New research by a team at the University of South Carolina has discovered a way to increase the body?s ability to heal after injury. The study led by Assistant Professor of Stem Cell Biology and Regenerative Medicine, has proved that adult stem cells will enter an alert state when the body sustains an injury. These ?alerted? stem cells have a greater ability to repair and heal damaged tissues.

It is theorized that after an injury a person?s blood can produce a state of alert. Using lab mice, the researchers injected healthy mice with blood from their injured counterparts. The stem cells in the healthy mice went into a state of alert. The team then identified the enzyme Hepatocyte Growth Factor Activator (HGFA), as the chemical mechanism that signaled cells to an alert state. HGFA is always in the bloodstream but only activates when the body experiences an injury. The enzyme signals adult stem cells to enter this state of alert once an injury occurs.

The team then decided to see what would happen if an injury occurred while the adult stem cells were already in a state of alert. Healthy mice were injected with HGFA. A few days later the mice were given muscle and skin injuries. The test mice were observed to heal faster, regrow missing fur and after just nine days returned to running on exercise wheels sooner. Twenty days after the injuries, the mice that had been injected with HGFA had regenerated larger muscle fibers compared to the untreated mice.

The findings support the idea that the presence of HGFA in the bloodstream prepares the body to respond faster and more efficiently to an injury. The response was similar to how vaccines prepare the body to fight specific diseases. HGFA prepares the cells to respond to tissue damage. By ?priming? the body, you can speed the process of tissue repair and recovery.

It is hoped that in the future people may be able to use HGFA prior to engaging in activities that might result in injury including sports, surgery and even combat. HGFA may also be able to be used therapeutically for people with compromised healing abilities. And this therapeutic approach may also be of value for the elderly. As we age, the body?s ability to heal itself slows down as stem cell activity diminishes with advancing age. The team posed the concept that it might be possible to restore youthful healing by activating the HGFA pathway!

Reference: Joseph T. Rodgers, Matthew D. Schroeder, Chanthia Ma, Thomas A. Rando. HGFA Is an Injury-Regulated Systemic Factor that Induces the Transition of Stem Cells into GAlert. Cell Reports, April 2017 DOI: 10.1016/j.celrep.2017.03.066

While cognitive abilities naturally decline with age, eating one serving of leafy green vegetables a day may aid in preserving memory and thinking skills as a person grows older, according to a study by researchers at Rush University Medical Center in Chicago. The study results were published in the December 20, issue of Neurology, the medical journal of the American Academy of Neurology.

“Adding a daily serving of green leafy vegetables to your diet may be a simple way to help promote brain health,” said study author Martha Clare Morris, ScD, a nutritional epidemiologist at Rush. “There continues to be sharp increases in the percentage of people with dementia as the oldest age groups continue to grow in number. Effective strategies to prevent dementia are critically needed.”

The study results suggest that people who ate one serving of green, leafy vegetables had a slower rate of decline on tests of memory and thinking skills than people who rarely or never ate them. The study results also suggest that older adults who ate at least one serving of leafy green vegetables showed an equivalent of being 11 years younger cognitively.

960 older adults completed food questionnaires and received annual cognitive assessments

The study enlisted volunteers already participating in the ongoing Rush Memory and Aging Project, which began in 1997 among residents of Chicago-area retirement communities and senior public housing complexes. A “food frequency questionnaire” was added from 2004 to February 2013, which 1,068 participants completed. Of them, 960 also received at least two cognitive assessments for the analyses of cognitive change.

This study involved these 960 people, who at the study start were an average age of 81 years old and did not have dementia. They had their thinking and memory skills tested every year and were followed for an average of 4.7 years. The participants also completed the food frequency questionnaire, which assessed how often and how many half-cup servings they ate of either spinach; kale/collards/greens; or a one-cup serving of lettuce/salad.

The study divided the participants into five groups based on how often they ate green leafy vegetables, and compared the cognitive assessments of those who ate the most (an average of about 1.3 servings per day) and those who ate the least (0.1 servings per day).

Overall, the participants’ scores on the thinking and memory tests declined at a rate of 0.08 standardized units per year. Over 10 years of follow-up, the rate of decline for those who ate the most leafy greens was slower by 0.05 standardized units per year than the rate for those who ate the least leafy greens. This difference was equivalent to being 11 years younger in age, according to Morris.

More research needed in younger and minority populations

The results remained valid after accounting for other factors that could affect brain health, such as seafood and alcohol consumption, smoking, high blood pressure, obesity, education level and amount of physical and cognitive activities.

In remote Italian villages nestled between the Mediterranean Sea and mountains lives a group of several hundred citizens over the age of 90. Researchers at the University of Rome La Sapienza and University of California San Diego School of Medicine have identified common psychological traits in members of this group.

The study, publishing in International Psychogeriatrics, found participants who were 90 to 101 years old had worse physical health, but better mental well-being than their younger family members ages 51 to 75.

“There have been a number of studies on very old adults, but they have mostly focused on genetics rather than their mental health or personalities,” said Dilip V. Jeste MD, senior author of the study, senior associate dean for the Center of Healthy Aging and Distinguished Professor of Psychiatry and Neurosciences at UC San Diego School of Medicine. “The main themes that emerged from our study, and appear to be the unique features associated with better mental health of this rural population, were positivity, work ethic, stubbornness and a strong bond with family, religion and land.”

There were 29 study participants from nine villages in the Cilento region of southern Italy. The researchers used quantitative rating scales for assessing mental and physical health, as well as qualitative interviews to gather personal narratives of the participants, including topics such as migrations, traumatic events and beliefs. Their children or other younger family members were also given the same rating scales and additionally asked to describe their impressions about the personality traits of their older relatives.

“The group’s love of their land is a common theme and gives them a purpose in life. Most of them are still working in their homes and on the land. They think, ‘This is my life and I’m not going to give it up,'” said Anna Scelzo, first author of the study with the Department of Mental Health and Substance Abuse in Chiavarese, Italy.

Interview responses also suggested that the participants had considerable self-confidence and decision-making skills.

“This paradox of aging supports the notion that well-being and wisdom increase with aging even though physical health is failing,” said Jeste, also the Estelle and Edgar Levi Chair in Aging and director of the Sam and Rose Stein Institute for Research on Aging at UC San Diego.

Some direct quotes from the study’s interviews include:

?”I lost my beloved wife only a month ago and I am very sad for this. We were married for 70 years. I was close to her during all of her illness and I have felt very empty after her loss. But thanks to my sons, I am now recovering and feeling much better. I have four children, ten grandchildren and nine great-grandchildren. I have fought all my life and I am always ready for changes. I think changes bring life and give chances to grow.”

?”I am always thinking for the best. There is always a solution in life. This is what my father has taught me: to always face difficulties and hope for the best.”

?”I am always active. I do not know what stress is. Life is what it is and must be faced … always.”

?”If I have to say, I feel younger now than when I was young.”

“We also found that this group tended to be domineering, stubborn and needed a sense of control, which can be a desirable trait as they are true to their convictions and care less about what others think,” said Scelzo. “This tendency to control the environment suggests notable grit that is balanced by a need to adapt to changing circumstances.”

The researchers plan to follow the participants with multiple longitudinal assessments and compare biological associations with physical and psychological health.

“Studying the strategies of exceptionally long-lived and lived-well individuals, who not just survive but also thrive and flourish, enhances our understanding of health and functional capacities in all age groups,” said Jeste.

Reference: Anna Scelzo, Salvatore Di Somma, Paola Antonini, Lori P. Montross, Nicholas Schork, David Brenner, Dilip V. Jeste. Mixed-methods quantitative?qualitative study of 29 nonagenarians and centenarians in rural Southern Italy: focus on positive psychological traits. International Psychogeriatrics, 2017; 1 DOI: 10.1017/S1041610217002721

Abstract: This was a study of positive psychological traits in a group of rural Italians aged 90 to 101 years, and their children or other family members.

Mixed-methods quantitative (standardized rating scales) and qualitative (semi-structured interviews) study.

Study participants? homes in nine villages in the Cilento region of southern Italy.

Twenty-nine nonagenarians and centenarians and 51 family members aged 51?75 years, selected by their general practitioners as a part of a larger study called CIAO (Cilento Initiative on Aging Outcomes).

We used published rating scales of mental and physical well-being, resilience, optimism, anxiety, depression, and perceived stress. Qualitative interviews gathered personal narratives of the oldest-old individuals, including migrations, traumatic events, and beliefs. Family members described their impressions about the personality traits of their older relative.

Participants age ?90 years had worse physical health but better mental well-being than their younger family members. Mental well-being correlated negatively with levels of depression and anxiety in both the groups. The main themes that emerged from qualitative interviews included positivity (resilience and optimism), working hard, and bond with family and religion, as described in previously published studies of the oldest old, but also a need for control and love of the land, which appeared to be unique features of this rural population.

Exceptional longevity was characterized by a balance between acceptance of and grit to overcome adversities along with a positive attitude and close ties to family, religion, and land, providing purpose in life.

Cardiovascular diseases are a major cause of death worldwide, in part because the cells in our most vital organ do not get renewed. As opposed to blood, hair or skin cells that can renew themselves throughout life, our heart cells cease to divide shortly after birth, and there is very little renewal in adulthood. New research at the Weizmann Institute of Science provides insight into the question of why the mammalian heart fails to regenerate, on one hand, and demonstrated, in adult mice, the possibility of turning back this fate. This research appeared in Nature Cell Biology.

Prof. Eldad Tzahor of the Institute’s Biological Regulation Department thought that part of the answer to the regeneration puzzle might lie in his area of expertise: embryonic development, especially of the heart. Indeed, it was known that a protein called ERBB2 is well studied and plays a role in heart development. ERBB2 generally works together with a second, related, receptor by binding a growth factor called Neuregulin 1 (NRG1) to transmit messages into the cells. NGR1 is already being tested in clinical studies for treating heart failure.

Dr. Gabriele D’Uva, a postdoctoral fellow in the research group of Prof. Eldad Tzahor, wanted to know exactly how NRG1 and ERBB2 are involved in heart regeneration. In mice, new heart muscle cells can be added up to a week after birth; newborn mice can regenerate damaged hearts, while seven day old mice already cannot. D’Uva and research student Alla Aharonov observed that heart muscle cells called cardiomyocytes that were treated with NRG1 continued to proliferate on the day of birth; but the effect dropped dramatically within a week, even with ample amounts of NRG1. Further investigation showed that the difference between a day and a week was in the amount of ERBB2 on the cardiomyocyte membranes.

The team then created mice in which the gene for ERBB2 was knocked out only in cardiomyocytes. This had a severe impact: The mice had hearts with walls that were thin and balloon like a cardiac pathology known as dilated cardiomyopathy. The conclusion was that cardiomyocytes lacking ERBB2 do not divide, even in the presence of NRG1. Next, the team reactivated the ERBB2 protein in adult mouse heart cells, in which cardiomyocytes normally no longer divide. This resulted in extreme cardiomyocyte proliferation and hypertrophy excessive growth of the individual cardiomyocytes leading to a giant heart (cardiomegaly) that left little room for blood to enter. Tzahor: “Too little or too much of this protein had a devastating impact on heart function.”

If one could activate ERBB2 for just a short period in an adult heart following a heart attack, might it be possible to get the positive results, i.e., cardiac cell renewal, without such negative ones as hypertrophy and scarring? Testing this idea, the team found that they could, indeed, activate ERBB2 in mice for a short interval only following an induced heart attack and obtain nearly complete heart regeneration within several weeks. “The results were amazing,” says Tzahor. “As opposed to extensive scarring in the control hearts, the ERBB2-expressing hearts had completely returned to their previous state.”

Investigation of the regenerative process through live imaging and molecular studies revealed how this happens: The cardiomyocytes “dedifferentiate” that is, they revert to an earlier form, something between an embryonic and an adult cell, which can then divide and differentiate into new heart cells. In other words, the ERBB2 took the cells back a step to an earlier, embryonic form; and then stopping its activity promoted the regeneration process.

In continuing research, Tzahor and his team began to outline the pathway the other proteins that respond to the NRG1 message inside the cell. “ERBB2 is clearly at the top of the chain. We have shown that it can induce cardiac regeneration on its own. But understanding the roles of the other proteins in the chain may present us with new drug targets for treating heart disease,” says D’Uva.

Tzahor points out that clinical trials of patients receiving the NRG1 treatment might not be overly successful if ERBB2 levels are not boosted as well. He and his team plan to continue researching this signaling pathway to suggest ways of improving the process, which may, in the future, point to ways of renewing heart cells. Because this pathway is also involved in cancer, well-grounded studies will be needed to understand exactly how to direct the cardiomyocyte renewal signal at the right place, the right time and in the right amount. “Much more research will be required to see if this principle could be applied to the human heart, but our findings are proof that it may be possible,” he says.

Reference: Gabriele D?Uva, Alla Aharonov, Mattia Lauriola, David Kain, Yfat Yahalom-Ronen, Silvia Carvalho, Karen Weisinger, Elad Bassat, Dana Rajchman, Oren Yifa, Marina Lysenko, Tal Konfino, Julius Hegesh, Ori Brenner, Michal Neeman, Yosef Yarden, Jonathan Leor, Rachel Sarig, Richard P. Harvey, Eldad Tzahor. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nature Cell Biology, 2015; DOI: 10.1038/ncb3149

Back in 2007 scientists announced that they had created embryonic like stem cells from adult human skin cells. IPS cells (induced pluripotent stem cells) have been very valuable in research, however converting them into any type of cell that could be used for actual stem cell therapy is extremely complicated and far from becoming safe or available. Embryonic stem cells exist to create an entire organism not to repair an adult. A new breakthrough allows researchers to take differentiated cells from potentially any part of the body and reverse age them without going all the way back to an embryonic like state. In a study of mice these have already been used successfully for cell replacement therapy. This may be the breakthrough needed to rebuild damaged, diseased or old organs with a few injections back to a young and healthy condition in the not too distant future.

A modified version of iPS methodology, the new approach is called interrupted reprogramming and it allows for a highly controlled, potentially safer, and more cost-effective strategy for generating progenitor-like cells from adult cells. As demonstrated November 30 in the journal Stem Cell Reports, researchers in Canada converted adult mouse respiratory tract cells called Club cells into large, pure populations of induced progenitor-like (iPL) cells, which retained a residual memory of their parental cell lineage and therefore specifically generated mature Club cells. Moreover, these cells showed potential as a cell replacement therapy in mice with cystic fibrosis.

“A major block in the critical path of regenerative medicine is the lack of suitable cells to restore function or repair damage,” says co-senior author Tom Waddell, a thoracic surgeon at the University of Toronto. “Our approach starts with purifying the cell type we want and then manipulating it to give those cell types characteristics of progenitor cells, which can grow rapidly but produce only a few cell types. As such, it is much more direct, more rapid, and the batches of cells are more purified.”

In recent years, induced pluripotent stem (iPS) cells have generated a great deal of interest as a potentially unlimited source of various cell types for transplantation. This method involves genetically reprogramming skin cells taken from adult donors to an embryonic stem-cell-like state, growing these immature cells to large numbers, and then converting them into specialized cell types found in different parts of the body. A major advantage of this approach is the ability to generate patient-specific iPS cells for transplantation, thereby minimizing the risk of harmful immune reactions.

Despite significant progress, these protocols remain limited by low yield and purity of the desired mature cell types, as well as the potential of immature cells to form tumors. Moreover, there is no standardized approach applicable to all cell types, and the development of personalized therapies based on patient-derived pluripotent cells remains very expensive and time consuming. “We have pursued cell therapy for lung diseases for many years,” Waddell says. “One key issue is how to get the right type of cells and lots of them. To avoid rejection, we need to use cells from the actual patient.”

To address these issues, Waddell and co-senior study author Andras Nagy of Mount Sinai Hospital developed an interrupted reprogramming strategy, which is a modified version of the iPS methodology. The researchers started to genetically reprogram adult Club cells isolated from mice, transiently expressing the four iPS reprogramming factors, but interrupted the process early, prior to reaching the pluripotent state, to generate progenitor-like cells, which are more committed to a specific lineage and show more controlled proliferation than pluripotent cells.

“The reprogramming process had previously been considered as an all-or-none process,” Waddell says. “We were surprised to the extent that it can be fine-tuned by the timing and dosing of the drug used to activate the reprogramming factors. That is interesting as it gives lots of opportunities for control, but it does mean we have lots of work to do to get it right.”

The researchers showed that the resulting Club-iPL cells could give rise to not only Club cells, but also to other respiratory tract cells such as mucus-secreting goblet cells and ciliated epithelial cells that produce the CFTR protein, which is mutated in patients with cystic fibrosis. When the Club-iPL cells were administered to CFTR-deficient mice, the cells incorporated into tissue lining the respiratory tract and partially restored levels of CFTR in the lungs without inducing tumor formation. This technology can theoretically be applied to almost any cell type that can be isolated and purified, and isolation of highly purified populations of adult cells from most organs is already possible with existing techniques.

“To create specialized cell types for use in cell therapy requires only that we insert the genes (or use non-transgenic approaches) and then test the drug dose and timing required for each cell type and each patient, so it should be relatively scalable at low cost compared to other approaches using each patient’s own cells,” Waddell says. “It should be very easy for other labs to use a similar approach.”

According to the authors, the approach could be used for a variety of regenerative medicine practices, including cell replacement therapy, disease modelling, and drug screening for human diseases. But there is still a long way to go before clinical translation. For their own part, the researchers plan to test this approach with other cell types, including human cells. They will also try to determine if there are safe ways to engraft these cells in human lungs. “The study is a proof of principle, the way this concept may ultimately be used in humans could be different, and it will be many years before this will be attempted in humans,” Waddell says.

Reference: Li Guo, Golnaz Karoubi, Pascal Duchesneau, Maria V. Shutova, Hoon-Ki Sung, Peter Tonge, Christine Bear, Ian Rogers, Andras Nagy, Thomas K. Waddell. Generation of Induced Progenitor-like Cells from Mature Epithelial Cells Using Interrupted Reprogramming. Stem Cell Reports, 2017; DOI: 10.1016/j.stemcr.2017.10.022