Green Tea Help’s Memory, Weight Loss and Brain Insulin Resistance

Green Tea

A study published online in The FASEB Journal, involving mice, suggests that EGCG (epigallocatechin-3-gallate), the most abundant catechin and biologically active component in green tea, could help insulin resistance and improve cognition. Previous research pointed to the potential of EGCG to help a variety of human conditions, yet until now, EGCG’s impact on insulin resistance and cognition triggered in the brain remained unclear.

“Green tea is the second most consumed beverage in the world after water, and is grown in at least 30 countries,” said Xuebo Liu, Ph.D., a researcher at the College of Food Science and Engineering, Northwest A&F University, in Yangling, China. The ancient habit of drinking green tea may be beneficial when it comes to combatting obesity, insulin resistance, and improving memory.

Liu and colleagues divided 3-month-old male C57BL/6J mice into three groups based on diet: 1) a control group fed with a standard diet, 2) a group fed with an HFFD diet (high-fat and high-fructose diet), and 3) a group fed with an HFFD diet and 2 grams of EGCG per liter of drinking water. For 16 weeks, researchers monitored the mice and found that those fed with HFFD had a higher final body weight than the control mice, and a significantly higher final body weight than the HFFD+EGCG mice. In performing a Morris water maze test, researchers found that mice in the HFFD group took longer to find the platform compared to mice in the control group. The HFFD+EGCG group had a significantly lower escape latency and escape distance than the HFFD group on each test day. When the hidden platform was removed to perform a probe trial, HFFD-treated mice spent less time in the target quadrant when compared with control mice, with fewer platform crossings. The HFFD+EGCG group exhibited a significant increase in the average time spent in the target quadrant and had greater numbers of platform crossings, showing that EGCG could improve HFFD-induced memory impairment.

“Many reports, anecdotal and to some extent research-based, are now greatly strengthened by this more penetrating study,” said Thoru Pederson, Ph.D., Editor-in-Chief of The FASEB Journal.

Brain Cells in the Hypothalamus Control the Rate of Aging

Brain

Scientists at Albert Einstein College of Medicine have found that stem cells in the brain’s hypothalamus govern how fast aging occurs in the body. The finding, made in mice, could lead to new strategies for warding off age-related diseases and extending lifespan. The paper was published in Nature.

The hypothalamus was known to regulate important processes including growth, development, reproduction and metabolism. In a 2013 Nature paper, Einstein researchers made the surprising finding that the hypothalamus also regulates aging throughout the body. Now, the scientists have pinpointed the cells in the hypothalamus that control aging: a tiny population of adult neural stem cells, which were known to be responsible for forming new brain neurons.

“Our research shows that the number of hypothalamic neural stem cells naturally declines over the life of the animal, and this decline accelerates aging,” says senior author Dongsheng Cai, M.D., Ph.D., (professor of molecular pharmacology at Einstein. “But we also found that the effects of this loss are reversible. By replenishing these stem cells or the molecules they produce, it’s possible to slow and even reverse various aspects of aging throughout the body.”

In studying whether stem cells in the hypothalamus held the key to aging, the researchers first looked at the fate of those cells as healthy mice got older. The number of hypothalamic stem cells began to diminish when the animals reached about 10 months, which is several months before the usual signs of aging start appearing. “By old age which is about two years in mice most of those cells were gone,” says Dr. Cai.

The researchers next wanted to learn whether this progressive loss of stem cells was actually causing aging and was not just associated with it. So they observed what happened when they selectively disrupted the hypothalamic stem cells in middle-aged mice. “This disruption greatly accelerated aging compared with control mice, and those animals with disrupted stem cells died earlier than normal,” says Dr. Cai.

Could adding stem cells to the hypothalamus counteract aging? To answer that question, the researchers injected hypothalamic stem cells into the brains of middle-aged mice whose stem cells had been destroyed as well as into the brains of normal old mice. In both groups of animals, the treatment slowed or reversed various measures of aging.

Dr. Cai and his colleagues found that the hypothalamic stem cells appear to exert their anti-aging effects by releasing molecules called microRNAs (miRNAs). They are not involved in protein synthesis but instead play key roles in regulating gene expression. miRNAs are packaged inside tiny particles called exosomes, which hypothalamic stem cells release into the cerebrospinal fluid of mice.

The researchers extracted miRNA-containing exosomes from hypothalamic stem cells and injected them into the cerebrospinal fluid of two groups of mice: middle-aged mice whose hypothalamic stem cells had been destroyed and normal middle-aged mice. This treatment significantly slowed aging in both groups of animals as measured by tissue analysis and behavioral testing that involved assessing changes in the animals’ muscle endurance, coordination, social behavior and cognitive ability.

The researchers are now trying to identify the particular populations of microRNAs and perhaps other factors secreted by these stem cells that are responsible for these anti-aging effects a first step toward possibly slowing the aging process and treating age-related diseases.

Abstract: “It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs.”

Reference: Yalin Zhang, Min Soo Kim, Baosen Jia, Jingqi Yan, Juan Pablo Zuniga-Hertz, Cheng Han, Dongsheng Cai. Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature, 2017; DOI: 10.1038/nature23282

Stem Cells Used to Produce New Arterial Cells

Blood Vessels

Stem cell biologists have tried unsuccessfully for years to produce cells that will give rise to functional arteries. Now new techniques developed at the Morgridge Institute for Research and the University of Wisconsin in Madison have produced, for the first time, functional arterial cells at both the quality and scale to be relevant for modeling and clinical application.

Reporting in the July 10 issue of the journal Proceedings of the National Academy of Sciences, scientists in the lab of stem cell pioneer James Thomson describe methods for generating and characterizing arterial endothelial cells which are the cells that initiate artery development and exhibit many of the specific functions required by the body.

Further, these cells contributed both to new artery formation. ?No one has been able to make those kinds of cells efficiently before,? says Jue Zhang, a Morgridge assistant scientist and lead author. ?The key finding here is a way to make arterial endothelial cells more functional and clinically useful.?

The Thomson lab has made arterial engineering one of its top research priorities. New techniques have produced, for the first time, functional arterial cells at both the quality and scale to be relevant for modeling and clinical application.

The challenge is that generic endothelial cells are relatively easy to create, but they lack true arterial properties and thus have little clinical value, Zhang says.

The research team applied two pioneering technologies to the project. First, they used single-cell RNA sequencing to identify the signaling pathways critical for arterial endothelial cell differentiation. They found about 40 genes of optimal relevance. Second, they used CRISPR-Cas9 gene editing technology that allowed them to create reporter cell lines to monitor arterial differentiation in real time.

?With this technology, you can test the function of these candidate genes and measure what percentage of cells are generating into our target arterial cells,? says Zhang.

The research group developed a protocol around five key growth factors that make the strongest contributions to arterial cell development. They also identified some very common growth factors used in stem cell science, such as insulin, that surprisingly inhibit arterial endothelial cell differentiation.

?Our ultimate goal is to apply this improved cell derivation process to the formation of functional arteries that can be used in cardiovascular surgery,? says Thomson, director of regenerative biology at Morgridge and a UW?Madison professor of cell and regenerative biology. ?This work provides valuable proof that we can eventually get a reliable source for functional arterial endothelial cells and make arteries that perform and behave like the real thing.?

Thomson?s team, along with many UW?Madison collaborators, is in the first year of a seven-year project supported by the National Institutes of Health on the feasibility of developing artery banks suitable for use in human transplantation.

?Now that we have a method to create these cells, we hope to continue the effort using a more universal donor cell line,? says Zhang. The lab will focus on cells banked from a unique population of people who are genetically compatible donors for a majority of the population.

Reference: Zhang, J., Chu, L., Hou, Z., Schwartz, M. P., Hacker, T., Vickerman, V., Thomson, J. A. (2017). Functional characterization of human pluripotent stem cell-derived arterial endothelial cells. Proceedings of the National Academy of Sciences, 201702295. doi:10.1073/pnas.1702295114

Converting Adult Stem Cells and IPS Cells Into Differentiated Cells

Adult Stem Cells

Whether using embryonic or adult stem cells, coercing these master cells to convert to the desired target cell and reproduce flawlessly is difficult. Now an international team of researchers has a two-part system that can convert the cells to the targets and then remove the remnants of that conversion, leaving only the desired DNA behind to duplicate.

“One difficulty with human pluripotent stem cells is that you can’t use them directly,” said Xiaojun Lian, assistant professor of biomechanical engineering, biology and a member of the Huck Institutes of the Life Sciences, Penn State. They need to be the right type of differentiated cells for each tissue in the body.

Normally, pluripotent stem cells induced from both adult and embryonic cells receive a chemical signal to change from a stem cell to a functional cell. Pluripotent stem cells can change to any cell in the human body. However, this natural cell change is part of a complex series of triggers controlled by DNA. Researchers have in the past inserted DNA into the pluripotent cells to convert them, but remnants of the inserted DNA remain.

In this current work, published in a recent issue of Scientific Reports, the researchers are not incorporating a piece of DNA that will tell the cells to convert, but DNA that will make the cell glow green when illuminated by a blue light. This marker allows the researchers to see that the DNA plasmid is incorporated into the cell, and that it is completely gone upon removal. A plasmid is a circular piece of DNA that contains functional DNA fragments that control gene expression in cells.

“We wanted to explore the limits for turning the conversion on and off and to have the ability to control the level of expression and removal of DNA after conversion,” said Lauren N. Randolph, doctoral student in bioengineering, Penn State.

Previous approaches incorporated the appropriate DNA to switch on the conversions, but did not completely remove all the DNA inserted.

The researchers are using a Tet-On 3G inducible PiggyBac system that is a plasmid they named XLone to achieve insertion, activation and removal. The PiggyBac portion of the system includes the DNA to insert that DNA into the cell’s DNA. The Tet-On 3G portion contains the necessary signaling information. This system also makes the cells more sensitive to doxycycline, which is the drug used to initiate the conversion.

“We are using abundant multiple copies of the plasmid to increase the likelihood that it gets in and does what it is supposed to do and actually follows through reproduction of the cells,” said Lian.

If only one or a few plasmids are inserted into the cell, the new DNA could just be silenced. Insertion of multiple plasmids assures that at least one will function.

“The first advantage with our system is that it does not have any leakage expression,” said Randolph. “If we don’t induce the system with doxycycline, we get nothing.”

The second advantage is that once the cells are reproducing as heart cells or nerve cells, the plasmid can be removed and the cells continue to reproduce without any remnant of the plasmid system.

While the researchers are currently aiming to understand and study gene function and directed cell differentiation in human stem cells, eventually they would like to be able to create cell-based therapies.

Reference: Lauren N. Randolph, Xiaoping Bao, Chikai Zhou, Xiaojun Lian. An all-in-one, Tet-On 3G inducible PiggyBac system for human pluripotent stem cells and derivatives. Scientific Reports, 2017; 7 (1) DOI: 10.1038/s41598-017-01684-6

Is 70 Years of Age is the New 60?

Fit 70 Year Old

Is 70 the new 60? A new Stony Brook University-led study to be published in PLOS ONE uses new measures of aging to scientifically illustrate that one’s actual age is not necessarily the best measure of human aging itself, but rather aging should be based on the number of years people are likely to live in a given country in the 21st Century.

The study combines the new measures of aging with probabilistic projections from the United Nations and predicts an end to population aging in the U.S. and other countries before the end of the century. Population aging when the median age rises in a country because of increasing life expectancy and lower fertility rates is a concern for countries because of the perception that population aging leads to declining numbers of working age people and additional social burdens.

According to Warren Sanderson, Professor of Economics at Stony Brook University and the lead author, this study’s projections imply that as life expectancies increase people are generally healthier with better cognition at older ages and countries can adjust public policies appropriately as to population aging.

Population aging could peak by 2040 in Germany and by 2070 in China, according to the study, which combines measures of aging with probabilistic population projections from the UN. In the USA, the study shows very little population aging at all in the coming century.

Traditional population projections categorize “old age” as a simple cutoff at age 65. But as life expectancies have increased, so too have the years that people remain healthy, active, and productive. In the last decade, IIASA researchers have published a large body of research showing that the very boundary of “old age” should shift with changes in life expectancy, and have introduced new measures of aging that are based on population characteristics, giving a more comprehensive view of population aging.

The study combines these new measures with UN probabilistic population projections to produce a new set of age structure projections for four countries: China, Germany, Iran, and the USA.

“Both of these demographic techniques are relatively new, and together they give us a very different, and more nuanced picture of what the future of aging might look like,” says Professor Sanderson, also a researcher at IIASA. He wrote the article with Sergei Scherbov, leader of the Re-Aging Project at IIASA, and Patrick Gerland, chief of the mortality section of the Population Division of the United Nations.

One of the measures used in the paper looks at life expectancy as well as years lived to adjust the definition of old age. Probabilistic projections produce a range of thousands of potential scenarios, so that they can show a range of possibilities of aging outcomes.

For China, Germany, and the USA, the study showed that population aging would peak and begin declining well before the end of the century. Iran, which had an extremely rapid fall in fertility rate in the last 20 years, has an unstable age distribution and the results for the country were highly uncertain.

“We chose these four countries for analysis because they have very different population structures and projections, and so they allow us to test this methodology across a range of possible scenarios,” summarizes Scherbov.

Abstract: “We merge two methodologies, prospective measures of population aging and probabilistic population forecasts. We compare the speed of change and variability in forecasts of the old age dependency ratio and the prospective old age dependency ratio as well as the same comparison for the median age and the prospective median age. While conventional measures of population aging are computed on the basis of the number of years people have already lived, prospective measures are computed also taking account of the expected number of years they have left to live. Those remaining life expectancies change over time and differ from place to place. We compare the probabilistic distributions of the conventional and prospective measures using examples from China, Germany, Iran, and the United States. The changes over time and the variability of the prospective indicators are smaller than those that are observed in the conventional ones. A wide variety of new results emerge from the combination of methodologies. For example, for Germany, Iran, and the United States the likelihood that the prospective median age of the population in 2098 will be lower than it is today is close to 100 percent.”

Reference: Warren C. Sanderson, Sergei Scherbov, Patrick Gerland. Probabilistic population aging. PLOS ONE, 2017; 12 (6): e0179171 DOI: 10.1371/journal.pone.0179171

No Known Limit On Human Lifespan

Infinity Symbol

Emma Morano passed away last April. At 117 years old, the Italian woman was the oldest known living human being.

Super centenarians, such as Morano and Jeanne Calment of France, who famously lived to be 122 years old, continue to fascinate scientists and have led them to wonder just how long humans can live. A study published in Nature last October concluded that the upper limit of human age is peaking at around 115 years.

Now, however, a new study in Nature by McGill University biologists Bryan G. Hughes and Siegfried Hekimi comes to a starkly different conclusion. By analyzing the lifespan of the longest-living individuals from the USA, the UK, France and Japan for each year since 1968, Hekimi and Hughes found no evidence for such a limit, and if such a maximum exists, it has yet to be reached or identified, Hekimi says.

Far into the foreseeable future

“We just don’t know what the age limit might be. In fact, by extending trend lines, we can show that maximum and average lifespans, could continue to increase far into the foreseeable future,” Hekimi says. Many people are aware of what has happened with average lifespans. In 1920, for example, the average newborn Canadian could expect to live 60 years; a Canadian born in 1980 could expect 76 years, and today, life expectancy has jumped to 82 years. Maximum lifespan seems to follow the same trend.

It’s impossible to predict what future lifespans in humans might look like, Hekimi says. Some scientists argue that technology, medical interventions, and improvements in living conditions could all push back the upper limit.

“It’s hard to guess,” Hekimi adds. “Three hundred years ago, many people lived only short lives. If we would have told them that one day most humans might live up to 100, they would have said we were crazy.”

Reference: Bryan G. Hughes, Siegfried Hekimi. Many possible maximum lifespan trajectories. Nature, 2017; 546 (7660): E8 DOI: 10.1038/nature22786

Toxins in Your Tap Water

Toxins in Your Tap Water

America has a drinking water crisis. An NRDC study has found that contaminants that may harm human health are found in tap water in every state in the nation. This is a problem even for people who don’t drink tap water since water borne toxins can be absorbed through the skin and lungs while bathing and into food if used for cooking.

Established in 1974, the Safe Drinking Water Act is one of the bedrock environmental laws in the United States, consisting of rules that regulate about 100 contaminants found in drinking water. NRDC has documented serious problems with our outdated and deteriorating water infrastructure, widespread violations and inadequate enforcement of the Safe Drinking Water Act for more than 25 years.

The study shows that in 2015 alone, there were more than 80,000 reported violations of the Safe Drinking Water Act by community water systems. Nearly 77 million people were served by more than 18,000 of these systems with violations in 2015. These violations included exceeding health-based standards, failing to properly test water for contaminants, and failing to report contamination to state authorities or the public. What?s worse, 2015 saw more than 12,000 health-based violations in some 5,000 community water systems serving more than 27 million people.

In 2016, the publication “What?s in Your Water: Flint and Beyond” detailed the lead crisis in Flint, Michigan, and contextualized a larger, national crisis around lead in drinking water. The new study picks up where that one left off, detailing a stunning number of violations of the Safe Drinking Water Act around the nation.

1. Combined Disinfectants and Disinfection Byproducts

Exposure to these contaminants can lead to cancer and may be linked to reproductive impacts such as miscarriages and birth defects. In 2015, there were 11,311 violations (4,591 health-based) at community water systems serving 25,173,431 people (12,584,936 health-based). Formal enforcement measures were taken in 12.4 percent of all cases and 23.0 percent of health-based cases.

2. Total Coliform

The presence of coliforms in drinking water indicates that possible presence of organisms that can cause diarrhea, cramps, nausea, and headaches in otherwise-healthy people. These impacts can be much more serious and even life-threatening for children, the elderly, and immune-compromised people. In 2015, there were 10,261 violations (2,574 health-based) at community water systems serving 17,768,807 people (10,118,586 health-based). Formal enforcement was taken in 8.8 percent of cases (and 8.3 percent of health-based cases).

3. Combined Surface, Ground Water, and Filter Backwash Rules

Exposure to some of these pathogens, such as Cryptosporidium or Giardia, can cause severe gastrointestinal distress, nausea, and diarrhea. They can cause serious, life-threatening infections for the very young, elderly, and immune-compromised. In 2015 there were 5,979 violations (1,790 health-based) at community water systems serving 17,312,604 people (5,336,435 health-based). Formal enforcement was taken in 13.7 percent of cases (28.2 percent of health-based cases).

4. Nitrites and Nitrates

Exposure can lead to blue baby syndrome in infants (potentially leading to death in extreme cases), developmental effects, and cardiovascular disease. In extreme cases, blue baby syndrome can be severe and lead to death. In 2015, there were 1,529 violations (459 health-based) at community water systems serving 3,867,431 people (1,364,494 health-based). Formal enforcement action was taken in 11.3 percent of all cases (and 27.9 percent of health-based cases).

5. Lead and Copper

Exposure to lead is particularly toxic to children and can cause serious, irreversible damage to their developing brains and nervous systems. Lead exposure can also cause miscarriages and stillbirths in pregnant women, as well as fertility issues, cardiovascular and kidney effects, cognitive dysfunction, and elevated blood pressure in healthy adults. In 2015, there were 8,044 violations (303 health-based) by systems serving 18,350,633 people (582,302 health-based). Formal enforcement action was taken in 12.0 percent of the cases (and in 14.2 percent of health-based cases).

6. Radionuclides

Exposure can lead to cancers and compromised kidney function. In 2015, there were 2,297 violations (962 health-based) in community water systems serving 1,471,364 people (445,969 health-based). Formal enforcement was taken in 11.7 percent of all cases (and 16.1 percent of health-based cases).

7. Arsenic

A known human carcinogen, exposure can lead to cancers, development effects, pulmonary disease, or cardiovascular disease. In 2015, there were 1,537 violations (1,135 health-based) at community water systems serving 1,842,594 people (358,323 health-based). Formal enforcement was taken in 28.9 percent of cases (37.1 percent of health-based cases).

8. Synthetic Organic Contaminants

Exposure can lead to cancers, developmental effects, central nervous system and reproductive difficulties, endocrine issues, or liver and kidney problems. In 2015 there were 6,864 violations (17 health-based) serving 2,669,594 people (301,099 health-based). Formal enforcement action was taken in 7.3 percent of cases (and 5.9 percent of health-based cases).

9. Inorganic Contaminants

Exposure can lead to increased cholesterol, kidney damage, hair loss, skin irritation, and cancer. In 2015, there were 1,505 violations (291 health-based) in community water systems serving 1,312,643 people (83,033 health-based). Formal enforcement was taken in 5.2 percent of cases (15.1 percent of health-based cases).

10. Volatile Organic Contaminants

Exposure can lead to cancers; developmental, skin, and reproductive issues; and cardiovascular problems. Exposure can also cause adverse effects on the liver, kidneys, and immune and nervous systems. In 2015 there were 10,383 violations (15 of them health-based) at community water systems serving 3,451,072 people (5,276 health-based). Formal enforcement was taken in 6.1 percent of cases (and 26.7 percent of health-based cases).

11. Public Notification

All community water systems are required to directly deliver information about their drinking water quality to each customer once a year. In 2015 there were 13, 202 violations by community water systems serving 8,381,050 people. Formal enforcement action was taken in 10.3 percent of cases.

The take away from this is to either install a water purifier or use natural spring water. Purifiers are also available for showers and are typically installed between the shower head and pipe.

High Activity Level Associated With Up To 9 Years Less Aging Based on Telomere Length

Walking my way to 100

New research from Brigham Young University reveals you may be able to slow one type of aging the kind that happens inside your cells. As long as you’re willing to sweat.

“Just because you’re 40, doesn’t mean you’re 40 years old biologically,” Tucker said. “We all know people that seem younger than their actual age. The more physically active we are, the less biological aging takes place in our bodies.”

The study, published in the medical journal Preventive Medicine, finds that people who have consistently high levels of physical activity have significantly longer telomeres than those who have sedentary lifestyles, as well as those who are moderately active.

Telomeres are the protein endcaps of our chromosomes. They’re like our biological clock and they’re extremely correlated with age; each time a cell replicates, we lose a tiny bit of the endcaps. Therefore, the older we get, the shorter our telomeres.

Exercise science professor Larry Tucker found adults with high physical activity levels have telomeres with a biological aging advantage of nine years over those who are sedentary, and a seven-year advantage compared to those who are moderately active. To be highly active, women had to engage in 30 minutes of jogging per day (40 minutes for men), five days a week.

“If you want to see a real difference in slowing your biological aging, it appears that a little exercise won’t cut it,” Tucker said. “You have to work out regularly at high levels.”

Tucker analyzed data from 5,823 adults who participated in the CDC’s National Health and Nutrition Examination Survey, one of the few indexes that includes telomere length values for study subjects. The index also includes data for 62 activities participants might have engaged in over a 30-day window, which Tucker analyzed to calculate levels of physical activity.

His study found the shortest telomeres came from sedentary people–they had 140 base pairs of DNA less at the end of their telomeres than highly active folks. Surprisingly, he also found there was no significant difference in telomere length between those with low or moderate physical activity and the sedentary people.

Although the exact mechanism for how exercise preserves telomeres is unknown, Tucker said it may be tied to inflammation and oxidative stress. Previous studies have shown telomere length is closely related to those two factors and it is known that exercise can suppress inflammation and oxidative stress over time.

“We know that regular physical activity helps to reduce mortality and prolong life, and now we know part of that advantage may be due to the preservation of telomeres,” Tucker said.

Reference: Larry A. Tucker. Physical activity and telomere length in U.S. men and women: An NHANES investigation. Preventive Medicine, Volume 100, July 2017, Pages 145?151

Stem Cells Utilized to Repair Severe Bone Fractures

Bone Fracture

A Cedars-Sinai-led team of investigators has successfully repaired severe limb fractures in laboratory animals with an innovative technique that cues bone to regrow its own tissue. If found to be safe and effective in humans, the pioneering method of combining ultrasound, stem cell and gene therapies could eventually replace grafting as a way to mend severely broken bones.

“We are just at the beginning of a revolution in orthopedics,” said Dan Gazit, PhD, DMD, co-director of the Skeletal Regeneration and Stem Cell Therapy Program in the Department of Surgery and the Cedars-Sinai Board of Governors Regenerative Medicine Institute. “We’re combining an engineering approach with a biological approach to advance regenerative engineering, which we believe is the future of medicine.”

Gazit was the principal investigator and co-senior author of the research study, published in the journal Science Translational Medicine.

More than 2 million bone grafts, frequently necessitated by severe injuries involving traffic accidents, war or tumor removal, are performed worldwide each year. Such injuries can create gaps between the edges of a fracture that are too large for the bone to bridge on its own. The grafts require implanting pieces from either the patient’s or a donor’s bone into the gap.

“Unfortunately, bone grafts carry disadvantages,” said Gazit, a professor of surgery at Cedars-Sinai. “There are huge unmet needs in skeleton repair.”

One problem is that enough healthy bone is not always available for repairs. Surgeries to remove a bone piece, typically from the pelvis, and implant it can lead to prolonged pain and expensive, lengthy hospitalizations. Further, grafts from donors may not integrate or grow properly, causing the repair to fail.

The new technique developed by the Cedars-Sinai-led team could provide a much-needed alternative to bone grafts.

In their experiment, the investigators constructed a matrix of collagen, a protein the body uses to build bones, and implanted it in the gap between the two sides of a fractured leg bone in laboratory animals. This matrix recruited the fractured leg’s own stem cells into the gap over a period of two weeks. To initiate the bone repair process, the team delivered a bone-inducing gene directly into the stem cells, using an ultrasound pulse and microbubbles that facilitated the entry of the gene into the cells.

Eight weeks after the surgery, the bone gap was closed and the leg fracture was healed in all the laboratory animals that received the treatment. Tests showed that the bone grown in the gap was as strong as that produced by surgical bone grafts, said Gadi Pelled, PhD, DMD, assistant professor of surgery at Cedars-Sinai and the study’s co-senior author.

“This study is the first to demonstrate that ultrasound-mediated gene delivery to an animal’s own stem cells can effectively be used to treat nonhealing bone fractures,” Pelled said. “It addresses a major orthopedic unmet need and offers new possibilities for clinical translation.”

The study involved six departments at Cedars-Sinai, plus investigators from Hebrew University in Jerusalem; the University of Rochester in Rochester, New York; and the University of California, Davis.

“Our project demonstrates how scientists from diverse disciplines can combine forces to find solutions to today’s medical challenges and help develop treatments for the patients of tomorrow,” said Bruce Gewertz, MD, surgeon-in-chief and chair of the Department of Surgery at Cedars-Sinai.

Reference: Maxim Bez, Dmitriy Sheyn, Wafa Tawackoli, Pablo Avalos, Galina Shapiro, 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, 2017; 9 (390): eaal3128 DOI: 10.1126/scitranslmed.aal3128

Sleep and Eating Times Affect Liver Health

Among all the organs in the human body, the liver is something of a superhero. Not only does it defend our bodies against the liquid toxins we regularly ingest, it has the ability to regenerate itself, and, as new research shows, it increases its size by nearly half over the course of a day.

Working in mice, researchers in Switzerland documented this process of regular stretching and shrinking, watching as liver cells swelled in size and contracted up to 40 percent along with the mice?s daily activities. There?s a catch though, a kind of hepatological kryptonite. Their livers only exhibited this ability when the mice followed their normal cycles of eating and resting. They?re nocturnal creatures, and if they began eating during the day when they usually rest, their livers stubbornly refused to grow.

The liver is the only organ known to display such significant cyclical growth, although it does make sense. During the half of the day when we?re not eating, our organs have far less to do. By growing and shrinking to meet demand, our livers are actually trying to save us wasted energy.

The Swiss researchers say that they observed hepatocytes, the main kind of cell in livers, growing during the night when mice were active, something they they attribute largely to an increase in ribosomes, structures in cells that take RNA instructions and use them to produce proteins, among other things. The liver takes material from the food and converts it into useful proteins and other molecules crucial for bodies to function, so possessing more ribosomes means they?re that much better at their jobs. When their daily cycle comes to a close, livers begin breaking down the ribosomes again, like street vendors packing up for the night.

It makes sense that livers would swell when they have to work the hardest. What the researchers found, though, was that it?s not just food intake that tells the liver to ramp up ribosome production ? it?s also dependent on what time of day it is. Cells in our livers are also sensitive to circadian rhythms and they found that mouse livers would only begin to grow at night when they ate. Mice fed during the day did not exhibit the same kind of liver growth that their nocturnal counterparts did. The cues that tell the liver to begin preparing for action don?t just come from our food, in other words, they also come from the environment.

Because a bigger liver can work faster and pull out nutrients more efficiently, there?s an obvious advantage to maintaining this kind of cycle. In mice kept nocturnal, there was a noticeable smooth curve of growing and shrinking, and the researchers noticed a 1.6-fold difference in the level of proteins in the liver between the two extremes. In day-fed mice, there was no difference, indicating that their livers weren?t able to produce as much. They published their work Thursday in Cell.

There is evidence that human livers may exhibit the same ability based on a 1986 study that used ultrasound to measure people?s livers over the course of six hours. They found variations of around 20 percent, although they didn?t take any measurements during the night, when our bodily rhythms slow down.

These findings in the liver add to a mounting case for returning to sleep cycles based on environmental cues. Illuminating the night with artificial brilliance has been tied to disrupted sleep cycles in humans, as well as an increased risk for obesity, diabetes, depression and some types of cancer. For millennia, our bodies regulated themselves with the daily rising and setting of the sun, ramping us up when it was light and settling us back down when it got dark. Now, it appears that this extends to our digestive systems as well.

Our livers cleanse toxins from our bodies, produce proteins and chemicals necessary for digestion, recycle old red blood cells and regulate glycogen levels in our bodies. If they aren?t working properly, we can die. While the authors don?t address the implications of their work for humans, their findings could help to explain why it’s unhealthy to go to bed late at night.

To view the original scientific study click below

Diurnal Oscillations in Liver Mass and Cell Size Accompany Ribosome Assembly Cycles.