Israeli scientists gave an artificial molecule they invented to 30 mice suffering from Alzheimer’s — and found that all of them recovered, regaining full cognitive abilities. They stress that this was a small sample of mice and that human testing is far off, but believe the result indicates that within a decade, their synthetic molecule could be developed into a drug for treating the degenerative disease. The peer-reviewed research, led by neuroscientists from Ben-Gurion University, was recently published in the journal Translational Neurodegeneration.

“We are taking a very different approach than efforts at Alzheimer’s medicines that we have seen so far,” Prof. Varda Shoshan-Barmatz, the lead author, told The Times of Israel. “Most are trying to address plaque that forms in the brain, but we are addressing dysfunction elsewhere. And we’re optimistic. Mice who had Alzheimer’s and received our molecule and then underwent tests had the same cognitive abilities as mice who’d never had Alzheimer’s.”

Interestingly, the molecule appears to have been effective without significantly reducing the amount of plaque, which she thinks indicates that scientists may have been overly fixated on the plaque. There is scientific literature on the dysfunction of mitochondria among people with Alzheimer’s. Mitochondria are organelles — tiny miniature organs within cells — that provide the cell with power. Scientists believe that when they malfunction and fail to produce the normal quantities of energy, it can lead to cell death, inflammation and reduced immune response.

Despite Alzheimer’s being linked to mitochondrial dysfunction, no drug candidates are currently focused on mitochondria. Drug research is mostly concerned with combatting the buildup of protein fragments between nerve cells in the brain, which are thought to be linked to Alzheimer’s. The Ben-Gurion University team set out to normalize mitochondrial activity by countering the harmful effects that occur when a protein called VDAC1 is over-produced. The protein plays a crucial role in regulating the metabolic and energetic functions of mitochondria when produced in normal quantities. But the scientists found that it is produced in huge levels in the brains of mice with Alzheimer’s, and interferes with mitochondrial activity.

“In our research, we have shifted the focus of Alzheimer’s treatments from the plaque to this protein, which is produced in the nerve cells around the plaque instead,” said Shoshan-Barmatz. “We prevent this protein from causing cell death, as the molecule interferes with its harmful effect.”

Source: https://in.bgu.ac.il/ 
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https://www.timesofisrael.com/

New research in the journal Nature Aging takes a page from the field of renewable energy and shows that genetically engineered mitochondria can convert light energy into chemical energy that cells can use, ultimately extending the life of the roundworm C. elegans.  While the prospect of sunlight-charged cells in humans is more science fiction than science, the findings shed light on important mechanisms in the aging process.

Caenorhabditis elegans (C. elegans) has been the source of major discoveries in molecular and cell biology

“We know that mitochondrial dysfunction is a consequence of aging,” said Andrew Wojtovich, Ph.D., associate professor of Pharmacology & Physiology at the University of Rochester Medical Center and senior author of the study.  “This study found that simply boosting metabolism using light-powered mitochondria gave laboratory worms longer, healthier lives.  These findings and new research tools will enable us to further study mitochondria and identify new ways to treat age-related diseases and age healthier.”

Mitochondria are organelles found in most cells in the body.  Often referred to as cellular power plants, mitochondria use glucose to produce adenosine triphosphate (ATP), the compound that provides energy for key functions in the cell, such as muscle contraction and the electrical impulses that help nerve cells communicate with each other.

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A step toward discovering the fountain of youth could involve protecting against the inevitable accumulation of “senescent” cells associated with aging and age-related diseases. Now, researchers from Japan have identified the MondoA protein as key to protecting against the accumulation of senescent cells.

In a study published this month in Cell Reports, researchers led by Osaka University have shown that MondoA delays cellular senescence, and therefore promotes longevity, by activating autophagy. Autophagy is a process whereby cells undergo controlled breakdown and recycling of their components, which is important for maintaining stable conditions in the cellular environment and for enabling adaptation to stress. Activation of autophagy by MondoA partly involves suppressing a protein called Rubicon, which is a negative regulator of autophagy. Rubicon can increase with aging in various tissues and model organisms, which can cause the decline in autophagy seen with aging.

Furthermore, MondoA is also essential to maintaining stable conditions of parts of the cell called mitochondria, which are responsible for energy production. MondoA does this by regulating another molecule, Prdx3, which is involved in mitochondrial turnover. Mitochondria are constantly fusing and dividing, which is important for maintaining their health. Prdx3 is part of the process by which autophagy occurs in mitochondria, preventing senescence. The research team led by Osaka University concluded that MondoA plays a key role in the regulation of Prdx3 and therefore in maintaining mitochondrial stability.

Particularly dense accumulation of senescent cells has been observed in the kidney. The researchers therefore looked at ischemic acute kidney injury (AKI) in mice.

“Mice with ischemic AKI and reduced levels of MondoA showed increased senescence,” explains lead author Hitomi Yamamoto-Imoto. “We also found that decreased MondoA in the nucleus correlated with human aging and ischemic AKI. MondoA therefore counteracts cellular senescence in aging and ischemic AKI in both mice and humans.”

Drugs that eliminate senescent cells, called senolytics, are currently being considered as treatment for age-associated diseases. However, senescent cells play important roles, and their complete removal may have considerable side effects. “Our work shows that the transcriptional activation of MondoA can protect against cellular senescence, kidney injury associated with aging, and organismal aging,” explains senior author Tamotsu Yoshimori. “Activation of MondoA and therefore autophagy could be a potentially safe therapeutic strategy.” This work could well open new and safer avenues for the treatment of aging and age-related diseases.

Source: https://phys.org/

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/

T cells are supposed to defend us from pathogens, but a new mouse study suggests they may also speed aging. Blocking inflammation caused by the cells or boosting their supply of a key metabolic molecule lessened the severity of some aging-related symptoms in rodents, raising the possibility these treatments could benefit older people. The discovery is “a fantastic result directly linking metabolism, inflammation, and aging,” says immunologist Kylie Quinn of RMIT University, Bundoora, in Australia. “They’ve done a really thorough job of making sure it’s the T cells” that are causing the mice to age quickly.

Our T cells let us down as we age, becoming weaker pathogen fighters. This decline helps explain why elderly people are more susceptible to infections and less responsive to vaccines. One reason T cells falter as we get older is that mitochondria, the structures that serve as power plants inside cells, begin to malfunction. But T cells might not just reflect aging. They could also promote it. Older people have chronic inflammation throughout the body, known as inflammaging, and researchers have proposed it spurs aging. T cells may stoke this process because they release inflammation-stimulating molecules.

To test that hypothesis, immunologist María Mittelbrunn of the University Hospital 12 October’s Health Research Institute and colleagues genetically modified mice to lack a protein in the mitochondria of their T cells. This alteration forces the cells to switch to a less efficient metabolic mechanism for obtaining energy.

By the time the rodents were 7 months old, typically the prime of life for a mouse, they already appeared to be in their dotage, the team reports today in Science. Compared with typical mice, the modified rodents were slow and sluggish. They had shrunken, weak muscles and were less resistant to infections. Like many elderly people, they suffered from weakened hearts and shed much of their body fat. T cells from the altered mice poured out molecules that trigger inflammation, the team found, suggesting the cells could be partially responsible for the animals’ physical deterioration. “The immune system plays a role in increasing the velocity of aging,” Mittelbrunn says.

The scientists also tested whether they could slow the aging clock. First they dosed the mice with a drug that blocks tumour necrosis factor alpha (TNF-alpha), one of the inflammation-inducing molecules that T cells unleash; the treatment increased the animals’ grip strength, improved their performance in a maze, and boosted the heart’s pumping power.

Mittelbrunn and colleagues also gave the animals a compound that raises levels of nicotinamide adenine dinucleotide (NAD), a molecule that’s vital for metabolic reactions that enable cells to extract energy from food. NAD’s cellular concentrations typically decline with age, and the researchers found that ramping it up in the mice made them more active and strengthened their hearts.

Source: https://researchbank.rmit.edu.au/
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https://www.sciencemag.org/

A physicist at The University of Texas at Arlington (UTA) has proposed a new concept for treating cancer cells. In a recently published paper in the journal Nanomedicine: Nanotechnology, Biology and Medicine, UTA physics Professor Wei Chen and a team of international collaborators advanced the idea of using titanium dioxide (TiO₂) nanoparticles stimulated by microwaves to trigger the death of cancer cells without damaging the normal cells around them.

The method is called microwave-induced radical therapy, which the team refers to as microdynamic therapy, or MDT. The use of TiO₂ nanoparticles activated by light and ultrasound in cancer treatments has been studied extensively, but this marks the first time researchers have shown that the nanoparticles can be effectively activated by microwaves for cancer cell destruction—potentially opening new doors to treatment for patients fighting the disease. Chen said the new therapy centers on reactive oxygen species, or ROS, which are a natural byproduct of the body’s metabolism of oxygen. ROS help kill toxins in the body, but can also be damaging to cells if they reach a critical level. TiO₂ enters cells and produces ROS, which are able to damage plasma membranes, mitochondria and DNA, causing cell death.

“Cancer cells are characterized by a higher steady-state saturation of ROS than normal, healthy cells,” Chen said. “This new therapy allows us to exploit that by raising the saturation of ROS in cancer cells to a critical level that triggers cell death without pushing the normal cells to that same threshold.”

The pilot study for this new treatment concept builds upon Chen’s expertise in the use of nanoparticles to combat cancer.

Chen’s collaborators hail from the Guangdong Academy of Medical Sciences and Beihang University. The team conducted experiments that demonstrate the nanoparticles can significantly suppress the growth of osteosarcomas under microwave irradiation.

While TiO₂ and low-power microwave irradiation alone did not effectively kill cancer cells, the combination of the two proved successful in creating a toxic effect for the tumor cells. Microwave ablation therapy has already proven to be an effective treatment against bone cancer, obtaining better results than MDT. However, MDT has applications for combatting other types of cancer, not just the osteosarcomas used for this pilot case.

Using light to activate ROS—as is seen in photodynamic therapy—can be challenging for the treatment of tumors deeply located within the body; in contrast, microwaves lend the ability to create deeper penetration that propagates through all types of tissues and non-metallic materials.

“This new discovery is exciting because it potentially creates new avenues for treating cancer patients without causing debilitating side effects,” Chen said. “This targeted, localized method allows us to keep healthy cells intact so patients are better equipped to battle the disease.”

Source: https://www.uta.edu/