Dr Bryant Villeponteau the formulator of Stem Cell 100 and other Life Code nutraceuticals was recently interviewed by Dr Mercola who owns the largest health web site on the internet. Dr. Villeponteau is also the author of Decoding Longevity an new book which will be released during December. He is a leading researcher in novel anti-aging therapies involving stem cells an area in which he has been a pioneer for over three decades.

Stem cell technology could have a dramatic influence on our ability to live longer and replace some of our failing parts, which is the inevitable result of the aging process. With an interest in aging and longevity, Dr. Villeponteau started out by studying developmental biology. “If we could understand development, we could understand aging,” he says. Later, his interest turned more toward the gene regulation aspects. While working as a professor at the University of Michigan at the Institute of Gerontology, he received, and accepted, a job offer from Geron Corporation—a Bay Area startup, in the early ‘90s.

“They were working on telomerase, which I was pretty excited about at the time. I joined them when they first started,” he says. “We had an all-out engagement there to clone human telomerase. It had been cloned in other animals but not in humans or mammals.”

If you were to unravel the tip of the chromosome, a telomere is about 15,000 bases long at the moment of conception in the womb. Immediately after conception, your cells begin to divide, and your telomeres begin to shorten each time the cell divides. Once your telomeres have been reduced to about 5,000 bases, you essentially die of old age.

“What you have to know about telomerase is that it’s only on in embryonic cells. In adult cells, it’s totally, for the most part, turned off, with the exception of adult stem cells,” Dr. Villeponteau explains. “Adult stem cells have some telomerase – not full and not like the embryonic stem cells, but they do have some telomerase activity.”

Most of the research currently being done, both in academia and industrial labs, revolves around either embryonic stem cells, or a second type called induced pluripotent stem cells (iPS). Dr. Villeponteau, on the other hand, believes adult stem cells are the easiest and most efficient way to achieve results.

That said, adult stem cells do have their drawbacks. While they’re your own cells, which eliminates the problem of immune-related issues, there’s just not enough of them. Especially as you get older, there are fewer and fewer adult stem cells, and they tend to become increasingly dysfunctional too. Yet another hurdle is that they don’t form the tissues that they need to form…

To solve such issues, Dr. Villeponteau has created a company with the technology and expertise to amplify your adult stem cells a million-fold or more, while still maintaining their ability to differentiate all the different cell types, and without causing the cells to age. Again, it is the adult stem cell’s ability to potentially cure, or at least ameliorate, many of our age-related diseases by regenerating tissue that makes this field so exciting.

Dr Villeponteau believes you can add many years, likely decades, to your life simply by eating right, exercising (which promotes the production of muscle stem cells, by the way) and living an otherwise clean and healthy lifestyle. Extreme life extension, on the other hand, is a different matter.

His book, Decoding Longevity, covers preventive strategies to prolong your life, mainly diet, exercise, and supplements. A portion of the book also covers future developments in the area of more radical life extension, such as stem cell technology.

If you would like to read the entire interview here is a link to the text version:

Transcript of Interview With Dr. Bryant Villeponteau by Dr. Joseph Mercola

lroot on January 18th, 2018

Now researchers have found a way not just to stop, but, reverse the aging process. The key is something called a telomere. We all have them. They are the tips or caps of your chromosomes. They are long and stable in young adults, but, as we age they become shorter, damaged and frayed. When they stop working we start aging and experience things like hearing and memory loss.

In a recent study published in the peer reviewed journal Nature scientists took mice that were prematurely aged to the equivalent of 80-year-old humans, added an enzyme and essentially turned their telomeres back on. After the treatment they were the physiological equivalent of young adults. You can see the before and after pictures in the videos above. Brain function improved, their fertility was restored it was a remarkable reversal of the aging process. In the top video the untreated mouse shows bad skin, gray hair and it is balding. The mouse with it’s telomeres switched back on has a dark coat color, the hair is restored and the coat has a nice healthy sheen to it. Even more dramatic is the change in brain size. Before treatment the aged mice had 75% of a normal size brain like a patient with severe Alzheimers. After the telomeres were reactivated the brain returned to normal size. As for humans while it is just one factor scientists say the longer the telomeres the better the chances for a more graceful aging.

The formal study Telomere dysfunction induces metabolic and mitochondrial compromise was published in Nature.

Additional information published by Harvard can be found in the following articles.

Scientists Find Root Molecular Cause of Declining Health in the Old

Decoding Immortality – Smithsonian Channel Video about the Discovery of Telomerase

While scientists are not yet able to accomplish the same results in humans we believe we have developed a nutraceutical to help prolong youth and possibly extend life until age reversal therapy for humans becomes available.

lroot on January 17th, 2018

New evidence that adult stem cells are critical to human aging has recently been published on a study done on a super-centenarian woman that lived to be 115 years. At death, her circulating stem cell pool had declined to just two active stem cells from stem cell counts that are typically more than a thousand in younger adults. Super-centenarians have survived all the normal diseases that kill 99.9% of us before 100 years of age, so it has been a mystery as to what actually kills these hardy individuals. This recent data suggest that stem cell decline may be the main contributor to aging. If so, stabilizing stem cells may be the best thing one can do to slow your rate of aging.

There are many theories of aging that have been proposed. For example, damage to cells and tissues from oxidative stress has been one of the most popular fundamental theories of aging for more than half a century. Yet antioxidant substances or genes that code antioxidant enzymes have proven largely ineffective in slowing aging when tested in model animals. Thus, interest by scientists has shifted to other hypotheses that might provide a better explanation for the slow declines in function with age.

Stem cells provide one such promising mechanism of aging. Of course, we all know that babies are young and vigorous, independent of the age of their parents. This is because adults have embryonic stem cells that can generate young new cells needed to form a complete young baby. Indeed, these embryonic stem cells are the product of continuously evolving stem cell populations that go back to the beginning of life on earth over 3.5 billion years ago!

In adults, the mostly immortal embryonic stem cells give rise to mortal adult stem cells in all the tissues of the body. These adult stem cells can regenerate your cells and tissues as they wear out and need replacement. Unfortunate, adult stem cells also age, which leads to fewer cells and/or loss of function in cell replacement. As functional stem cells decline, skin and organs decline with age.

Blood from world’s oldest woman suggests life limit

Time Magazine: Long-Life Secrets From The 115-Year-Old Woman

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

Abstract
The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

lroot on January 12th, 2018

Stand for Longer Telomeres

During the past few years a number of studies have been published showing that sitting for long periods of time may decrease lifespan and contribute to other health problems. Now new research has studied the opposite side of this. Instead of measuring only the negative effects of prolonged sitting the scientists measured the benefits of standing. Interestingly it turns out that standing contributes to longevity and longer telomeres!

Research conducted by a team at the Karolinska Hospital in Sweden found that decreasing the amount of time elderly people spend sitting protects the DNA. Additionally, standing was associated with longer telomeres. As many of our readers know telomeres are caps which protect the end of chromosomes and the genetic code inside them. They are important for cell division and also ensure the genetic code is passed on to new cells. Telomeres are compared to the plastic tip at the end of shoelaces which protect the shoelace. Each time a cell divides, the telomeres are shortened. When telomeres become too short, cell division will stop. These shorter telomeres are indicators of disease, aging and early death. We can have as many as 8000 – 10,000 base pairs of telomeres when we are born. Every time a cell divides it loses base pairs of telomeres. As people age the number decreases to 5000 or less at which time cells become senescent and can no longer reproduce. Senescent cells also may malfunction and start producing free radicals and other toxins that can damage adjacent cells.

Dr. Mai-Lis Hellenius who led the Karolinska team, observed 49 predominantly overweight and sedentary adults, all in their late 60’s. Half of the group took part in a six month exercise regime while the other half did not take part in any physical activity. Blood was taken from each individual at the beginning of the six months and then at the end of the six months. The groups were assessed using a diary, questionnaire and pedometer to measure the total number of footsteps taken each day. The group who reduced their time spent sitting and increased their exercise were associated with telomere lengthening. The other less active group, exhibited shortened telomeres. The reduction in sitting time was of the greatest importance than in an increase in exercise time. While exercise indicates an overall healthier profile, the most significant factor appears to be home much time people spend sitting.

Dr. Joan Vernikos, former director of NASA’s Life Sciences, has observed that when astronauts returned from space they had lost muscle tissue and had experienced other damage to this health. Their sedentary lifestyle while in space contributed to a host of health issues another indicator that sitting for long periods of time was damaging to a person’s overall health and aging processes.

Stand up more and live longer! A sedentary lifestyle increases risk of death. Standing will contribute to better posture, increased energy and a lower risk for a host of serious diseases. So take a standing break as often as possible. If you have a desk job consider getting sit/stand desk which allows for raising the height to periodically work from a standing position. Another option is to set a timer and take a walking break for a few minutes every half hour or so. This also applies to any sitting whether watching television or prolonged driving. Get up and stretch, pace around or go outside and take a breath of fresh air! Protect your DNA and your telomeres by standing up for health!

Reference: Per Sjögren, Rachel Fisher, Lena Kallings, Ulrika Svenson, Göran Roos, Mai-Lis Hellénius; Stand up for health—avoiding sedentary behaviour might lengthen your telomeres: secondary outcomes from a physical activity RCT in older people. Br J Sports Med Published Online First: 03 September 2014. doi: 10.1136/bjsports-2013-093342

lroot on December 22nd, 2017

Luigi Cornaro

It has been known for decades that caloric restriction significantly increases lifespan and health span in animals. Limiting food intake of mice, worms, and flies starting from birth lengthens their lifespan by 30% or more. Even more significant is that maximum lifespan increases not just the average. Of course there is no ethical or practical way to decrease calorie intake of humans during an entire lifetime so a different approach was needed. Instead of measuring actual lifespan scientists looked at the rate of biological aging in a group of 145 calorie restricted volunteers over a period of two years.

Research analysis of the data obtained through a trial study known as “CALERIE” has shown evidence that suggests caloric restriction may benefit life span by slowing down biological aging in humans. One of the hallmarks of biologic aging is the deterioration of the human body’s systems over time. It has been known that caloric restriction hinders the aging process in animals at the physiological level. If biological aging can be slowed down through dietary caloric restriction in humans, it may be possible to prevent or slow down a variety of age-related diseases and disabilities. While chronological aging increases the same for everyone, biological aging will occur faster in some humans and slower in others.

The CALERIE study is the first study to gauge the effects of caloric restriction in human beings in a randomized setting. With population aging and the threat of an increase in disability and disease, the new field of “geroscience” is responding to the challenge by studying and devising therapies known as “geroprotective” therapies to assist in the extension of healthy life years.

The CALERIE study conducted by The National Institute of Aging, consisted of 220 individuals with 145 randomly restricted to a 12% caloric restriction over the 2 year course of the study, while the other 75 were allowed to maintain their existing caloric intake. Biological age for all participants was calculated according to their chronological age as well as taking into consideration biomarkers that gauge liver, kidney, metabolic system, immune system and cardiovascular functions. In addition, systolic blood pressure, cholesterol and hemoglobin levels were accounted for. At the beginning of the study the average chronological age was 38 years with an average biological age of 37 years.

At the one-year follow-up, there was an average biological age increase of 0.11 years in the group that were placed on caloric restriction. The group that was allowed to continue with their normal dietary intake indicated an average biological age increase of 0.71 years. The significant difference between the 2 groups indicated caloric restriction did slow down the rate of biological aging.

It is well known that overeating can lead to a variety of health issues that can shorten life span. Studies have shown that caloric restriction with proper nutrition reduces reactive oxygen species in the body. By restricting calories, the levels of hormones and lipid metabolites are changed and energy metabolism is altered and all of these can help lower the risk for most degenerative diseases related to aging. It also appears that caloric restriction provides a benefit to the processes of autophagy which is the way in which cells remove damaged components and replace them with new replacement parts. Research has shown that over time some specific types of damaged cellular components can contribute to damage and age-related decline to the body’s machinery. Caloric restriction is believed to have a protective effect on cells which may help cells better use antioxidants to help avoid damage caused by free radicals.

Caloric restriction has been shown to be associated with longevity and is the single non-genetic and non-pharmaceutical strategy currently shown to provide not only healthy benefits, but also slow down the biological aging process and the diseases associated with it. It is plausible that caloric restriction could be as dramatic as gains and benefits associated with exercise!

Reference: Daniel W Belsky, Kim M Huffman, Carl F Pieper, Idan Shalev, William E Kraus; Change in the Rate of Biological Aging in Response to Caloric Restriction: CALERIE Biobank Analysis; The Journals of Gerontology: Series A, Volume 73, Issue 1, 12 December 2017, Pages 4–10

lroot on December 22nd, 2017

Adult Stem Cells

The stem cells found within the average adult human are capable of restoring dying cells while also fixing damaged tissue. Nothing is safe from the aging process, though, and as we get older we begin to lose the very same stem cells that once kept our bodies in functional condition. But there could be a way around that: new stem cell research has revealed a nutrient sensing pathway called TOR can be subdued in order to prevent or restore such loses. TOR plays a key role in the aging process and is largely responsible for the loss of stem cells in the human body.

The research examining the relationship between stem cells and TOR, published in the journal Cell Stem Cell, was carried out at the Buck Institute for Research on Aging in California, as well as at Stanford University. Samantha Haller, Ph.D. led the work at Buck Institute, which started with fruit flies before advancing to mice; a move made due to the similar traits shared by both. At Stanford, meanwhile, researchers also worked with mice.

The mice at Buck Institute were put on varying schedules of rapamycin treatment. Rapamycin, also known as Sirolimus, is a drug used to prevent the rejection of kidney transplants. In this study, it was used to suppress the effects of TOR. According to Buck professor and senior author Heinrich Jasper, Ph.D., rapamycin was able to successfully maintain and restore stem cells regardless of the age of the mouse. One mouse in the study was around 15 months old, which roughly equates to a 50-year-old human.

“In every case we saw a decline in the number of stem cells, and rapamycin would bring it back,” said Jasper.

When stem cell division occurs, a “daughter” cell is created that then proliferates into new cells that can repair the damaged tissue. The process is always asymmetrical, meaning one cell will become a repair cell while the other remains a stem cell. When rapamycin is introduced, the stem cells are recovered — though Jasper notes the current work done by Buck and Stanford is unable to confirm how, exactly, the cells are restored. It could be a simple replenishment of cells, or that the stem cells are creating two daughter cells instead of one during the division process. It could be another process altogether that the researchers have yet to uncover.

“It’s all about maintaining a balance between stem cell renewal and differentiation,” said Jasper. “It’s easy to see how a loss of adult stem cells might accrue over a lifetime and accelerate with aging. We are excited to have a means of rescuing stem cells, boosting their ability to maintain healthy tissue.”

Going forward, Jasper explains that researchers will be focusing on better understanding TOR and how it governs stem cells, specifically asking questions like “Is there a chronic increase in TOR over a lifetime, or is activation stronger in aging animals? What happens downstream of TOR?”

It was an exciting year for research involving stem cells and aging: back in July, scientists were able to slow the aging process in mice using stem cells. The Cedars-Sinai Heart Institute revealed in August that stem cells from younger hearts could reverse the aging process in humans.

Some, like SENS Research Foundation co-founder Aubrey de Grey, believe we’re on the verge of fully understanding aging, and it’s becoming increasingly likely that stem cells will play a key role in that enlightenment.

Stem Cells

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.

lroot on December 12th, 2017

Italian Centenarians

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.

lroot on December 1st, 2017

heart

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

lroot on November 30th, 2017

Progenitor Cells

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