Reversal of Aging is Closer

The cure for aging has long been the Holy Grail of medicine. Emerging technologies, like the gene editing tool CRISPR, have opened the floodgates to what may be possible for the future of medical science. The key to slowing down aging, however, may lie in a simple and age-old technique. For the first time, Israeli scientists showed the reversal of aging in two key biological clocks in humans, by giving patients oxygen therapy in a pressurized chamber. The results appear in the journal Aging.

As you grow older and your cells continue to divide, sequences of DNA at the end of chromosomes, called telomeres, gradually become shorter. Once the telomeres become too short, the cell can no longer replicate and eventually dies. This isn’t necessarily a bad thing.

Telomere shortening can prevent rogue cancerous cells from multiplying uncontrollably, but unfortunately, this comes with the cost of genetic aging. These geriatric cells that can no longer divide are also known as senescent cells, which accumulate over the period of your life and are believed to be one of the leading causes of aging. In a clinical trial, 35 healthy adults aged 64 and older received 60 oxygen therapy sessions daily over the course of three months. The scientists collected the subjects’ blood samples prior to treatment, after the first and second months of the trial, and two weeks after the trial was over. None of the patients had any lifestyle, diet, or medication changes throughout the study, and yet their blood work showed significant increases in the telomere length of their cells and a decrease in the number of their senescent cells. This isn’t the first time doctors have put patients into pressurized oxygen chambers. Hyperbaric oxygen therapy (HBOT) has been used for almost a century to treat a number of illnesses, including decompression sickness in deep-sea divers and carbon monoxide poisoning.

The therapy involves breathing pure oxygen in a pressurized chamber, which causes blood and tissues in your body to become saturated with oxygen. Strangely enough, this can trigger similar physiological effects that occur when your body is starved of oxygen, known as hypoxia. While previous research shows these effects can stimulate your brain and increase your cognitive abilities, this is the first study to show the therapy may also reverse aging.

Since telomere shortening is considered the ‘Holy Grail’ of the biology of aging, many pharmacological and environmental interventions are being extensively explored in the hopes of enabling telomere elongation,” said study coauthor Shai Efrati, a professor at the Sackler School of Medicine at Tel Aviv University. The significant improvement of telomere length shown during and after these unique HBOT protocols provides the scientific community with a new foundation of understanding that aging can, indeed, be targeted and reversed at the basic cellular-biological level.

This also isn’t the first time scientists have claimed to reverse aging. Several studies using pharmacological drugs, such as danazol, have been shown to elongate telomeres. Additionally, lifestyle changes, including exercise and healthy diets, have been shown to have small effects on the growth of telomeres. “Until now, interventions such as lifestyle modifications and intense exercise were shown to have some inhibition effect on the expected telomere length shortening. However, what is remarkable to note in our study, is that in just three months of HBOT, we were able to achieve such significant telomere elongation—at rates far beyond any of the current available interventions or lifestyle modifications,” study coauthor Amir Hadanny, a neurosurgeon at the Sagol Center of Hyperbaric Medicine and Research in Israel, explained in the press release.

Source: https://www.popularmechanics.com/

LDL Receptor Identified as Therapeutic Target for Alzheimer’s

By the time people with Alzheimer’s disease start exhibiting difficulty remembering and thinking, the disease has been developing in their brains for two decades or more, and their brain tissue already has sustained damage. As the disease progresses, the damage accumulates, and their symptoms worsen.

Researchers at Washington University School of Medicine in St. Louis have found that high levels of a normal protein associated with reduced heart disease also protect against Alzheimer’s-like brain damage – at least in mice. The findings, published in Neuron, suggest that raising levels of the protein — known as low-density lipoprotein receptor (LDL receptor) — could potentially be a way to slow or stop cognitive decline.

The discovery of LDL receptor as a potential therapeutic target for dementia is surprising since the protein is much better known for its role in cholesterol metabolism. Statins and PCSK9 inhibitors, two groups of drugs widely prescribed for cardiovascular disease, work in part by increasing levels of LDL receptor in the liver and some other tissues. It is not known whether they affect LDL receptor levels in the brain.

There are not yet clearly effective therapies to preserve cognitive function in people with Alzheimer’s disease,” said senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. “We found that increasing LDL receptor in the brain strongly decreases neurodegeneration and protects against brain injury in mice. If you could increase LDL receptor in the brain with a small molecule or other approach, it could be a very attractive treatment strategy.”

The key to the importance of LDL receptor lies in a different protein, APOE, that also is linked to both cholesterol metabolism and Alzheimer’s disease. High cholesterol in the blood is associated with increased risk of Alzheimer’s disease, although the exact nature of the association is unclear.

During the long, slow development of Alzheimer’s disease, plaques of a protein called amyloid gradually accumulate in the brain. After many years, another brain protein called tau starts forming tangles that become detectable just before Alzheimer’s symptoms arise. The tangles are thought to be toxic to neurons, and their spread through the brain foretells the death of brain tissue and cognitive decline. First author Yang Shi, PhD, a postdoctoral researcher, and Holtzman previously showed that APOE drives tau-mediated degeneration in the brain by activating microglia, the brain’s cellular janitorial crew. Once activated, microglia can injure neural tissue in their zeal to clean up molecular debris.

Higher levels of LDL receptor limit the damage APOE can do in part by binding to APOE and degrading it. Higher levels of LDL receptor in the brain, therefore, should pull more APOE out of the fluid surrounding brain cells and mitigate damage even further, the researchers reasoned.

Targeted delivery of therapeutic RNAs directly to cancer cells

Tel Aviv University‘s groundbreaking technology may revolutionize the treatment of cancer and a wide range of diseases and medical conditions. In the framework of this study, the researchers were able to create a new method of transporting RNA-based drugs to a subpopulation of immune cells involved in the inflammation process, and target the disease-inflamed cell without causing damage to other cells.

The study was led by Prof. Dan Peer, a global pioneer in the development of RNA-based therapeutic delivery. He is Tel Aviv University‘s Vice President for Research and Development, head of the Center for Translational Medicine and a member of both the Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, and the Center for Nanoscience and Nanotechnology. The study was published in the prestigious scientific journal Nature Nanotechnology.

Our development actually changes the world of therapeutic antibodies. Today we flood the body with antibodies that, although selective, damage all the  that express a specific receptor, regardless of their current form. We have now taken out of the equation  that can help us, that is, uninflamed cells, and via a simple injection into the bloodstream can silence, express or edit a particular gene exclusively in the cells that are inflamed at that given moment,” explains Prof. Peer.

As part of the study, Prof. Peer and his team were able to demonstrate this groundbreaking development in animal models of inflammatory bowel diseases such as Crohn’s disease and colitis, and improve all inflammatory symptoms, without performing any manipulation on about 85% of the immune system cells. Behind the innovative development stands a simple concept, targeting to a specific receptor conformation. “On every cell envelope in the body, that is, on the , there are receptors that select which substances enter the cell,” explains Prof. Peer. “If we want to inject a drug, we have to adapt it to the specific receptors on the , otherwise it will circulate in the bloodstream and do nothing. But some of these receptors are dynamic—they change shape on the membrane according to external or internal signals. We are the first in the world to succeed in creating a drug delivery system that knows how to bind to receptors only in a certain situation, and to skip over the other identical cells, that is, to deliver the drug exclusively to cells that are currently relevant to the disease.”

Source: https://phys.org/

CRISPR Gene Editing Breakthrough could Treat many More Diseases

CRISPR gene editing already promises to fight diseases that were once thought unassailable, but techniques so far have required injecting the tools directly into affected cells. That’s not very practical for some conditions. However, there’s just been a breakthrough. NPR reports that researchers have published results showing that you can inject CRISPR-Cas9 into the bloodstream to make edits, opening the door to the use of gene editing for treating many common diseases.

The experimental treatment tackled a rare genetic disease, transthyretin amyloidosis. Scientists injected volunteers with CRISPR-loaded nanoparticles that were absorbed by the patients’ livers, editing a gene in the organ to disable production of a harmful protein. Levels of that protein plunged within weeks of the injection, saving patients from an illness that can rapidly destroy nerves and other tissues in their bodies.

The test involved just six people, and the research team still has to conduct long-term studies to check for possible negative effects. If this method proves viable on a large scale, though, it could be used to treat illnesses where existing CRISPR techniques aren’t practical, ranging from Alzheimer’s to heart disease.

There are some ethical considerations. Some are already wary about the potential for abusing CRISPR for ‘designer babies‘ and other less-than-altruistic purposes. Bloodstream injections would make it that much easier to perform dubious edits. If used properly, however, this new CRISPR method could avoid (or prevent) suffering that was once considered inevitable.

Source: https://www.npr.org/
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https://www.engadget.com/

Holistic Immune Response Against Covid-19

Researchers say it’s the first real look at exactly what types of “red flags” the human body uses to enlist the help of T cells—killers the immune system sends out to destroy infected cells. Until now, COVID vaccines have focused on activating a different type of immune cell, B cells, which are responsible for creating antibodies. Developing vaccines to activate the other arm of the immune system—the T cells—could dramatically increase immunity against coronavirus, and importantly, its variants.

As reported in the journal Cell, the researchers say current vaccines might lack some important bits of viral material capable of triggering a holistic immune response in the human body.

Companies should reevaluate their vaccine designs,” says Mohsan Saeed, a virologist at Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) and co-corresponding author of the paper.

Saeed, an assistant professor of biochemistry at the School of Medicine, performed experiments on human cells infected with coronavirus. He isolated and identified those missing pieces of SARS-CoV-2 proteins inside one of the NEIDL’s Biosafety Level 3 (BSL-3) labs.

This was a big undertaking because many research techniques are difficult to adapt for high containment levels [such as BSL-3],” Saeed says. “The overall coronavirus research pipeline we’ve created at the NEIDL, and the support of our entire NEIDL team, has helped us along the way.”

Saeed got involved when computational geneticists Pardis Sabeti and Shira Weingarten-Gabbay contacted him. They hoped to identify fragments of SARS-CoV-2 that activate the immune system’s T cells.

The emergence of viral variants, an active area of research in my lab, is a major concern for vaccine development,” says Sabeti, a leader in the Broad Institute’s Infectious Disease and Microbiome Program. She is also a Harvard University professor of systems biology.

We swung into full action right away because my laboratory had [already] generated human cell lines that could be readily infected with SARS-CoV-2,” Saeed says. The group’s efforts were spearheaded by two members of the Saeed lab: Da-Yuan Chen, a postdoctoral associate, and Hasahn Conway, a lab technician.

Source:  https://www.futurity.org/

What is the Human Cortex?

The cerebral cortex is the thin surface layer of the brain found in vertebrate animals that has evolved most recently, showing the greatest variation in size among different mammals (it is especially large in humans). Each part of the cerebral cortex is six layered (e.g., L2), with different kinds of nerve cells (e.g., spiny stellate) in each layer. The cerebral cortex plays a crucial role in most higher level cognitive functions, such as thinking, memory, planning, perception, language, and attention. Although there has been some progress in understanding the macroscopic organization of this very complicated tissue, its organization at the level of individual nerve cells and their interconnecting synapses is largely unknown.

Petabyte connectomic reconstruction of a volume of human neocortex. Left: Small subvolume of the dataset. Right: A subgraph of 5000 neurons and excitatory (green) and inhibitory (red) connections in the dataset. The full graph (connectome) would be far too dense to visualize.

Mapping the structure of the brain at the resolution of individual synapses requires high-resolution microscopy techniques that can image biochemically stabilized (fixed) tissue. We collaborated with brain surgeons at Massachusetts General Hospital in Boston (MGH) who sometimes remove pieces of normal human cerebral cortex when performing a surgery to cure epilepsy in order to gain access to a site in the deeper brain where an epileptic seizure is being initiated. Patients anonymously donated this tissue, which is normally discarded, to our colleagues in the Lichtman lab. The Harvard researchers cut the tissue into ~5300 individual 30 nanometer sections using an automated tape collecting ultra-microtome, mounted those sections onto silicon wafers, and then imaged the brain tissue at 4 nm resolution in a customized 61-beam parallelized scanning electron microscope for rapid image acquisition.

Imaging the ~5300 physical sections produced 225 million individual 2D images. The team then computationally stitched and aligned this data to produce a single 3D volume. While the quality of the data was generally excellent, these alignment pipelines had to robustly handle a number of challenges, including imaging artifacts, missing sections, variation in microscope parameters, and physical stretching and compression of the tissue. Once aligned, a multiscale flood-filling network pipeline was applied (using thousands of Google Cloud TPUs) to produce a 3D segmentation of each individual cell in the tissue. Additional machine learning pipelines were applied to identify and characterize 130 million synapses, classify each 3D fragment into various “subcompartments” (e.g., axon, dendrite, or cell body), and identify other structures of interest such as myelin and cilia. Automated reconstruction results were imperfect, so manual efforts were used to “proofread” roughly one hundred cells in the data. Over time, the scientists expect to add additional cells to this verified set through additional manual efforts and further advances in automation.

Source: https://ai.googleblog.com/

RNA Could Be The Future of Cancer Treatment

Cells are the basic building blocks of all living things. So, in order to treat or cure almost any disease or condition – including cancer – you first need to have a fundamental understanding of cell biology. While researchers have a pretty good understanding of what each component of a cell does, there are still things we don’t know about them – including the role that some RNAs molecules play in a cell.

Finding the answer to this may be key in developing further cancer treatments, which is what our research has sought to uncover. Three types of molecules carry information in a cell, and each of these molecules performs its own important function. The first is DNA, which contains hard-wired genetic information (like a book of instructions). . The second, RNA, is a temporary copy of one particular instruction that is derived from DNA. Last are the proteins produced thanks to the information provided by the RNA. These proteins are the “workhorses” of the cells, which perform specific functions, such as helping cells move, reproduce, and generate energy.

In line with this model, RNA has long been seen as nothing more than an intermediary between DNA and proteins. But researchers are starting to discover that RNA is much more than an intermediary. In fact, this overlooked molecule may hold the secret to cancer progression. The scientists group recently discovered a new type of RNA that drives cancer progression without producing any protein. We think that this type of discovery may pave the way for an entirely new way of targeting cancer cells. But to understand how this is possible, it’s first important to know the different types of RNA we have in our body. Only about 1% of DNA is copied into RNAs that make proteins. Other RNAs help the production of proteins. The rest (known as non-coding RNAs) were long assumed to serve no function in the human body. But recent studies are challenging these assumptions, showing these “uselessRNAs actually performvery specific purpose. In fact, these “non-coding” RNAs regulate the functions of many genes, thereby controlling key aspects of the cells’ lives (such as their ability to move around).

The most abundant type of non-coding RNAs are long non-coding RNAs (lncRNAs). These are long molecules which interact with many different molecules in the cell. And, as researchers have now discovered, these complex structures allow many different functions to take place between cells.

For example, some lncRNAsgrab” different proteins and gather them to work in a specific cellular space – such as the same gene segment. This function is essential for controlling the inactivation of some genes during development.

Source: https://nationalinterest.org/

Skin and Bones Repaired by Bioprinting

Fixing traumatic injuries to the skin and bones of the face and skull is difficult because of the many layers of different types of tissues involved, but now, researchers have repaired such defects in a rat model using bioprinting during surgery, and their work may lead to faster and better methods of healing skin and bones.

Schematic of the skin and bone bioprinting process. After scanning, the bone and then skin layers are bioprinted creating a layered repair with bone, a barrier layer, and dermis and epidermis

This work is clinically significant,” said Ibrahim T. Ozbolat, Associate Professor of Biomedical Engineering and Neurosurgery, Penn State. “Dealing with composite defects, fixing hard and soft tissues at once, is difficult. And for the craniofacial area, the results have to be esthetically pleasing.

Currently, fixing a hole in the skull involving both bone and soft tissue requires  using bone from another part of the patient’s body or a cadaver. The bone must be covered by soft tissue with blood flow, also harvested from somewhere else, or the bone will die. Then surgeons need to repair the soft tissue and skin. Ozbolat and his team used extrusion bioprinting and droplet bioprinting of mixtures of cells and carrier materials to print both bone and soft tissueThere is no surgical method for repairing soft and hard tissue at once,” said Ozbolat. “This is why we aimed to demonstrate a technology where we can reconstruct the whole defect — bone to epidermis — at once.”

The researchers attacked the problem of bone replacement first, beginning in the laboratory and moving to an animal model. They needed something that was printable and nontoxic and could repair a 5-millimeter hole in the skull. The “hard tissue ink” consisted of collagen, chitosan, nano-hydroxyapatite and other compounds and mesenchymal stem cells — multipotent cells found in bone marrow that create bone, cartilage and bone marrow fat. The hard tissue ink extrudes at room temperature but heats up to body temperature when applied. This creates physical cross-linkage of the collagen and other portions of the ink without any chemical changes or the necessity of a crosslinker additive.

The researchers used droplet printing to create the soft tissue with thinner layers than the bone. They used collagen and fibrinogen in alternating layers with crosslinking and growth enhancing compounds. Each layer of skin including the epidermis and dermis differs, so the bioprinted soft tissue layers differed in composition. Experiments repairing 6 mm holes in full thickness skin proved successful. Once the team understood skin and bone separately, they moved on to repairing both during the same surgical procedure. “This approach was an extremely challenging process and we actually spent a lot of time finding the right material for bone, skin and the right bioprinting techniques,” said Ozbolat.

The scientists have reported their results in Advanced Functional Materials.

Source: https://news.psu.edu/

How to Speed up Bone Implant Recovery

An international research team led by Monash University has uncovered a new technique that could speed up recovery from bone replacements by altering the shape and nucleus of individual stem cells. The research collaboration involving Monash University, the Melbourne Centre for Nanofabrication, CSIRO, the Max Planck Institute for Medical Research and the Swiss Federal Institute of Technology in Lausanne, developed micropillar arrays using UV nanoimprint lithography that essentially ‘trick’ the cells to become boneNanoimprint lithography allows for the creation of microscale patterns with low cost, high throughput and high resolution.

When implanted into the body as part of a bone replacement procedure, such as a hip or knee, researchers found these pillars – which are 10 times smaller than the width of a human hair – changed the shape, nucleus and genetic material inside stem cells. Not only was the research team able to define the topography of the pillar sizes and the effects it had on stem cells, but they discovered four times as much bone could be produced compared to current methods.

Novel micropillars, 10 times smaller than the width of a human hair, can change the size, shape and nucleus of individual stem cells and ‘trick’ them to become bone

What this means is, with further testing, we can speed up the process of locking bone replacements with surrounding tissue, in addition to reducing the risks of infection,” Associate Professor Jessica Frith from Monash University’s Department of Materials Science and Engineering said. “We’ve also been able to determine what form these pillar structures take and what size they need to be in order to facilitate the changes to each stem cell, and select one that works best for the application.

Researchers are now advancing this study into animal model testing to see how they perform on medical implants. Engineers, scientists and medical professionals have known for some time that cells can take complex mechanical cues from the microenvironment, which in turn influences their development.

However, Dr Victor Cadarso from Monash University’s Department of Mechanical and Aerospace Engineering says their results point to a previously undefined mechanism where ‘mechanotransductory signalling’ can be harnessed using microtopographies for future clinical settings. “Harnessing surface microtopography instead of biological factor supplementation to direct cell fate has far-reaching ramifications for smart cell cultureware in stem cell technologies and cell therapy, as well as for the design of smart implant materials with enhanced osteo-inductive capacity,” Dr Cadarso said.

The findings were published in Advanced Science.

Source: https://www.monash.edu/

Self-Assembling Nanofibers Prevent Damage from Inflammation

Biomedical engineers at Duke University have developed a self-assembling nanomaterial that can help limit damage caused by inflammatory diseases by activating key cells in the immune system. In mouse models of psoriasis, the nanofiber-based drug has been shown to mitigate damaging inflammation as effectively as a gold-standard therapy. One of the hallmarks of inflammatory diseases, like rheumatoid arthritis, Crohn’s disease and psoriasis, is the overproduction of signaling proteins, called cytokines, that cause inflammation. One of the most significant inflammatory cytokines is a protein called TNF. Currently, the best treatment for these diseases involves the use of manufactured antibodies, called monoclonal antibodies, which are designed to target and destroy TNF and reduce inflammation.

Although monoclonal antibodies have enabled better treatment of inflammatory diseases, the therapy is not without its drawbacks, including a high cost and the need for patients to regularly inject themselves. Most significantly, the drugs also have uneven efficacy, as they may sometimes not work at all or eventually stop working as the body learns to make antibodies that can destroy the manufactured drug. To circumvent these issues, researchers have been exploring how immunotherapies can help teach the immune system how to generate its own therapeutic antibodies that can specifically limit inflammation.

The graphic shows the peptide nanofiber bearing complement protein C3dg (blue) and key components of the TNF protein, which include B-cell epitopes (green), and T-cell epitopes (purple)

We’re essentially looking for ways to use nanomaterials to induce the body’s immune system to become an anti-inflammatory antibody factory,” said Joel Collier, a professor of biomedical engineering at Duke University. “If these therapies are successful, patients need fewer doses of the therapy, which would ideally improve patient compliance and tolerance. It would be a whole new way of treating inflammatory disease.”

In their new paper, which appeared online in the Proceedings of the National Academy of Sciences (PNAS), Collier and Kelly Hainline, a graduate student in the Collier lab, describe how novel nanomaterials could assemble into long nanofibers that include a specialized protein, called C3dg. These fibers then were able to activate immune system B-cells to generate antibodies. “C3dg is a protein that you’d normally find in your body,” said Hainline. “The protein helps the innate immune system and the adaptive immune system communicate, so it can activate specific white blood cells and antibodies to clear out damaged cells and destroy antigens.”

Due to the protein’s ability to interface between different cells in the immune system and activate the creation of antibodies without causing inflammation, researchers have been exploring how C3dg could be used as a vaccine adjuvant, which is a protein that can help boost the immune response to a desired target or pathogen.

Source: https://pratt.duke.edu/