New Drug Could Protect Against Aging

Senolytics are an emerging class of drugs designed to target zombie-like cells that have stopped dividing and build up in the body as we age, and the past few years have seen some exciting discoveries that demonstrate their potential. Adding another to the list are Mayo Clinic researchers, who have shown that these drugs can protect against aging and its related diseases, by acting on a protein long associated with longevity. The zombie-like cells involved in this research are known as senescent cells, and their accumulation during aging is associated with a range of diseases. Recent studies have shown that using senolytics to clear them out could serve as new and effective treatments for dementia and diabetes, and also improve health and lifespan more broadly.

The Mayo Clinic team were exploring how senolytics can influence levels of a protein called a-klotho, known to help protect older people from the effects of aging. The role of this protein in the aging process is well established and has placed it at the center of much research in this space, with studies demonstrating how it could help reverse osteoarthritis and regenerate old musclesLevels of a-klotho are also known to decrease with age, and studies have shown these declines shorten the lifespan of mice. Conversely, inserting genes that encode for the protein has been shown to increase the lifespan of mice by 30 percent. Boosting its levels in humans has been problematic, however, as its larger size would require it to be administered intravenously. But now the Mayo Clinic scientists believe they have found another route, as senolytic drugs can be administered orally.

They first showed that senescent cells reduce levels of a-klotho in human cells. They then demonstrated that using a combination of senolytic drugs on three different types of mice could counter this and increase levels of a-klotho. This effect was then observed in follow-up experiments on patients with idiopathic pulmonary fibrosis, a lung disease that can cause breathing difficulty, frailty and death.

“We show that there is an avenue for an orally active, small-molecule approach to increase this beneficial protein and also to amplify the action of senolytic drugs,” says James Kirkland, M.D., Ph.D., a Mayo Clinic internist and senior author of the study.

Source: https://www.thelancet.com/

Could Sound Replace Pacemakers and Insulin Pumps?

Imagine a future in which crippling epileptic seizures, faltering hearts and diabetes could all be treated not with scalpels, stitches and syringes, but with sound. Though it may seem the stuff of science fiction, a new study shows that this has solid real-world potential.

Sonogenetics – the use of ultrasound to non-invasively manipulate neurons and other cells – is a nascent field of study that remains obscure amongst non-specialists, but if it proves successful it could herald a new era in medicine.

In the new study published in Nature Communications, researchers from the Salk Institute for Biological Studies in California, US, describe a significant leap forward for the field, documenting their success in engineering mammalian cells to be activated using ultrasound. The team say their method, which they used to activate human cells in a dish and brain cells inside living mice, paves the way toward non-invasive versions of deep brain stimulation, pacemakers and insulin pumps.

Going wireless is the future for just about everything,” says senior author Dr Sreekanth Chalasani, an associate professor in Salk’s Molecular Neurobiology Laboratory. “We already know that ultrasound is safe, and that it can go through bone, muscle and other tissues, making it the ultimate tool for manipulating cells deep in the body.

Chalasani is the mastermind who first established the field of sonogenetics a decade ago. He discovered that ultrasound sound waves beyond the range of human hearing — can be harnessed to control cells. Since sound is a form of mechanical energy, he surmised that if brain cells could be made mechanically sensitive, then they could be modified with ultrasound.

In 2015 his research group provided the first successful demonstration of the theory, adding a protein to cells of a roundworm, Caenorhabditis elegans, that made them sensitive to low-frequency ultrasound and thus enabled them to be activated at the behest of researchers.

Chalasani and his colleagues set out to search for a new protein that would work in mammals. Although a few proteins were already known to be ultrasound sensitive, no existing candidates were sensitive at the clinically safe frequency of 7MHz – so this was where the team set their sights. To test whether TRPA1 protein could activate cell types of clinical interest in response to ultrasound, the team used a gene therapy approach to add the genes for human TRPA1 to a specific group of neurons in the brains of living mice. When they then administered ultrasound to the mice, only the neurons with the TRPA1 genes were activated.

Clinicians treating conditions including Parkinson’s disease and epilepsy currently use deep brain stimulation, which involves surgically implanting electrodes in the brain, to activate certain subsets of neurons. Chalasani says that sonogenetics could one day replace this approach—the next step would be developing a gene therapy delivery method that can cross the blood-brain barrier, something that is already being studied. Perhaps sooner, he says, sonogenetics could be used to activate cells in the heart, as a kind of pacemaker that requires no implantation.

Source: https://www.salk.edu/
AND
https://cosmosmagazine.com/

Higher Risk of Dementia for Millions with Eye Conditions

Millions of people with eye conditions including age-related macular degeneration, cataracts and diabetes-related eye disease have an increased risk of developing dementia, new research shows. Vision impairment can be one of the first signs of the disease, which is predicted to affect more than 130 million people worldwide by 2050.

Previous research has suggested there could be a link between eye conditions that cause vision impairment, and cognitive impairment. However, the incidence of these conditions increases with age, as do systemic conditions such as diabetes, high blood pressure, heart disease, depression and stroke, which are all accepted risk factors for dementia. That meant it was unclear whether eye conditions were linked with a higher incidence of dementia independently of systemic conditions.

Now researchers have found that age-related macular degeneration, cataracts and diabetes-related eye disease are independently associated with increased risk of dementia, according to a new study published in the British Journal of Ophthalmology.

The research examined data from 12,364 British adults aged 55 to 73, who were taking part in the UK Biobank study. They were assessed in 2006 and again in 2010 with their health information tracked until early 2021. More than 2,300 cases of dementia were documented, according to the international team of experts led by academics from the Guangdong Eye Institute in China. After assessing health data, researchers found those with age-related macular degeneration had a 26% increased risk of developing dementia. Those with cataracts had an 11% increased risk and people with diabetes-related eye disease had a 61% heightened risk. Glaucoma was not linked to a significant increase in risk.

Researchers also found that people with conditions including diabetes, heart disease, stroke and depression were also more likely to be diagnosed with dementia. Risk was highest among people with one of these conditions who also had some form of eye condition, they said.

Age-related macular degeneration, cataract and diabetes-related eye disease but not glaucoma are associated with an increased risk of dementia,” the authors concluded.

Individuals with both ophthalmic and systemic conditions are at higher risk of dementia compared with those with an ophthalmic or systemic condition only.”

The study comes as Alzheimer’s Research UK says public willingness to get involved with medical research is at an “all-time high”. The charity said 29% of adults were more likely to consider getting involved in medical research because of the pandemic, according to a poll of 1,000 adults across England, Scotland and Wales.

The survey found that 69% said they would be willing to get involved with dementia research, compared with 50% of a sample of people from a year ago.

This is positive news for the thousands of studies waiting to get under way to help understand and tackle health conditions like dementia, cancer, and heart disease,” said Hilary Evans, the chief executive of Alzheimer’s Research UK.

Source: https://www.theguardian.com/

Anti-diabetic Medication at a Specific Dosage Makes you Loose Weight

A weight-loss drug described as a ‘game-changer by obesity researchers has just been approved by the US Food and Drug Administration (FDA), representing the first time the agency has endorsed such a treatment in several years. Wegovy, a weight-management therapy to be manufactured by Danish pharmaceutical company Novo Nordisk, is the the first FDA-approved weight-loss drug since 2014, but it’s not entirely a new medication.

The same drug, called semaglutide, has been used in the US and other countries as an anti-diabetic medication for years. More recently, however, evidence has shown that semaglutide at a different dosage also functions as a powerful and effective appetite-suppressant. In a study published earlier in the year involving almost 2,000 obese adults from 16 different countries, researchers reported that long-term treatment with the medicine led to almost 15 percent weight loss on average across the cohort.

Some lost even more, with over 30 percent of the group dropping in excess of 20 percent of their body weight – results that the scientists singled out as remarkable.

No other drug has come close to producing this level of weight loss – this really is a game-changer,” obesity researcher Rachel Batterham from University College London said at the time.

For the first time, people can achieve through drugs what was only possible through weight-loss surgery.”

Source: https://www.sciencealert.com/

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/

Immune System Killer Cells Controlled By Circadian Rhythms

An analysis of an exhaustive dataset on cells essential to the mammalian immune system shows that our ability to fight disease may rely more heavily on daily circadian cycles than previously assumed.

Malfunctions in , the process that keeps our bodies in tune with the day/night cycles, are increasingly associated with diabetes, cancer, Alzheimer’s, and many other diseases. An investigation published today in Genome Research shows that the activity of macrophagescells within us that seek and destroy intruders like bacteria—may time daily changes in their responses to pathogens and stress through the circadian control of metabolism. In this study, Jennifer Hurley, the Richard Baruch M.D. Career Development Assistant Professor of Biological Sciences at Rensselaer Polytechnic Institute and senior author on this study, and her team investigated how the levels of RNA and proteins in macrophages change over two days.

We have shown there is an incredible amount of circadian timing of macrophage behavior, but the clock is timing macrophages in unexpected ways” said Hurley.

The circadian system is comprised of a set of core clock proteins that anticipate the day/night cycle by causing daily oscillations in levels of enzymes and hormones, and ultimately affecting physiological parameters such as body temperature and the immune response. This molecular clock marks time through a self-regulating cycle of  production and decay. The “positive” element proteins of the clock trigger production of the “negative” element proteins, which in turn block production of positive element proteins until the negative element proteins decay, thus creating a negative feedback cycle that occurs once every 24 hours.

Positive element proteins also regulate fluctuations in a substantial number of gene products, known as messenger RNA or mRNA. Genetic instructions are transcribed from DNA to mRNA, which are then used as a recipe for assembling proteins, the functional building blocks of the cell. It has long been assumed that the levels of each subsequent step could be predicted from the previous. If that were the case, oscillating mRNA would correspond with oscillating levels of cellular proteins, and therefore, if one could track mRNA, they would know what proteins the circadian clock controlled in the cell.

However, this investigation showed that this paradigm may not always be true. The analysis of the macrophage dataset revealed that there was a substantial mismatch between the proteins and mRNAs that are controlled by the circadian clock. This data paralleled research published in Cell Systems in 2018 by the Hurley lab, showing that about 40% of oscillating proteins in the fungus and circadian model system, Neurospora crassa, had no corresponding oscillating mRNA.

But the scale of the difference in macrophages really surprised us,” Hurley said. “Eighty percent of the proteins that oscillate don’t have associated oscillating mRNA in macrophages. That means we were really missing how the clock was timing immunity.”

Source: https://medicalxpress.com/

Diabetics die 3 times more of Covid-19

From the outset of the pandemic, data coming out of early coronavirus hot spots like China, Italy, and New York City foretold that certain groups of people would be more vulnerable to Covid-19. The disease hit older people and people with underlying medical conditions the hardest. As early as February, diabetes had emerged as one of the conditions associated with the highest risk. In one large study out of China, people with diabetes were more than three times as likely to die of Covid-19 than the overall population.

But that’s not what brought four diabetes experts from Australia and the United Kingdom onto a Zoom call back in April. They were supposed to just be catching up—a virtual tea among friends. But talk soon turned to something strange that they’d been seeing in their own hospitals and hearing about through the grapevine. The weird thing was that people were showing up in Covid-19 wards, after having tested positive for the virus, with lots of sugar in their blood. These were people with no known history of diabetes. But you wouldn’t know it from their lab results.

After that call, the experts reached out to colleagues in other countries to see if they’d seen or heard of similar cases. They had. Acute viral infections of all sorts can stress the body, causing blood sugar levels to rise. So that in itself wasn’t unusual, says Francesco Rubino, a bariatric surgeon and diabetes researcher at King’s College in London, who was on that first Zoom call. “What we were seeing and hearing was a little bit different.”

Doctors around the world had described to him strange situations in which Covid-19 patients were showing symptoms of diabetes that didn’t fit the typical two-flavor manifestation of the disease. In most people with type 1 diabetes, their immune cells suddenly turn traitorous, destroying the cells in the pancreas that produce insulin—the hormone that allows glucose to exit the bloodstream and enter cells. People with type 2 diabetes have a different problem; their body slowly becomes resistant to the insulin it does produce. Rubino and his colleagues were seeing blended features of both types showing up spontaneously in people who’d recently been diagnosed with Covid-19.

That was the first clinical puzzle,” he says. For clues to an explanation, Rubino and his colleagues looked to ACE2, the protein receptor that SARS-CoV-2 uses to invade human cells. It appears in the airways, yes, but also in other organs involved in controlling blood sugar, including the gut. Doctors in China discovered copies of the coronavirus in the poop of their Covid-19 patients. And a meta-analysis found that gastrointestinal symptoms plague one out of 10 Covid-19 sufferers.

In the last few decades, scientists have discovered that the gut is not the passive digestive organ once thought. It actually is a major endocrine player—responsible for producing hormone signals that talk to the pancreas, telling it to make more insulin, and to the brain, ordering it to make its owner stop eating. If the coronavirus is messing with these signals, that could provide a biological basis for why Covid-19 would be associated with different forms of diabetes, including hybrid and previously unknown manifestations of the disease. Rubino is one of a growing number of researchers who think that the relationship between the coronavirus and diabetes is actually a two-way street. Having diabetes doesn’t just tip the odds toward contracting a worse case of Covid-19. In some people, the virus might actually trigger the onset of diabetes, and the potential for a lifetime of having to manage it.

Source: https://www.wired.com/

How To Reverse Diabetes

Using induced pluripotent stem cells produced from the skin of a patient with a rare, genetic form of insulin-dependent diabetes called Wolfram syndrome, researchers transformed the human stem cells into insulin-producing cells and used the gene-editing tool CRISPR-Cas9 to correct a genetic defect that had caused the syndrome. They then implanted the cells into lab mice and cured the unrelenting diabetes in those mice.

The findings, from researchers at Washington University School of Medicine in St. Louis, suggest the CRISPR-Cas9 technique may hold promise as a treatment for diabetes, particularly the forms caused by a single gene mutation, and it also may be useful one day in some patients with the more common forms of diabetes, such as type 1 and type 2.

Wolfram syndrome is caused by mutations to a single gene, providing the researchers an opportunity to determine whether combining stem cell technology with CRISPR to correct the genetic error also might correct the diabetes caused by the mutation. Patients with Wolfram syndrome develop diabetes during childhood or adolescence and quickly require insulin-replacement therapy, requiring insulin injections multiple times each day. Most go on to develop problems with vision and balance, as well as other issues, and in many patients, the syndrome contributes to an early death.

ImageJ=1.52a
unit=micron

Researchers at Washington University School of Medicine in St. Louis have transformed stem cells into insulin-producing cells. They used the CRISPR gene-editing tool to correct a defect that caused a form of diabetes, and implanted the cells into mice to reverse diabetes in the animals. Shown is a microscopic image of insulin-secreting beta cells (insulin is green) that were made from stem cells produced from the skin of a patient with Wolfram syndrome.

This is the first time CRISPR has been used to fix a patient’s diabetes-causing genetic defect and successfully reverse diabetes,” said co-senior investigator Jeffrey R. Millman, PhD, an assistant professor of medicine and of biomedical engineering at Washington University. “For this study, we used cells from a patient with Wolfram syndrome because, conceptually, we knew it would be easier to correct a defect caused by a single gene. But we see this as a stepping stone toward applying gene therapy to a broader population of patients with diabetes.

The study is published online in the journal Science Translational Medicine.

Source: https://medicine.wustl.edu/

Molecular ‘Switch’ Reverses Chronic Inflammation And Aging

Chronic inflammation, which results when old age, stress or environmental toxins keep the body’s immune system in overdrive, can contribute to a variety of devastating diseases, from Alzheimer’s and Parkinson’s to diabetes and cancer.

Now, scientists at the University of California, Berkeley, have identified a molecularswitch” that controls the immune machinery responsible for chronic inflammation in the body. The finding, which appears online  in the journal Cell Metabolism, could lead to new ways to halt or even reverse many of these age-related conditions.

My lab is very interested in understanding the reversibility of aging,” said senior author Danica Chen, associate professor of metabolic biology, nutritional sciences and toxicology at UC Berkeley. “In the past, we showed that aged stem cells can be rejuvenated. Now, we are asking: to what extent can aging be reversed? And we are doing that by looking at physiological conditions, like inflammation and insulin resistance, that have been associated with aging-related degeneration and diseases.”

In the study, Chen and her team show that a bulky collection of immune proteins called the NLRP3 inflammasome — responsible for sensing potential threats to the body and launching an inflammation response — can be essentially switched off by removing a small bit of molecular matter in a process called deacetylation.

Overactivation of the NLRP3 inflammasome has been linked to a variety of chronic conditions, including multiple sclerosis, cancer, diabetes and dementia. Chen’s results suggest that drugs targeted toward deacetylating, or switching off, this NLRP3 inflammasome might help prevent or treat these conditions and possibly age-related degeneration in general.

This acetylation can serve as a switch,” Chen said. “So, when it is acetylated, this inflammasome is on. When it is deacetylated, the inflammasome is off.”

Source: https://news.berkeley.edu/

New Vaccine Brings Revolution In Preventing Chronic Inflammation Related To 60% Of Death

As we learn more and more about health, well-being, and all the factors that affect both, inflammation has become a major player in the conversation. Linked with symptoms ranging from bloating and acne to more serious things like depression and cancer, chronic inflammation, researchers believe, could continue to increase in prevalence. But a new vaccine offers hope for the future of preventing inflammatory diseases.

The vaccine, which is currently for animals, was developed by Institut Cochin in France. Researchers already knew about a connection between inflammation, gut health, and the protein flagellin: Flagellin essentially allows into the rest of the body, resulting in inflammation, and while antibodies exist within that intestinal barrier to help prevent leaky gut, it’s harder to keep all the bacteria contained if your microbiome is out of balance. Researchers hypothesized they could boost the flagellin antibodies within the gut, thereby keeping harmful bacteria from spreading into the body. They administered a flagellin vaccine to mice by injecting it directly into their intestinal lining, spurring the production of the flagellin-fighting antibodies. Chronic inflammation is thought to be related to 60% of deaths worldwide, due to its connection to stroke, diabetes, cancer, and more. This vaccine could be a game-changer if scientists are able to replicate the findings in a version for humans, which researcher Benoît Chassaing says they’re working on.

This vaccine strategy can be envisaged in humans, because such abnormalities of the microbiota have been observed in patients with inflammatory and metabolic diseases. With this in mind, we are currently working on a means of locally administering flagellin to the intestinal mucosa,” he says.

They’re also looking into testing the vaccine on animals that already have chronic inflammatory diseases, to see if it can be used for inflammatory treatment, as opposed to just prevention. But until such a vaccine for humans exists, there are lots of ways to combat inflammation naturally. If you’re still looking for more information, check out the Ultimate Guide to Inflammation class.. When inflammation was induced, the unvaccinated mice became obese, and the vaccinated mice did not. Immunization quelled intestinal inflammation by lowering levels of the flagellin-expressing bacteria in their microbiota, intestines, and intestinal lining.

Source: https://www.mindbodygreen.com/