Mature cells in the stomach sometimes revert back to behaving like rapidly dividing stem cells. Now, researchers have found that this process may be universal; no matter the organ, when tissue responds to certain types of injury, mature cells seem to get younger and begin dividing rapidly, creating scenarios that can lead to cancer. Older cells may be dangerous because when they revert to stem cell-like behavior, they carry with them all of the potential cancer-causing mutations that have accumulated during their lifespans. However, because mature cells in the stomach, pancreas, liver and kidney all activate the same genes and go through the same process when they begin to divide again, the findings could mean that cancer initiation is much more similar across organs than scientists have thought. That could support using the same strategies to treat or prevent cancer in a variety of different organs.

The process by which mature cells begin dividing again has been named paligenosis. "When we began the war on cancer in the 1970s, scientists thought all cancers were similar. It turned out cancers are very different from one organ to another and from person to person. But if, as this study suggests, the way that cells become proliferative again is similar across many different organs, we can imagine therapies that interfere with cancer initiation in a more global way, regardless of where that cancer may appear in the body."

Studying cells from the stomach and pancreas in humans and mice, as well as mouse kidney and liver cells, and cells from more than 800 tumor and precancerous lesions in people, the researchers found when tissue is injured by infections or trauma, mature cells can revert back to a stem-cell state in which they divide repeatedly. Paligenosis appears similar to apoptosis - the programmed death of cells as a normal part of an organism's growth and development - in that it seems to happen the same way in every cell, regardless of its location in the body. "Nature has provided a way for mature cells to begin dividing again, and that process is the same in every tissue we've studied."

In 1900, it was speculated that a sequence of context-independent energetic and structural changes governed the reversion of differentiated cells to a proliferative, regenerative state. Accordingly, we show here that differentiated cells in diverse organs become proliferative via a shared program. Metaplasia-inducing injury caused both gastric chief and pancreatic acinar cells to decrease mTORC1 activity and massively upregulate lysosomes/autophagosomes; then increase damage associated metaplastic genes such as Sox9; and finally reactivate mTORC1 and re-enter the cell cycle.

Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re-entry at S-phase. In kidney and liver regeneration and in human gastric metaplasia, mTORC1 also correlated with proliferation. In lysosome-defective Gnptab-/- mice, both metaplasia-associated gene expression changes and mTORC1-mediated proliferation were deficient in pancreas and stomach.

Our findings indicate differentiated cells become proliferative using a sequential program with intervening checkpoints: (i) differentiated cell structure degradation; (ii) metaplasia- or progenitor-associated gene induction; (iii) cell cycle re-entry. We propose this program, which we term "paligenosis", is a fundamental process, like apoptosis, available to differentiated cells to fuel regeneration following injury.

Obese people live shorter lives and have a greater proportion of life with cardiovascular disease, reports a new study. The study examined individual level data from 190,672 in-person examinations across 10 large prospective cohorts with an aggregate of 3.2 million years of follow-up. The study shows similar longevity between normal weight and overweight (but not obese) people, but a higher risk for those who are overweight of developing cardiovascular disease during their lifespan and more years spent with cardiovascular disease. This is the first study to provide a lifespan perspective on the risks of developing cardiovascular disease and dying after a diagnosis of cardiovascular disease for normal weight, overweight and obese individuals.

"The obesity paradox caused a lot of confusion and potential damage because we know there are cardiovascular and non-cardiovascular risks associated with obesity, I get a lot of patients who ask, 'Why do I need to lose weight, if research says I'm going to live longer?' I tell them losing weight doesn't just reduce the risk of developing heart disease, but other diseases like cancer. Our data show you will live longer and healthier at a normal weight."

The likelihood of having a stroke, heart attack, heart failure or cardiovascular death in overweight middle-aged men 40 to 59 years old was 21 percent higher than in normal weight men. The odds were 32 percent higher in overweight women than normal weight women. The likelihood of having a stroke, heart attack, heart failure or cardiovascular death in obese middle-aged men 40 to 59 years old was 67 percent higher than in normal weight men. The odds were 85 percent higher in obese women than normal weight women. Normal weight middle-aged men also lived 1.9 years longer than obese men and six years longer than morbidly obese. Normal weight men had similar longevity to overweight men. Normal weight middle-aged women lived 1.4 years longer than overweight women, 3.4 years longer than obese women and six years longer than morbidly obese women.

Overweight and obesity are highly prevalent in the United States, have increased dramatically over the past 3 decades, and affect approximately 2.1 billion adults worldwide. In recent years, controversy about the health implications of overweight status has grown, given findings of similar or lower all-cause mortality rates in overweight compared with normal-weight groups. However, current studies have not taken into account the age at onset and duration of cardiovascular disease (CVD), limiting the ability to account for proportion of life lived with CVD morbidity in individuals who are overweight and obese compared with normal weight. This is especially important because disease burden associated with development of CVD results in less healthful years of life, poorer quality of life, and increased health care expenditures.

In this large study of US adults free of clinical CVD at baseline, lifetime risk for incident CVD was high for all adults and was greater in adults who were overweight and obese. Adults who were obese had an earlier onset of incident CVD, a greater proportion of life lived with CVD morbidity (unhealthy life years), and shorter overall survival compared with adults with normal body mass index (BMI). In addition, the proportion of adults with incident CVD events (compared with non-CVD death) was significantly higher in adults who were overweight or obese compared with adults in the normal BMI group. Overweight and obesity were associated with increased hazards of incident CVD event after adjustment for competing risks of non-CVD death across all index age ranges.

While health hazards of obesity have long been recognized, recent studies have spurred controversy about the specific relationship between overweight status and mortality. Among these prior analyses, measurement bias may be present owing to inclusion of self-reported height and weight data. Further, inclusion of participants with comorbidities at baseline, specifically prevalent CVD, may contribute to selection and survival bias because of protopathic bias (reverse causation) related to unintentional weight loss. In our study, we were able to leverage long-term follow-up in a large group of adults free of CVD at baseline to estimate risk of incident CVD and associated CVD morbidity (unhealthy years lived with CVD). While we do observe evidence of the well-described overweight and obesity paradox, in which heavier individuals appear to live longer on average after diagnosis of CVD compared with individuals with normal BMI, our data when following up individuals prior to the onset of CVD indicate that this occurs because of a trend toward earlier onset of disease in individuals who are overweight and obese. This false reassurance is akin to the phenomenon of lead-time bias observed in other situations, such as with cancer screening.

The "free radical theory of aging" - where is that theory at now?

It's dead. Well, let's be a bit more precise. The free radical theory of aging dates back to the 1950s, and then there were decades of research on it, which was all very good research scientifically speaking, but it was always in artificial settings with high doses of free radicals that never occur in real life. In real life, in healthy model organisms or humans, free radicals occur in very low doses, and they have very different functions from high doses of free radicals, where they serve as signaling molecules that increase our body's defense mechanisms against external stressors. So in the 1990s, evidence emerged that small doses of free radicals serve as signaling molecules in cells. Around 2006 or 2007 we showed that in C. elegans that we could increase free radical production and that would make the worm live longer.

If normal amounts of free radicals aren't harmful, what's the story with antioxidants?

Well, this was an important issue we looked at a bit later in 2009. It's also well known that exercise produces free radicals, which was already surprising because exercise is probably the most healthy intervention a person can use, and that conundrum lead us to the hypothesis that the increase in free radicals would explain the health-promoting effects of exercise. And we tested this by seeing whether the antioxidant supplementation would kill the effects of exercise in humans, and that was exactly the case - the guys who got the placebo showed the expected effects of exercise on metabolism, and the guys who got the antioxidants had almost none of the effects.

About six or seven years later, another group had even more data available from the public domain, and they found that antioxidants increase all mortality. Meanwhile, experimental groups have shown that antioxidant supplementation in mice increases cancer and metastasis rates. The evidence out there is very straightforward and very bad for the antioxidant industry, but it's widely ignored. Consumption has not decreased for years, but at least it's not increasing.

So we've discussed this effect called hormesis, where substances that are toxic at high doses can actually be helpful in low doses. There's a related word that pops up a lot in your research, "mitohormesis" - what is that?

It's an abbreviation of mitochondrial hormesis, and it essentially translates this hormesis principle, which normally applies to compounds and drugs, to whatever comes out the mitochondria. So mitochondria send out signals that promote health and lifespan at low doses, and at higher doses these signals do the opposite. The most well-established signal from the mitochondria is reactive oxygen species (ROS), but there are also other signals.

Does free radical production become a problem as mitochondria get older and start producing more free radicals?

While older mitochondria do produce more free radicals, it's unclear whether that really accelerates aging. I think it does at very high, artificial doses. For example, one very artificial mouse model showed that mice with a mutation in their mitochondria aged horribly. For human examples, you can look at the hundreds of mitochondrial diseases that cause premature aging and increased cancer and so on, but again, these are very rare. There wasn't much evidence about the effect of mitochondrial ROS production on normal aging until recently. A paper looked at naturally occurring mutations in mice and compared their lifespans, and, contrary to their expectations, they found that the mice producing more ROS lived longer than the mice producing less ROS. And these mice were otherwise genetically identical. So I think that fits in well with the results we've seen with exercise.

You're a big proponent of a particular intervention that plays off of mitohormesis to increase lifespan - glucosamine.

Back in 2007 when we showed that increased ROS extends lifespan in C. elegans, we used a compound that completely blocks glucose metabolism, deoxyglucose. Since the cell can't metabolize glucose anymore, it enters an energy deficit similar to starvation, and responds by switching on its mitochondria. It turned out to be toxic in mice. Then a student in my lab said, "Why don't we use glucosamine?" Glucosamine only slightly inhibits glucose metabolism (glycolysis), and it's known to be completely harmless to humans. It's like the cell being on a diet: it still activates its mitochondria, still produces a bit more ROS, but not to the excessive level that it would with deoxyglucose. We took two year old mice, which is equivalent to something like 55 or 60 in humans, and gave them glucosamine, which caused both males and females to live longer. The effect was stronger in females, but it was independently detectable in both sexes.

Do you think there will be a trial for glucosamine akin to the TAME trial for metformin?

There should be. I think it's long overdue. It's an ideal supplement because it's cheap, there's no intellectual property attached to it, and it could improve healthspan significantly at almost no cost. The return on investment for both insurers and individuals would be significant. The evidence for glucosamine in C. elegans and mice is about the same as for metformin.

Are there compounds besides glucosamine that you find promising as geroprotectors?

Both my lab and others have been working on lithium, which is found in drinking water, and we've both seen it extend lifespan in C. elegans. Then we did a study with some Japanese colleagues who had data on lithium concentrations in drinking water all over Japan, and they worked out that areas with more lithium in the drinking water lived longer on average, so there was a positive correlation between lithium concentration and lifespan. And then another study from Texas came out a month or two ago saying the same thing, so there's several lines of very independent evidence that all points in the same direction. So that could have a pretty direct impact on supplementation. Low-dose lithium is something people could start to think about incorporating.

And can you tell us what motivates your research?

Well, first of all, I always like to question established concepts. That's probably the most driving source, especially when it's evident that something is wrong and no one is discussing it - like the common wisdom around reactive oxygen species, for instance. So that's one side of things. The other is that I'd ideally like to work on something that impacts quality of life for humans. That's quite distant from questioning fundamental concepts, but on certain occasions they come together - for instance, questioning antioxidants, or finding safe, easily available compounds like glucosamine that could make a huge difference. Of course, there's also increasingly good evidence that preventing age-related diseases while people are still healthy is so much smarter than treating existing diseases later on, and that's a very unique win/win situation. It's one of the rare cases where tremendous increases in individual quality of life and decreases in socioeconomic costs coincide, because normally it's either one or the other. And so I think it's almost mandatory to work on something like that.

What are the biggest challenges you see ahead?

In Western medicine nowadays, you only start taking care of health once it's gone, and I think that approach is totally wrong. That perception will have to change. Instead we need to prevent diseases from occurring in the first place, and people can do that by eating healthily, and exercising, and so on. And individuals are willing to take care of that - but only to a limited extent. We could make the success rate much higher if we came up with a drug or combination that mimicked certain aspects of healthy lifestyle, rather than requesting that everyone follow all of these rules their whole lives. Because the majority of us are simply not willing or capable of following them at all times, and I think that's just human nature. I'm not endorsing it, but I think it's a matter of fact.

During aging, bone homeostasis is interrupted with the chaos of the marrow microenvironment, including a disrupted hematopoietic stem cell (HSC) niche, decreased vessel formation and abnormal inflammation factor release. As a result, increased cellular senescence in bone marrow can be induced by cellular damage or environment changes. It is reported that senescent cells (SnCs) accumulate in bone marrow with aging and contribute to age-related pathologies through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Although cell senescence has been well studied in recent decades, the mechanisms and local treatment targets for SnCs-induced bone degenerative disease are not well understood.

Mesenchymal stromal cells (MSCs), including mesenchymal stem/progenitor cells (MSPCs), play an essential role in bone metabolism and HSC maintenance. MSC senescence during aging markedly impairs the HSC niche, decreases osteoblast numbers and disrupts epithelial-mesenchymal transition. LepR+ cells in bone marrow were a major source of MSPCs in adult and formed bone, cartilage, and adipocytes in culture and upon transplantation. Additionally, LepR+ cells are essential for maintaining the HSC niche. However, little is known about whether LepR+ cells are senescent and dysfunctional during aging.

Tetramethylpyrazine (TMP), the bioactive component extracted from Ligusticum wallichii Franchat (Chuanxiong) which is widely used for the treatment of ischaemic stroke, cerebral infarction, and degenerative diseases of the central nervous system, has been reported to have anti-inflammatory and anticancer effects in certain cell types. In this study, we aimed to investigate the local effect of TMP on the bone marrow of aging mice and to determine whether the senescent phenotype of MSCs could be eliminated. Our findings revealed that local delivery of TMP eliminates the senescent phenotype of LepR+ MSCs via epigenetically modulating . Moreover, TMP maintains the HSCs niche and creates an anti-inflammatory and angiogenic environment in aging mice.

Senescent cell (SnC) accumulation in bone marrow with aging leads to aging-related pathologies, and local ablation of SnCs attenuates several pathologic processes and extends a healthy lifespan. In this study, we found that senescent LepR+ MSPCs accumulated in the bone marrow of aging mice with bone degeneration and that local delivery of TMP in bone marrow inhibited LepR+ MSPC senescence. In this study, we just began to understand that local elimination of senescent MSPCs in bone marrow is critical to aging-related bone degenerative change and microenvironment disruption. Identification of the local treatment for cellular senescence and the underlying mechanism of the crosstalk between SnCs and niche cells in maintaining whole bone homeostasis remain interesting for further investigation, which will provide insight into extensive clinical studies in use of local treatment for bone degenerative and regenerative applications.

Bone loss is one of the most common comorbidities of patients with rheumatoid arthritis (RA). Depending on the population studied, 10-56% of RA patients suffer from osteoporosis. In healthy individuals, bone homeostasis is maintained by a balance between bone formation and bone resorption. A link between inflammation and bone loss has been suggested for decades, and it was supported by in vitro observations and animal models showing enhanced bone resorption under the influence of pro-inflammatory cytokines. T-cells are one of the most important promoters of osteoclastogenesis, and the first evidence for the capacity of T-cells to cause bone loss was provided in 1999 by illustrating that T-cell-produced RANKL triggered osteoclastogenesis directly in a mouse model of arthritis. More recently, another study showed that T-cell-deficient mice were resistant to bone loss.

Premature immunosenescence including the accumulation of senescent CD4+ T-cells seems to be a hallmark feature of RA. Senescent T-cells are characterized by the loss of CD28, eroded telomeres, the lower content of T-cell receptor excision circles, the expression of pro-inflammatory molecules, and the gain of effector functions. Notably, senescent CD28- T-cell prevalence correlated with disease severity in RA. The role of immunosenescence in the context of osteoporosis, however, is elusive so far. The aim of this study was to investigate whether senescent CD4+28- T-cells are associated with early bone loss in RA patients.

We show that patients with systemic bone loss have a higher prevalence of circulating senescent CD4+CD28- T-cells than individuals with normal bone mineral density (BMD). RANKL is expressed at higher levels on senescent CD4+ T-cells compared to that on CD28+ T-cells, and its production can be stimulated with IL-15, a key cytokine in the pathogenesis of RA. Senescent CD4+ T-cells induce osteoclastogenesis more efficiently than CD28+ T-cells. Several studies demonstrated that T-cells are involved in the bone-remodeling system and that RANKL-expressing T-cells promote local and systemic osteoporosis. Besides, it has been demonstrated that senescent CD4+ T-cells were increased in patients with severe disease manifestations, and at the same time, these patients were at an increased risk of osteoporosis. These findings support our conclusion that senescent CD4+CD28- T-cells play an important role in the promotion of osteoporosis in RA as well as in non-RA individuals. Interestingly, we observed similar frequencies of CD4+CD28- T-cells in our RA and non-RA cohorts.

While a regenerative response is limited in the mammalian adult heart, it has been recently shown that the neonatal mammalian heart possesses a marked but transient capacity for regeneration after cardiac injury, including myocardial infarction. These findings evidence that the mammalian heart still retains a regenerative capacity and highlights the concept that the expression of distinct molecular switches (that activate or inhibit cellular mechanisms regulating tissue development and regeneration) vary during different stages of life, indicating that cardiac regeneration is an age-dependent process. Thus, understanding the mechanisms underpinning regeneration in the neonatal-infarcted heart is crucial to develop new treatments aimed at improving cardiovascular regeneration in the adult.

The present review summarizes the current knowledge on the pathways and factors that are known to determine cardiac regeneration in the neonatal-infarcted heart. In particular, we will focus on the effects of microRNA manipulation in regulating cardiomyocyte proliferation and regeneration, as well as on the role of the Hippo signaling pathway and Meis1 in the regenerative response of the neonatal-infarcted heart. We will also briefly comment on the role of macrophages in scar formation of the adult-infarcted heart or their contribution for scar-free regeneration of the neonatal mouse heart after myocardial infarction. Although additional research is needed in order to identify other factors that regulate cardiovascular regeneration, these pathways represent potential therapeutic targets for rejuvenation of aging hearts and for improving regeneration of the adult-infarcted heart.

LyGenesis, Inc. is an organ regeneration company enabling a patient's own lymph nodes to be used as bioreactors to regrow functioning ectopic organs. Our initial target organ for clinical development is liver regeneration, with a focus on helping patients with end stage liver disease (ESLD). Instead of one donor organ treating one patient, LyGenesis enables one donor organ to treat dozens of patients. Instead of major surgery, LyGenesis uses outpatient endoscopy for transplantation of donor cells, which grow and become a functioning ectopic organ.

A decade age, scientists in the field of ectopic transplantation research began a series of experiments that would form the foundation for LyGenesis. They discovered that hepatocytes (liver cells) transplanted into lymph nodes would not just survive, but thrive, organize and begin to function as miniature ectopic livers. The research confirms that it is possible to harness the body's lymph nodes as bioreactors for organ regeneration.

Strange as it might sound, it appears to work in mice, where the surrogate mini-livers made up for the missing function of a diseased liver. Tests in pigs have been encouraging, too, and now trials in humans could begin late in 2018 if the founders can raise about 10 million for their startup, LyGenesis.

Age is the greatest risk factor not only for the probability of death, but also for the majority of morbidities associated with mortality. However, studies to identify factors that alter patterns of aging using animal models have focused on lifespan and age-specific mortality, rather than the underlying patterns of morbidity that lead to death. This gap is due in part to the difficulty of measuring causes of mortality in the standard animal models in aging studies. For example, age-related morbidity and causes of mortality in the commonly studied models of aging range from the not well understood (and often not studied) in mice, to the poorly understood in flies and worms, to nonexistent in yeast.

In addition, many diseases important to human aging (e.g., cardiovascular disease and dementia) do not develop spontaneously in our commonly studied model organisms. To this end, we need a model organism that allows us to understand not only age-related mortality, but also age-related morbidity and causes of death. The companion dog (i.e., dogs that reside under their owner's care) has the potential to fill this gap and to enable us to better understand the genetic and environmental factors that affect lifespan, and the underlying forces that shape age-specific morbidity and mortality.

Over the last 200 years, individual dog breeds have been highly inbred, with the result that genetic variation is relatively limited within breeds, but considerable among breeds. Thanks in large part to this history of intense breeding for specific morphological and behavioral traits, dogs are the most phenotypically diverse mammalian species on the planet. This diversity is found not only in morphology and behavior, but also in life-history traits, where across breeds, dogs exhibit an almost twofold difference in average longevity and enormous variation in risk of specific diseases.

Dogs also have a sophisticated veterinary healthcare system, second only to that of humans, allowing clinicians to diagnose and treat specific diseases, and to identify exact causes of death. For example, unlike mice, companion dogs experience a diversity of spontaneously occurring diseases similar to those of humans, such as age-related neurologic disease, renal disease, endocrine disease, and also experience obesity and its attendant risks. These phenomena allow researchers not only to study the pathologies that influence mortality, but also to understand different comorbidities and multiple chronic conditions that canines exhibit.

Surprisingly, while we know a great deal about the age-specificity of human morbidity, substantially less is known about the degree to which other species, including dogs, show similar disease-specific patterns of aging. Such comparisons are critical in our efforts to develop powerful models to identify the genetic and environmental determinants of morbidity and mortality. Here, we present a comparative analysis of causes of mortality in both humans and companion dogs. We determine the extent to which the companion dog may provide an excellent model of human aging and the degree to which causes of mortality correlate between the two species. Our results lay the groundwork for future use of the domestic dog as a model of human aging and longevity.

The rate of aging differs among individuals due to variations in the genetic and environment background. Chronological age, which is simply calculated according to birth date, is an imprecise measure of biological aging. The disconnection between chronological age and lifespan has led to a search for effective and validated biomarkers of aging. A good aging biomarker should be based on mechanisms described by major theories of aging, which mainly include oxidative stress, protein glycation, DNA methylation, inflammation, cellular senescence and hormonal deregulation. The current consensus is that aging is driven by the lifelong gradual accumulation of a broad variety of molecular faults in the cells and tissues.

Any error occurring on a DNA template or in messenger RNA will eventually lead to the production of abnormal proteins. However, the exposure of a double-stranded DNA chain or single-stranded RNA chain to free radicals, which are by-products of normal metabolism, can cause oxidative damage to biomolecules. 8-Oxo-7,8-dihydro-2′-deoxyguanine (8-oxodGsn) is by far the most studied DNA oxidative product. Similarly, mismatch of 8-oxo-7,8-dihydroguanine (8-oxoGsn) in RNA leads to transcriptional errors and produces abnormal protein. These excision products can be transported across the cell membranes and excreted into cerebrospinal fluid, plasma, and urine without any further metabolism.

Under the free radical theory of aging, urinary 8-oxodGsn and 8-oxoGsn are molecules that may reflect the oxidative state of the whole body rather than a specific organ, and these are promising biomarkers of aging. We previously established a liquid chromatography-mass spectrometry system and determined the oxidized nucleosides in senescence-acceleration-resistant mouse 1 (SAMR1), demonstrating that the measurement of 8-oxoGsn in urine had potential as a novel means of evaluating the aging process. In the present study, we applied this procedure to human urine samples to see if such samples can be used to estimate the physiologic age.

We have taken a keen interest in the relationship between oxidation markers and age. Most previous studies have reported a rise in the urinary 8-oxodGsn level with age. Our previous study showed an age-dependent increase in the two biomarkers in mice, rats and monkeys. In the present study, the same trend was noted in humans. Compared with other studies, the current studies covered larger range of ages, from neonates to 90-year-olds. The lowest 8-oxodGsn and 8-oxoGsn levels appeared in the young adults (11-30 years of age). As people age, the antioxidant defense systems degenerate, and the levels of 8-oxodGsn and 8-oxoGsn increase gradually until the end of life.

To date, most studies have dealt with urinary 8-oxodGsn, and a very limited number of studies have focused on 8-oxoGsn. Our study demonstrated that 8-oxoGsn is a better aging marker than 8-oxodGsn in two respects. First, the level of 8-oxoGsn was higher (approximately 2-fold) than 8-oxodGsn in age-matched counterparts. Second and more importantly, the levels of 8-oxoGsn correlated better with the rate of aging. The 8-oxoGsn content does not always correlate with chronological aging but instead reflects the actual physiological stage of aging.

People with naturally occurring mutations that cause a loss of function in the gene for ANGPTL3 have reduced blood triglycerides, LDL cholesterol, and risk of coronary heart disease, with no apparent detrimental consequences to their health. This makes the ANGPTL3 protein an attractive target for new heart disease drugs. Earlier studies found that single copies of inactivating mutations in ANGPTL3 are found in about one in every 250 people of European heritage; however, people with mutations in both copies of the gene are more rare.

Researchers assessed in a mouse model whether base editing - a variation of CRISPR genome editing that does not require breaks in the double-strand of DNA - might be used in humans one day to introduce mutations into ANGPTL3 to reduce blood lipid levels. The study took a three-part approach. First, the team injected normal mice with the base-editing treatment for the ANGPTL3 gene. After a week, sequencing of the ANGPTL3 target site in liver samples from the mice revealed a median 35 percent editing rate in the target gene and no off-target mutations. In addition, the mean levels of blood lipids were significantly lower in the treated mice by up to 30 percent compared to untreated mice.

Second, the researchers compared mice with the modified ANGPTL3 gene to those injected with a base-editing treatment for another liver gene, PCSK9, for plasma cholesterol and triglycerides. After a week, ANGPTL3 targeting caused a similar reduction in cholesterol but a much greater decline in triglycerides compared to targeting PCSK9. The PCSK9 protein is the target of currently available medications, including evinacumab, which has been shown to reduce cholesterol (but not triglycerides) as well as the risk of heart attack and stroke.

Third, they looked at how base editing of the ANGPTL3 gene performed in a mouse model of homozygous familial hypercholesterolemia (in which knocking out PCSK9 had little effect). After two weeks, the treated mice showed substantially reduced triglycerides (56 percent) and cholesterol (51 percent) compared to untreated mice. The researchers are now preparing to test CRISPR-based treatments against the human ANGPTL3 gene in human liver cells transplanted into mice. This will provide important information on efficacy and safety that will be needed before human trials can move forward.

Everyone knows that freezing things is an imperfect process. Take frozen food, for example - most have experienced those frozen ice crystals that change the texture and taste of their favourite meal. The medical field experiences a similar problem when freezing cells (stem cells) and tissues, except the result is cellular death or lower quality. Two investigators founded a startup company, PanTHERA CryoSolutions, to commercialize a revolutionary product for the cryopreservation, or freezing, of cells and tissues, resulting in better quality cells for cellular therapies and superior products.

"Cryopreservation is a common strategy, but the technology that was developed to do it is 70 to 80 years old. With current technology, when you freeze something, you get a large amount of cell death that occurs, so you don't recover all those cells. In addition, we're actually adversely affecting the functional capacity of those cells." The process that causes the majority of this cellular damage and death is called ice recrystallization. PanTHERA CryoSolutions has discovered a small molecule inhibitor that prevents ice recrystallization - something that none of the current cryoprotectants available on the market can do - making it a unique technology. "Our technology uses small molecular structures that have the ability to inhibit the ice recrystallization process. They actually prevent that damage from occurring, so when we thaw that product, it's a superior product and it's also functional."

The proof of concept for this technology was established with a project that looked at hematopoietic stem cells. "The results have clearly indicated that this ice recrystallization inhibitor technology really works and makes a superior product where we get faster engraftment and increased incidence of engraftment, which is exactly what you want in a clinical setting." PanTHERA CryoSolutions aims to have a product commercially available in 2018 for a specific therapy, but the founders see the potential to apply this technology to many areas, including cellular therapies, regenerative medicine, reproductive biology, and 3-D bioprinting applications.

Typical human cells are mortal and cannot forever renew themselves. As demonstrated a half-century ago, human cells have a limited replicative lifespan, with older cells reaching this limit sooner than younger cells. This "Hayflick limit" of cellular lifespan is directly related to the number of unique DNA repeats found at the ends of the genetic material-bearing chromosomes. These DNA repeats are part of the protective capping structures, termed "telomeres," which safeguard the ends of chromosomes from unwanted and unwarranted DNA rearrangements that destabilize the genome. Each time the cell divides, the telomeric DNA shrinks and will eventually fail to secure the chromosome ends. This continuous reduction of telomere length functions as a "molecular clock" that counts down to the end of cell growth. The diminished ability for cells to grow is strongly associated with the aging process, with the reduced cell population directly contributing to weakness, illness, and organ failure.

Telomerase lengthens telomeres by repeatedly synthesizing very short DNA repeats of six nucleotides - the building blocks of DNA - with the sequence "GGTTAG" onto the chromosome ends from an RNA template located within the enzyme itself. However, the activity of the telomerase enzyme is insufficient to completely restore the lost telomeric DNA repeats. Understanding the regulation and limitation of the telomerase enzyme holds the promise of reversing telomere shortening and cellular aging with the potential to extend human lifespan and improve the health and wellness of elderly individuals. Researchers recently uncovered a crucial step in the telomerase catalytic cycle that limits the ability of telomerase to synthesize telomeric DNA repeats onto chromosome ends. "Telomerase has a built-in braking system to ensure precise synthesis of correct telomeric DNA repeats. This safe-guarding brake, however, also limits the overall activity of the telomerase enzyme. Finding a way to properly release the brakes on the telomerase enzyme has the potential to restore the lost telomere length of adult stem cells."

This intrinsic brake of telomerase refers to a pause signal, encoded within the RNA template of telomerase itself, for the enzyme to stop DNA synthesis at the end of the sequence 'GGTTAG'. When telomerase restarts DNA synthesis for the next DNA repeat, this pause signal is still active and limits DNA synthesis. Moreover, the revelation of the braking system finally solves the decades-old mystery of why a single, specific nucleotide stimulates telomerase activity. By specifically targeting the pause signal that prevents restarting DNA repeat synthesis, telomerase enzymatic function can be supercharged to better stave off telomere length reduction, with the potential to restore the activity of aging human adult stem cells.

In the embryo, human heart cells can divide and multiply, allowing the heart to grow and develop. The problem is that, right after birth, cardiomyocytes (heart muscle cells) lose their ability to divide. The same is true for many other human cells, including those of the brain, spinal cord, and pancreas. "If we could find a way to get these cells to divide again, we could regenerate a number of tissues." For decades, the scientific community has been trying to do just that, with limited success. Until now, attempts have been ineffective and poorly reproducible.

Researchers have now developed the first efficient and stable method to make adult cardiomyocytes divide and repair hearts damaged by heart attacks, at least in animal models. The team identified four genes involved in controlling the cycle of cell division, these being cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1. They found that when combined - and only when combined - these genes cause mature cardiomyocytes to re-enter the cell cycle. This results in the cells dividing and rapidly reproducing.

The scientists tested their technique in animal models and cardiomyocytes derived from human stem cells. They used a rigorous approach to track whether the adult cells were truly dividing in the heart by genetically marking newly divided cells with a specific color that could be easily monitored. They demonstrated that 15-20 percent of the cardiomyocytes were able to divide and stay alive due to the four-gene cocktail. "This represents a considerable increase in efficiency and reliability when compared to previous studies that could only cause up to 1 percent of cells to divide."

To further simplify their technique, the team looked for ways to reduce the number of genes needed for cell division while maintaining efficiency. They found they could achieve the same results by replacing two of the four genes with two drug-like molecules. The researchers believe that their technique could also be used to coax other types of adult cells to divide again, given that the four genes they used are not unique to the heart.

Brain tissue from people with Alzheimer's disease shows clumping of two types of proteins. One, amyloid beta, accumulates outside of brain cells; the other, called tau protein, collects within the cells. Both of these toxic proteins are thought to cause the brain cell death seen in Alzheimer's. Recent research suggests that these proteins accumulate because of a defect in the system that ferries proteins within the cell. The proteins are shipped in membrane-bound packages, called endosomes. The system that shuttles them around the cell is the endosomal network. For proteins to be properly processed, eliminated or recycled, this system must function correctly.

Researchers used human brain cells created from stem cells to investigate whether enhancing the function of the endosomal network, in a laboratory setting, would affect amyloid beta and tau protein in these human cells. The scientists tested a compound that had been shown in animal studies to stabilize and boost the function of a protein assembly called the retromer. The retromer is a key player in directing how the endosomal "packages" are shuttled about in the endosomal network to be delivered to the right destination.

The researchers found that the compound, called R33, did enhance the function of the retromer. This led to considerable reduction in the production of both the amyloid beta and the form of tau protein that readily aggregates, phosphorylated tau. The findings suggest that targeting defects in the endosomal network, through the discovery of drugs or other therapeutics, such as gene therapy, may be a promising strategy against Alzheimer's disease. "This also suggests that something upstream is affecting the production of amyloid beta and phosphorylated tau independently. So one thing we're going to work on going forward will be to identify what this upstream defect might be and whether it, too, could be a target for new therapeutics to treat Alzheimer's."