

 Even moderate amounts of walking may help protect brain function and slow changes linked to Alzheimer’s disease.

New research reveals a modest amount of daily movement may help protect the brain from Alzheimer’s disease, but the apparent benefit does not involve the biological target researchers expected.

Using pedometers, researchers followed nearly 300 older adults with early brain changes associated with Alzheimer’s for nine to 11 years. Physical activity was not associated with lower levels of amyloid plaques, the toxic deposits targeted by many current Alzheimer’s treatments.

Walking slowed a different disease marker

Among participants who already had amyloid plaques, however, greater physical activity was linked to slower accumulation of misfolded tau proteins in certain brain regions. Tau develops later in Alzheimer’s and is more closely associated with declining memory, thinking, and everyday function. More active participants experienced nearly half as much cognitive and functional decline.

The association appeared at about 3,000 steps a day, equal to roughly 30 minutes of moderate walking. Benefits were strongest between 5,000 and 7,500 daily steps, then leveled off. Walking beyond that range did not necessarily provide additional protection, suggesting that older adults with sedentary lifestyles may not need to reach the commonly promoted goal of 10,000 steps.

The findings have important limitations. The study included a relatively small sample of mostly white, highly educated adults in the United States and did not account for every health or lifestyle factor that might influence the results. Walking may also protect the brain through mechanisms not measured in the research. Even so, the findings add to broader evidence linking physical activity with a lower risk of dementia.

Modest activity repeatedly predicts lower risk

A UK study of 1,139 people over 50 found that those who were moderately to vigorously active had a 34-50% reduction in dementia risk when followed over eight to ten years. Among those who developed dementia, staying active reduced their memory decline, particularly in older women.

A larger 2022 UK study tracked 78,430 people for seven years using wrist accelerometers. It found a 25% reduction in dementia risk with just 3,800 steps daily, rising to 50% at 9,800 steps.

However, people who walked more also had better cardiovascular health – lower cholesterol, better sleep and blood pressure, and reduced diabetes risk. Since these heart and stroke risk factors also increase dementia risk, the picture is complex.

Healthy habits often go together. People who exercise are more likely to eat well, not smoke, look after their heart health, and have fewer financial stresses. This makes it hard to know which factor is having the biggest effect. The researchers tried to account for this, but because these habits are so closely linked, it’s difficult to say that exercise alone is responsible.

Exercise and heart health overlap

However, there is a strong case for this as there are multiple ways exercise might support the brain: improving cardiovascular health, increasing blood flow, and boosting chemicals that promote brain-cell connections.

One such substance is irisin, a hormone produced by muscles that acts on almost all faulty brain mechanisms associated with Alzheimer’s, including inflammation. This and other chemicals, such as BDNF, associated with exercise, provide plausible biological pathways for how physical activity might directly influence brain health beyond its cardiovascular benefits.

But the relationship might work in reverse, too. People may become less active because of early Alzheimer’s symptoms. Those with hearing problems, for instance – itself a dementia risk factor – often report barriers that make them stop being active before other dementia symptoms appear.

Reduced activity then accelerates memory decline. This creates a vicious circle. Early disease symptoms – such as not hearing – can affect self-esteem and reduce engagment in physical activity, which in turn worsens cognitive decline.

Achievable walks may still help

Brisk walking might be particularly beneficial. A small trial of 15 people with mild to moderate Alzheimer’s who did Nordic walking (an enhanced walking technique that uses poles to work your upper body as well as your legs) maintained brain function over 24 weeks, with some functions even improving.

The 15 who received only standard care showed decline or no improvement. Though small, the trial suggests that even people already diagnosed with Alzheimer’s might benefit from increased physical activity, including brisk walking.

Getting outside, particularly in nature, may be especially beneficial for preventing dementia – possibly because it improves mood and sleep while reducing isolation – all dementia risk factors. The combination of physical movement, natural light exposure, and social interaction when walking outdoors may create multiple protective effects that complement each other.

The challenge now is helping people overcome barriers to outdoor activity, such as safety concerns, fear of falling, or simply preferring the comfort of the sofa – particularly during wetter, colder months. But the evidence suggests that even a few minutes of walking could make a difference, and that modest, achievable targets – a half-hour stroll rather than a marathon training regime – may offer substantial protection against cognitive decline.

Source: ScitechDaily

Scientists Discover the Brain Protein That Helps Alzheimer’s Spread Through the Brain

 Scientists have identified a brain protein that may help Alzheimer’s spread, revealing a potential new target for slowing the disease’s progression.

Alzheimer’s disease is closely linked to the accumulation of a toxic form of the protein Tau inside the brain. As Tau damage reaches additional brain regions, more neurons are harmed, symptoms intensify, and the disease can eventually become fatal.

Researchers have now identified a brain protein that may help this harmful process spread. In experiments involving mice, they found that a protein called Arc can carry toxic Tau from diseased brain cells into healthy ones.

The finding raises the possibility of developing treatments that interrupt this movement between cells. Rather than repairing damage that has already occurred, such therapies might help prevent Alzheimer’s disease from advancing.

“I’m excited by the fact that we’ve identified a new way of potentially stopping the progression of Alzheimer’s disease,” says Jason Shepherd, PhD, professor of neurobiology at University of Utah Health and senior author on the study.

How Toxic Tau Moves Between Brain Cells

The research team studied a mouse model of Alzheimer’s disease in animals that either had Arc or lacked the protein. Their experiments showed that Arc plays an important role in allowing toxic Tau to travel through the brain.

Under normal conditions, Arc acts as a messenger between neurons. The protein packages itself inside a microscopic bubble known as an extracellular vesicle or EV. This bubble can move from one neuron to another while carrying information between cells.

Toxic Tau, however, appears able to attach itself to Arc and use the same delivery system. In this way, Tau can leave a diseased neuron and reach a healthy one.

Tau is naturally present in both healthy and unhealthy brain cells. In Alzheimer’s disease, however, it begins sticking together and forming large tangles inside neurons. These accumulations disrupt normal cell activity and eventually kill the affected neurons.

Mitali Tyagi, PhD, postdoctoral research associate at Washington University in St. Louis and first author on the paper, who did the research while a neuroscience graduate student in the Shepherd Lab at U of U Health, compares Tau tangles to “glue monsters.”

“They glue together and block transportation within the neuron,” Tyagi explains. “But they can break down into smaller glue monsters, called Tau seeds, which can then get transferred to a new neuron. And once this Tau seed comes into contact with healthy Tau, it is able to corrupt it. So, the pathology starts all over again in a healthy neuron.”

Arc Acts as a Carrier for Tau

In the Alzheimer’s mouse model, the researchers found EVs in the brain that contained both Arc and “sticky” Tau. These tiny bubbles were able to enter healthy cells and trigger the formation of new Tau tangles.

The situation changed dramatically in mice that did not have Arc. Their brain EVs contained almost no Tau and were largely unable to carry the disease process into new cells.

“When we removed Arc, we saw that the transfer of Tau was severely, severely reduced,” Tyagi says. “It was almost gone.”

A Protein With Both Harmful and Helpful Effects

At first, blocking Arc might seem like an obvious way to slow Alzheimer’s disease. The findings, however, suggest that Arc has a more complicated role.

During the early stages of disease, Arc may actually help damaged neurons survive by allowing them to release excess toxic Tau. Without this escape route, Tau remains trapped inside the cell and builds up more quickly.

The researchers found that diseased neurons died faster in mice without Arc because they could not remove the toxic protein.

“When Arc is absent, Tau becomes trapped inside neurons and accumulates to toxic levels. When Arc is present, Tau can be released in extracellular vesicles. While this helps reduce Tau buildup within the original neuron, the released Tau can be taken up by neighboring healthy neurons, promoting the spread of pathology,” Tyagi says.

These results suggest that completely stopping Tau from leaving sick neurons may do more harm than good. A more promising strategy could be to prevent Tau-containing EVs from entering healthy brain cells.

Source: Scitech Daily

This Experimental Drug Repaired the Gut and Reversed Severe Fatty Liver Disease

 An experimental drug repaired the gut and reversed severe fatty liver disease in animals, opening the door to a promising new treatment for MASH.

Researchers at Michigan Medicine have identified how an experimental drug may treat severe fatty liver disease by repairing damage in the gut, according to findings published in The Journal of Clinical Investigation.

The compound, a glycine-based tripeptide called DT-109, reversed metabolic dysfunction-associated steatohepatitis (MASH) in animal models. It worked by interrupting a harmful biological pathway that connects the intestines and liver.

MASH affects an estimated 7% of people worldwide. The disease can progress to cirrhosis, liver cancer, and liver failure, yet treatment options remain limited despite recent advances.

“We see clear evidence that DT-109 protects the gut epithelial barrier, reducing the systemic influx of harmful microbial products that are thought to contribute to MASH development and progression,” said Eugene Chen, M.D., Ph.D., senior author of the study and Frederick G. L. Huetwell Professor of Cardiovascular Medicine at the University of Michigan Medical School.

“This compound shows benefits to the gastrointestinal system and has great potential as a treatment for MASH.”

How Gut Damage Can Drive Liver Disease

Earlier animal studies from Chen’s team had already suggested that DT-109 could be effective against MASH. The new research helps explain why the treatment appears to work.

Before evaluating the drug’s effects, the researchers confirmed an important contributor to MASH: the rapid growth of Clostridium perfringens, a bacterium that produces ammonia inside the gut.

When ammonia levels rise, they can damage the inner lining of the digestive tract and weaken the intestinal barrier. This allows toxins and other harmful microbial products to enter the bloodstream, reach the liver, and provoke inflammatory immune activity, including excessive activation of CD8+ T cells.

Through a series of experiments, the researchers found that DT-109 disrupted this damaging chain of events and helped restore the health of both the gut and liver.

The treatment reduced Clostridium perfringens levels and lowered ammonia production in the intestines of mice and nonhuman primates. These changes strengthened the intestinal barrier and limited the movement of harmful substances out of the gut.

DT-109 Reduced Liver Inflammation

The results in nonhuman primates were especially encouraging because their livers and gut microbiota are more similar to those of humans. In these animals, DT-109 reduced liver inflammation and eased the severity of MASH.

“DT-109 connects microbiota modulation with liver protection by restoring gut barrier integrity and limiting the systemic translocation of ammonia and other pro-inflammatory microbial products within the gut-liver axis,” said Jifeng Zhang, Ph.D., co-author and research professor of cardiovascular medicine at U-M Medical School.

“We also found that DT-109 primarily acts in the gastrointestinal tract, but its reach stretches much further.”

The findings suggest that DT-109 may eventually have uses beyond severe fatty liver disease.

Previous research has shown that the compound can reduce the development of atherosclerosis plaques and prevent vascular calcification in nonhuman primates. Those effects make it a potential candidate for treating cardiovascular disease as well.

Because a weakened intestinal barrier also plays a role in several digestive disorders, the researchers believe DT-109 could one day be explored as a possible treatment for conditions such as inflammatory bowel disease (IBD).

Moving Toward Human Clinical Trials

The next phase of research will involve additional testing of DT-109 with the goal of advancing it toward clinical trials. Those studies will be needed to determine whether the compound is safe and effective in humans.

“This study presents novel evidence about the pathogenesis of MASH and provides excitement about a therapeutic avenue to explore for a condition that remains difficult to treat,” said Elliot Tapper, M.D., Academic Director of Hepatology at Michigan Medicine.

“What patients with MASH need is a safe and effective therapy capable of improving their liver and heart health – of course we are excited about these developments.”

Source: Scitech Daily

39 Sweeteners Put to the Test Produced Surprising Gut Changes

 Scientists found that sweeteners can behave unexpectedly inside a simulated gut, especially when combined with common medications.

Cambridge researchers have found that many widely used sweeteners can directly slow or alter the growth of bacteria found in the human gut. The strongest effect appeared when isosteviol, a sweetener used in foods and beverages, was combined with the antidepressant duloxetine.

In laboratory experiments, that combination sharply reduced two important bacterial species associated with digestive health and blood sugar regulation. It also produced changes that could influence inflammation and immune activity.

The researchers caution that the findings come from controlled laboratory tests, not studies involving people. More work will be needed to determine whether the same interactions occur inside the human body and whether they have meaningful health consequences.

Sweeteners May Not Be Biologically Inactive

Sweeteners are found in a wide range of everyday products, including soft drinks, candy, desserts, snacks, cereals, and some medications. They are often promoted as alternatives that provide sweetness with less sugar or fewer calories.

However, growing evidence has linked the consumption of some sweeteners with conditions including type 2 diabetes, obesity, and cancer. These associations do not necessarily prove that sweeteners directly cause those diseases, but they have raised questions about how the compounds behave inside the body.

One possible link is the gut microbiome, the enormous community of bacteria and other microorganisms living throughout the digestive tract. These microbes help break down food, produce useful compounds, support the intestinal barrier, and communicate with the immune system.

Despite the widespread use of sweeteners, relatively few studies have examined whether they interact directly with individual gut bacteria.

Professor Kiran Patil from the Medical Research Council (MRC) Toxicology Unit at the University of Cambridge said: “Most of what we know about the potential impact of sweeteners on our health comes from animal research or from population studies. While these studies have indicated involvement of the microbiome in mediating the effect of sweeteners, it’s difficult to know how sweeteners act in the body – is it through direct interactions with our gut bacteria?”

“Answering this is further complicated by the fact that we rarely ever take sweeteners by themselves – we take them with drinks, in snacks, or even in medication to mask bitterness,” added Dr. Sonja Blasche, a lead author of the study, also the MRC Toxicology Unit.

Researchers Tested 39 Common Sweeteners

For the study, published in Molecular Systems Biology, Dr. Blasche and her colleagues investigated how artificial and low-calorie sweeteners affect gut bacteria under laboratory conditions. They also examined whether those effects changed when the sweeteners were mixed with other substances commonly consumed at the same time.

The team grew 25 bacterial species individually. The collection included microbes considered beneficial, neutral, or potentially harmful.

Each bacterial culture was then exposed to 39 commercially used sweeteners, including both natural and artificial varieties. The researchers measured whether the bacteria continued multiplying normally, grew more slowly, or stopped growing.

About three-quarters of the sweeteners altered the growth of at least one bacterial species. Some significantly slowed or completely halted the growth of microbes associated with a healthy gut.

More Than 100 Hidden Interactions

People rarely consume sweeteners in isolation, so the scientists next combined them with other common compounds. These included caffeine, vanillin (vanilla extract), advantame (an artificial sweetener), and eight widely used medications.

The results revealed more than 100 interactions in which a sweetener affected bacteria differently when another compound was present. In 34 cases, the second substance strengthened the sweetener’s effect. In 68 cases, it weakened the effect.

This suggests that the biological impact of a sweetener may depend partly on what is eaten, drunk, or taken with it.

One Sweetener and Antidepressant Stood Out

The most dramatic response involved isosteviol and duloxetine. Isosteviol is used in the food and beverage industry, while duloxetine is prescribed for depression and several other conditions.

Together, the two compounds strongly suppressed Roseburia intestinalis and Parabacteroides merdae. Both bacteria are associated with functions that help maintain digestive and metabolic health.

Duloxetine is also widely prescribed. In the US in 2023, more than 4.2 million patients received the medication.

Source: ScitechDaily

Where You Live May Shape Your Dementia Risk More Than Scientists Realized

 A major global study found that the leading modifiable risk factors for dementia vary significantly from one country to another, challenging the idea of a universal prevention plan.

A large international study led by USC has found that the most common preventable or manageable risk factors for dementia differ sharply around the world. The analysis included more than 214,000 older adults from 14 countries and regions and examined factors such as limited education, high blood pressure, and smoking.

The results suggest that dementia prevention cannot rely on the same strategy everywhere. The risks that affect the greatest number of people in one country may be far less common in another.

The findings were presented at the Alzheimer’s Association International Conference 2026 in London and published in The Lancet Healthy Longevity. AAIC is the largest international gathering devoted to dementia research.

Expanding Dementia Research Beyond Wealthy Countries

Much of the existing evidence about dementia prevention comes from studies conducted in wealthier nations, particularly the United States and countries in Western Europe. Researchers from USC, Brown University, and Johns Hopkins University wanted to determine whether the same risk patterns also appear in low- and middle-income countries.

Their analysis uncovered major differences between populations, along with some unexpected similarities.

Low education affected 85.6% of older adults in China, compared with only 12.0% in the United States. High BMI (a measure of excess body weight), by contrast, was found in 44.9% of participants in the United States but only 13.3% of those in India.

Despite these differences, certain risks frequently appeared together in similar combinations across the world. Cardiovascular problems, including high cholesterol and hypertension, often formed one cluster. Behaviors such as smoking and drinking commonly formed another.

Similar Risk Patterns Across Different Populations

Lead author Emma Nichols, a research scientist with the Center for Economic and Social Research at the USC Schaeffer Institute for Public Policy & Government Service, said these shared patterns were among the study’s most surprising results.

“I was less surprised by the differences and more surprised by some of the similarities, particularly in the ways these risks are patterned across settings,” Nichols said. “That has real implications for how we design prevention strategies and interventions, because some things are more consistent across places than we might expect.”

Click here for a graphic depicting differences and similarities in dementia risk across different countries.

Data From More Than 214,000 Older Adults

Researchers with the Gateway to Global Aging Data team brought together standardized survey information from long-running aging studies in 14 locations. These included the United States, England, Ireland, Northern Ireland, four regions of Europe, Korea, Mexico, China, Malaysia, Brazil, and India. The data were collected between 2009 and 2023. (Jinkook Lee of the Center for Economic and Social Research at the USC Schaeffer Institute is principal investigator of the Gateway to Global Aging Data project as well as the Longitudinal Aging Study in India.)

The team examined 12 modifiable dementia risk factors identified by the Lancet Commission on dementia. Modifiable risk factors are conditions or behaviors that may be changed or managed over time. The factors included hearing loss, depression, physical inactivity, and social isolation.

Researchers compared how frequently each risk appeared, how prevalence differed according to age, gender, and education, and how often several risks occurred in the same person.

Why Dementia Prevention Must Be Tailored

The findings could help governments, health systems, and other organizations create prevention programs that better match the needs of their populations.

For instance, a program designed to connect people with diabetes care could be expanded to address a broader group of related cardiometabolic risks, including hypertension and high cholesterol. Targeting several connected risks together may be more effective than treating each one separately.

The research also carries an encouraging message for individuals. Dementia risk is not necessarily fixed, and many contributing factors can be influenced throughout life.

“Risk for these late-life outcomes isn’t predetermined. These are risk factors you experience over the life course, and you can have an impact on changing your own risk — while also recognizing the ways broader societal factors shape that risk, too.”

Future Research Will Include More Countries

Future studies may examine newer potential risk factors, including poor sleep. Researchers also plan to add more countries as additional standardized data become available.

Source:Scitech Daily

Why AI May Never Reach Human Intelligence

 A new analysis argues that AI may never truly think like humans because the most important parts of human intelligence cannot be programmed into machines.

A prominent computer scientist argues that a proposal made by Alan Turing, widely regarded as the father of theoretical computer science, sent artificial intelligence research in the wrong direction for the past 75 years.

In his new analysis, “Turing’s Mistake: Escaping the Yoke of Unintelligent Machines,” Peter J. Denning examines ideas Turing advanced in 1950. At the time, many scientists believed that human intelligence could exist independently of the body and might therefore be recreated as software running on a digital computer.

Denning also disputes the idea that machine intelligence can be demonstrated through an imitation game (now known as the Turing test).

“These two claims have shaped much of AI research and development,” Denning writes. “My premise is that our acquiescence to these claims has led to the AI mess in which we find ourselves today.”

According to Denning, the artificial intelligence (AI) systems now being developed are unlikely to produce human-level intelligence, known as artificial general intelligence (AGI). Instead, he warns, they may create serious dangers without ever thinking like humans.

Why Tacit Knowledge Matters

Central to Denning’s argument is the idea of tacit knowledge. This refers to the enormous amount of human understanding that people possess but cannot fully express in words or translate into symbols that a machine can process.

Denning describes five broad forms of tacit knowledge that he says ‘elude machine learning’. They include common sense, everyday interactions with people and the environment, feelings and perceptions, practical skills, and the cultural and historical background shared by societies.

Researchers have spent decades trying to record common sense in a form computers can use. Beginning in the 1980s, Douglas Lenat’s ambitious Cyc project set out to build a vast database of common-sense facts. After 40 years of work, the project contained 25 million entries.

“Yet even this treasury could not add up to a background of common sense sufficient to make expert systems smart enough to be experts,” Denning notes. “Cyc validated that much of the knowledge that makes people experts cannot be articulated as propositions.”

Knowing What Is Not the Same as Knowing How

Practical skill creates another major obstacle, Denning argues.

“Our performance skills in thousands of domains cannot be communicated to machines,” Denning explains. “Whereas descriptions of skillful outcomes (‘know what’) can often be represented as bits and stored in a machine, we do not know how to encode the embodied knowledge for skillful performance (‘know how’).”

Music offers a clear example of this difference. Denning says: “A virtuoso violinist can play beautiful music yet cannot describe to an acolyte how to produce it.

“Even if a robot could observe and imitate skilled humans, having no biological body, a robot cannot grasp how the musician feels when playing beautiful music or how an audience feels when hearing it.”

Intuition, gut feelings, spontaneous creativity, and imagination are other forms of tacit knowledge that resist being reduced to computer instructions.

The Representation Problem

Denning calls the central obstacle ‘the representation problem’.

Computers can only perform calculations when data and instructions are encoded in physical forms they can recognize and process. Tacit knowledge, however, cannot easily be converted into such a format.

“Behind every word is a deep well of tacit knowledge that gives it meaning,” Denning says. “Words are but symbolic representations of meanings, not the meanings themselves. Commonly used Large Language Models, such as ChatGPT, Claude and Gemini only manipulate words, they cannot know or understand the meaning of what they are saying.”

This creates what Denning sees as an unbridgeable gap. Because scientists do not fully understand how tacit knowledge operates within humans, they cannot determine how to transfer it to a machine.

“How we host tacit knowledge is largely a mystery,” Denning admits. “All we know is that it is embodied. We have no idea what we might observe and measure in our bodies to reveal it.”

Why Context Changes Meaning

Denning also stresses the importance of context, or the surrounding circumstances that give human words and actions their meaning and purpose.

A statement can mean very different things depending on whether the speaker is sincere, sarcastic, angry, playful, or teasing. Context also helps people decide when to use humor, when to show tact, and how to interpret what someone leaves unsaid.

Source: ScitechDaily

Researchers Finally Solve a Decades-Old Mystery About Cellular Aging

 A new study identifies the molecular switch that determines when aging cells permanently stop dividing.

Every time a human cell divides, the tips of its chromosomes get a little shorter. Those tips, called telomeres, act like protective caps. Once they shrink too far, the cell treats the exposed chromosome ends as DNA damage and stops dividing for good.

That shutdown, known as replicative senescence, is one of the body’s built-in defenses against cancer. By forcing damaged or risky cells into permanent arrest, it can stop early cancer clones before they become full tumors. A new study in Molecular Cell now shows that this safety mechanism depends entirely on ATM kinase, a signaling protein that senses DNA breaks and helps protect genomic stability.

The work also helps explain a puzzle that has bothered cell biologists for decades. Cells grown in standard lab air, which contains far more oxygen than most tissues in the body, stop dividing sooner than cells kept at lower oxygen levels. According to the new findings, high oxygen makes ATM unusually reactive, causing cells to become less tolerant of short telomeres.

“Our results have illuminated the mechanism underlying the aging of human cells through replicative senescence,” says Titia de Lange, head of the Laboratory of Cell Biology and Genetics. “These insights are critical for understanding how this tumor suppression pathway prevents cancer.”

Creating the right conditions

Replicative senescence begins when telomeres can no longer recruit enough TRF2, a shelterin protein that helps hide chromosome ends from the DNA damage machinery. Without sufficient TRF2, telomeres start to look like broken DNA, setting off the signal that brings cell division to a halt.

This matters because short telomeres are not only a sign of cellular aging. They are also a warning that a cell may be entering dangerous territory. By stopping such cells from dividing, replicative senescence helps prevent early-stage cancers from expanding.

“Replicative senescence is a remarkably effective tumor suppressor pathway,” de Lange says. “We know this from patients with long telomeres in which this system does not work properly. These patients can get as many as five different cancers before the age of 70, indicating that in people with normal-length telomeres, the telomere tumor suppressor pathway prevents many cancers.”

Even so, the exact wiring of this cancer prevention system had remained unclear. Earlier studies suggested that either ATM or ATR, two major DNA damage signaling pathways, might be involved. Oxygen added another complication. Researchers had long known that cells cultured at about 20 percent oxygen reach senescence faster than cells grown at more body-like levels, roughly 1 to 8 percent oxygen. The obvious explanation, that high oxygen simply makes telomeres erode faster, had already been ruled out.

o solve the problem, de Lange and colleagues followed replicative senescence in primary human fibroblasts grown at either 3 percent or 20 percent oxygen. The lower oxygen condition was closer to what many cells experience inside the body, but it also made the experiments much more demanding. Even routine steps such as moving plates, adding reagents, or breaking open cells had to be done quickly to avoid exposing the samples to ordinary air.

“Any time the cells or the reagents are outside of the special low-oxygen incubator, they are exposed to 20 percent oxygen, which can change the molecular environment within minutes,” says Alexander Stuart, a former graduate student in the de Lange lab who now holds a postdoc position at Harvard. “That means you’re often in a race to do all the standard protocol steps extremely quickly so you can keep the samples at low oxygen as much as possible.”

Stuart found that ATM alone was responsible for enforcing senescence at both oxygen levels. When ATM was inhibited, or when TRF2 was overproduced, cells continued dividing past the point where they would normally stop. Blocking ATM signaling in already arrested cells also allowed them to resume growth, showing that the arrest was reversible and fully dependent on ATM.

The impact of high oxygen

The next question was why oxygen changed the timing of senescence so strongly. Stuart and de Lange found that high oxygen does not simply age cells faster in a general way. Instead, it puts ATM into a hyperactive state.

That difference changed how cells responded to extremely short telomeres. At 3 percent oxygen, cells could keep dividing even after many telomeres had become very short. When those same cells were shifted to 20 percent oxygen, ATM responded much more aggressively, treating the short telomeres as serious DNA damage and pushing the cells into senescence.

“I don’t think of it as low oxygen extending the lifespan of human cells—that’s the physiological state of our bodies. Rather, the question was: why do high oxygen conditions shorten cellular lifespan? One could then extend that question: why aren’t high oxygen conditions accurate systems for studying senescence?” Stuart says. “We’ve now shown that high oxygen represents a hyperactive ATM setting, which leads to fewer divisions than cells would naturally undergo.”

Source: SciTech Daily