By 2050, the number of people over the age of 80 will triple globally, which could come at great cost to individuals and economies. In a commentary published July 24 in Nature, three experts call for moving forward with preclinical and clinical strategies for people that have been shown to delay aging in animals. In addition to promoting a healthy diet and regular exercise, these strategies include slowing the metabolic and molecular causes of human aging, such as the incremental accumulation of cellular damage that occurs over time.

Unfortunately, medicine focuses almost entirely on fighting chronic diseases in a piecemeal fashion as symptoms develop. Instead, more efforts should be directed to promoting interventions that have the potential to prevent multiple chronic diseases and extend healthy lifespans.

The researchers, at Washington University School of Medicine in St. Louis, Brescia University in Italy, the Buck Institute for Aging and Research and the Longevity Institute at the University of Southern California, write that unfortunately, economic incentives in biomedical research and health care reward treating disease more than promoting good health.

The problems of old age come as a package. More than 70% of people over 65 have two or more chronic conditions. Studies of diet, genes and drugs indicate that delaying one age-related disease probably staves off others. At least a dozen molecular pathways seem to set the pace of physiological ageing.

Researchers have tweaked these pathways to give rodents long and healthy lives. Restricting calorie intake in mice or introducing mutations in nutrient-sensing pathways can extend lifespans by as much as 50%. And these ‘Methuselah mice’ are more likely than controls to die without any apparent diseases. In other words, extending lifespan also seems to increase ‘healthspan’, the time lived without chronic age-related conditions.

Research has highlighted potential benefits from dietary restriction in extending healthy life span. People who eat significantly fewer calories, while still getting optimal nutrition, have ?younger,? more flexible hearts. They also have significantly lower blood pressure, much less inflammation in their bodies and their skeletal muscles function in ways similar to muscles in people who are significantly younger.

These insights have made hardly a dent in human medicine. Biomedicine takes on conditions one at a time. Rather, it should learn to stall incremental cellular damage and changes that eventually yield several infirmities.

The current tools for extending healthy life ? better diets and regular exercise ? are effective. But there is room for improvement, especially in personalizing treatments. Molecular insights from animals should be tested in humans to identify interventions to delay ageing and associated conditions. Together, preclinical and clinical researchers must develop meaningful endpoints for human trials.

Longevity pathways identified in model organisms seem to be conserved in humans and can be manipulated in similar ways. Genetic surveys of centenarians implicate hormonal and metabolic systems. Long-term calorie restriction in humans induces drastic metabolic and molecular changes that resemble those of younger people, notably in inflammatory and nutrient-sensing pathways. Mice engineered to have reduced signalling in these pathways live longer.

Several molecular pathways that increase longevity in animals are affected by approved and experimental drugs. The sirtuin proteins, involved in a similar range of cellular processes, are activated by high concentrations of naturally occurring compounds and extend lifespan in metabolically abnormal obese mice. A plethora of natural and synthetic molecules affect pathways that are shared by ageing and conditions related to ageing.

Diet has similar effects. The drugs rapamycin and metformin mimic changes observed in animals fed calorie and protein-restricted diets. And fasting triggers cellular responses that boost stress resistance, and reduce oxidative damage and inflammation. In rodents, fasting protects against diabetes, cancer, heart disease and neurodegeneration9. There are many anti-ageing interventions that could be considered for clinical trials.

Ignored opportunities

Scientists are not set up to capitalize on these leads to combat the looming ageing crisis. Clinicians do not realize how much is understood about the molecular mechanisms of ageing and its broad effects on diseases. Researchers of all stripes focus too much on easing or reversing the progression of diseases.

The problem is calcified by the funding gap. Budgets for ageing research are small compared to disease-centred research. The Division of Aging Biology in the US National Institute on Aging receives less than 1% of the National Institutes of Health’s budget even though it supports research into the mechanisms underlying most disabilities and chronic diseases. Most grants focus on diseases of specific systems. Most study sections are not set up to evaluate multidisciplinary research on healthspan. The situation is similar in Europe and Japan.

How should we test interventions that extend healthspan? Human data from dietary restriction and genetic-association studies of healthy ageing could help to channel the most promising pathways identified in preclinical studies. Animal studies should be designed to better mimic human ageing. For example, frailty indices are often used in human studies. Comparable indices should be developed for mice.

Suitable endpoints for human trials are needed. Animal work suggests many candidates as potential biomarkers, such as accumulation of molecular damage to DNA, proteins and lipids from oxidative stress. Publicly funded clinical trials could also collect crucial samples of blood, muscle and fat for molecular analysis.

Funding agencies should establish committees of translational scientists to review which markers of biological ageing are most consistent between animals and humans, and prioritize the most practical for further assessment. Chosen biomarkers could be evaluated in clinical studies over a broad age range of patients already being treated with drugs that increase lifespan in animal models. Assessments must also be developed for dietary or other interventions that do not involve drugs.

The most important change must be in mindset. Economic incentives in both biomedical research and health care reward treating diseases more than promoting health. The launch of a few anti-ageing biotech companies such as Calico, created last year by Google, is promising. But public money must be invested in extending healthy lifespan by slowing ageing. Otherwise we will founder in a demographic crisis of increased disability and escalating health-care costs.

A number of studies show that people who sleep approximately 6 1/2 – 7 hours each night live longer and have better cognitive function than those sleeping 8 hours or more.

Daniel F. Kripke, an Emeritus Professor of Psychiatry at the University of California San Diego, analyzed the data on 1.1 million people over a six year period who participated in a cancer study. Published in JAMA Psychiatry the study showed that people who reported they slept 6.5 – 7.4 hours had a lower mortality rate than those who slept for a shorter or longer length of time.

In another study, published in the journal Sleep Medicine in 2011, Dr. Kripke found further evidence that the optimal amount of sleep might be less than the traditional eight hours. The researchers recorded the sleep activity of about 450 elderly women using devices on their wrist for a week. Some 10 years later the researchers found that those who slept fewer than five hours or more than 6.5 hours had a higher mortality.

A study in the journal Frontiers in Human Neuroscience last year used data from users of the cognitive-training website Lumosity. Researchers looked at the self-reported sleeping habits of about 160,000 users who took spatial-memory and matching tests and about 127,000 users who took an arithmetic test. They found that cognitive performance increased as people got more sleep, reaching a peak at seven hours before starting to decline.

A study in the current issue of Journal of Clinical Sleep Medicine tracked five healthy adults who were placed in what the researchers called Stone-Age-like conditions in Germany for more than two months? without electricity, clocks, or running water. Participants fell asleep about two hours earlier and got on average 1.5 hours more sleep than was estimated in their normal lives, the study said. Their average amount of sleep per night was 7.2 hours.

We do not have to lose our independence and ability to live life in our 70’s or 80’s. Even at the age of 100 years old Fauja Singh completed a marathon.

The race ended just after Fauja Singh crossed the line in 3,851st place. By finishing then he would do what no man before him had ever done. Amid the bundled and cheering crowd in Toronto, underneath a distended but gracious sky, he would complete a marathon. And he would do so at 100 years old.

Was it pain he felt as he approached the end, just footsteps away from redefining the limits of human endurance? No, this wasn’t pain. Fauja knew pain. This wasn’t pain but exhaustion. And Fauja could handle exhaustion, because exhaustion foreshadowed euphoria. When Fauja got tired, it often meant a record would soon fall.

He’d already broken a few. Fastest to run a marathon (male, over age 90), fastest to run 5,000 meters (male, over age 100), fastest to run 3,000 meters (male, over age 100), and on and on they went. But those records didn’t roll off the tongue the way this one would. Oldest person to complete a marathon (male): Fauja Singh.

So Fauja ran in Toronto, arms swinging, yellow turban bobbing, chest-length Zeusian beard swaying in the wind. He was joined by other runners with roots in the Indian region of Punjab, their appearance in keeping with the traditions of their Sikh faith. Fauja trotted for the first three miles, until his coach encouraged him to slow to a jog. Speed was fleeting, the enemy of endurance. By mile 6, he’d downshifted to a toddle. After a break for a rubdown and some tea at mile 18, he settled into a walk.

The exhaustion took hold sometime around mile 20, but Fauja stayed upbeat about the remaining distance. Finally Fauja saw the only mile-marker that mattered: the finish line. What had been silence between footsteps was now music and cheers. The slog to the finish reminded Fauja of his wedding day, of the joy that awaited at the end of the long aisle. He waved to the crowd as he walked across the line, then lifted his arms and accepted a medal. He’d finished in 8 hours, 25 minutes. There were smiles and handshakes and photos with friends and strangers, then a rambling news conference for Fauja to reflect on his record.

Researchers at the University of California, Berkeley, have discovered that the hormone oxytocin plays a critical role in healthy muscle maintenance and repair. After a nine-day treatment of old mice, scientists found that the muscles of the group that had received oxytocin injections healed far better than those of a control group without oxytocin.
?The action of oxytocin was fast,? said Elabd a University of California Researcher. ?The repair of muscle in the old mice was at about 80 percent of what we saw in the young mice.?

A few other biochemical factors in blood have been connected to aging and disease in recent years, but oxytocin is the first anti-aging molecule identified that is approved by the Food and Drug Administration for clinical use in humans.

Oxytocin is a hormone associated with maternal nurturing, social attachments, childbirth and sex and is indispensable for healthy muscle maintenance and repair, and that in mice, it declines with age.

The new study published in the journal Nature Communications, presents oxytocin as the latest treatment target for age-related muscle wasting, or sarcopenia.

A few other biochemical factors in blood have been connected to aging and disease in recent years, but oxytocin is the first anti-aging molecule identified that is approved by the Food and Drug Administration for clinical use in humans, the researchers said. Pitocin, a synthetic form of oxytocin, is already used to help with labor and to control bleeding after childbirth. Clinical trials of an oxytocin nasal spray are also underway to alleviate symptoms associated with mental disorders such as autism, schizophrenia and dementia.

Oxytocin is sometimes referred to as the “trust hormone” because of its association with romance and friendship. It is released with a warm hug, a grasped hand or a loving gaze, and it increases libido. The hormone kicks into high gear during and after childbirth, helping new mothers bond with and breastfeed their new babies.

“This is the hormone that makes your heart melt when you see kittens, puppies and human babies,” said Conboy, who is also a member of the Berkeley Stem Cell Center and of the California Institute for Quantitative Biosciences (QB3). “There is an ongoing joke among my research team that we’re all happy, friendly and trusting because oxytocin permeates the lab.”

The researchers pointed out that while oxytocin is found in both young boys and girls, it is not yet known when levels of the hormone start to decline in humans, and what levels are necessary for maintaining healthy tissues.

Christian Elabd and Wendy Cousin, both senior scientists in Conboy’s lab, were co-lead authors on this study.

Previous research by Elabd found that administering oxytocin helped prevent the development of osteoporosis in mice that had their ovaries removed to mimic menopause.

The new study determined that in mice, blood levels of oxytocin declined with age. They also showed that there are fewer receptors for oxytocin in muscle stem cells in old versus young mice.

To tease out oxytocin’s role in muscle repair, the researchers injected the hormone under the skin of old mice for four days, and then for five days more after the muscles were injured. After the nine-day treatment, they found that the muscles of the mice that had received oxytocin injections healed far better than those of a control group of mice without oxytocin.

“The action of oxytocin was fast,” said Elabd. “The repair of muscle in the old mice was at about 80 percent of what we saw in the young mice.”

Interestingly, giving young mice an extra boost of oxytocin did not seem to cause a significant change in muscle regeneration.

“This is good because it demonstrates that extra oxytocin boosts aged tissue stem cells without making muscle stem cells divide uncontrollably,” Cousin added.

The researchers also found that blocking the effects of oxytocin in young mice rapidly compromised their ability to repair muscle, which resembled old tissue after an injury.

The researchers also studied mice whose gene for oxytocin was disabled, and compared them with a group of control mice. At a young age, there was no significant difference between the two groups in muscle mass or repair efficiency after an injury. It wasn’t until the mice with the disabled oxytocin gene reached adulthood that signs of premature aging began to appear.

“When disabling other types of genes associated with tissue repair, defects appear right away either during embryonic development, or early in life,” said Conboy. “To our knowledge, the oxytocin gene is the only one whose impact is seen later in life, suggesting that its role is closely linked to the aging process.”

Cousin noted that oxytocin could become a viable alternative to hormone replacement therapy as a way to combat the symptoms of both female and male aging, and for long-term health. Hormone therapy did not show improvements in agility or muscle regeneration ability, and it is no longer recommended for disease prevention because research has found that the therapy’s benefits did not outweigh its health risks.

In addition to healthy muscle, oxytocin is predicted to improve bone health, and it might be important in combating obesity.

Conboy said her lab plans to examine oxytocin’s role in extending a healthy life in animals, and in conserving its beneficial anti-aging effects in humans.

She noted that there is a growing circle of scientists who believe that aging is the underlying cause of a number of chronic diseases.

“If you target processes associated with aging, you may be tackling those diseases at the same time,” said Conboy. “Aging is a natural process, but I believe that we can meaningfully intervene with age-imposed organ degeneration, thereby slowing down the rate at which we become progressively unhealthy.”

The reduced ability to respond to stress is a major characteristic of aging. Indeed, aging itself is a stressful condition. Therefore, reducing chronic causes of stress can promote longevity. Some of the best protein protectors against stress and aging are the Heat Shock Proteins (HSPs). The protective HSPs are induced whenever your body is exposed to stressing agents such as:

1. Alcohol, which is one of the likely reasons that one drink per day helps prolong life
2. Elevated body temperature
3. Environmental toxins such as heavy metals or toxic chemicals
4. Oxidative stress, which may explain part of the reason that limited exercise is beneficial

Besides their effects on stress response, HSPs also have a protective role in disease and aging. For example, much research has shown that HSPs help with cardiovascular, metabolic, and neurological disorders.

At the recent AGE research conference (May 31 to June 2, 2014), new data on HSPs was presented by Kalie Kavanagh at Wake Forest University in North Carolina. Long lived Centenarians have better heat shock response and some may have gene variants of HSPs that are protective. HSP levels typically decline with age. Experiments in monkeys to raise their HSPs preserved insulin sensitivity, lowered blood pressure, and increased endurance.

The most interesting information to come out of the HSP talk was the potential to increase your own HSP levels. The HSPs can be stimulated by raising your body temperature slightly for 10 to 30 minutes using available methods: soaking in a hot tub at 104 degrees or sitting in a steam sauna bath, or participating in any exercise in which you build up a sweat for 5 minutes or more. These activities all lead to higher HSP levels, which can remain elevated and protective for 24 hours or more.

Have you ever wondered why aging occurs and how one might slow its progression? Aging expert Dr. Villeponteau describes dietary, exercise, and supplement routines that can add decades to your healthspan. Decoding Longevity condenses a wealth of practical information for those interesting in extending their health and longevity. Decoding Longevity also discusses the exponential increases in technology that will likely lead to greatly expanded longevity while maintaining health and indpendence in the next 20 to 40 years.

Decoding Longevity offers a full spectrum biological and genetic analysis of the aging process in layman’s language. Starting with an analysis of why life expectancy increased 57% in the 20th Century, it then focuses on recommended lifestyle choices that can significantly extend your healthspan and youthful fitness. The third part looks in some detail at the last 20 years of aging research, while the final section explores future developments that will provide powerful tools for extending healthspan and longevity in the next 20 to 40 years.

The Author: Dr. Bryant Villeponteau has 25 years of scientific leadership in aging research and some 60 scientific journal and patent publications. He has a Ph.D. in Biology from UCLA and was Assistant Professor of Biological Chemistry at the University of Michigan Medical School in the Institute of Gerontology. Dr. Villeponteau later led the research group at Geron Corporation, where he was the lead inventor in cloning human telomerase, thereby winning the Distinguished Inventor Award for the 2nd best US patent of 1997. Since 2008, Dr. Villeponteau has used genetics and machine learning technologies to develop antiaging supplements and drugs. He also cofounded Centagen, a Colorado stem cell company.

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That chicken wing you’re eating could be as deadly as a cigarette. In a new study that tracked a large sample of adults for nearly two decades, researchers have found that eating a diet rich in animal proteins during middle age makes you four times more likely to die of cancer than someone with a low-protein diet — a mortality risk factor comparable to smoking.

“There’s a misconception that because we all eat, understanding nutrition is simple. But the question is not whether a certain diet allows you to do well for three days, but can it help you survive to be 100?” said corresponding author Valter Longo, the Edna M. Jones Professor of Biogerontology at the USC Davis School of Gerontology and director of the USC Longevity Institute.

Not only is excessive protein consumption linked to a dramatic rise in cancer mortality, but middle-aged people who eat lots of proteins from animal sources — including meat, milk and cheese — are also more susceptible to early death in general, reveals the study to be published March 4 in Cell Metabolism. Protein-lovers were 74 percent more likely to die of any cause within the study period than their more low-protein counterparts. They were also several times more likely to die of diabetes.

But how much protein we should eat has long been a controversial topic — muddled by the popularity of protein-heavy diets such as Paleo and Atkins. Before this study, researchers had never shown a definitive correlation between high protein consumption and mortality risk.

Rather than look at adulthood as one monolithic phase of life, as other researchers have done, the latest study considers how biology changes as we age, and how decisions in middle life may play out across the human lifespan.

In other words, what’s good for you at one age may be damaging at another. Protein controls the growth hormone IGF-I, which helps our bodies grow but has been linked to cancer susceptibility. Levels of IGF-I drop off dramatically after age 65, leading to potential frailty and muscle loss. The study shows that while high protein intake during middle age is very harmful, it is protective for older adults: those over 65 who ate a moderate- or high-protein diet were less susceptible to disease.

? High protein intake especially if from animal sources is linked to increased cancer, diabetes, and overall mortality

? Higher protein consumption may be protective for older adults

? Plant-derived proteins are associated with lower mortality than animal-derived proteins

? High IGF-1 levels increased the relationship between mortality and high protein

The latest paper draws from Longo’s past research on IGF-I, including on an Ecuadorian cohort that seemed to have little cancer or diabetes susceptibility because of a genetic mutation that lowered levels of IGF-I; the members of the cohort were all less than five-feet tall.

“The research shows that a low-protein diet in middle age is useful for preventing cancer and overall mortality, through a process that involves regulating IGF-I and possibly insulin levels,” said co-author Eileen Crimmins, the AARP Chair in Gerontology at USC. “However, we also propose that at older ages, it may be important to avoid a low-protein diet to allow the maintenance of healthy weight and protection from frailty.”

Crucially, the researchers found that plant-based proteins, such as those from beans, did not seem to have the same mortality effects as animal proteins. Rates of cancer and death also did not seem to be affected by controlling for carbohydrate or fat consumption, suggesting that animal protein is the main culprit.

“The majority of Americans are eating about twice as much proteins as they should, and it seems that the best change would be to lower the daily intake of all proteins but especially animal-derived proteins,” Longo said. “But don’t get extreme in cutting out protein; you can go from protected to malnourished very quickly.”

Longo’s findings support recommendations from several leading health agencies to consume about 0.8 grams of protein per kilogram of body weight every day in middle age. For example, a 130-pound person should eat about 45-50 grams of protein a day, with preference for those derived from plants such as legumes, Longo explains.

The researchers define a “high-protein” diet as deriving at least 20 percent of calories from protein, including both plant-based and animal-based protein. A “moderate” protein diet includes 10-19 percent of calories from protein, and a “low-protein” diet includes less than 10 percent protein.

Even moderate amounts of protein had detrimental effects during middle age, the researchers found. Across all 6,318 adults over the age of 50 in the study, average protein intake was about 16 percent of total daily calories with about two-thirds from animal protein — corresponding to data about national protein consumption. The study sample was representative across ethnicity, education and health background.

People who ate a moderate amount of protein were still three times more likely to die of cancer than those who ate a low-protein diet in middle age, the study shows. Overall, even the small change of decreasing protein intake from moderate levels to low levels reduced likelihood of early death by 21 percent.

For a randomly selected smaller portion of the sample – 2,253 people – levels of the growth hormone IGF-I were recorded directly. The results show that for every 10 ng/ml increase in IGF-I, those on a high-protein diet were 9 percent more likely to die from cancer than those on a low-protein diet, in line with past research associating IGF-I levels to cancer risk.

The researchers also extended their findings about high-protein diets and mortality risk, looking at causality in mice and cellular models. In a study of tumor rates and progression among mice, the researchers show lower cancer incidence and 45 percent smaller average tumor size among mice on a low-protein diet than those on a high-protein diet by the end of the two-month experiment.

“Almost everyone is going to have a cancer cell or pre-cancer cell in them at some point. The question is: Does it progress?” Longo said. “Turns out one of the major factors in determining if it does is is protein intake.” The study suggests that low protein intake during middle age followed by moderate to high protein consumption in old adults may optimize healthspan and longevity.

Reference: https://www.cell.com/cell-metabolism/retrieve/pii/S155041311400062X

The power of regenerative medicine appears to have turned science fiction into scientific reality — by allowing scientists to transform skin cells into cells that closely resemble beating heart cells. However, the methods required are complex, and the transformation is often incomplete. But now, scientists at the Gladstone Institutes have devised a new method that allows for the more efficient — and, importantly, more complete — reprogramming of skin cells into cells that are virtually indistinguishable from heart muscle cells. These findings, based on animal models and described in the latest issue of Cell Reports, offer new-found optimism in the hunt for a way to regenerate muscle lost in a heart attack.

Heart disease is the world’s leading cause of death, but recent advances in science and medicine have improved the chances of surviving a heart attack. In the United States alone, nearly 1 million people have survived an attack, but are living with heart failure — a chronic condition in which the heart, having lost muscle during the attack, does not beat at full capacity. So, scientists have begun to look toward cellular reprogramming as a way to regenerate this damaged heart muscle.

The reprogramming of skin cells into heart cells, an approach pioneered by Gladstone Investigator, Deepak Srivastava, MD, has required the insertion of several genetic factors to spur the reprogramming process. However, scientists have recognized potential problems with scaling this gene-based method into successful therapies. So some experts, including Gladstone Senior Investigator Sheng Ding, PhD, have taken a somewhat different approach.

“Scientists have previously shown that the insertion of between four and seven genetic factors can result in a skin cell being directly reprogrammed into a beating heart cell,” explained Dr. Ding, the paper’s senior author and a professor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “But in my lab, we set out to see if we could perform a similar transformation by eliminating — or at least reducing — the reliance on this type of genetic manipulation.”

To that effect, the research team used skin cells extracted from adult mice to screen for chemical compounds, so-called ‘small molecules,’ that could replace the genetic factors. Dr. Ding and his research team have previously harnessed the power of small molecules to reprogram skin cells into neurons and, more recently, insulin-producing pancreas cells. They reasoned that a similar technique could be used to do the same with heart cells.

“After testing various combinations of small molecules, we narrowed down the list to a four-molecule ‘cocktail,’ which we called SPCF, that could guide the skin cells into becoming more like heart cells,” said Gladstone Postdoctoral Scholar Haixia Wang, PhD, the paper’s lead author. “These newly reprogramed cells exhibited some of the twitching and contracting normally seen in mature heart cells, but the transformation wasn’t entirely complete.”

So, Drs. Ding and Wang decided to add one genetic factor, called Oct4, to the small molecule cocktail. And by doing so, the research team was able to generate a completely reprogrammed beating heart cell.

“Once we added Oct4 to the mix, we observed clusters of contracting cells after a period of just 20 days,” explained Dr. Ding. “Remarkably, additional analysis revealed that these cells showed the same patterns of gene activation and electric signaling patterns normally seen in the ventricles of the heart.”

Dr. Ding and his team believe that these results may point to a more desirable method for reprogramming, as ventricular heart cells are the type of cells typically lost during a heart attack. These findings give the team newfound optimism that the research is well on its way towards an entirely pharmaceutical-based method to regrow heart muscle.

“The fact that the combination of Oct4 and small molecules appears to generate beating heart cells in an accelerated fashion is encouraging,” said Joseph Wu, MD, PhD, Director of the Stanford Cardiovascular Institute, who was not involved in this study. “Future advances by Dr. Ding and others will likely focus on improving the efficiency of conversion as well as duplicating the data in adult human cells.”

Reference:

Haixia Wang, Nan Cao, C. Ian Spencer, Baoming Nie, Tianhua Ma, Tao Xu, Yu Zhang, Xiaojing Wang, Deepak Srivastava, Sheng Ding. Small Molecules Enable Cardiac Reprogramming of Mouse Fibroblasts with a Single Factor, Oct4. Cell Reports, February 2014 DOI: 10.1016/j.celrep.2014.01.038

One of the major causes of hearing loss is damage to the sound-sensing hair cells in the inner ear. For years, scientists have thought that these cells are not replaced once they’re lost, but new research appearing online February 20 in the journal Stem Cell Reports reveals that supporting cells in the ear can turn into hair cells in newborn mice. If the findings can be applied to older animals, they may lead to ways to help stimulate cell replacement in adults and to the design of new treatment strategies for people suffering from deafness due to hair cell loss.

Whereas previous research indicated that hair cells are not replaced, this latest study found that replacement does indeed occur, but at very low levels. “The finding that newborn hair cells regenerate spontaneously is novel,” says senior author Dr. Albert Edge of Harvard Medical School and Massachusetts Eye and Ear Infirmary.

The team’s previous research revealed that inhibition of the Notch signaling pathway increases hair cell differentiation and can help restore hearing to mice with noise-induced deafness. In their latest work, the investigators found that blocking the Notch pathway increases the formation of new hair cells not from remaining hair cells but from certain nearby supporting cells that express a protein called Lgr5.

“By using an inhibitor of Notch signaling, we could push even more cells to differentiate into hair cells,” says Dr. Edge. “It was surprising that the Lgr5-expressing cells were the only supporting cells that differentiated under these conditions.”

Combining this new knowledge about Lgr5-expressing cells with the previous finding that Notch inhibition can regenerate hair cells will allow the scientists to design new hair cell regeneration strategies to treat hearing loss and deafness.

Reference:

Naomi F. Bramhall, Fuxin Shi, Katrin Arnold, Konrad Hochedlinger, Albert S.B. Edge. Lgr5-Positive Supporting Cells Generate New Hair Cells in the Postnatal Cochlea. Stem Cell Reports, February 2014 DOI: 10.1016/j.stemcr.2014.01.008

A cure for type 1 diabetes has alluded researchers. Not because scientists do not know what must be done — but because the tools have not been available to do it. Now scientists at the Gladstone Institutes, harnessing the power of regenerative medicine, have developed a technique in animal models that could replenish the very cells destroyed by the disease. The team’s findings, published online in the journal Cell Stem Cell, are an important step towards freeing an entire generation of patients from the life-long injections that characterize this devastating disease.

Type 1 diabetes, which usually manifests during childhood, is caused by the destruction of ?-cells, a type of cell that normally resides in the pancreas and produces a hormone called insulin. Without insulin, the body’s organs have difficulty absorbing sugars, such as glucose, from the blood. Once a death sentence, the disease can now be managed with regular glucose monitoring and insulin injections. A more permanent solution, however, would be to replace the missing ?-cells. But these cells are hard to come by, so researchers have looked towards stem cell technology as a way to make them.

“The power of regenerative medicine is that it can potentially provide an unlimited source of functional, insulin-producing ?-cells that can then be transplanted into the patient,” said Dr. Ding, who is also a professor at the University of California, San Francisco (UCSF), with which Gladstone is affiliated. “But previous attempts to produce large quantities of healthy ?-cells — and to develop a workable delivery system — have not been entirely successful. So we took a somewhat different approach.”

One of the major challenges to generating large quantities of ?-cells is that these cells have limited regenerative ability; once they mature it’s difficult to make more. So the team decided to go one step backwards in the life cycle of the cell.

The team first collected skin cells, called fibroblasts, from laboratory mice. Then, by treating the fibroblasts with a unique ‘cocktail’ of molecules and reprogramming factors, they transformed the cells into endoderm-like cells. Endoderm cells are a type of cell found in the early embryo, and which eventually mature into the body’s major organs — including the pancreas.

“Using another chemical cocktail, we then transformed these endoderm-like cells into cells that mimicked early pancreas-like cells, which we called PPLC’s,” said Gladstone Postdoctoral Scholar Ke Li, PhD, the paper’s lead author. “Our initial goal was to see whether we could coax these PPLC’s to mature into cells that, like ?-cells, respond to the correct chemical signals and — most importantly — secrete insulin. And our initial experiments, performed in a petri dish, revealed that they did.”

The research team then wanted to see whether the same would occur in live animal models. So they transplanted PPLC’s into mice modified to have hyperglycemia (high glucose levels), a key indicator of diabetes.

“Importantly, just one week post-transplant, the animals’ glucose levels started to decrease gradually approaching normal levels,” continued Dr. Li. “And when we removed the transplanted cells, we saw an immediate glucose spike, revealing a direct link between the transplantation of the PPLC’s and reduced hyperglycemia.”

But it was when the team tested the mice eight weeks post-transplant that they saw more dramatic changes: the PPLC’s had given rise to fully functional, insulin-secreting ?-cells.

“These results not only highlight the power of small molecules in cellular reprogramming, they are proof-of-principle that could one day be used as a personalized therapeutic approach in patients,” explained Dr. Ding.

“I am particularly excited about the prospect of translating these findings to the human system,” said Matthias Hebrok, PhD, one of the study’s authors and director of the UCSF Diabetes Center. “Most immediately, this technology in human cells could significantly advance our understanding of how inherent defects in ?-cells result in diabetes, bringing us notably closer to a much-needed cure.”