Amazing Human Organ Newly Discovered

Researchers have identified a previously unknown feature of human anatomy with implications for the function of all organs, most tissues and the mechanisms of most major diseases.

Published March 27 in Scientific Reports, a new study co-led by an NYU School of Medicine pathologist reveals that layers of the body long thought to be dense, connective tissues below the skin’s surface, lining the digestive tract, lungs and urinary systems, and surrounding arteries, veins, and the fascia between muscles are instead interconnected, fluid-filled compartments.

This series of spaces, supported by a meshwork of strong (collagen) and flexible (elastin) connective tissue proteins, may act like shock absorbers that keep tissues from tearing as organs, muscles, and vessels squeeze, pump, and pulse as part of daily function.

Importantly, the finding that this layer is a highway of moving fluid may explain why cancer that invades it becomes much more likely to spread. Draining into the lymphatic system, the newfound network is the source of lymph, the fluid vital to the functioning of immune cells that generate inflammation. Furthermore, the cells that reside in the space, and collagen bundles they line, change with age, and may contribute to the wrinkling of skin, the stiffening of limbs, and the progression of fibrotic, sclerotic and inflammatory diseases.

The field has long known that more than half the fluid in the body resides within cells, and about a seventh inside the heart, blood vessels, lymph nodes, and lymph vessels. The remaining fluid is “interstitial,” and the current study is the first to define the interstitium as an organ in its own right, and as one of the largest of the body, say the authors.

The researchers say that no one saw these spaces before because of the medical field’s dependence on the examination of fixed tissue on microscope slides, believed to offer the most accurate view of biological reality. Scientists prepare tissue this examination by treating it with chemicals, slicing it thinly, and dying it to highlight key features. The “fixing” process makes vivid details of cells and structures, but drains away any fluid. The current research team found that the removal of fluid as slides are made causes the connective protein meshwork surrounding once fluid-filled compartments to pancake, like the floors of a collapsed building.

“This fixation artifact of collapse has made a fluid-filled tissue type throughout the body appear solid in biopsy slides for decades, and our results correct for this to expand the anatomy of most tissues,” says co-senior author Neil Theise, MD, professor in the Department of Pathology at NYU Langone Health. “This finding has potential to drive dramatic advances in medicine, including the possibility that the direct sampling of interstitial fluid may become a powerful diagnostic tool.”

The study findings are based on newer technology called probe-based confocal laser endomicroscopy, which combines the slender camera-toting probe traditionally snaked down the throat to view the insides of organs (an endoscope) with a laser that lights up tissues, and sensors that analyze the reflected fluorescent patterns. It offers a microscopic view of living tissues instead of fixed ones.

Using this technology in the fall of 2015 at Beth Israel Medical Center, endoscopists and study co-authors David Carr-Locke, MD, and Petros Benias, MD, saw something strange while probing a patient’s bile duct for cancer spread. It was a series of interconnected cavities in this submucosal tissue level that not match any known anatomy.

Faced with a mystery, the endoscopists walked the images into the office of their partnering pathologist in Theise. Strangely, when Theise made biopsy slides out of the same tissue, the reticular pattern found by endomicroscopy disappeared. The team would later confirm that very thin spaces seen in biopsy slides, traditionally dismissed as tears in the tissue, were instead the remnants of collapsed, previously fluid-filled compartments.

For the current study, the team collected tissue specimens of bile ducts during twelve cancer surgeries that were removing the pancreas and the bile duct. Minutes prior to clamping off blood flow to the target tissue, patients underwent confocal microscopy for live tissue imaging.

Once the team recognized this new space in images of bile ducts, they quickly recognized it throughout the body, wherever tissues moved or were compressed by force. The cells lining the space are also unusual, perhaps responsible for creating the supporting collagen bundles around them, say the authors. The cells may also be mesenchymal stem cells, says Theise, which are known to be capable of contributing to the formation of scar tissue seen in inflammatory diseases. Lastly, the protein bundles seen in the space are likely to generate electrical current as they bend with the movements of organs and muscles, and may play a role in techniques like acupuncture, he says.

Reference: Petros C. Benias, Rebecca G. Wells, Bridget Sackey-Aboagye, Heather Klavan, Jason Reidy, Darren Buonocore, Markus Miranda, Susan Kornacki, Michael Wayne, David L. Carr-Locke, Neil D. Theise. Structure and Distribution of an Unrecognized Interstitium in Human Tissues. Scientific Reports, 2018; 8 (1) DOI: 10.1038/s41598-018-23062-6

Mesenchymal Stem Cells Accelerate Healing

Ever notice how a cut inside the mouth heals much faster than a cut to the skin? Gum tissue repairs itself roughly twice as fast as skin and with reduced scar formation. One reason might be because of the characteristics of gingival mesenchymal stem cells, or GMSCs, which can give rise to a variety of cell types. Mesenchymal stem cells are also found in bone marrow and adipose (fat) tissue.

“This study represents the convergence of a few different paths we’ve been exploring,” says Songtao Shi, chair and professor of Penn Dental Medicine’s Department of Anatomy and Cell Biology and the senior author on the study. “First, we know as dentists that the healing process is different in the mouth; it’s much faster than in the skin. Second, we discovered in 2009 that the gingiva contains mesenchymal stem cells and that they can do a lot of good therapeutically. And, third, we know that mesenchymal stem cells release a lot of proteins. So here we asked, How are the gingival mesenchymal stem cells releasing all of these materials, and are they accelerating wound healing in the mucosal tissues?”

Xiaoxing Kou, a visiting scholar at Penn Dental Medicine, was the first author on the work. Shi and Kou collaborated with colleagues Chider Chen and Anh Le from Penn Dental Medicine as well as Yanheng Zhou from Peking University, Xingtian Xu from the University of Southern California, Los Angeles, Claudio Giraudo and Maria L. Sanmillan from the Children’s Hospital of Philadelphia, and Tao Cai from the National Institute of Dental and Craniofacial Research.

From earlier work by Shi’s group and others, it was clear that mesenchymal stem cells perform many of their functions by releasing signaling molecules in extracellular vesicles. So to understand what distinguishes mesenchymal stem cells in the gingiva from those in the skin, the Penn-led team began by comparing these extracellular vesicles between the two types. They found that the GMSCs contained more proteins overall, including the inflammation-dampening IL-1RA, which blocks a proinflammatory cytokine. IL-1RA also happens to be used as a therapy to treat rheumatoid arthrisits, an inflammatory condition.

Next the team zoomed in to look at what might be controlling the release of IL-1RA and other cytokines. They had a suspect in the protein Fas, which they had earlier connected to immune regulation. They found that in gingival MSCs had more Fas than skin MSCs, and that mice deficient in Fas had reduced IL-1RA as well as reduced secretion of IL-1RA.

Further molecular probing revealed that Fas formed a protein complex with Fap-1 and Cav-1 to trigger the release of small extracellular vesicles. To identify the connection with wound healing, they examined wound tissue and found that IL-1RA was increased in GMSCs around the margins of wounds. Mice lacking IL-1RA or in which the protein was inhibited took longer to heal gingival wounds.

In contrast, when the researchers isolated IL-1RA that had been secreted from GMSCs and injected it into wounds, it significantly accelerated wound healing.

“We found that mesenchymal stem cells, and especially gingival mesenchymal stem cells, release large amount of cytokines through an extracellular vesicle,” says Kou.

These findings may have special significance for people with diabetes, a major complication of which is delayed wound healing. In the study, the researchers found that GMSCs in mice with diabetes were less able to secrete extracellular vesicles compared to GMSCs in healthy mice, and their GMSCs also had less IL-1RA secretion. Introducing extracellular vesicles secreted from the GMSCs of healthy mice reduced wound healing time in diabetic mice.

“Our paper is just part of the mechanism of how these stem cells affect wound healing,” Kou says, “but I think we can build on this and use these cells or the extracellular vesicles to target a lot of different diseases, including the delayed wound healing seen in diabetic patients.” Moving forward, Shi, Kou and colleagues want to move their work into the clinic.

“We are targeting translational therapies,” says Shi. “These cells are easy to harvest from the gingiva, and that makes them a beautiful cell for clinical use. We have a lot of work ahead of us, but I can see using these cells to reduce scar formation, improve wound healing, and even treat many inflammatory and autoimmune diseases.”

Reference: Xiaoxing Kou, Xingtian Xu, Chider Chen, Maria Laura Sanmillan, Tao Cai, Yanheng Zhou, Claudio Giraudo, Anh Le, Songtao Shi. The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing. Science Translational Medicine, 2018; 10 (432): eaai8524 DOI: 10.1126/scitranslmed.aai8524

Working Out in Groups Adds Health Benefits Beyond Exercise

Working out in groups and with friends can be a big bonus. One of the benefits researchers discovered was that it lowered stress in a study by 26 percent and significantly improved the quality of life! Dayna Yorks, lead researcher for the study conducted by the University of New England College of Osteopathic Medicine, says the communal benefits of friends and colleagues coming together and working out together pays dividends beyond exercising alone. Doing something difficult while encouraging one another, supports the concept of a physical, emotional and mental approach to health that is important to reducing stress.

The study involved 69 medical students a group known for a self-reported low quality of life and with high levels of stress. The students were allowed to self select a twelve week exercise program either as individuals or within a group setting. A control group was included which abstained from exercise other than biking or walking for transportation purposes. Every four weeks the study completed a survey which asked them to rate their levels of quality of life and perceived stress in three categories including mental, emotional and physical.

The participants who worked out in a group spent at least 30 minutes at least once a week in CXWORX, a core strengthening and functional fitness training program. At the end of the twelve week study period, the mean monthly survey scores showed significant improvements in all three quality of life categories mental (12.6% increase), physical (24.8% increase) and emotional (26% increase). The students also reported a 26.2% reduction in perceived stress levels.

The individual fitness participants were allowed to engage in any exercise regimen they preferred which could include weight lifting and running but they had to work out alone or with no more than two partners. The individual exercisers worked out twice as long, but saw no significant changes in any category except mental (11% increase). The control group also saw no significant changes in quality of life or perceived stress.

Dr. York suggests that given the findings, not only should medical schools consider adding group fitness opportunities to their students, but anyone should think about engaging in more group exercise programs. This type of exercise regimen is an excellent outlet to manage stress and feel better mentally, physically and emotionally!

Reference: Dayna M. Yorks, Christopher A. Frothingham, Mark D. Schuenke. Effects of Group Fitness Classes on Stress and Quality of Life of Medical Students. The Journal of the American Osteopathic Association, 2017; 117 (11): e17 DOI: 10.7556/jaoa.2017.140

How Exercise Slows Down Aging

Staying active helps keep the body young and healthy! And a lifetime of regular exercise can help defy the aging process! A study conducted by researchers at the University of Birmingham and King?s College London, found that older people who had exercised all of their lives had the immunity, muscle mass and cholesterol levels of a young person.

The study included 125 amateur cyclists aged 55 to 79 ? 41 were female and 84 were male. The women had to be able to cycle 60 km in 5.5 hours and the men 100 km in under 6.5 hours. Anyone with high blood pressure or other health conditions, smokers and heavy drinkers were excluded.

The group underwent a variety of tests in a laboratory. The participants were compared to a group of adults who did not partake in regular physical activity. This group consisted of 75 healthy adults aged 57 to 80 and 55 healthy younger adults aged 20 to 36. The study showed that the active adults who exercised regularly did not show loss of muscle mass and strength. The cyclists also did not increase body fat or cholesterol levels with age and interestingly the men?s testosterone levels remained high indicating they may have avoided most of male menopause. The cyclists also had an immune system that did not seem to age either. The researchers also discovered that the thymus which makes immune cells called T cells and shrinks from the age of 20 and makes less T cells, was as active in the cyclists as those of a young person.

The research shows there is strong evidence that getting people to commit to regular exercise throughout their lives is a viable solution to living a longer, healthier life. Findings show that less than half of people over 65 do not exercise enough to remain healthy. And per Professor Janet Lord, Director of the Institute of Inflammation and Aging at the University of Birmingham, the findings debunk the assumption that aging means frailty. The studies findings indicate that the cyclists do not exercise because they are healthy, but because they had been exercising for a large portion of their lives, they are healthy. The exercise has allowed their bodies to age optimally, free from a lot of the problems caused by inactivity. Remove their activity, and the researchers agree that their health would most likely begin to decline.

Nearly everyone can exercise. It is a matter of finding an exercise that suits a person and can make a habit of it. It may lead to a later life that is healthier and productive! Hippocrates in 400 BC said ?Exercise is man?s best medicine?. Unfortunately, his message has been lost over time and we have become an increasingly sedentary society.

Reference: Ross D. Pollock, Katie A. O’Brien, Lorna J. Daniels, Kathrine B. Nielsen, Anthea Rowlerson, Niharika A. Duggal, Norman R. Lazarus, Janet M. Lord, Andrew Philp, Stephen D. R. Harridge. Properties of the vastus lateralis muscle in relation to age and physiological function in master cyclists aged 55-79 years. Aging Cell, 2018; e12735 DOI: 10.1111/acel.12735

Low-Fat vs. Low-Carbohydrate Diet: Which is Better?

A new study has shown that it isn?t so much the type of diet, Low-Fat vs. Low Carb, but a more a matter of quality of the diet! A Stanford University study published in the Journal of the American Medical Association, has concluded that both diets can work equally well at shedding unwanted pounds as long as people consume healthy vegetables and whole foods and cutting back on refined grains, sugar and highly processed foods. And of course people have to stick to the diet!

Christopher Gardner, Director of Nutrition Studies at the Stanford Prevention Research Center, states they found no evidence that a person?s genotype (genetic makeup) or the individual way their body responds to insulin determines which diet type most likely to help them with their weight loss. Past research has indicated that genetic and insulin levels might explain why some people lost more weight on a low-carb diet vs. a low-fat diet or vice versa. The Stanford colleagues decided to study those assumptions by conducting a randomized clinical trial which is considered the gold standard for testing hypothesis.

The researchers recruited 609 adults aged 18 to 50 and evenly divided between men and women. All had a body mass index of between 28 and 40. All underwent a variety of tests at the beginning of the study including one test that looked for genetic variants linked to the metabolism of fasts and carbohydrates and one that measured the body?s response to insulin.

Participants were randomly assigned to either a low-carb diet or a low-fat diet which they were to follow for one year. Those on the low-fat diet were encouraged to cut down to 20 grams of fat per day for the first eight weeks of the study. Those in the low-carb group were asked to cut down to 20 grams of carbs per day. These were fairly large changes from what they had a their baselines.

During the first two months they were told they could add back small, incremental amount of carbs and fats until they reached a level they felt they could successfully maintain for the rest of their lives. At the end of the year study, those on the low-fat diet averaged 57 grams of fat daily and those on the low-carb diet were averaging 132 grams of carbohydrates daily which is much lower than the 83 grams of fat and 247 grams of carbs the groups were averaging at the beginning of the study.

During the study the groups were counseled on how to eat a healthy low-carb or low-fat diet. The main point was eating quality including buying fresh food and produce at the Farmer?s Market, cooking more yourself, eating with others, and watching snacking habits. They were also told to eat very little refined grains and sugar and focus on eating a lot of vegetables. And they were told to eat so that they didn?t feel deprived or hungry.

The main findings showed that the weight loss at the end of the year for both groups was very similar ? an average of 11 pound loss for the low-fat group and an average of just over 13 pounds for the low-carb group. The data also showed that people with genetic variations linked to a low-fat diet response were not more likely to lose weight on a low-fat diet nor were people with genetic variations linked to a low-carb diet response were likely to lose weight on a low-carb diet. Additionally, those with a poor insulin response were not more likely to lose weight on a low-carb diet vs. a low-fat diet. This proved the researchers original hypotheses true.

The study did have some limits. The participants tended to have higher levels of education that the general public and resources that enabled them access to high quality food. And the participants were only followed for one year. The studies findings do offer the best evidence to date for how low-fat and low-carb diets compare when it comes to weight loss and genetic factors.

Reference: Gardner CD, Trepanowski JF, Del Gobbo LC, Hauser ME, Rigdon J, Ioannidis JPA, Desai M, King AC. Effect of Low-Fat vs Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association With Genotype Pattern or Insulin SecretionThe DIETFITS Randomized Clinical Trial. JAMA. 2018;319(7):667?679. doi:10.1001/jama.2018.0245

Repairing Spinal Cord Injuries with Stem Cells

Spinal Cord

Led by researchers at University of California San Diego School of Medicine, a diverse team of neuroscientists and surgeons successfully grafted human neural progenitor cells into rhesus monkeys with spinal cord injuries. The grafts not only survived, but grew hundreds of thousands of human axons and synapses, resulting in improved forelimb function in the monkeys.

The findings, published online in the February 26 issue of Nature Medicine, represent a significant step in translating similar, earlier work in rodents closer to human clinical trials and a potential remedy for paralyzing spinal cord injuries in people.

“For more than three decades, spinal cord injury research has slowly moved toward the elusive goal of abundant, long-distance regeneration of injured axons, which is fundamental to any real restoration of physical function,” said Mark Tuszynski, MD, PhD, professor of neuroscience and director of the UC San Diego Translational Neuroscience Institute.

“While there was real progress in research using small animal models, there were also enormous uncertainties that we felt could only be addressed by progressing to models more like humans before we conduct trials with people,” Tuszynski said.

“We discovered, for example, that the grafting methods used with rodents didn’t work in larger, non-human primates. There were critical issues of scale, immunosuppression, timing and other features of methodology that had to be altered or invented. Had we attempted human transplantation without prior large animal testing, there would have been substantial risk of clinical trial failure, not because neural stem cells failed to reach their biological potential but because of things we did not know in terms of grafting and supporting the grafted cells.”

Gregoire Courtine, PhD, a professor and investigator at the Center for Neuroprosthetics and at the Brain Mind Institute, both part of the Swiss Federal Institute of Technology (EPFL) in Geneva, also conducts research seeking to restore function after spinal cord injury. He underscored the importance of the new findings.

“Dr. Tuszynski and his collaborators overcame a number of methodological difficulties specific to primates to obtain this breakthrough,” he said. “Direct translation of their work to humans would have failed, and yet too many studies are bypassing vital translational work in primate models that is necessary before human clinical trials.”

Successfully growing and proliferating functional grafted stem cells in spinal cord injuries is hindered by a multitude of innate, biological challenges. For example, the region surrounding the injury site — the so-called extracellular matrix inhibits growth in the same way that a superficial scar never resembles the original tissue in form or function. The injury site is abundant with inhibitory myelin proteins (used to make the insulating sheath around many nerve fibers) but lacks growth-promoting factors, such as neurotrophins, that would encourage regeneration of nerve cells’ axons and synapses.

Previous work by Tuszynski and others have found solutions or work-arounds for many of these obstacles, reporting notable progress using rodent models. The new work involves the use of human spinal cord-derived neural progenitor cells (NPCs) — stem cells destined to become nerve cells in the central nervous system (CNS) in rhesus monkeys, whose biology and physiology is much more similar to humans. Because the NPCs were derived from an 8-week-old human embryonic spinal cord, they possessed active growth programs that supported robust axon extension and appeared to be insensitive to inhibitors present in the adult CNS.

Two weeks after the initial injury (a period intended to represent the time required for an injured person to medically stabilize undergoing neural stem cell therapy), researchers grafted 20 million NPCs into the injury lesions in the monkeys, supported by a cocktail of growth factors and immune suppression drugs.

The work was done at the California National Primate Research Center at UC Davis. Most of the investigators are from UC campuses. “This highly complex translational project shows the value of collaborative research across UC campuses with unique facilities,” said co-author Michael Beattie, PhD, professor and director of research at the Brain and Spinal Injury Center at UC San Francisco.

Over the next nine months, the grafts grew, expressing key neural markers and sending hundreds of thousands of axons — the fibers through which nerve cells conduct signals to other nerve cells through the injury site to undamaged cells and tissue on the other side. Several months into the study, researchers noted that the monkeys began to display partial recovery of movement in their affected forelimbs.

Notably, the team documented regeneration of corticospinal axons, which are essential for voluntary movement in humans, into the lesion sites the first such known documentation in a primate model.

Courtine at EPFL, who was not involved in the study, said the findings challenge decades of work on the mechanisms of regeneration failure and “definitely represent a landmark in regeneration medicine.” Nonetheless, he noted that the degree of functional improvement remained limited. “It is not surprising given that the functional integration of new cells and connections into the operation of the nervous system would require time and specific rehabilitation procedures,” he said.

“It’s possible that given a longer period of observation, greater recovery may have occurred,” said the study’s first author, Ephron S. Rosenzweig, PhD, an assistant adjunct professor in Tuszynski’s lab. “Axon regeneration, synapse formation, myelination these all take time, and are critical for neural function. Grafts, and the new circuitry they were part of, were still maturing at the end of our observations, so it seems possible that recovery might have continued.”

Tuszynski said work remains to be done before initiating human clinical trials, including production of a candidate neural stem cell line from humans that meets requirements of the Food and Drug Administration, and additional studies of safety. His group also continues to explore ways to further enhance the growth, distance and functionality of the regenerated cells.

“We seem to have overcome some major barriers, including the inhibitory nature of adult myelin against axon growth,” he said. “Our work has taught us that stem cells will take a long time to mature after transplantation to an injury site, and that patience will be required when moving to humans. Still, the growth we observe from these cells is remarkable — and unlike anything I thought possible even ten years ago. There is clearly significant potential here that we hope will benefit humans with spinal cord injury.”

Reference: Ephron S Rosenzweig, John H Brock, Paul Lu, Hiromi Kumamaru, Ernesto A Salegio, Ken Kadoya, Janet L Weber, Justine J Liang, Rod Moseanko, Stephanie Hawbecker, J Russell Huie, Leif A Havton, Yvette S Nout-Lomas, Adam R Ferguson, Michael S Beattie, Jacqueline C Bresnahan, Mark H Tuszynski. Restorative effects of human neural stem cell grafts on the primate spinal cord. Nature Medicine, 2018; DOI: 10.1038/nm.4502

Abstract: “We grafted human spinal cord?derived neural progenitor cells (NPCs) into sites of cervical spinal cord injury in rhesus monkeys (Macaca mulatta). Under three-drug immunosuppression, grafts survived at least 9 months post injury and expressed both neuronal and glial markers. Monkey axons regenerated into grafts and formed synapses. Hundreds of thousands of human axons extended out from grafts through monkey white matter and synapsed in distal gray matter. Grafts gradually matured over 9 months and improved forelimb function beginning several months after grafting. These findings in a ‘preclinical trial’ support translation of NPC graft therapy to humans with the objective of reconstituting both a neuronal and glial milieu in the site of spinal cord injury.”

Super-Agers Amazing Brain Health

A Super-aging Study being led by neuroscientist Emily Rogalski at Chicago?s Northwestern University may give new insight into how some people in the 80?s and 90?s keep the same sharp memory as someone else several decades younger. The work is a turn on the disappointing hunt for new drugs to help or prevent a variety of dementia related diseases as humans age.

The study team has conducted a battery of tests on more than 1,000 people who were thought to qualify and about 5 percent passed. The key memory challenge was for the participants to listen to 15 unrelated words and then a half-hour later recall at least nine of them which is the norm for 50-year-olds. The average 80-year old recalls five super-agers remember them all. Super-agers tend to be extroverts and have strong social networks, otherwise they come from all walks of life. Some were college graduates, some weren?t. Some have very high IQ?s while others are average. Some participants had experienced enormous trauma. Some were fitness buffs while others smoked. Some enjoyed alcohol while others were teetotalers. The differences made it difficult for the researchers to find a common trait for brain health.

Parts of the brain do shrink as people age. But it is deep within the brain that the researchers found compelling evidence that super-agers brains are more resilient against the ravages of aging. It turns out that super-agers brains do not shrink nearly as fast. Autopsies performed on some of the first super-agers in the study to die, show their brains harbor a lot more of a special kind of nerve cell in a deep brain region. Brain scans also showed that a super-agers cortex, an outer brain layer critical to memory and other key functions, is much thicker than normal for the individual?s age. It looks more like the cortex of a healthy 50 or 60 year old person?s brain. That could be related to what they were born with, but the researchers also say another clue is that their cortex just doesn?t shrink as fast over 18 months average 80 year olds experienced more than twice the rate of loss compared to super-agers.

Researchers also discovered that deep in the brain of the super-agers the attention region is much larger. And inside, autopsies showed that region of the brain was packed with unusual large, spindly von Economo meurons special and little understood neurons thought to play a role in social processing and awareness. The super-agers had four to five times more of those types of neurons compared to the typical octogenarian and even more than the average young adult.

The super-agers are living long and living well. Rogalski wonders?are there modifiable things people can do today in everyday lives to do the same. The study is still looking for Super-ager clients who are in the 80?s and 90?s ? who are very active intellectually or physically who can contribute to the study. Another study being conducted at the University of California, Irvine, is also studying the old people in their 90?s and above. Some of these participants have Alzheimer’s, some have maintained excellent memories and some are in between. About 40 percent of the participants who had died, showed no symptoms of Alzheimer?s disease at death although their brains showed full-fledged signs of Alzheimer’s in their brains. Interestingly, the researchers found varying amounts of amyloid and tau, hallmark proteins in people with Alzheimer’s, in the brains of some of these super=agers which makes the researchers wonder how these people deflect damage perhaps they have different pathways to brain health.

Gut Microbiota Study Brings New Hope for Improving Health

Our microbiome is the personal complement of mostly friendly bacteria we carry around with us. Study after study has found that our microbiome affects nearly every aspect of our health; and its microbial composition, which varies from individual to individual, may hold the key to everything from weight gain to moods. Some microbiome researchers had suggested that this variation begins with differences in our genes; but a large-scale study conducted at the Weizmann Institute of Science challenges this idea and provides evidence that the connection between microbiome and health may be even more important than we thought.

Indeed, the working hypothesis has been that genetics plays a major role in determining microbiome variation among people. According to this view, our genes determine the environment our microbiome occupies, and each particular environment allows certain bacterial strains to thrive. However, the Weizmann researchers were surprised to discover that the host’s genetics play a very minor role in determining microbiome composition only accounting for about 2% of the variation between populations.

The research was led by research students Daphna Rothschild, Dr. Omer Weissbrod and Dr. Elad Barkan from the lab of Prof. Eran Segal of the Computer Science and Applied Mathematics Department, together with members of Prof. Eran Elinav’s group of the Immunology Department, all at the Weizmann Institute of Science. Their findings, which were recently published in Nature, were based on a unique database of around 1,000 Israelis who had participated in a longitudinal study of personalized nutrition. Israel has a highly diverse population, which presents an ideal experimental setting for investigating the effects of genetic differences. In addition to genetic data and microbiome composition, the information collected for each study participant included dietary habits, lifestyle, medications and additional measurements. The scientists analyzing this data concluded that diet and lifestyle are by far the most dominant factors shaping our microbiome composition.

If microbiome populations are not shaped by our genetics, how do they nonetheless interact with our genes to modify our health? The scientists investigated the connections between microbiome and the measurements in the database of cholesterol, weight, blood glucose levels, and other clinical parameters. The study results were very surprising: For most of these clinical measures, the association with bacterial genomes was at least as strong, and in some cases stronger, than the association with the host’s human genome.

According to the scientists, these findings provide solid evidence that understanding the factors that shape our microbiome may be key to understanding and treating many common health problems.

In Tampa, Florida a group of doctors have already discovered how to permanently transplant the gut microbiota from a healthy person to someone with various health challenges and poor microbiota. This is being done, however currently is limited to only certain serious conditions.

According to Segal “We cannot change our genes, but we now know that we can affect and even reshape the composition of the different kinds of bacteria we host in our bodies. So the findings of our research are quite hopeful; they suggest that our microbiome could be a powerful means for improving our health.”

The field of microbiome research is relatively young; the database of 1,000 individuals collected at the Weizmann institute is one of the most extensive in the world. Segal and Elinav believe that over time, with the further addition of data to their study and those of others, these recent findings may be further validated, and the connection between our microbiome, our genetics and our health will become clearer.

Reference: Daphna Rothschild, Omer Weissbrod, Elad Barkan, Alexander Kurilshikov, Tal Korem, David Zeevi, Paul I. Costea, Anastasia Godneva, Iris N. Kalka, Noam Bar, Smadar Shilo, Dar Lador, Arnau Vich Vila, Niv Zmora, Meirav Pevsner-Fischer, David Israeli, Noa Kosower, Gal Malka, Bat Chen Wolf, Tali Avnit-Sagi, Maya Lotan-Pompan, Adina Weinberger, Zamir Halpern, Shai Carmi, Jingyuan Fu, Cisca Wijmenga, Alexandra Zhernakova, Eran Elinav, Eran Segal. Environment dominates over host genetics in shaping human gut microbiota. Nature, 2018; DOI: 10.1038/nature25973

Stem Cell and Gene Therapy Utilized to Repair Severe Bone Fractures

A Study led by a team of researchers at Cedars-Sinai has completed a study that may revolutionize orthopedics. They have successfully repaired severe limb fractures in laboratory animals. They used an innovative technique that signaled bones to regrow its own tissue combining an engineering approach with a biological approach for advancing regenerative engineering. Six different departments at Cedar-Sinai and researchers from Hebrew University, University of Rochester and University of California were involved in the study further demonstrating the effectiveness of utilizing a variety of diverse disciplines to further solutions to today?s medical challenges.

Currently more than 2 million bone grafts are performed worldwide each year due to severe injuries such as traffic accidents, war or major surgery. These injuries many times create a large gap between the edges of a fracture resulting in the inability of the bone to bridge the gap on its own. Currently pieces from a patient?s or a donor?s bone must be implanted into the gap. These bone grafts unfortunately carry disadvantages in skeletal repair. Many times healthy bones are not available for the repairs and implants that do occur can prolong pain and longer hospital stays. And some repairs fail.

The researchers devised a new technique as a possible alternative to the bone grafts. They constructed a matrix of collagen which they implanted in the space between two sides of a fractured leg bone in the animals. Collagen is a protein that the body uses to build bones. The matrix recruited the broken leg?s own stem cells into the gap over two weeks. The team delivered a bone-inducing gene directly into the stem cells to being the bone repair process. The process involved using an ultrasound pulse and micro-bubbles which facilitated the gene entry into the cells. Just eight weeks after the surgery, the bone gaps were closed and the fractured legs were healed in all lab animals used in the treatment process. Furthermore, the bone growth that occurred in the gap was as strong as surgical bone grafts.

By demonstrating that gene delivery into an animal?s own stem cells through ultra-sound was effective, the study has opened up new possibilities for treating non-healing bone fractures.

Reference: Maxim Bez1, Dmitriy Sheyn, Wafa Tawackoli, Pablo Avalos, Galina Shapiro1, Joseph C. Giaconi, Xiaoyu Da, Shiran Ben David, Jayne Gavrity, Hani A. Awad, Hyun W. Bae, Eric J. Ley, Thomas J. Kremen, Zulma Gazit, Katherine W. Ferrara, Gadi Pelled, Dan Gazit; In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs; Science Translational Medicine, 17 May 2017: Vol. 9, Issue 390, eaal3128 DOI: 10.1126/scitranslmed.aal3128

Abstract: More than 2 million bone-grafting procedures are performed each year using autografts or allografts. However, both options carry disadvantages, and there remains a clear medical need for the development of new therapies for massive bone loss and fracture nonunions. We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would induce efficient bone regeneration and fracture repair. To test this hypothesis, we surgically created a critical-sized bone fracture in the tibiae of Yucat?n mini-pigs, a clinically relevant large animal model. A collagen scaffold was implanted in the fracture to facilitate recruitment of endogenous mesenchymal stem/progenitor cells (MSCs) into the fracture site. Two weeks later, transcutaneous ultrasound-mediated reporter gene delivery successfully transfected 40% of cells at the fracture site, and flow cytometry showed that 80% of the transfected cells expressed MSC markers. Human bone morphogenetic protein-6 (BMP-6) plasmid DNA was delivered using ultrasound in the same animal model, leading to transient expression and secretion of BMP-6 localized to the fracture area. Micro?computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to complete radiographic and functional fracture healing in all animals 6 weeks after treatment, whereas nonunion was evident in control animals. Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchymal progenitor cells can effectively treat nonhealing bone fractures in large animals, thereby addressing a major orthopedic unmet need and offering new possibilities for clinical translation.

Why Do Naked Mole Rats Live Such Long Cancer Free Lives?

With their large buck teeth and wrinkled, hairless bodies, naked mole rats won’t be winning any awards for cutest rodent. But their long life span of up to 30 years is the longest of any rodent and their remarkable resistance to age-related diseases, offer scientists key clues to the mysteries of aging and cancer. Mice are about the same size, however they only live 2 or 3 years and often develop cancer.

That’s why University of Rochester biology professors Vera Gorbunova and Andrei Seluanov and postdoctoral associate Yang Zhao studied naked mole rats to see if the rodents exhibit an anticancer mechanism called cellular senescence and, if so, “how the mechanism might work differently than in short-lived animals, like mice,” says Zhao, the lead author of the study, published in PNAS.

Cellular senescence is an evolutionary adaptation that prevents damaged cells from dividing out of control and developing into full-blown cancer. However, senescence has a negative side too: by stopping cell division in order to prevent potential tumors, it also accelerates aging.

Previous studies indicated that when cells that had undergone senescence were removed from mice, the mice were less frail in advanced age as compared to mice that aged naturally with senescent cells intact.

Researchers therefore believed senescence held the key to the proverbial fountain of youth; removing senescent cells rejuvenated mice, so perhaps it could work with human beings. Companies began investigating drugs known as senolytic agents that would kill senescent cells and translate the anti-aging effects to humans.

But is eliminating senescence actually the key to preventing or reversing age-related diseases, namely cancer?

“In humans, as in mice, aging and cancer have competing interests,” Gorbunova says. “In order to prevent cancer, you need to stop cells from dividing. However, to prevent aging, you want to keep cells dividing in order to replenish tissues.”

Gorbunova and Seluanov have long researched cancer and its relation to aging and DNA repair. They have identified several mechanisms that contribute to longevity and cancer resistance in naked mole rats, including the chemical HMW-HA (high molecular weight hyaluronan). But they believe there are more pieces to the puzzle.

In their recent study, Zhao, Seluanov, Gorbunova, and their collaborators compared the senescence response of naked mole rats to that of mice, which live a tenth as long only about two to three years. “We wanted to look at these animals that pretty much don’t age and see if they also had senescent cells or if they evolved to get rid of cell senescence,” Seluanov says.

Their unexpected discovery? Naked mole rats do experience cellular senescence, yet they continue to live long, healthy lives; eliminating the senescence mechanism is not the key to their long life span. “It was surprising to us that despite its remarkable longevity the naked mole rat has cells that undergo senescence like mouse cells,” Gorbunova says.

The researchers found that although naked mole rats exhibited cellular senescence similar to mice, their senescent cells also displayed unique features that may contribute to their cancer resistance and longevity.

The cellular senescence mechanism permanently arrests a cell to prevent it from dividing, but the cell still continues to metabolize. The researchers found that naked mole rats are able to more strongly inhibit the metabolic process of the senescent cells, resulting in higher resistance to the damaging effects of senescence.

“In naked mole rats, senescent cells are better behaved,” Gorbunova says. “When you compare the signals from the mouse versus from the naked mole rat, all the genes in the mouse are a mess. In the naked mole rat, everything is more organized. The naked mole rat didn’t get rid of the senescence, but maybe it made it a bit more structured.”

Although their long life span is not a result of eliminating senescence, the more structured response to senescence allows them to have more systematic changes in their genes and have more orchestrated pathways being regulated. We believe this is beneficial for longevity and cancer resistance.”

Reference: Yang Zhao, Alexander Tyshkovskiy, Daniel Mu?oz-Esp?n, Xiao Tian, Manuel Serrano, Joao Pedro de Magalhaes, Eviatar Nevo, Vadim N. Gladyshev, Andrei Seluanov, Vera Gorbunova. Naked mole rats can undergo developmental, oncogene-induced and DNA damage-induced cellular senescence. Proceedings of the National Academy of Sciences, 2018; 201721160 DOI: 10.1073/pnas.1721160115

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