Fight Aging! Newsletter, February 24th 2020

Group 2 innate lymphoid cells (ILC2s) reside in specific tissues of the body and help to repair them when they are damaged. Recently, for example, ILC2s in the spinal cord were shown to promote healing after spinal cord injury. Researchers examined the brains of both young and old mice and found that ILC2s accumulated with age in a structure called the choroid plexus. This structure produces cerebrospinal fluid and is close to the hippocampus, a region of the brain that plays a key role in learning and memory. Older mouse brains had up to five times as many ILC2 cells as younger brains. Crucially, the researchers also saw large numbers of ILC2s in the choroid plexus of elderly humans.

The ILC2s in old mouse brains were largely in an inactive, or quiescent, state, but the researchers were able to activate them by treating the animals with a cell signaling molecule called IL-33, causing the cells to proliferate and produce proteins that stimulate the formation and survival of neurons. Compared with ILC2s from younger animals, ILC2s from older mice were able to live longer and produce more ILC2 upon activation, the researchers found. Additionally, treating old mice with IL-33, or injecting them with ILC2 cells pre-activated in the lab, improved the animals' performance in a series of cognitive tests designed to measure their learning and memory.

One of the proteins produced by activated ILC2s is the signaling molecule IL-5. The research team found that treating old mice with IL-5 increased the formation of new nerve cells in the hippocampus and reduced the amount of potentially damaging inflammation in the brain. Again, IL-5 treatment improved the cognitive performance of aged mice in a number of tests.

In this study, we report the accumulation of tissue-resident ILC2 in the choroid plexus of the aged brain, with ILC2 comprising a major subset of lymphocytes in the choroid plexus of aged mice and humans. ILC2 in the aged brain are long-lived and capable of reversibly switching between cell cycle dormancy and proliferation. They are relatively resistant to cellular senescence and exhaustion under replication stress, leading to enhanced self-renewal capability. They are functionally quiescent at homeostasis but can be activated by exogenous IL-33 to produce large amounts of IL-5 and IL-13 as well as a variety of other effector molecules in vitro and in vivo.

When activated in vitro and transferred intracerebroventricularly, they revitalized the aged brains and enhanced cognitive function of aged mice. Administration of IL-5, a major ILC2 product, repressed aging-associated neuroinflammation and alleviated aging-associated cognitive decline. Together, these results suggest that aging may expand a unique population of brain-resident ILC2 with enhanced cellular fitness and potent neuroprotective capability. Targeting ILC2 in the aged brain may unlock therapies to combat aging-related neurodegenerative disorders.

The rate-limiting factor for successful pregnancy is oocyte quality, which significantly declines from late in the third decade of life in humans. Despite the enormous demand, there are no clinically viable strategies to either preserve or rejuvenate oocyte quality during aging, which is defined by the capacity of the oocyte to support meiotic maturation, fertilization, and subsequent embryonic development. A non-invasive, pharmacological treatment to maintain or restore oocyte quality during aging would alleviate a rate-limiting barrier to pregnancy with increasing age that has driven demand for assisted reproduction technologies (ARTs) such as in vitro fertilization (IVF), which is invasive, carries health risks, is expensive, and has a limited success rate.

Although somatic tissues undergo continual regeneration through turnover by a self-renewing population of resident precursor stem cells, oocytes in the ovary are laid down during in utero development in humans, where they form a finite pool that does not undergo self-renewal. Oocytes are therefore highly susceptible to age-related dysfunction. The molecular basis for the decline in oocyte quality with advancing age implicates genome instability, reduced mitochondrial bioenergetics, increased reactive oxygen species (ROS), and disturbances during meiotic chromosome segregation due to compromised function of the spindle assembly checkpoint (SAC) surveillance system. The molecular cause of chromosome mis-segregation in oocytes with advancing age is still unknown, and as a result, there are no pharmacological strategies to correct this problem. Understanding the molecular or metabolic basis of this defect could lead to therapies that could maintain or even rescue female fertility with advancing age.

The metabolite nicotinamide adenine dinucleotide (NAD+/NADH) is a prominent redox cofactor and enzyme substrate that is essential to energy metabolism, DNA repair, and epigenetic homeostasis. Levels of this essential cofactor decline with age in somatic tissues, and reversing this decline through treatment with metabolic precursors for NAD+ has gained attention as a treatment for maintaining late-life health. Here, we show that loss of oocyte quality with age accompanies declining levels of NAD+. Treatment with the NAD+ metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD+-dependent deacylase SIRT2, though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD+ levels represents an opportunity to rescue female reproductive function in mammals.

Stem cells are critical to tissue regeneration and homeostasis during aging and disease. As a hallmark of aging, stem cell dysfunction is critical to improving the quality of life for people with advanced age. Stem cell-based therapy holds considerable promise for treating aging-related diseases, with hematopoietic stem cells (HSCs) being the most widely used for stem cell therapies. It is becoming increasingly clear that age-related changes in the niche space can induce alterations in hematopoiesis, including myeloid lineage skewing. However, extrinsic stimulation of HSCs with cytokines is highly dependent on intrinsic determinants. To date, the "gold standard" measure of HSC functionality remains an in vivo repopulating assay to determine their ability to re-establish lineage cell production in recipients during hematopoietic stem cell transplantation (HSCT). Unfortunately, conventional HSCT procedures require harsh cytotoxic conditioning - irradiation and/or chemotherapy - that alters HSC niches in the bone marrow, permanently damaging bone architecture. These limitations have confounded efforts to assess health-associated benefits of HSC replacement and rejuvenation.

The majority of HSCs reside in specialized niches within the bone marrow, although some HSCs leave these niches and migrate into the blood, ~1-5% of total HSCs each day. Mobilization of HSCs into the peripheral blood can be achieved through administration of G-CSF, an effect that is dramatically increased when G-CSF is administered in combination with other mobilizers, such as AMD3100. This HSC mobilization strategy constitutes the basic mechanism underlying collection of peripheral blood donor stem cells in the clinic. Critically, this increased mobilization also creates temporarily empty niches in the bone marrow, opening a window of opportunity for donor cell engraftment. Here, we use a novel mobilization-based HSCT procedure to investigate the health-associated benefits of replacing HSCs from aged recipients with young-donor HSCs. Additionally, we take advantage of the niche-preserving properties of this mobilization-based HSCT to investigate the influence of aged niche signaling upon a low percentage of young-donor HSCs.

Using this approach, we are the first to report an increase in median lifespan (12%) and a decrease in overall mortality hazard (hazard ratio: 0.42) in aged mice following transplantation of young-donor HSCs. The increase in longevity was accompanied by reductions of frailty measures and increases in food intake and body weight of aged recipients. Young-donor HSCs not only preserved youthful function within the aged bone marrow stroma, but also at least partially ameliorated the dysfunctional hematopoietic phenotypes of aged recipients. This compelling evidence that mammalian health and lifespan can be extended through stem cell therapy adds a new category to the very limited list of successful anti-aging/life-extending interventions. Our findings have implications for further development of stem cell therapies for increasing health and lifespan.

In addition to being one of the most devastating diseases of the 21st century, Alzheimer's disease (AD) remains incurable. The cognitive symptoms and neurodegeneration appear to be mostly related to the extensive synaptic dysfunction and neuronal death observed in the brain. In turn, neuronal loss and synaptic damage appears to be mediated by the progressive misfolding, aggregation, and deposition of amyloid-β (Aβ) and tau proteins forming protein aggregates able to spread from cell-to-cell by a prion-like mechanism. Genetics alone cannot account for the complex process of protein misfolding, aggregation and subsequent neurodegeneration observed in AD, particularly because the large majority of the cases are not associated to genetic mutations. Thus, it is likely that diverse environmental factors and age-related abnormalities play an important role on the initiation of the pathological abnormalities. In this sense, various studies have shown that bacterial infection, as well as alterations in the intestinal microbiome may be implicated in the AD pathology.

Here, we report the first evidence for the capacity of extracellular DNA from certain bacterial species to substantially promote tau misfolding and aggregation. The promoting effect of DNA on tau aggregation was observed in a wide range of concentrations from 10 to 1000 ng. The use of these concentrations were informed by the range of cerebrospinal fluid DNA concentrations observed in patients with different diseases: 1-600 ng/mL. The sources of bacterial and fungal DNA were selected based on the literature and personal data that showed associations of certain microorganisms with AD. Among the bacteria previously cultivated directly from the brains of patients with AD, or those whose components (such as nucleic acids, lipopolysaccharides, enzymes) were identified in the cerebrospinal fluid, amyloid plaques, or brains of patients with AD, we used the DNA from B. burgdorferi, P. gingivalis, C. albicans, and E. coli.

Our data indicate that DNA from various, unrelated gram-positive and gram-negative bacteria significantly accelerated Tau aggregation. One of the best promoters was DNA from E. coli species, which is interesting for several reasons. First, it was demonstrated that some strains of E. coli were detectable immunocytochemically in brain parenchyma and vessels in AD patients more frequently compared to control brains. Second, E. coli and P. gingivalis are known to share properties of facultative intracellular parasites and be localized within hippocampal neurons; the latter finding is significant, as the hippocampus is extensively damaged in AD. The intracellular localization of E. coli introduces unique possibilities regarding the interaction of bacterial DNA with tau proteins inside the neuron; e.g. DNA can be secreted via transportation to the outer membrane or released following prophage induction and directly access the host neuron's cytosol, where tau is normally present. Of note, in brains of patients with AD, P. gingivalis is also localized intracellularly; therefore, as in the case of E. coli the same processes for the intracellular interaction of its DNA with tau are applicable for this microorganism.

Future studies should further investigate the possible role of DNA as an initial seeding factor for protein misfolding using cellular and in vivo models as well as the effect of DNA on inducing misfolding of other proteins, including those associated with neurodegeneration, autoimmune diseases, and cancer. Moreover, subsequent studies should explore the targeting of DNA as a therapeutic strategy to prevent tau aggregation.

Werner syndrome (WRN) is a canonical member of a family of genetically determined disorders that include multiple phenotypes consistent with their characterizations as segmental progeroid syndromes. It is important to note, however, that these syndromes may include discordances with the usual phenotypic features of aging. For example, the ratio of epithelial to non-epithelial cancers in WRN is 1:1, whereas the ratio seen in usual aging is 10:1. Moreover, while WRN research has contributed to the widespread acceptance of genomic instability as one of the hallmarks of aging, features such as variegated translocation mosaicism and a preponderance of large deletions are particularly characteristic of WRN.

Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes. The vast majority (more than 90%) of differentially methylated CpGs and regions (DMRs) in WRN were not affected by aging, consistent with the view that WRN is not merely accelerated normal aging. A particularly striking finding was that DMRs were enriched in genes associated with transcription factor activity, leading us to hypothesize that WRN might best be conceptualized as a disease based upon aberrant controls of the expressions of a wide array of genetic loci, some of which are plausibly related to clinical phenotypes of WRN. Moreover, given that the methylation changes in the highest ranking DMR in the promoter region of the HOXA4 gene as well as in other DMRs preceded disease manifestation, it seems likely that these transcriptional aberrations began early in development. That finding reinforces the concept that how well one builds an organism makes a great deal of difference on how long it lasts and how well it functions!

The epigenome of an individual is most plastic during early development and is shaped by a plethora of stochastic, internal (i.e. genetic variation), and external factors (i.e. environmental exposures). The epigenetic changes associated with WRN and other segmental progerias are widespread but are all of small effect size. Both premature and normal aging phenotypes may manifest when the adverse factors exceed a critical threshold. Individuals with WRN may be endowed with an epigenome early in life which lowers their threshold for developing a number of specific aging phenotype.

Can you describe in more detail Juvena's approach to developing protein therapeutics that promote tissue regeneration in the elderly?

We are utilizing the secretome of human embryonic stem cells. We know that human embryonic stem cells have the capability to develop every tissue in the body, an entire human being. I and my colleagues discovered, nearly a decade ago, that by isolating a sub-fraction of the proteins that they themselves secrete and produce in order to signal to stem cells to develop every tissue in the body, concentrating these proteins, and then adding them directly onto old muscle precursor cells isolated from humans over the age of 65, we could enhance their regenerative potential. When we injected this cocktail of proteins into injured old mice, we saw muscle regeneration returned to levels of younger animals, two-month old mice that are like people in their 20s, and this is a cocktail of human proteins.

The way that Juvena Therapeutics is taking this discovery into the clinic is by establishing a very efficient identification, high-throughput screening, and preclinical development pipeline, which has become ever more predictive and accelerated with the use of AI tools in order to identify what proteins in this original cocktail are actually driving the rejuvenation process, which ones are master regulators of signal transduction and key regulatory pathways involved in tissue differentiation and regeneration. By identifying those proteins and their sequences and exactly what they are compositionally, we can then test them individually and in combinations for their ability to promote human muscle precursor cell function and promote tissue regeneration in mouse models of human aging and human diseases.

Why did you choose to focus on muscle cell regeneration?

Interesting fact about muscle: It's the largest internal tissue organ in the body. One of the first hallmarks of aging is the fact that once we hit our 30s, everybody, for the rest of our lives, heads downhill. We're losing muscle strength and mass every year, but it accelerates with every decade so that by the time we're in your 60s, everyone has some form of muscle wasting, some people more severe than others, so severe enough, in fact, that it prevents their daily functions and daily living and can be so severe that they can be clinically diagnosed with the disease of sarcopenia. Because there is now an ICD-10 code for sarcopenia, which was only issued at the end of 2016, meaning it's an age-related disease that has a clinical indication, we can actually make therapies to target it. There's zero FDA approved therapies, so it's a huge unmet need and a huge market.

Excitingly, one of the best experimental models that we have today to really understand how stem cells decline and function with age is the muscle system. Key discoveries made by my former co-thesis advisor, Irina Conboy, and other pioneers in the field, really paved the way for us to understand mechanistically how stem cells decline and function with age in muscle and develop methods to repair and rejuvenate them, so it's a great first tissue to focus on. Juvena will use this as a way to then launch into other tissue types. Laser-like focus on muscle first; once we find the proteins that are secreted by human embryonic stem cells that can drive muscle regeneration, we'll then apply our platform and our technology and our approach to identifying therapeutics, approaching candidates that can act as therapeutics to promote the brain and prevent things like dementia, really targeting regenerative diseases, as well as go after other tissue types, such as the heart, the skin, and other ones that are really affected with age and decline in function in part by loss of stem cell function.

This study examined the relationship between body height and dementia and explored the impact of intelligence level, educational attainment, early life environment, and familial factors. A total of 666,333 men, 70,608 brothers, and 7388 twin brothers born 1939-1959 and examined at the conscript board were followed in Danish nationwide registers (1969-2016). Cox regression models were applied to analyze the association between body height and dementia. The findings of this current study provide substantial support to previous evidence of a link between body height and dementia. All previous studies had accounted for educational level and other socioeconomic indicators, yet none of these studies had adjusted for intelligence level earlier in life. Intelligence level has been suggested to be a stronger marker of brain and cognitive reserve than educational level. Intelligence level is furthermore correlated with body height and by itself associated with dementia.

In contrast to previous studies, we also investigated the impact of other potential early-life familial factors including genetics and socioeconomic resources in the family that may influence both body height and later risk of dementia. Body height has been shown to have a strong genetic component with around 80% of the variation in populations being explained by genetic differences between individuals. The genetic component of height has furthermore been found to be consistent across countries independent of living standards. The genetic and environmental variation influencing body height, but not risk of dementia, is smaller within brothers than between men in general, which may weaken the association between body height and dementia in the latter compared to the former group. Through this mechanism, the finding of a stronger association within brothers may be explained by less dilution of the effects of different harmful exposures early in life influencing both body growth and risk of dementia. These findings furthermore suggests that genetics has a minor role in the association of body height and dementia.

In conclusion, taller body height at the entry to adulthood, supposed to be a marker of early-life environment, is associated with lower risk of dementia diagnosis later in life. The association persisted when adjusted for educational level and intelligence test scores in young adulthood, suggesting that height is not just acting as an indicator of cognitive reserve.

Everyone ages, but how aging affects health varies from person to person. This means that how old someone seems or feels does not always match the number of years they have been alive; in other words, someone's "biological age" can often differ from their "chronological age". Scientists are now looking at the physiological changes related to aging to better predict who is at the greatest risk of age-related health problems. Several measurements of biological age have been put forward to capture information about various age-related changes. For example, some measurements look at changes to DNA molecules, while others measure signs of frailty, or deterioration in cognitive or physical abilities. However, to date, most studies into measures of biological age have looked at them individually and less is known about how these physiological changes interact, which is likely to be important.

In a new study, researchers have looked at data on nine different measures of biological age in a group of 845 Swedish adults, aged between 50 and 90, that was collected several times over a follow-up period of about 20 years. The dataset also gave details of the individuals' birth year, sex, height, weight, smoking status, and education. The year of death was also collected from national registers for all individual in the group who had since died. The nine measures were telomere length, four different epigenetic clocks, physiological age derived from a list of age-correlated biomarkers, chronological age, functional aging index, and frailty index. Researchers found that all nine biological age measures could be used to explain the risk of individuals in the group dying during the follow-up period. In other words, when comparing individuals with the same chronological age in the group under study, the person with a higher biological age measure was more likely to die earlier. The analysis also revealed that biological aging appears to accelerate as individuals approach 70 years old, and that there are noticeable differences in the aging process between men and women.

Lastly, when combining all nine biological age measures, some of them worked better than others. Measurements of methylation groups added to DNA (known as DNA methylation age) and frailty (the frailty index) led to improved predictions for an individual's risk of death. Ultimately, if future studies confirm these results for measures from single individuals, DNA methylation and the frailty index may be used to help identify people who may benefit the most from interventions to prevent age-related health conditions.

Many of our readers are familiar with CAR-T immunotherapy, which has enjoyed some success, but it's not without considerable challenges. How does your approach differ?

We are using a simpler approach of just manufacturing a monoclonal antibody. Of course, we do that in Chinese Hamster Ovary (CHO) cells and purify and produce a monoclonal antibody product so that we don't have to modify patient cells or any other cells in order to apply our treatment. It's just a straight typical monoclonal antibody product, the same sort of immunotherapy that's used in a variety of cancer therapies. In this case, we've found a marker that's on cancer cells and senescent cells because of the way the markers are produced, and therefore the monoclonal antibody can enable removal of those cancer cells.

Can you summarize a bit more how that antibody SIWA 318H works?

It binds to proteins on the surface of oxidatively damaged cells that may be senescent or cancerous, or just very dysfunctional. By doing so, it provokes an immune response, initially an innate immune response with the natural killer cells. The bottom line is, the immune response not only destroys and removes the cells to which the antibody binds, but immune cells also secrete factors that promote regeneration. So, while we're removing cells that are not going to function properly, we're promoting their replacement with new cells from adult stem cell populations. The interesting thing about the markers is that they are a product of glycolysis, and high levels of glycolysis were associated even back before World War Two by Otto Warburg. They were shown on cancer cells. Cancer cells and senescent cells have their peculiarities, and they are high producers of this particular marker; therefore, we can hone in on those two types of cells.

Is it a coincidence that the marker is present on both senescent and cancerous cells? Or is there a reason for that?

Both types of cells conducted an elevated level of glycolysis and there are various explanations in the scientific literature. Both are highly metabolically active. Some people think of senescent cells as almost dead, but, in fact, they are among the most metabolically active of cells, and cancer cells are as well because of high proliferation. Both types of cells have a high need for ATP. One explanation in the literature is that they both resort to glycolysis to get additional ATP. The senescent cells put all of their efforts into the senescence associated secretory phenotype, so they're producing a lot of cytokines and other molecules, so they need to use glycolysis, but they're not using it to divide. A simplified way of looking at it is that senescent cells grow, and they need energy for growth; they basically get to the size that a cell would normally be when it divides, and then they just don't divide. When you look under the microscope, you see large, flattened cells that are senescent cells, because they've grown but they just didn't divide. Cancer cells, of course, will go ahead and do the division and you'll have two daughter cells. The bottom line is that they both have to grow to that large size.

Does this mean a vaccine might be developed for senescent cells or even cancer?

Yes, and we are working on what we have. We've done preliminary studies in mice, and now we're looking at expanding it into other species, even beyond humans, but we do have a candidate vaccine already in the works. As with any drug, you do want to be careful about certain conditions, pregnancy or other conditions where you don't want to disrupt any things happening. For example, senescent cells have been found in fetuses. The one common thing, strangely enough, with senescent cells is every situation in which they're beneficial, they're removed. After they form the different structures in the fetus, they're eliminated. The same thing is true in wound healing, which is often given as an example of a beneficial effect. Initially, senescence promotes proliferation of repairing cells, but if that's allowed to go on too long, the wound tends to produce scar tissue, fibrosis, and the bottom line is that in the natural healing process, senescent cells appear for a time and then are removed. Although you do have to be somewhat careful, you don't want to interfere with the initial stage of wound healing or with fetal development, otherwise, it's a good rule of thumb that removing a senescent cell or a cancer cell is not a bad thing.

The exact cause of Alzheimer's disease is unknown, but pathological changes in the brain, including neuron loss and an accumulation of protein aggregates called beta-amyloid plaques, are a diagnostic hallmark of Alzheimer's disease. Mild cognitive impairment (MCI) describes the slight but measurable changes in cognitive function that are often a precursor to Alzheimer's disease. However, despite the importance of MCI, very little is known about the changes that occur in the brain during the progression from MCI to Alzheimer's.

Researchers have now found that neuronal death occurs much earlier than originally thought, with higher levels of necrosis seen in patients with MCI than in patients with full-blown Alzheimer's disease. The researchers also observed a significant decrease in the levels of a protein known as YAP in Alzheimer's disease model mice and human patients with MCI. YAP positively affects the activity of a second protein called TEAD, a deficiency of which leads to neuronal necrosis. Microscopic examination revealed that the missing YAP was sequestered within beta-amyloid plaques, which have also been linked to neuronal toxicity.

By directly injecting a gene therapy vector expressing YAP analog into the cerebrospinal fluid of mice that were genetically engineered to provide a model of Alzheimer's, the researchers were able to prevent early-stage neuron loss, restore cognitive function, and prevent the development of beta-amyloid plaques. "Confirming that neuronal necrosis was dependent on YAP was really the pivotal moment for us, but observing the almost transformative effects of YAP supplementation was hugely exciting. By showing that neuronal necrosis is YAP-dependent and begins prior to the onset of most symptoms, we predict that novel Alzheimer's disease therapies will be developed to prevent the initiation of Alzheimer's disease."

Aging is defined as a progressive decrease in physiological function accompanied by a steady increase in mortality. The antagonistic pleiotropy theory proposes that aging is largely due to the natural selection of genes and pathways that increase fitness and decrease mortality early in life but contribute to deleterious effects and pathologies later in life. Cellular senescence is one such mechanism, which results in a permanent cell cycle arrest that has been described as a mechanism to limit cancer cell growth. However, recent studies have also suggested a dark side of senescence in which a build-up of senescent cells with age leads to increased inflammation due to a senescence-associated secretory phenotype (SASP). This phenotype that includes many cytokines promotes tumorigenesis and can exhaust the pool of immune cells in the body.

In a 2006 primate study, it was observed that senescent cells, as estimated by ATM activation do accumulate and can reach over 15% of the total cell population in aged individuals. In contrast to the vast majority of in vitro studies, this was one of the first studies showing a clear association between aging and the accumulation of senescent cells in vivo. Although this established a strong correlation, efforts were underway to establish causation between the accumulation of senescent cells and aging in vivo. In 2011, the researchers showed that removing p16Ink4a positive senescent cells delayed age-related disorders and increased healthspan in a BubR1 progeroid accelerated model of aging mice. Later studies confirmed the beneficial effects of senescent cell removal in wild type mice that showed increased median lifespan, delayed tumorigenesis, and attenuated age-related multi-organ deterioration. Removal of senescent cells in mice has also been shown to attenuate markers of age-associated neurodegenerative diseases such as tau hyperphosphorylation and neurofibrillary tangle deposition.

Substantial evidence in the last decade connecting senescent cell accumulation, age-related ailments, and roles in lifespan and healthspan fueled the search for therapeutic compounds that could selectively target senescent cells. A transcriptomic analysis between senescent cells and proliferating cells showed increased expression of pro-survival/anti-apoptotic genes such as Bcl-xL, a member of the Bcl-2 family of proteins that regulates programmed cell death by blocking caspase activation. This provided evidence to support the observation that senescent cells accumulate with age by being resistant to a variety of stresses that would normally induce apoptosis. Consistent with this idea, siRNAs to reduce Bcl-xL expression selectively reduced survival and viability in senescent cells while not affecting proliferating cells. Quercetin and dasatinib were obtained as hits from a drug screen based on these observations.

These compounds form one of the first discovered members of the senolytic class of drugs that selectively induce apoptosis in senescent cells. Four years after their initial identification as candidate senolytics, a dasatinib and quercetin combination was reported to decrease the senescent cell burden in humans as part of a Phase-1 clinical trial in diabetic kidney disease patients. This 2019 study was the first peer-reviewed study to demonstrate the efficacy of senolytics to decrease senescent cell burden in humans. This was carried out after an initial pilot study in early 2019 in 14 idiopathic pulmonary fibrosis (IPF) patients was completed to evaluate the feasibility of implementing a senolytic treatment. What now remains to be determined is whether future clinical trials will demonstrate any positive medical outcomes resulting from decreased senescent cell burden in diabetes and other age-associated ailments.

EnClear Therapies, a life sciences company developing device-based therapies for the treatment of neurodegenerative disease, today announced a 10 million Series A financing. "We are thrilled to have a strong syndicate committed to our team and platform technology, enabling EnClear to move our therapeutic system to our first-in-human clinical trial in Amyotrophic Lateral Sclerosis, as well as expand our platform into new applications and strategic partnerships. Our differentiated technology has the potential to transform not only the treatment of this devastating disease, but also many other conditions related to the central nervous system."

"The founders of EnClear are focused on producing a technology that could revolutionize the field by allowing fast diagnosis, delivery of any drug directly into the cerebrospinal fluid, and the development of new CNS-focused therapeutics. I am excited to help EnClear grow their business to help the millions of patients living with CNS diseases. We believe that EnClear's technology has the potential to fundamentally change the way neurodegenerative diseases are treated and ultimately improve patients' lives."

While the vast majority of myelin sheaths in the brain are laid down early in life, new studies reveal that a fresh supply of the fatty axonal conductor is required to establish and maintain memories in the adult brain. One reported that newly minted, myelin-producing oligodendrocytes act to cement unpleasant memories in mice. The other reported that the birth of new oligodendrocytes plummets with age - a slowdown that could underlie age-related memory loss. In both, a drug that fosters the growth of new oligodendrocytes improved memory. The studies add to growing evidence that active myelination plays a crucial role in memory function, and mesh with recent studies implicating myelination malfunctions in neurodegenerative disease.

Part and parcel of most functional axons, myelin sheaths speed up the conductance of neuronal signals in the brain. While much of the myelin in the brain is as old as the axons themselves, a fraction of myelin continues to be produced by a small pool of new oligodendrocytes that develop throughout life, in response to new experiences and learning. This experience-dependent myelination is thought to bestow structural plasticity on the brain. Such myelination has been implicated in motor learning, and drugs that interfere with oligodendrocyte function reportedly cause memory deficits in mice.

If new oligodendrocytes are important in memory, might a slowdown in their production underlie age-related memory loss? Researchers started by tracking myelin production in mice with age. Using transgenic mice in which newly formed oligodendrocytes and myelin sheaths can be inducibly labeled, the researchers spotted numerous myelin-producing newbies in four- to six-month-old mice in the corpus callosum, but by 13 months of age, new oligodendrocytes were few and far between. As the spigot of fresh myelin started to pinch, age-related memory deficits emerged. Compared with 4-month-old mice, 13-month-olds took longer to learn the location of a submerged platform in the Morris water maze test of spatial memory. The hippocampus is crucial for storage of spatial memory, and the researchers found far fewer newly minted, myelin-producing oligodendrocytes in the CA1 region of the hippocampus in 13-month-old than in younger adult mice. Expression of myelin basic protein (MBP) - the building block of myelin sheaths - was also lower in the hippocampi of older mice.

Wielding a menagerie of mouse models, the researchers went on to reveal that blocking differentiation of oligodendrocytes led to memory loss in 4-month-old mice, while revving up the maturation of new oligodendrocytes prevented memory deficits in older mice, and even upped the density of synaptic puncta in the hippocampus.

The burden of heart failure (HF) in terms of health care expenditures, hospitalizations, and mortality is substantial and growing. The failing heart has been described as "energy-deprived" and mitochondrial dysfunction is a driving force associated with this energy supply-demand imbalance. Existing HF therapies provide symptomatic and longevity benefit by reducing cardiac workload through heart rate reduction and reduction of preload and afterload but do not address the underlying causes of abnormal myocardial energetic nor directly target mitochondrial abnormalities.

Numerous studies in animal models of HF as well as myocardial tissue from explanted failed human hearts have shown that the failing heart manifests abnormalities of mitochondrial structure, dynamics, and function that lead to a marked increase in the formation of damaging reactive oxygen species (ROS) and a marked reduction in on demand adenosine triphosphate (ATP) synthesis. Correcting mitochondrial dysfunction to enhance the energy supply of the failing heart to meet the desired energy needs offers considerable potential to improve cardiac function, reduce symptoms, and improve exercise tolerance in HF, and ultimately offer improved quality of life and survival for patients, and reduce the overall economic burden of this condition.

Elamipretide (SS-31) is a water-soluble, aromatic-cationic mitochondria-targeting tetrapeptide that readily penetrates and transiently localizes to the inner mitochondrial membrane and associates with cardiolipin to restore mitochondrial bioenergetics. Studies in dogs with coronary microembolization-induced chronic HF showed that 3 months of treatment with daily subcutaneous injections of elamipretide improved left ventricle (LV) systolic function and prevented progressive LV dilation without affecting heart rate, blood pressure, or systemic vascular resistance. Elamipretide also elicited a normalization of mitochondrial function evidenced by improved respiration, normalization of membrane potential, reduced ROS formation, and improved maximum rate of ATP synthesis.