SENS Research Foundation (SRF) has launched a new research program focused on dysfunctional white blood cells in collaboration with the Buck Institute for Research on Aging. Judith Campisi, a leading global expert on aging and age-related diseases, will be running the project in her lab at the Buck. Various types of unwanted cells accumulate during aging and affect the function of many systems, including the immune system. Some of these cells are cleared by the immune system, but some are not, possibly leading to a vicious cycle of decline. It is therefore a priority to explore techniques for eliminating these cells and rejuvenating the body, by forcing the unwanted cells to "commit suicide", and/or by augmenting the cell-killing function of healthy immune cells.

"One of our major goals is to find treatments to augment the aging immune system's defenses against senescent cells. This collaboration with SRF will enable us to explore a range of hitherto neglected ways to do that. We are extremely proud to be partnering once again with Judith Campisi's lab and the Buck on this critical project." This research has been made possible through the generous support of the Forever Healthy Foundation and its founder Michael Greve, as well as the support of our other donors.

UNITY Biotechnology, Inc. announced today the publication of new research demonstrating that the selective elimination of senescent cells with a drug may delay, prevent, or even reverse the progression of osteoarthritis (OA), the age-associated inflammatory condition causing chronic joint pain in 80% of people over 65. Researchers found that senescent cells accumulate in the knees of mice, and that the selective elimination of these senescent cells using UBX0101 - UNITY's first-in-class senolytic molecule - slowed the progression of disease, reduced pain, and induced cartilage production in human knee tissue grown in culture.

"For decades, OA has been thought of as a chronic inflammatory disease. The big mystery in OA was where the inflammatory molecules were coming from. Our new work answers this question, at least in part. It appears that the inflammatory factors that drive OA are made by senescent cells. You eliminate senescent cells, and you stop OA. This is a unique approach to the treatment of osteoarthritis and if it can be translated into a therapeutic approach for human OA, it could result in a major change in the way we treat the disease."

Osteoarthritis was induced in both young and old mice by using a standard ACL transection (ACLT) model. The resulting mechanical instability of the joint drives the accumulation of senescent cells in the articular cartilage and synovial membranes of the knees. The senescent cells appear within weeks of ACL transection and symptoms of OA are evident at 30 days. A similar accumulation of senescent cells occurs naturally over time as mice age, resulting in cartilage destruction without any surgical intervention. In mice, elimination of senescent cells from 12 months onwards maintains youthful cartilage, even in animals as old as 28 months (equivalent to approximately 80 years old for people). Following clearance of senescent cells with UBX0101 in the ACLT model, both OA-related pain and cartilage erosion were reduced, and cartilage began to regenerate. In cartilage grown from human knees with advanced OA, UBX0101 selectively eliminated senescent cells, increased proliferation of healthy chondrocytes, and induced new cartilage growth.

Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown.

To test the idea that SnCs might play a causative role in OA, we used a transgenic mouse model that allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.

Researchers have identified a previously unrecognized step in stem cell-mediated muscle regeneration. The study provides new insights on the molecular mechanisms that impair muscle stem cells (MuSCs) during the age-associated decline in muscle function that typically occurs in geriatric individuals. It also provides further insight into the connection between accelerated MuSC aging and muscular dystrophies. "In adult skeletal muscle, the process of generating muscle - myogenesis - depends on activating MuSCs that are in a resting, or quiescent, state. As we age, our MuSCs transition to a permanently inactive state called senescence, from which they can't be 'woken up' to form new muscle fibers. If we could encourage senescent MuSCs to start replicating and advance through myogenesis - perhaps through pharmacological interventions - we may have a way to help build muscle in patients that need it."

The goal of the study was to define the molecular determinants that lead to irreversible MuSC senescence. Using a combination of a mouse model and human fibroblasts, the team found that the reason old MuSCs can't be activated to generate muscle cells is that they spontaneously activate a DNA damage response (DDR) even in the absence of exposure to exogenous genotoxic agents. This senescence-associated DDR chronically turns on the machinery needed to repair breaks and errors in DNA, and activate cell cycle checkpoints, which inhibit cells from dividing. "In our study, we found that the senescence-associated DDR prevents MuSCs from differentiating by disabling MyoD-mediated activation of the muscle gene program. We also learned that a prerequisite for activating the muscle gene program is progression into the cell cycle, a process that is irreversibly inhibited in senescent cells. We did identify experimental strategies to get senescent cells to move through the cell cycle and activate myogenesis, which is a promising result. However, we also discovered that enforcing old MuSCs to form new muscles might lead to the formation of myofibers with nuclear abnormalities resulting from genomic alterations generated during aging."

"Given the tremendous impact that decline in muscle function has on aging and lifespan, research that elucidates pathways and networks that contribute to the progressive impairment of MuSCs - such as that reported here - may lead to targeted pharmacological interventions that improve human health. However, the findings from this study should warn against overenthusiasm for strategies aimed at rejuvenating muscle of elderly individuals by enforcing the regeneration process, as they might carry a sort of trade-off at the expense of the genomic and possibly functional integrity of the newly formed muscles."

The molecular determinants of muscle progenitor impairment to regenerate aged muscles are currently unclear. We show that, in a mouse model of replicative senescence, decline in muscle satellite cell-mediated regeneration coincides with activation of DNA damage response (DDR) and impaired ability to differentiate into myotubes. Inhibition of DDR restored satellite cell differentiation ability. Moreover, in replicative human senescent fibroblasts, DDR precluded MYOD-mediated activation of the myogenic program.

A DDR-resistant MYOD mutant could overcome this barrier by resuming cell cycle progression. Likewise, DDR inhibition could also restore MYOD's ability to activate the myogenic program in human senescent fibroblasts. Of note, we found that cell cycle progression is necessary for the DDR-resistant MYOD mutant to reverse senescence-mediated inhibition of the myogenic program. These data provide the first evidence of DDR-mediated functional antagonism between senescence and MYOD-activated gene expression and indicate a previously unrecognized requirement of cell cycle progression for the activation of the myogenic program.

In 2013, Time magazine ran a cover story titled Google vs. Death about Calico, a then-new Google-run health venture focused on understanding aging - and how to beat it. "We should shoot for the things that are really, really important, so 10 or 20 years from now we have those things done," Google CEO Larry Page told Time. But how exactly would Calico help humans live longer, healthier lives? How would it invest its vast 1.5 billion pool of funds? Beyond sharing the company's ambitious mission - to better understand the biology of aging and treat aging as a disease - Page was vague. I recently started poking around in Silicon Valley and talking to researchers who study aging and mortality, and discovered that four years after its launch, we still don't know what Calico is doing.

I asked everyone I could about Calico and what it's up to - and quickly learned that it's an impenetrable fortress. Among the little more than a dozen press releases Calico has put out, there were only broad descriptions of collaborations with outside labs and pharmaceutical companies - most of them focused on that overwhelmingly vague mission of researching aging and associated diseases. The media contacts there didn't so much as respond to multiple requests for interviews. People who work at Calico, Calico's outside collaborators, and even folks who were no longer with the company, stonewalled me. There were no clinical trials or patents filed publicly under the Calico brand that I could find and only a few aging-related scientific papers.

The five-year study reveals how the enzyme TDP1 - which is already known to have a role in repairing damaged DNA in the cell's nucleus - is also responsible for repairing damage to mitochondrial DNA (mtDNA). Mitochondria are the powerhouses of cells, they generate the energy required for all cellular activity and have their own DNA - the genetic material which they rely upon to produce important proteins for their function. During the process of energy production and making proteins, a large amount of rogue reactive oxygen species are produced which constantly attack the DNA in the mitochondria. These attacks break their DNA, however the new findings show mitochondria have their very own repair toolkits which are constantly active to maintain their own DNA integrity.

"Each mitochondria repair toolkit has unique components - enzymes - which can cut, hammer and seal the breaks. The presence of these enzymes is important for energy production. Defects in repairing DNA breaks in the mitochondria affect vital organs that rely heavily on energy such as the brain." Although much research has focused on how free radicals damage the DNA in the cell's nucleus, their effect on mitochondrial DNA is less well understood despite this damage to mtDNA being responsible for many different types of disease such as neurological disorders.

The team further identified a mechanism through which mtDNA can be damaged and then fixed, via a protein called TOP1, which is responsible for untangling coils of mtDNA. When the long strands become tangled, TOP1 breaks and quickly repairs the strands to unravel the knots. If free radicals are also attacking the mitochondrial DNA, then TOP1 proteins can become trapped on the mitochondrial DNA strands, making repair even more difficult. Researchers believe the findings could pave the way for the development of new therapies for mitochondrial disease that boost their DNA repair capacity, or for cancer treatments which could use TDP1 inhibitors to prevent mtDNA repair selectively in cancer cells.

Breakage of one strand of DNA is the most common form of DNA damage. Most damaged DNA termini require end-processing in preparation for ligation. The importance of this step is highlighted by the association of defects in the 3′-end processing enzyme tyrosyl DNA phosphodiesterase 1 (TDP1) and neurodegeneration and by the cytotoxic induction of protein-linked DNA breaks (PDBs) and oxidized nucleic acid intermediates during chemotherapy and radiotherapy. Although much is known about the repair of PDBs in the nucleus, little is known about this process in the mitochondria.

We reveal that TDP1 resolves mitochondrial PDBs (mtPDBs), thereby promoting mitochondrial gene transcription. Overexpression of a toxic form of mitochondrial topoisomerase I (TOP1), which generates excessive mtPDBs, results in a TDP1-dependent compensatory up-regulation of mitochondrial gene transcription. In the absence of TDP1, the imbalance in transcription of mitochondrial- and nuclear-encoded electron transport chain (ETC) subunits results in misassembly of ETC complex III. Bioenergetics profiling further reveals that TDP1 promotes oxidative phosphorylation under both basal and high energy demands. Together, our data show that TDP1 resolves mtPDBs, thereby regulating mitochondrial gene transcription and oxygen consumption by oxidative phosphorylation, thus conferring cellular protection against reactive oxygen species-induced damage.

Using cells from mice and human livers, researchers demonstrated for the first time how under specific conditions, such as obesity, liver CD8+ T cells, white blood cells which play an important role in the control of viral infections, become highly activated and inflammatory, reprogramming themselves into disease-driving cells. Scientists have been trying for many years to discover why the liver continues to pump out too much glucose in people with diabetes. This paper sheds light on the markers of activation and inflammation in CD8+ T cells and the Interferon-1 pathway which helps stimulate their function. In fact, the normal function of the immune cells becomes misdirected. The pathways they would typically use to fight infection create inflammation, unleashing a chemical cascade which impacts insulin and glucose metabolism.

In the study, researchers fed mice a high-fat diet, 60 per cent of which was saturated fat, for 16 weeks. Compared with normal chow diet-fed mice, the high-fat diet mice showed worsened blood sugar, increased triglycerides, a type of fat (lipid) in the blood, and a substantial increase in the numbers of CD8+ T cells in the liver. Instead of responding to viruses or other foreign invaders in the body, the activated CD8+ T cells launch an inflammatory response to fat, and to bacterial components that migrate to the liver from the gut through the blood. The activated T-cells divide rapidly, pumping out increased numbers of cytokines, proteins that assist them in an active and excessive immune response. This pro-inflammatory response in turn interferes with normal metabolism in the liver, specifically jamming up or blocking insulin signaling to the liver cells.

Since the liver stores and manufactures glucose or sugar depending upon the body's need, the hormone insulin signals whether the liver should store or release glucose. This system keeps circulating blood sugar levels in check. If that signal is disrupted or blocked, the liver continues to make more sugar, pouring it into the bloodstream. If the liver is over-producing glucose, it becomes difficult to regulate blood sugar. "We're moving from studying diabetes as a metabolic syndrome - a combination of nutritional and hormonal imbalances - to include the role of the immune system and inflammation. That's the developing link. Inflammation is emerging to be a major mediator of insulin resistance."

The researchers found that in genetically-modified mice lacking Interferon-1, who were also fed a high-fat diet, the CD8+ T cells did not produce an inflammatory response, and the mice had near normal blood sugar levels. In further investigations of human liver cells from nearly 50 donor tissues of humans with varying degrees of body mass index (BMI) and liver fat, higher levels of CD8+ T cells were linked with higher levels of blood sugar or more advanced fatty liver disease.

Affecting approximately 3.8% of the global population, osteoarthritis (OA) is regarded as a prevalent cause of morbidity and disability worldwide. OA shows many disease characteristics, such as cartilage degradation, moderate synovial inflammation, pain, alteration of bony structure, and impaired mobility. However, despite the severity of the disease, relatively little is known about its exact etiology. Recent compelling investigations have attributed the onset of OA to various person-level factors such as age, sex, obesity, and diet and joint-level factors such as injury, malalignment, and abnormal joint loading. Although more and more researchers have recently presented hypotheses concerning the involvement of these factors in OA, especially for person-level factors, few of their hypotheses have been demonstrated experimentally, and some have even been challenged by the latest observational studies and clinical trials.

Of the several factors potentially involved in the pathogenesis of OA, T cell-mediated immune responses and their influence on the biology of OA are the focus of this review. The scientific community once understood OA to be induced by mechanical stress in the form of cartilage destruction, with minimal if any involvement of immune responses. Thus, OA was regarded as a non-inflammatory disease, in contrast with rheumatoid arthritis (RA), an inflammatory disease. However, recent studies suggest that at least in certain patients, OA is an inflammatory disease; patients have frequently been found to exhibit inflammatory infiltration of synovial membranes. Most recent studies have shown that the number of inflammatory cells in the synovial tissue is lower in patients with OA than in patients with RA, but higher than that in healthy subjects. Indeed, little difference has been found in the percentages of T cells, B cells, and natural killer cells in the peripheral blood between patients with OA and RA. The similarity of the immune cell profiles of RA and OA and suggested that abnormalities in T cells may also contribute to the pathogenesis of OA.

Further experiments indicated that inflammation in OA is anatomically restricted and varies in intensity. The synovial membranes in regions rimming the cartilage of OA patients, which contain T cells bordered by B lymphocytes and plasma cells, showed a pronounced inflammatory response. In contrast, only a few infiltrating lymphocytes were observed in the synovial membranes taken from macroscopically non-inflamed areas in OA patients. This may explain the suggestion made by some researchers that immune responses are not involved in the pathogenesis of OA. When synovial samples from patients with knee OA were analyzed, the synovial lining cells showed strong immunoreactivity and phagocytic potential with cluster of differentiation (CD) 68 antibodies. These findings suggested that macrophages may be associated with the pathogenesis of knee OA. Of 20 osteoarthritic synovial membranes, 5 showed lymphoid follicles containing T cells, B cells, and macrophages, and 10 (including the latter five) displayed a diffuse cellular infiltrate containing T and B cells, macrophages, and granulocytes. These results suggested that B cells and granulocytes may also be involved in the pathogenesis of knee OA.

A combination of aerobic and resistance exercises can significantly boost the brain power of the over 50s, finds the most comprehensive review of the available evidence to date. The effects were evident irrespective of the current state of an individual's brain health, the analysis shows. Physical exercise for older adults is seen as a promising means of warding off or halting a decline in brain health and cognitive abilities. Yet the evidence for its benefits is inconclusive, largely because of overly restrictive inclusion criteria in the reviews published to date, say the researchers. In a bid to try and plug some of these gaps, they systematically reviewed 39 relevant studies published up to the end of 2016 to assess the potential impact of varying types, intensities, and durations of exercise on the brain health of the over 50s. They included aerobic exercise; resistance training (such as weights); multi-component exercise, which contains elements of both aerobic and resistance training; tai chi; and yoga in their analysis.

They analysed the potential impact of these activities on overall brain capacity (global cognition); attention (sustained alertness, including the ability to process information rapidly); executive function (processes responsible for goal oriented behaviours); memory (storage and retrieval); and working memory (short term application of found information). Pooled analysis of the data showed that exercise improves the brain power of the over 50s, irrespective of the current state of their brain health. Aerobic exercise significantly enhanced cognitive abilities while resistance training had a pronounced effect on executive function, memory, and working memory. The evidence is strong enough to recommend prescribing both types of exercise to improve brain health in the over 50s, say the researchers.

Cellular immunotherapy is beginning to bring new hope to patients with certain blood cancers. Tumors that form solid masses, such as breast and pancreatic cancer, are the next frontier for the strategy - but scientists are still grappling with how to overcome the unique challenges large clusters of tumor cells present to engineered immune cells. Researchers have now shown that a dissolving biopolymer sponge packed with therapeutic ingredients can shrink tumors and extend survival in laboratory models of cancer. Loaded with engineered immune cells, molecules that help stimulate those cells' ability to eliminate cancer, and a special ingredient that recruits a patient's own immune cells for a second round of anti-cancer attacks, the spongey, lattice-like scaffold offers a new strategy for tackling genetically variable and crowded masses of tumor cells.

Cellular immunotherapies currently being tested - and showing promise - in clinical trials are delivered intravenously. This can work well in some patients with blood cancers like leukemia, as the engineered cells fan out to hunt down cancer cells circulating in the blood (or residing in the bone marrow). But because solid tumors like breast cancer present millions upon millions of diseased cells all packed together, they require a concentrated effort. Merely injecting a solution of T cells onto a tumor would result in most of them seeping away without a chance to get a toehold in the tumor. The new approach is to concentrate engineered immune cells known as CAR T cells directly at the site of the tumor using the scaffold. A T cell is a specialized type of immune cell capable of recognizing and eliminating diseased cells. Researchers genetically engineer T cells with a scientist-designed chimeric antigen receptor, or CAR, that gives them the ability to "see" cancer cells with specific targets on their surface.

The biopolymer sponge, which lasts for about a week before dissolving harmlessly in the body, gives the CAR T cells a comfortable home base and retains them right where they're needed. The synthetic T-cell headquarters is well-stocked with molecules that help energize the T cells. Because tumors release a number of molecules that switch T cells to a lethargic state, the immune boosters are necessary to ensure that the scaffold-delivered T cells are on high alert for cancer cells and ready to pounce as they exit the implant. When the researchers tested their strategy in a mouse model of pancreatic cancer, they found that CAR T cells delivered with immune-boosting nourishment via the scaffold multiplied their numbers and responded robustly to the cancer: The animals' tumors shrank. In contrast, CAR T cells that were injected into tumors (without activating molecules to support their attack) didn't expand their numbers and reacted anemically in the face of millions of tumor cells.

Tiny particles in air pollution have been associated with cardiovascular disease, which can lead to premature death. But how particles inhaled into the lungs can affect blood vessels and the heart has remained a mystery. Now, scientists have found evidence in human and animal studies that inhaled nanoparticles can travel from the lungs into the bloodstream, potentially explaining the link between air pollution and cardiovascular disease.

The World Health Organization estimates that in 2012, about 72 percent of premature deaths related to outdoor air pollution were due to ischemic heart disease and strokes. Pulmonary disease, respiratory infections and lung cancer were linked to the other 28 percent. Many scientists have suspected that fine particles travel from the lungs into the bloodstream, but evidence supporting this assumption in humans has been challenging to collect. So researchers used a selection of specialized techniques to track the fate of inhaled gold nanoparticles.

In the new study, 14 healthy volunteers, 12 surgical patients and several mouse models inhaled gold nanoparticles, which have been safely used in medical imaging and drug delivery. Soon after exposure, the nanoparticles were detected in blood and urine. Importantly, the nanoparticles appeared to preferentially accumulate at inflamed vascular sites, including carotid plaques in patients at risk of a stroke. The findings suggest that nanoparticles can travel from the lungs into the bloodstream and reach susceptible areas of the cardiovascular system where they could possibly increase the likelihood of a heart attack or stroke.

Researchers have developed a first-of-its-kind nanoparticle vaccine immunotherapy that targets several different cancer types. The nanovaccine consists of tumor antigens - tumor proteins that can be recognized by the immune system - inside a synthetic polymer nanoparticle. Nanoparticle vaccines deliver minuscule particulates that stimulate the immune system to mount an immune response. The goal is to help people's own bodies fight cancer. "What is unique about our design is the simplicity of the single-polymer composition that can precisely deliver tumor antigens to immune cells while stimulating innate immunity. These actions result in safe and robust production of tumor-specific T cells that kill cancer cells."

Typical vaccines require immune cells to pick up tumor antigens in a "depot system" and then travel to the lymphoid organs for T cell activation. Instead, nanoparticle vaccines can travel directly to the body's lymph nodes to activate tumor-specific immune responses. "For nanoparticle vaccines to work, they must deliver antigens to proper cellular compartments within specialized immune cells called antigen-presenting cells and stimulate innate immunity. Our nanovaccine did all of those things." In this case, the experimental nanovaccine works by activating an adaptor protein called STING, which in turn stimulates the body's immune defense system to ward off cancer. The scientists examined a variety of tumor models in mice: melanoma, colorectal cancer, and HPV-related cancers of the cervix, head, neck, and anogenital regions. In most cases, the nanovaccine slowed tumor growth and extended the animals' lives. The investigative team is now working with physicians to explore clinical testing of the STING-activating nanovaccines for a variety of cancer indications.

Cellular organelles are no longer conceived as isolated entities with defined and unique functions, but as dynamic signaling nodes, where a single organelle may engage and influence the functioning of several cellular compartments and processes. Interorganelle interactions are facilitated by specialized structures that tie them together structurally and functionally. Mitochondria-associated membranes (MAMs) are subdomains that bring the endoplasmic reticulum (ER) and mitochondria into close proximity, enabling a complex cross talk. This physical association shapes mitochondrial morphology and dynamics, in addition to participate in the response to various stress stimuli, modulating metabolism, redox control, and apoptosis.

The ER is the primary site where transmembrane and secretory proteins are folded; in addition to operate as the main intracellular calcium reservoir and a site of lipid biosynthesis. Abnormal accumulation of misfolded proteins within the ER lumen may result in the loss of proteostasis, a condition referred to as ER stress. ER stress is triggered by physiological demands including high secretory activity, in addition to pathological conditions that may perturb protein folding and maturation, calcium homeostasis, redox balance, among other events. Under ER stress the unfolded protein response (UPR) is engaged, operating as a dynamic signaling network that enforces adaptive programs to restore proteostasis by reducing the load of unfolded proteins through the upregulation of genes involved in almost every aspect of the secretory pathway. However, if ER homeostasis cannot be restored, the UPR switches its signaling toward a proapoptotic mode to eliminate irreversibly damaged cells. Thus, the UPR is a central adjustor to control cell fate under ER stress, contributing to diverse pathological conditions including cancer, neurodegeneration, and diabetes, among others.

Interorganelle communication is emerging as a homeostatic network determining the switch from adaptive programs to cell death under stress conditions, where specialized sentinels are localized at organelle membranes to induce the core apoptosis pathway. Mitochondria represent an ancestral integrator of stress signals, modulating metabolic demands on a constantly fluctuating environment. Although the literature is still poor in relating the activity of the UPR to mitochondrial function, a new model is emerging where proteostasis and metabolic control are tightly interconnected at the structural and functional levels. This integration might be particularly relevant in pathological conditions such as diabetes and cancer, where the ER and mitochondria undergo high metabolic demands. The physical and functional relation between the ER and mitochondria has pleiotropic consequences to the cell by regulating autophagy, ROS production, metabolism, and protein synthesis.

At the intersection of all these processes, calcium mobilization is considered a key player in the dynamic cross talk between the ER and mitochondria. Importantly, different core members of the UPR are highly mutated in cancer, suggesting a direct contribution to disease initiation. Several pharmacological agents are available to target the UPR with interesting protective effects in cancer. It remains to be determined whether these therapeutic agents influence mitochondrial function through MAMs. Overall, the relevance of the intersection between ER and mitochondria is gaining increasing attention in recent years, and thus the specific activities of the UPR at MAMs needs to be systematically studied. Strategies to dissect and manipulate compartmentalized UPR responses may generate novel therapeutic insights, expanding the avenues in the area of drug discovery.

Researchers have discovered a way to curb chronic pain by modulating genes that reduce tissue- and cell-damaging inflammation. The team's discovery was published in a new paper this month. "In this study we demonstrate the use of clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing to alter cell response to inflammatory environments by repressing inflammatory cytokine cell receptors, specifically TNFR1 and IL1R1. This has applications for many inflammatory-driven diseases. It could be applied for arthritis or to therapeutic cells that are being delivered to inflammatory environments that need to be protected from inflammation."

In chronic back pain, for example, slipped or herniated discs are a result of damaged tissue when inflammation causes cells to create molecules that break down tissue. Typically, inflammation is nature's way of alerting the immune system to repair tissue or tackle infection. But chronic inflammation can instead lead to tissue degeneration and pain. The team is using the CRISPR system - new technology of modifying human genetics - to stop cell death and keep the cells from producing molecules that damage tissue and result in chronic pain. But it doesn't do this by editing or replacing genes, which is what CRISPR tools are typically used for. Instead, it modulates the way genes turn on and off in order to protect cells from inflammation and thus breaking down tissue. "So they won't respond to inflammation. It disrupts this chronic inflammation pattern that leads to tissue degeneration and pain. We're not changing what is in your genetic code. We're altering what is expressed. Normally, cells do this themselves, but we are taking engineering control over these cells to tell them what to turn on and turn off."

Now that researchers know they can do this, doctors will be able to modify the genes via an injection directly to the affected area and delay the degeneration of tissue. In the case of back pain, a patient may get a discectomy to remove part of a herniated disc to relieve the pain, but tissue near the spinal cord may continue to breakdown, leading to future pain. This method could stave off additional surgeries by stopping the tissue damage.

Early in evolution, sugar intake and the regulation of life span were linked with each other. The hormone insulin is crucial here. It reduces blood sugar levels by binding to its receptor on the cell surface. However, many processes for stress management and survival are shut down at the same time. When there is a good supply of food, they appear unnecessary to the organism, although this reduces life expectancy over the long term. The insulin receptor thus acts like a brake on life expectancy. Genetically altered laboratory animals in which the insulin receptor no longer functions actually live much longer than normal. But how is the insulin receptor normally kept in check in our cells and tissue? A recent study answers this fundamental question.

The team of researchers shows that the protein CHIP plays a crucial role here. It acts like a disposal helper, in that it supplies the insulin receptor to the cellular breakdown and recycling systems by affixing the molecule ubiquitin onto the receptor. The life expectancy brake is thus released and CHIP unfurls anti-aging activity. CHIP fulfils this function in nematodes, as well as in fruit flies and in humans. The findings were initially very surprising, as CHIP had so far been associated with completely different breakdown processes. Specifically, CHIP also disposes of faulty and damaged proteins, which increasingly occur at an older age and the accumulation of which leads to dementia and muscle weakness. The researchers actually recreated such degenerative illnesses in the nematode and in human cells and observed that there was no longer enough CHIP available to break down the insulin receptor. Premature aging is the result.

Can the dream of a fountain of youth be made a reality and life extended in that researchers encourage cells to form more CHIP? Unfortunately, it's not that easy. When there is too much CHIP, undamaged proteins are also recycled and the organism is weakened. However, the researchers are already looking for mechanisms that control CHIP when breaking down the insulin receptor and that could one day also be used for new treatments.

Researchers have generated the first immortalised cell lines which allow more efficient manufacture of red blood cells. The team were able to manufacture red blood cells in a more efficient scale than was previously possible. The results, could, if successfully tested in clinical trials, eventually lead to a safe source of transfusions for people with rare blood types, and in areas of the world where blood supplies are inadequate or unsafe. Previously, research in this field focused on growing donated stem cells straight into mature red blood cells. However that method presently produces small numbers of mature cells and requires repeat donations. The researchers have now developed a robust and reproducible technique which allows the production of immortalised erythroid cell lines from adult stem cells. These premature red cells can be cultured indefinitely, allowing larger-scale production, before being differentiated into mature red blood cells.

"Previous approaches to producing red blood cells have relied on various sources of stem cells which can only presently produce very limited quantities. By taking an alternative approach we have generated the first human immortalised adult erythroid line (Bristol Erythroid Line Adult or BEL-A), and in doing so, have demonstrated a feasible way to sustainably manufacture red cells for clinical use from in vitro culture. Globally, there is a need for an alternative red cell product. Cultured red blood cells have advantages over donor blood, such as reduced risk of infectious disease transmission. Scientists have been working for years on how to manufacture red blood cells to offer an alternative to donated blood to treat patients. The first therapeutic use of a cultured red cell product is likely to be for patients with rare blood groups because suitable conventional red blood cell donations can be difficult to source. The patients who stand to potentially benefit most are those with complex and life-limiting conditions like sickle cell disease and thalassemia, which can require multiple transfusions of well-matched blood."