Fight Aging! Newsletter, May 13th 2019

Repair Biotechnologies, Inc. announced today 2.15 million in seed venture funding, to accelerate the preclinical development of its pipeline of drugs targeting thymus regeneration, cancer, and atherosclerosis. The 2.15 million in funding was led by Jim Mellon, the billionaire investor and chairman of Juvenescence Ltd. Also participating in the round are Emerging Longevity Ventures, Thynk Capital, and SENS Research Foundation.

"We are committed to developing treatments for the root causes of aging and its associated diseases through the damage repair approach," said Reason, co-founder and CEO. "With this funding round, we will be able to further develop our therapies and validate them in animal models, bringing them closer to the clinic and patients."

The thymus gland is vital to the adaptive immune system, but with age, the thymus shrinks, leading to a decreased immune cell production and a compromised immune system. Repair Biotechnologies is developing a therapy with the aim of reverting this atrophy of the thymus, which the company believes can be an effective treatment against some forms of cancer. Repair Biotechnologies' second major project relates to atherosclerosis, which is caused by the accumulation of intracellular waste in arteries. While present therapies focus on reducing cholesterol, Repair Biotechnologies has licensed a technology to make the macrophage cells responsible for repairing arteries resilient to excess cholesterol, and thus able to repair atherosclerotic damage.

"SENS Research Foundation was founded to push forward proof-of-concept work demonstrating the validity of the SENS paradigm to the point at which people can actually do something with it. Now we're seeing some of these technologies getting the recognition from investors that they deserve, which in turn is driving critical growth in the private-sector side of the field," said Aubrey de Grey, co-founder and Chief Science Officer of SENS Research Foundation. "I'm thrilled to see Repair Biotechnologies taking things in this area to the next level."

Could you start by introducing yourself?

Ok, so my name is Jim Mellon, and I'm the chairman of a relatively new company called Juvenescence Ltd. I've been in the biotech business for about 12 years, and I've done other stuff in my career history, including fund management, mining, and German property investment. We still have our German property investment, some in Berlin some around the rest of Germany. The main focus at the moment is on our company, which is engaged in longevity science investment, which is called Juvenescence.

What is your motivation for that?

There are three motivations. One is self-preservation, so in other words a selfish interest in living longer, as I like living. The second is that this is obviously something that is going to have a huge human impact for the positive, so this is the ultimate ESG investment, if you know what ESG is. The third thing is that obviously we are a commercial organization and we are looking to make returns for our shareholders, of which we are the largest.

How would you describe your work and your engagement in aging research?

We have three partners in our business, and fifteen employees at the moment. The company started a year and a bit ago. We've raised about 160 million for our company, and we put in 35 million ourselves, of our own money. So it is quite well funded, and we've invested in 18 projects so far, ranging from small molecules, which is the specialization of our team, to stem cells, where as you may or may not know we own 46% of AgeX Therapeutics, which has been presenting here at this conference, and Aubrey de Grey is a senior vice president here, to organ regeneration. Our first product to go into a sick patient will be in the first quarter of next year, with a company called Lygenesis, which is working on liver regeneration.

So basically we are triaging investments with our team to find the most appropriate investments, to both advance science and get commercial products into the market, and we're doing that as quickly as we can, given that this is a relatively early stage science from the commercial point of view. We expect our company to list on the New York Stock Exchange, on the NASDAQ, in early 2020. So we're moving very, very quickly in this field.

What would you say to people in Germany who are indifferent to the whole aging research thing, and don't know much about it?

Well that is a great question, who would not want to live, in a healthy condition, for longer, even if it is only five or ten years? That is now possible. So for the first time in human history it is possible to bioengineer humans to get that effect. All of the increases in life expectancy up to this point, as you know, have been due to environmental improvements. Now, for the first time, with the unveiling of the human genome, the discovery of pathways, the use of animal models to manipulate those pathways, demonstrates that, for sure, something is going to work in prolonging human healthspan. We don't know exactly what yet, but there are some human trials underway at the moment, so that gives us great optimism. We are very lucky to be the first cohort ever on the planet to have that indulgence, that we may be able to live longer and in a healthier condition.

We recognized that fairly early on. Most people, as you rightly point out, are indifferent to it, or don't believe it. We certainly do believe it, and our history is a good one in biotech. We've set up a number of biotech companies. One is already listed on the New York Stock Exchange. It is about a 3 billion market capitalization. We set up that company four years ago, and it has a cure for migraine, which will be on the market in America next year. We can demonstrate that we can deliver new drugs and new therapies to human beings, and now we're going to do that in the longevity space. So we're very excited and very, very focused on that.

You need lots of money for that of course, and what the German Party for Health Research wants is much more money for research and development from the government. How much are we talking about? What would you recommend?

I don't think there is any upper limit to the amount that could be usefully deployed. Obviously governments are cash constrained, so it is not just governments but individuals, corporations, and so forth that should get on to this bandwagon. We're in the dial-up phase of the internet in the early 1980s. We're in the very early stage of this industry. We're at the front end of a huge investment curve. Money will start coming in: Samumed has raised a great deal of funding, Calico has a great deal of funding from Google and Abbvie. We've raised quite a large amount of funding, and there are other companies such as Unity Biotechnology and resTORbio that have raised funds.

But this is just the beginning of what will be an enormous amount of funding coming in. The UK government - I'm a British citizen - has devoted 300 million to this area under the auspices of Oxford University and John Bell. The German government should do the same. Governments across Europe should do the same, so that this is not just an Americn science, not just something that belongs to California or to Texas. It needs to be a universal science. So I fully endorse the aims and motivations of your party and I wish you very well in the forthcoming elections.

Let's go 20 years into the future: how do you want an 80 year old living in 20 years?

Well my father just turned 90 as an example, and he is in robust health. I want him to benefit from metformin and rapamycin and the coming therapies, and to maintain his healthy life span until at least 120. From a personal motivational point of view, I would like him to be as healthy as he is today, for a fairly advanced stage, in 20 or 30 years. I believe it to be possible. Just to show you how dedicated we are to maintaining him in good health, and others like him, we are having his 90th birthday party in Ibiza, which is not normally associated with raves for old people. Well, that's where we are having the party!

Bioengineers have cleared a major hurdle on the path to 3D printing replacement organs with a breakthrough technique for bioprinting tissues. The new innovation allows scientists to create exquisitely entangled vascular networks that mimic the body's natural passageways for blood, air, lymph and other vital fluids. "One of the biggest road blocks to generating functional tissue replacements has been our inability to print the complex vasculature that can supply nutrients to densely populated tissues. Further, our organs actually contain independent vascular networks - like the airways and blood vessels of the lung or the bile ducts and blood vessels in the liver. These interpenetrating networks are physically and biochemically entangled, and the architecture itself is intimately related to tissue function. Ours is the first bioprinting technology that addresses the challenge of multivascularization in a direct and comprehensive way."

Layers are printed from a liquid pre-hydrogel solution that becomes a solid when exposed to blue light. A digital light processing projector shines light from below, displaying sequential 2D slices of the structure at high resolution, with pixel sizes ranging from 10-50 microns. With each layer solidified in turn, an overhead arm raises the growing 3D gel just enough to expose liquid to the next image from the projector. The key insight was the addition of food dyes that absorb blue light. These photoabsorbers confine the solidification to a very fine layer. In this way, the system can produce soft, water-based, biocompatible gels with intricate internal architecture in a matter of minutes.

Tests of the lung-mimicking structure showed that the tissues were sturdy enough to avoid bursting during blood flow and pulsatile "breathing," a rhythmic intake and outflow of air that simulated the pressures and frequencies of human breathing. Tests found that red blood cells could take up oxygen as they flowed through a network of blood vessels surrounding the "breathing" air sac. This movement of oxygen is similar to the gas exchange that occurs in the lung's alveolar air sacs.

Solid organs transport fluids through distinct vascular networks that are biophysically and biochemically entangled, creating complex three-dimensional (3D) transport regimes that have remained difficult to produce and study. We establish intravascular and multivascular design freedoms with photopolymerizable hydrogels by using food dye additives as biocompatible yet potent photoabsorbers for projection stereolithography. We demonstrate monolithic transparent hydrogels, produced in minutes, comprising efficient intravascular 3D fluid mixers and functional bicuspid valves. We further elaborate entangled vascular networks from space-filling mathematical topologies and explore the oxygenation and flow of human red blood cells during tidal ventilation and distension of a proximate airway. In addition, we deploy structured biodegradable hydrogel carriers in a rodent model of chronic liver injury to highlight the potential translational utility of this materials innovation.

Elderly individuals are at increased risk to develop infections, which results in significant morbidity and mortality, accounting for 9% of deaths in elderly subjects. Attempts to reduce infection rates by employing vaccinations have only limited success due to the decline in immune system function. Efforts to improve vaccine efficacy by refining antigen delivery have also failed to provide the desirable immune protection. Hence, novel technologies that target the elderly patient immune system and enhance its responsiveness to vaccinations and pathogens, thereby overcoming the immunodeficiency associated with aging, are required.

Among the most promising interventions in recent years, with demonstrated rejuvenating capacity in mouse models, is the removal of "old" tissues or cells. Indeed, when applying this approach in the hematopoietic system, we have demonstrated that removal of "old" B cells reverses B-cell senescence through reactivation of B lymphopoiesis in the bone marrow (BM) of aged mice. Similar outcomes have also been reported for other tissues. Considering that senescence of the B lineage is reversible and subjected to homeostatic regulation, the current study tested whether this new paradigm can be translated to enhance immune response in elderly individuals that have been treated for B-cell malignancies by transient B-cell depletion.

We show here that B-cell depletion in both elderly mice and humans rejuvenates the peripheral B-cell compartments both phenotypically and functionally, through the induction of de novo B lymphopoiesis. However, we found that B-cell rejuvenation by itself is insufficient to significantly enhance responsiveness to vaccination in aged mice and humans and to prolong survival of old mice.

Our current findings suggest that B-cell recovery following depletion is not just a "recapturing" process, which returns B cells to the same stage they have been in before being exposed to depletion, but a rejuvenation process, in which the B-cell repertoire becomes younger both phenotypically and functionally, resulting from de novo B lymphopoiesis. This rejuvenation is observed in both aged experimental mice and in elderly humans. We proposed that B lymphopoiesis in aging is suppressed by the accumulated antigen-experienced B cells in the periphery.

These findings suggest that the in vivo immune response evoked post-B-cell depletion, at least to these stimuli, may still be suboptimal, due to concurrent, age-related impairments in other essential components of immunity. Indeed, age-related defects have been reported in T lymphocytes, dendritic cells, monocytes, and NK cells. Thus, although B-cell depletion provides a proof of principle for a rejuvenation approach in the immune system, it is insufficient to completely restore immune competence, since all other essential counterparts of cellular immunity are still "old".

Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD+ metabolism influences both tissue ageing and cancer. However, the role of NAD+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest.

NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA-NAMPT-NAD+ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD+ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.

Alzheimer's is the most common form of dementia, which is the loss of cognitive functions - thinking, remembering, and reasoning - and everyday behavioral abilities. In the past, Alzheimer's and dementia were often considered to be the same. Now there is rising appreciation that a variety of diseases and disease processes contribute to dementia. Each of these diseases appear differently when a brain sample is examined at autopsy. However, it has been increasingly clear that in advanced age, a large number of people had symptoms of dementia without the telltale signs in their brain at autopsy. Emerging research seems to indicate that the protein TDP-43 - though not a stand-alone explanation - contributes to that phenomenon.

TDP-43 (transactive response DNA binding protein of 43 kDa) is a protein that normally helps to regulate gene expression in the brain and other tissues. Prior studies found that unusually misfolded TDP-43 has a causative role in most cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. However, these are relatively uncommon diseases. A significant new development seen in recent research is that misfolded TDP-43 protein is very common in older adults. Roughly 25 percent of individuals over 85 years of age have enough misfolded TDP-43 protein to affect their memory and/or thinking abilities.

TDP-43 pathology is also commonly associated with hippocampal sclerosis, the severe shrinkage of the hippocampal region of the brain - the part of the brain that deals with learning and memory. Hippocampal sclerosis and its clinical symptoms of cognitive impairment can be very similar to the effects of Alzheimer's. "Recent research and clinical trials in Alzheimer's disease have taught us two things: First, not all of the people we thought had Alzheimer's have it; second, it is very important to understand the other contributors to dementia." Scientists have now described the newly-named pathway to dementia as Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE.

LATE is an under-recognized condition with a very large impact on public health. Researchers emphasized that the "oldest-old" are at greatest risk and, importantly, they believe that the public health impact of LATE is at least as large as Alzheimer's in this group. The clinical and neurocognitive features of LATE affect multiple areas of cognition, ultimately impairing activities of daily life. Additionally, based on existing research, the authors suggested that LATE progresses more gradually than Alzheimer's. However, LATE combined with Alzheimer's - which is common for these two highly prevalent brain diseases - appears to cause a more rapid decline than either would alone.

The most common cause of age-related dementia, Alzheimer's disease is marked by the aggregation of amyloid proteins, which can kill off surrounding neurons. The areas of amyloid accumulation and associated nerve cell death, called plaques, are a hallmark of the disease. Researchers found that a specific brain cell type, called oligodendrocyte progenitor cells, appears in high numbers near plaques. In a healthy brain, oligodendrocyte progenitor cells develop into cells that support nerve cells, wrapping them in a protective layer that heals injury and removes waste. The environment created by the amyloid proteins causes these progenitors to stop dividing and conducting their normal functions. In diseases such as Alzheimer's, the oligodendrocytes instead send out inflammatory signals that contribute more damage to the surrounding brain tissue. "We believe the amyloid is damaging the neurons, and although the oligodendrocytes move in to repair them, for some reason the amyloid causes them to senesce rather than complete their job."

The researchers suspected that if they could selectively remove malfunctioning senescent oligodendrocyte progenitor cells, they could slow Alzheimer's disease progression. The researchers tested the concept in mice that were genetically engineered to have some of the characteristics of Alzheimer's disease, such as aggregated amyloid plaques. To remove the senescent cells, the researchers devised a treatment with a mixture of two FDA-approved drugs: dasatinib and quercetin. Dasatinib was originally developed as an anti-cancer drug, and quercetin is a compound found in many fruits and vegetables. The drug combination was proven as an effective way to eliminate senescent cells in previous studies of other diseases. The researchers administered the drugs to groups of the Alzheimer's mice for nine days, then examined sections of the mice's brains for signs of damage and the presence of senescent oligodendrocyte progenitor cells.

They report that the mice treated with the drugs had approximately the same amount of amyloid plaques as mice that received no treatment. However, the researchers say they found that the number of senescent cells present around these plaques was reduced by more than 90 percent in mice treated with the drug combination. They also found that the drugs caused the senescent oligodendrocyte progenitor cells to die off. Together, these results show that the dasatinib and quercetin treatment can effectively eliminate the burden of senescent oligodendrocyte progenitor cells.

The researchers next tested whether the physical benefits of the dasatinib and quercetin treatment could protect the mice against the cognitive decline associated with Alzheimer's disease. To do that, the researchers fed the genetically engineered mice the dasatinib and quercetin drug combination once weekly for 11 weeks, beginning when the mice were 3 1/2 months old. The researchers periodically evaluated the mice's cognitive function by observing how they navigated mazes. They found that after 11 weeks, control mice who got no drug treatment took twice as long to solve the maze as their counterparts treated with dasatinib and quercetin. After 11 weeks, the researchers again analyzed the brains of the mice and found 50 percent less inflammation in mice treated with dasatinib and quercetin, compared with nontreated mice. The researchers say these results show that eliminating senescent cells from the brains of affected mice protected cognitive function and reduced inflammation linked to Alzheimer's disease-like plaques.

Alzheimer's disease (AD) is characterized by typical biochemical lesions (β-amyloid peptide [Aβ] plaques and tau tangles) accompanied by extensive cellular changes (neuronal dystrophic alterations, neuronal cell loss, astrogliosis, and microgliosis). Rare mutations in amyloid precursor protein (APP), presenilin 1 and presenilin 2 trigger Aβ plaque accumulation and are sufficient to induce the full biochemical and morphological signature of AD. While this clearly indicates a major role for Aβ in AD pathology even in these genetic forms, a decades-long asymptomatic phase is present. Thus, in addition to Aβ plaques, other pathological processes, either in response to or in parallel to Aβ accumulation, need activation to cause neurodegenerative disease.

The search for the genetic risk determinants in sporadic AD has highlighted the central role of non-neuronal genes in pathways that do not appear directly related to Aβ metabolism. Most of the genes associated with the ∼40 loci identified by genome-wide association (GWA) analysis or by rare variant sequencing studies are expressed in glial cells. Moreover, analysis of available single-cell transcriptome datasets for human brain cells reported an association between AD GWA signals and microglia as well as astrocytes. Analysis of regulatory networks of genes differentially expressed in AD patients indicates that immune- and microglia-specific gene modules are key contributors to AD pathology.

Thus, genetic and molecular evidence suggest that Aβ accumulation is the trigger of a series of pathogenic processes in which microglia play a central role. No consistent hypothesis, however, links the causality implied by the mutations in the amyloid pathway genes to the genetic risk linking sporadic AD to inflammatory pathways. One possible resolution is that amyloid pathology acts only as a trigger in sporadic AD; i.e., Aβ accumulation is necessary but insufficient to cause full-blown disease. The cellular response, determined by the genetic makeup of the patients, tilts the table from a rather benign Aβ proteopathy to the severe neurodegeneration with inflammation and tau pathology that characterizes AD. In this regard, further understanding of the microglia response to amyloid pathology and the role of risk factors for AD in this response is key.

Here, we set out to address in a systematic way the question of how microglia respond over time, in cortex and hippocampus, to progressive Aβ deposition and whether this is affected by the three major risk factors for AD, i.e., age, sex, and genetics. We use an App knockin mouse model, which displays progressive amyloidosis and microgliosis. We show that the microglial responses to Aβ pathology are complex but, surprisingly, largely reproducible cell states that are also appearing during normal aging, albeit slower and quantitatively more limited. Moreover, we show that microglia in female mice tend to react earlier and in a more pronounced way than microglia in male mice, particularly in older mice. Interestingly, the major response of microglia to amyloid pathology is enriched for AD risk genes, with Apoe expression, in particular, becoming highly upregulated. This is partially confirmed in human tissue.

Increase in maximum lifespan (MLS) is the most significant indicator of hitting the basic mechanisms of aging, in particular, regarding age-related loss of stem cells and cell damage accumulation. In this study, a significant (30%) increase in maximum lifespan of mice was found after nonablative transplantation of 100 million nucleated bone marrow (BM) cells from young donors, initiated at the age that is equivalent to 75 years for humans. Moreover, rejuvenation was accompanied by a high degree of BM chimerism for the nonablative approach. Six months after the transplantation, 28% of recipients' BM cells were of donor origin. The relatively high chimerism efficiency that we found is most likely due to the advanced age of our recipients having a depleted BM pool.

In addition to the higher incorporation rates, there are more reasons why the nonablative setting is preferable for old recipients. These are lesser risks of infections and of graft-vs-host disease, threatening to ablated patients, while graft rejection by nonablated recipients is less probable in the elderly than at a younger age because of naturally weaker immune system in the elderly. Even in the absence of histocompatibility, when allogeneic BM was used in a nonablative experiment instead of syngeneic BM, no lifespan shortening of the experimental group was observed.

Obviously, at an old age the immune system is already too passive to reject donor BM, but it still efficiently suppresses infection and graft-vs.-host reaction, which makes it unnecessary and undesirable to use ablative conditioning in the elderly. On the bases of the above and our data, we advocate a more rapid implementation of nonablative stem cell transplantation into the clinic not only for pathology treatment, but also for rejuvenation.

The nucleolus has gained prominent attention in molecular research over the past two decades, due to its emerging role in various cellular processes. Among them, the production of ribosomes is seemingly the most important, as it controls translation of all proteins in the cell and thus governs cell growth and proliferation. A number of studies have demonstrated that the disruption of virtually any step in ribosome biogenesis can result in cell cycle arrest, primarily through activation of the tumor suppressor protein p53. This particular process was recently termed as the Impaired Ribosome Biogenesis Checkpoint (IRBC).

Numerous studies presented a direct connection between dysregulated ribosome biogenesis and aging. For instance, the downregulation of ribosome biogenesis components or nutrient sensing pathways, which stimulate ribosome production, have been shown to increase the lifespan of multiple organisms including C. elegans, D. melanogaster, yeast, mice, and human. Therefore, enhanced ribosome biogenesis, visualized by enlarged nucleoli, is believed to accelerate aging. Indeed, consistent with this idea, the size of the nucleoli and the amount of rRNA increases during aging in human primary fibroblasts and a single, large nucleolus is often observed in senescent cells. Furthermore, fibroblasts isolated from patients suffering from the premature aging disease Hutchinson-Gilford progeria, have enlarged nucleoli and upregulated ribosome biogenesis.

Since the rate of protein translation is proportional to the rate of ribosome biogenesis it was suggested that upregulation of protein synthesis and disruption of global proteostasis is the mechanism through which ribosome biogenesis promotes aging. This theory is supported by studies showing that reduction in the rate of translation can increase lifespan, and furthermore that altered proteostasis is a hallmark of aging. Additionally, caloric restriction that has been shown to promote longevity, leads to the downregulation of ribosome biogenesis by several mechanisms.

One of the processes hypothesized to underlie age-related functional decline in organ systems throughout the body is cellular senescence. This state of cell cycle arrest is believed to be irreversible under physiological conditions. In human skin, the prevalence of senescent cells is higher in aged individuals than in young. Previously, we observed that the number of skin cells positive for the cell cycle control protein p16INK4a, commonly accepted to be a marker of cellular senescence, was lower in offspring from long-living families and linked to cardiovascular disease. This suggests that skin aging occurs at a different pace in different individuals.

While the skin constitutes an important barrier, the immune system represents another organ system essential for protection against harmful environmental exposures throughout life. With age, several changes occur in the adaptive immune system, broadly termed immunosenescence. The number of naïve T cells decreases with age and differentiated memory, and effector T-cell numbers increase.

To study whether senescence occurs at the same pace in different organ systems, we studied 80 participants (aged 45-81 years) of the Leiden Longevity Study (LLS), assessing whether the amount of p16INK4a-positive cells in skin correlates with the amount of putatively immunosenescent T cells in blood. The mean age was 61 years, 48.8% were female, and half were seropositive for cytomegalovirus (CMV). Epidermal p16INK4a positivity was associated with neither CD4+ nor CD8+ T-cell immunosenescence phenotype composites, i.e., end-stage differentiated/senescent T cells. Dermal p16INK4a positivity was significantly associated with the CD4+, but not with the CD8+ immunosenescence composite. We therefore conclude that there is limited evidence for a link between skin senescence and immunosenescence within individuals.

Although the mammalian retina does not spontaneously regenerate, researchers have now found that it has a regenerative capacity that is kept dormant by a cellular mechanism called the Hippo pathway. The discovery opens the possibility of activating the retina's ability to restore lost vision by manipulating this pathway. Damage to the retina can lead to irreparable loss of vision in humans and other mammals because their retinas do not regenerate. However, other animals such as zebrafish can reverse blindness thanks to specialized cells in the retina called Müller glial cells. When the retina is damaged, Müller glial cells proliferate and differentiate into the lost retinal neurons, effectively replacing injured cells with fully functional ones.

Although Müller glial cells in injured mammalian retina do not restore vision as their counterpart in zebrafish do, other researchers have shown that, when the mammalian retina is injured, a small subset of Müller glial cells takes the first steps needed to enter the proliferation cycle, such as acquiring molecular markers scientists expect to see in a proliferating cell. This attempt to proliferate is transient; after acquiring some of the cell markers the cells shut off. These observations suggested that the mechanism that drives cell repair in zebrafish also might be present in mammals, but it is actively suppressed.

Searching for the proposed suppressing mechanism, researchers focused their attention on the Hippo pathway, a network of molecular events that contributes to organ growth during development and to the regulation of heart tissue regeneration in response to myocardial infarction. The researchers first determined that the Hippo pathway is expressed in mammalian Müller glial cells. Then, they investigated whether altering the Hippo pathway in these cells would affect their ability to proliferate. Creating a malfunctioning Hippo pathway by eliminating two of its molecular steps resulted in modest cell proliferation. And when the researchers genetically engineered Müller glial cells to carry a version of YAP that is impervious to the inhibitory influence of Hippo, the cells showed major proliferation and acquired a progenitor cell phenotype. Importantly, a small subset of these Müller glia-derived progenitor cells showed signs of spontaneous differentiation into new retinal neurons. "Our next step is to develop a strategy to guide proliferating Müller glial cells into differentiation pathways leading to retinal cells capable of restoring vision."

Scientists report that adult cells reprogrammed to become primitive stem cells, called induced pluripotent stem cells (iPSCs), make more extracellular vesicles than other kinds of adult stem cells commonly used for this purpose in research. Extracellular vesicles are naturally abundant in many types of cells, which use the cargo-containing spheres to communicate with other cells. They are about one one-hundredth the diameter of a cell and can carry anything from fats and proteins to nucleic acids. When a cell releases an extracellular vesicle, other cells nearby slurp up the tiny packet and its contents, making it an attractive target for packaging treatments for diseased cells that are deteriorating or aging prematurely.

To package a potential treatment in an extracellular vesicle, scientists typically use a cell called a mesenchymal stem cell, which is found among fat or bone marrow cells and gives rise to other fat and bone cells. Scientists genetically modify the stem cell to produce vesicles with the treatment-related cellular therapy - usually a protein. But mesenchymal stem cells aren't the best sources for extracellular vesicles. The cells don't multiply as often as iPSCs, and more cells are necessary to produce larger quantities of extracellular vesicles needed for therapeutic use. In addition, mesenchymal cells grow best in a liquid called fetal bovine serum, which contains potentially treatment-contaminating extracellular vesicles that are difficult to distinguish and separate from extracellular vesicles derived from mesenchymal cells.

By contrast, the liquid used to store and feed human iPSCs in the laboratory, called Essential 8, is free of extracellular vesicles and animal proteins, and scientists found the cells could produce 16 times more vesicles than mesenchymal stem cells. "We wanted to show other scientists working on such potential therapies that human iPSCs can efficiently produce highly purified extracellular vesicles that could, one day, be used to treat aging-related diseases."

Scientists have long studied leucine tRNA-synthetases, or LRS, for its role in protein synthesis. In the last 5-10 years, scientists have begun to realize that LRS and other proteins like it have functions independent of protein synthesis, such as regulation of cell growth. Researchers used mammalian cell cultures and mice in the new study. They compared the speed of muscle repair in mice with normal and lower-than-normal LRS levels. They discovered that mice with lower levels of LRS in their tissues recovered from muscle injury much more quickly than their counterparts with normal LRS levels. A 70% reduction of LRS proteins in the cell does not affect protein synthesis. "But lower levels do positively influence muscle regeneration. We saw that, seven days after injury, the repaired muscle cells are bigger when LRS is lower."

The researchers further unraveled the exact molecular mechanism by which LRS influences muscle regeneration. This led them to hypothesize that a nontoxic inhibitor would block the effect of LRS on muscle cells without interfering with its role in protein synthesis. The inhibitor was shown to work both in mammalian cells and in mice. Muscle repair occurred more rapidly - and the regenerated muscles were stronger - when the inhibitor was present. Researchers are now investigating the effect of LRS on older mice, which tend to rebuild their muscles more slowly and have less muscle tone than younger mice.