Fight Aging! Newsletter, July 31st 2017

Does your waist measure more than half your height? In developed countries up to 90 percent of adult males and 50 percent of children may suffer from this condition. In the top overfat countries, 80 percent of women fall into this category. The term overfat refers to the presence of excess body fat that can impair health, and may include even normal-weight non-obese individuals. Excess body fat, especially abdominal fat, is associated with increased risk of chronic diseases, increased morbidity and mortality, and reduced quality of life. Researchers reported earlier this year that up to 76 percent of the world's population may be overfat. Now these same researchers have focused their efforts on data from 30 of the top developed countries, with even more alarming findings.

The relationship between the overfat condition and poor health is a spectrum or progression in which the vicious cycle of excess body fat, insulin resistance and chronic inflammation lie at one end, causing abnormal blood fats (cholesterol and triglycerides) and glucose, and elevated blood pressure, which then produces a variety of common diseases at the other end. Being overfat is linked to hypertension, dyslipidemia, coronary heart disease, stroke, cancer, type 2 diabetes, gallbladder disease, osteoarthritis and gout, pulmonary diseases, sleep apnea and others. Traditional means of assessment, such as stepping on a scale or calculating Body Mass Index (BMI), are ineffective at determining whether someone is overfat. Instead, researchers recommend taking a measure of the waistline (at the level of the belly button) and comparing it to height.

It was recently estimated that between 62% and 76% of the world's population have reached body fat levels that can impair health. This condition, which can now be labeled a pandemic, was described by the catch-all term overfat. It is well-recognized that the overweight and obese conditions represent a continuing threat to world health, replacing more traditional problems of undernutrition and infectious diseases. Indeed, being overfat shares direct links to insulin resistance and chronic inflammation, and to hypertension, dyslipidemia, coronary heart disease, stroke, cancer, Type 2 diabetes, gallbladder disease, osteoarthritis and gout, pulmonary diseases, sleep apnea, and others. Global rates of these conditions in adults and children (including adolescents) have risen significantly over the past ~40 years, paralleling significant increases in the numbers classified as being overweight and obese, and considerably affecting people of all ages and incomes in both developed and developing countries.

While the prevalence of being overweight and obese is well known, many normal-weight and non-obese individuals exhibit excess levels of body fat that can adversely affect their health. Indeed, reliance of body mass index (BMI) for determination of being overweight and obese may misclassify up to 50% or more of patients with excess body fat who may have increased health risks. The notion of a metabolically obese normal weight (MONW) individual is based on the finding that obesity-associated disorders such as high circulating insulin levels in people with cardiovascular disease or Type 2 diabetes can occur in those with normal BMI. Many at-risk individuals have been identified in a BMI range of 23-25 or lower. Overfat individuals who are not overweight and obese include MONW individuals, those with sarcopenic obesity, and many who have increased abdominal fat stores. Abdominal and visceral fat accumulation, regardless of weight status, has been found to increase risk of cardiovascular and metabolic (cardiometabolic) disease to the greatest degree.

Based on BMI evaluations, there appears to be a leveling off of the trend in rising obesity rates in some developed nations. However, the incidence of central adiposity - the excess accumulation of visceral fat in the abdominal region, sometimes called abdominal obesity - is increasing. This form of overfat is concerning because the potential health risks of central adiposity are more pronounced than those for increased subcutaneous fat in other regions of the body. The continued increase in abdominal obesity includes those who are normal weight and non-obese, with US population averages of 54.2%, and an increased prevalence in women (up to 68.3%). The estimate of overfat in the world's 30 top developed nations is substantially higher than the prevalence of overweight and obese adults and children worldwide. Regardless of BMI values, overfat individuals have excess body fat, a high degree of cardiometabolic dysregulation that can promote disease risk factors and chronic disease, increased morbidity and mortality, reduced quality of life, and pose a rising economic burden.

The economic fallout from the overfat pandemic has raised a serious global challenge. In 2011, the WHO estimated that the economic burden of preventable, non-communicable disease (in particular cardiovascular disease, cancer, and diabetes) is expected to create a cumulative output loss of 47 trillion over the next two decades. In 2010, this represented 75% of global GDP (63 trillion) - enough capital to lift the 2.5 billion people currently below the poverty line, out of poverty for more than half a century. While it is difficult to determine the absolute burden of the overfat pandemic, it is clearly a strong causal factor in the development of a significant portion of chronic disease and reduced quality of life.

The hypothalamus was known to regulate important processes including growth, development, reproduction and metabolism. In a 2013 paper, researchers made the surprising finding that the hypothalamus also regulates aging throughout the body. Now, the scientists have pinpointed the cells in the hypothalamus that control aging: a tiny population of adult neural stem cells, which were known to be responsible for forming new brain neurons. "Our research shows that the number of hypothalamic neural stem cells naturally declines over the life of the animal, and this decline accelerates aging. But we also found that the effects of this loss are not irreversible. By replenishing these stem cells or the molecules they produce, it's possible to slow and even reverse various aspects of aging throughout the body."

In studying whether stem cells in the hypothalamus held the key to aging, the researchers first looked at the fate of those cells as healthy mice got older. The number of hypothalamic stem cells began to diminish when the animals reached about 10 months, which is several months before the usual signs of aging start appearing. "By old age - about two years of age in mice - most of those cells were gone." The researchers next wanted to learn whether this progressive loss of stem cells was actually causing aging and was not just associated with it. So they observed what happened when they selectively disrupted the hypothalamic stem cells in middle-aged mice. "This disruption greatly accelerated aging compared with control mice, and those animals with disrupted stem cells died earlier than normal." Could adding stem cells to the hypothalamus counteract aging? To answer that question, the researchers injected hypothalamic stem cells into the brains of middle-aged mice whose stem cells had been destroyed as well as into the brains of normal old mice. In both groups of animals, the treatment slowed or reversed various measures of aging.

The researchers found that the hypothalamic stem cells appear to exert their anti-aging effects by releasing molecules called microRNAs (miRNAs). They are not involved in protein synthesis but instead play key roles in regulating gene expression. miRNAs are packaged inside tiny particles called exosomes, which hypothalamic stem cells release into the cerebrospinal fluid of mice. The researchers extracted miRNA-containing exosomes from hypothalamic stem cells and injected them into the cerebrospinal fluid of two groups of mice: middle-aged mice whose hypothalamic stem cells had been destroyed and normal middle-aged mice. This treatment significantly slowed aging in both groups of animals as measured by tissue analysis and behavioral testing.

Although the nervous system clearly has a role in ageing, and research has demonstrated that the hypothalamus is particularly important, the cellular mechanism responsible for ageing is still unknown. It has been shown that adult neural stem/progenitor cells (NSCs) reside in a few brain regions that mediate local ­neurogenesis and therefore several aspects of brain functioning. Studies on adult neurogenesis have focused on the hippocampus and the sub-ventricular zone of the lateral ventricle in the brain. Decreased neurogenesis in these regions often correlates with the advent of related ageing-­associated disorders. More recently, it has been shown that adult NSCs are present in the hypothalamus, in particular in the mediobasal hypothalamic region (MBH), which is crucial for the neuroendocrine regulation of the physiological homeostasis of the whole body. We have previously shown that the hypothalamus has a programmatic role in causing systemic ageing. In this context, we investigated whether these hypothalamic NSCs (htNSCs) might be mechanistically responsible for this process.

We show that loss of htNSCs is an important cause of ageing in the whole body. This understanding aligns with our previous research showing that the hypothalamus has a programmatic role in systemic ageing. The underlying basis could be related to two functions of these cells: endocrine secretion and neurogenesis. Here we report that the modulation of ageing by htNSCs was achieved in a relatively short period, which should not have a major contribution from neurogenesis, while an endocrine function of these cells provided a neurogenesis-independent mechanism. In this context, we show that the anti-ageing effect of htNSCs is partially mediated by exosomal miRNAs secreted from these cells. Therefore, besides the classical endocrine function of the hypothalamus in secreting peptidyl hormones, htNSCs have a new type of endocrine function by secreting exosomal miRNAs.

Given this finding, we still predict that neuropeptide secretion by htNSCs, although not addressed in this work, also participates in the regulation of systemic ageing. This is partly because we previously found that GnRH is involved in the hypothalamic control of ageing and we observed here that some implanted htNSCs gave rise to GnRH-expressing cells. Thus, neuropeptide-based endocrine functions of htNSCs and their differentiated offsprings can contribute to the anti-ageing effects of these cells from other perspectives. Despite these outstanding questions, the overall findings in this work support that htNSCs are essential for the control of ageing speed.

It has long been assumed that Alzheimer's disease completely erases memories. The condition involves clumps of proteins known as amyloid plaques and tau tangles accumulating in the brain, where they are thought to destroy the neurons that store our memories. But experiments suggest that memories may not be wiped by Alzheimer's disease, but instead become harder to access. What's more, these memories can be reawakened by artificially activating the neurons they are stored in.

To examine how memory is affected by Alzheimer's disease, the researchers developed a way of visualising individual memories in mouse brains. They genetically engineered mice with neurons that glow yellow when activated during memory storage, and red when activated during memory recall. Two sets of these mice were created - one set that was healthy, and one with a condition resembling human Alzheimer's disease. Both sets of mice took a memory test. First, they were exposed to a lemon scent and given an electric shock. Then, a week later, they were exposed to the same lemon scent. The healthy mice immediately froze in anticipation of being shocked again. But the mice with Alzheimer's disease froze almost half as much as the healthy mice, suggesting they did not remember the link between the smell and shock so strongly.

This behaviour matched what the team saw in the hippocampi of the mice - the brain regions that record memories. In healthy mice, the red and yellow neurons overlapped, showing that the mice were retrieving the lemon-shock memory from the same place it had been stored. But in the Alzheimer's mice, different cells glowed red during recall, suggesting that they were calling up the wrong memories. This might help explain why people with Alzheimer's disease commonly experience false memories.

Using a genetic engineering technique called optogenetics, the team went on to reactivate the lemon-shock memory in the Alzheimer's mice. By shining a blue laser down a fibre optic cable into the brain, they were able to stimulate the yellow memory-storing neurons, prompting the mice to freeze when they smelled the lemon scent. This shows that "lost" memories may still exist in the brain, and can be recovered. Optogenetics is not a technique that can be used in people yet, because it isn't yet safe or practical to tinker with our neurons or stick lasers in our brains. But in the future, targeted drugs or techniques like deep-brain stimulation may help people with Alzheimer's access their forgotten memories. The next step will be to confirm that the same memory storage and retrieval mechanisms exist in people with Alzheimer's disease, because mouse models do not perfectly reflect the condition in humans. In particular, the number of neurons that die in mouse models of Alzheimer's disease is far lower than in humans.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. APPswe/PS1dE9 (APP/PS1) mice have been developed as an AD model and are characterized by plaque formation at 4-6 months of age. Here, we sought to better understand AD-related cognitive decline by characterizing various types of memory. In order to better understand how memory declines with AD, APP/PS1 mice were bred with ArcCreERT2 mice. In this line, neural ensembles activated during memory encoding can be indelibly tagged and directly compared with neural ensembles activated during memory retrieval (i.e., memory traces/engrams).

We first administered a battery of tests examining depressive- and anxiety-like behaviors, as well as spatial, social, and cognitive memory to APP/PS1 × ArcCreERT2 × channelrhodopsin (ChR2)-enhanced yellow fluorescent protein (EYFP) mice. Dentate gyrus (DG) neural ensembles were then optogenetically stimulated in these mice to improve memory impairment. AD mice had the most extensive differences in fear memory, as assessed by contextual fear conditioning (CFC), which was accompanied by impaired DG memory traces. Optogenetic stimulation of DG neural ensembles representing a CFC memory increased memory retrieval in the appropriate context in AD mice when compared with control mice. Moreover, optogenetic stimulation facilitated reactivation of the neural ensembles that were previously activated during memory encoding. These data suggest that activating previously learned DG memory traces can rescue cognitive impairments and point to DG manipulation as a potential target to treat memory loss commonly seen in AD.

Biogerontologist Aubrey de Grey, the father of SENS, a plan for the development of rejuvenation therapies based on repair of cell and tissue damage, always likes to answer to all objections and concerns regarding rejuvenation with two general arguments. The core of the first argument can be expressed quite succinctly: are any of the potential problems that might be caused by rejuvenation in the future worse than the actual problem of ageing we have today? By and large, the yardstick by which we measure a problem's magnitude is typically the amount of suffering, misery, and death it inflicts on people. For example, when war breaks out we do regret the destruction of landmarks and infrastructure, but that's hardly how we measure how bad the war was - rather, we speak of how many lives it has claimed or how many people it has maimed. Around 100,000 people die every day of ageing - that is, of the pathologies of old age and their complications. This is a huge number, and it is a whopping 2/3 of the deaths that occur every day (around 150,000). In a year, that adds up to around 36,500,000 deaths. According to the most conservative estimates, around 50,000,000 people died in World War II (1939-1945); on average, that is about 8,400,000 people a year. Thus, in a year, ageing kills about four times as many people as WWII did in the same timespan.

By this measure, the problem of ageing is really bad, killing every day more people than all the other causes of death put together, and causing enormous suffering as well. If we successfully implemented a comprehensive rejuvenation platform, the problem of ageing, and all the misery it causes, would disappear altogether. Do we think that the potential side effects of defeating ageing may be so bad that we would be better off not doing it at all? For each problem that you think the defeat of ageing might cause, you can ask yourself if it would be worse than the problem we have today - the misery, suffering, and death caused by ageing, not to mention the socio-economical problems it causes as well.

The second argument is that we should not presume to know better than the people of the future. There are many objections concerning potential future problems. However, the truth is we know very little about the future, especially compared to what will be known by the people who live in that future. It would be arrogant to assume that a problem today will necessarily be a problem in the future as well. Just imagine if our forefathers two hundred years ago had reasoned: "Vaccines could cause the population to spiral out of control! They would save a lot of lives, but those very lives would go on increasing our numbers, in a way or another, and in a couple of centuries billions of people would be walking the Earth! How could we possibly feed so many mouths? Better to forget about vaccines and let nature take its course. It's a necessary evil."

Today, we are in the same situation as our ancestors in the example above. If we say 'no' to creating rejuvenation today, we would be condemning not only ourselves, but the people of the future as well, to the diseases of ageing; worse still, we would be doing so on the questionable assumption that we know enough about the world of the future to decide rejuvenation would do it more bad than good. If we develop rejuvenation, we will give our descendants (and possibly ourselves) the option to use it; if we don't, we will deny them this option and force them to suffer from aging. One day, our descendants may either be thankful that we gave them a choice between health and disease, or regret that their arrogant and unimaginative forefathers didn't think the matter through before deciding on behalf of humanity of the future.

The proportion of elderly people is rising worldwide, especial in the developed countries. Aging-related changes in the immune system contribute to the increased susceptibility of the elderly to infectious diseases, cardiovascular disease and stroke caused by atherosclerosis, autoimmune disease such as rheumatoid arthritis, cancer, and degenerative diseases including Alzheimer's disease. Further, metabolic syndrome, which is caused by obesity, occurs from middle age, and proceeds to tissue failure such as renal failure in advanced age, is tightly related to the immune system. Chronic infections such as hepatitis induce tissue damage, which arouses immune responses and wound repair responses. Chronic inflammation follows tissue fibrosis in advanced age proceeding to tissue failure such as chronic obstructive pulmonary disease.

The most prominent cause of age-related immune dysfunction is T cell immunosenescence. There are three causes of T cell immunosenescence. One is the age-related hematopoietic stem cells (HSCs) deviation from lymphoid lineage to myeloid lineage. Second is the shrinkage of thymus. Third is expansion of T cell clones to cytomegalovirus (CMV). Changes of HSCs also affect immunosenescence. HSCs deviate to myeloid lineage by aging. Both in mice and humans the myeloid-lymphoid ratio elevates by aging, which induces the decline of lymphoid cells (T and B cells) and erythrocytes, and contributes to decline of adaptive immunity. The number of aged B cells decline and affinity and diversity of antibodies are low. Ageing related myeloid deviation increases the number of myeloid cells. However, the oxidative burst and phagocytosis of both neutrophils and macrophages are decreased. The antigen presentation of aged dendritic cells and the cytolysis of natural killer cells are low.

Pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and IL-1β are elevated in elderly people, a state that is called inflammaging, and in conjunction with obesity induce metabolic syndrome, type II diabetes, atherosclerosis, cardiac diseases. However, other reports have shown that pro-inflammatory (M1) macrophages are replaced by anti-inflammatory (M2) macrophages by aging. Here to solve this discrepancy we propose to classify age-related immune changes as follows. Age-related pathological changes are classified as firstly immune cell intrinsic changes caused by aging and secondly as the involvement of immune cells in age-related pathological changes. Increased susceptibility of the elderly to infectious diseases is mainly caused by age-related immune cell intrinsic changes, and is usually called immunosenescence. Metabolic syndrome and other related diseases, which occur at aged people, are mainly caused by immune cell attack in response to age-related tissue changes. Age-related tissue failure is then caused by repeated immune cell attack.

There is a persistent view that life extension advocacy is something that does not require any investment and can be done in your spare time. Fundraising for overheads is like an elephant in the room: it is hard not to notice it is there, but people try to avoid talking about it. Without a doubt, talking to friends about the promise of rejuvenation technologies or reposting research news on your Facebook feed is useful and it can be done for free. But what if the goal is more ambitious - to change local legislation to make it more longevity-friendly, to convert decision makers of the state grant system to allocate more money to rejuvenation research, or to reach out to wealthy individuals able to fund more studies? These activities require money.

Every member of our community hopes for rejuvenation therapies to be developed, implemented and delivered at an affordable price as soon as possible. Preferably in their and their relatives' lifetime. And even though there is a steady progress, it would be good to see it speed up. How? Mostly by removing things that are holding us back. The list of bottlenecks include the following aspects: insufficient research funding due to rejuvenation projects being innovative and not well understood by the decisionmakers in different funding bodies; flaws within the grant system: unnecessarily detailed grant applications and reports, making the scientists spend time on them, rigid rules on how money should be disposed during the project, delays in funding delivery; young scientists turning to mainstream topics like single diseases instead of rejuvenation to avoid reputational risks and problems with funding; lack of public awareness on the promise of rejuvenation technologies and the positive aspects of their massive implementation for our society; and many more. One could call life extension advocate successful if he or she is removing or mitigating some of these bottlenecks so the overall situation in the field measurably improves.

To write one popular but accurate article about aging research progress in a specific field, the activist has to spend 2-3 hours to familiarise himself with the latest publications on the topic. Writing 2-3 pages with scientific references can also take several hours. So one article usually takes a half of the working day. If the writer is also involved in social media development (which requires posting new original materials every day) this can no longer be considered a hobby: it becomes at the least a part-time job and that should be paid. Have a look at the level of salaries of scientific writers for financial reference.

The usual places to promote rejuvenation research and corresponding policies are scientific conferences, public events and meetings of working groups discussing necessary changes in a law. In addition to the conference fee, going to a conference implies travel expenditures and booking a hotel, which can stand for from several hundred to a few thousand per person, depending on the region where the conference takes place, and its duration. Promotion of a cause on a regular basis means an organization has to be represented at 10-20 events per year and often even more. Even if half of them do not have a registration fee, it means spending around 10k on the registration and up to 20k on travel and accommodation per person per year. Costs aside, going to a conference for advocacy reasons is a significant workload. In the case of lobbying for changes in the law (which can take several years), the activist has to attend from 5 to 20 meetings of the working group per year, to ensure the proposed changes are still being considered and keep being included in the new version of the law. Each meeting can take a half of a working day and implies some follow-up analytical and networking activities. You can view estimates of salaries of professional lobbyists or government relations managers for comparison.

Life extension advocacy groups are constantly seeking grant opportunities to cover their administrative needs. But all the same reasons that impede the scientists trying to receive a grant for rejuvenation research, also impede advocacy projects in our field. Due to the novelty of the idea of aging prevention, not many grant givers are keen to provide resources for its promotion. So before you ignore the "Donate" button that you see on the site of a life extension advocacy group, and before frowning at the line with administrative costs in their report, consider this: you and other members of our community are so far the only part of population who dislikes aging strongly enough to invest in the solution. And the best time to step in is always the same: now.

Over the past decades, the compression of morbidity was a basic strategy in gerontology. This strategy is aimed at limiting morbidity to a short time period near the end of life, thereby reducing the burden of diseases and disabilities through delay in the age at onset of the most common aging-related pathological conditions. A few years ago, a new direction in geriatric medicine, geroscience, began to develop. This interdisciplinary field of research is aimed at understanding the mechanistic links between aging and aging-associated diseases and centered primarily on extension of healthspan. According to the "geroscience hypothesis", aging could be manipulated in such a way that will in parallel allow delay the onset of all age-associated chronic disorders, because these pathologies share the same primary underlying risk factor, age.

Healthspan extension is a central component of activities aimed at achievement of 'optimal longevity', a condition defined as 'living long, but with good health and quality of life' including improved productivity, functioning and independence. Currently, the research attempted to enhance healthspan are focused primarily on slowing the biological processes underlying aging such as dysfunctions of mitochondria, impaired proteostasis and stem cell function and maintenance, deregulated sensing of cell energy status and growth pathways, cellular senescence, age-related decrease in stress resistance, as well as oxidative and inflammatory stress. These processes interact, influencing each other in order to maintain the normal pathways of cellular signaling and to support organismal homeostasis. The compensatory mechanisms mediating these processes, however, became exhausted when reaching a certain age and various aging aspects are manifested, enhancing as a consequence the risk of functional declines and progression of age-associated chronic pathologies.

Aging is traditionally regarded as 'natural' and consequently unpreventable process. However, in the opinion of many field experts, the idea that aging is inevitable part of human nature is rather questionable. Indeed, most present-day evolutionary theories postulate that aging has arisen as a by-product of fundamental evolutionary processes and does not have any specific function. If aging is in fact not an inadmissible component of life, then it might be manipulated like other processes that are commonly believed to be pathological or unnatural. The basic supposition underlying anti-aging research is that age-associated senescence may be regarded as a complex of pathophysiological processes that could be prevented, delayed, or even reversed.

The further elaboration of pharmaceuticals (both supplements and clinically approved drugs) specifically targeted at age-related pathologies is one of the most rapidly developing fields in modern biogerontology. An important point is, however, that most substances with potential anti-aging properties are apparently multifunctional and targeted at various molecular pathways that mediate aging. Furthermore, there is only limited evidence to demonstrate overall health benefits of using such substances so far. Findings from epidemiological studies reporting the long-term health impacts of these agents are rather inconsistent.

Another reasonable approach in anti-aging pharmacology is evaluation of the geroprotective potential of medications already approved by regulatory authorities for treating various pathological conditions related to aging. Among them, metformin, statins, beta-blockers, thiazolidinediones, newer generation β-adrenergic receptor inhibitors, renin-angiotensin-aldosterone system inhibitors, as well as anti-inflammatory medications appear to be the most promising drug candidates in this respect. The safety of these drugs has been confirmed in a number of clinical trials. This is also compelling evidence that they may improve health, well-being and physiological functioning in elderly patients suffering from chronic pathologies. One problem is that these substances are not used currently for treating age-related pathological conditions in the absence of clinical manifestations of particular illness. There are, however, good reasons to suggest that these agents could theoretically be redirected to preventing or treating other syndromes or conditions commonly associated with aging.

Despite an extraordinary rapid technological progress in pharmacology, there are few new preparations in the development pipeline now. Thereby, drugs generated on the basis of new knowledge gained from biogerontological research that can delay or prevent most age-associated disorders would apparently become "blockbusters" of modern pharmaceutical industry and market. That follows the idea that the extension of the healthy life expectancy by slowing aging process is the most efficient way to combat aging-related chronic illnesses and disabling conditions representing serious medical, social and economic issue in modern societies. This idea is referred to as the "longevity dividend" in the contemporary literature. Discovery and development of anti-aging drugs could likely provide an opportunity for revitalization of the drug development pipeline. Indeed, if it would be possible to slow down the aging process per se, then that would allow delay or prevent most aging-related disorders rather than combating them one by one, which is the conventional approach in the present-day disease-based paradigm of drug development.

Engineering human livers is a lofty goal. Human liver cells, hepatocytes, are particularly difficult to grow in the laboratory as they lose liver functions quickly in a dish. Now, researchers show that a "seed" of human hepatocytes and supporting cells assembled and patterned within a scaffold can grow out to 50 times its original size when implanted into mice. These engineered livers, which begin to resemble the natural structure of the organ, offer an approach to study organ development and as a potential strategy for organ engineering. "When we implant these tissues into a mouse with liver injury, the tissue seeds just blossom. Nature takes over and self-assembles a structure that looks like a human liver and has many liver-associated functions."

In 2011, the researchers showed that human liver-cell aggregates could be grown in mice. They assembled human hepatocytes and supportive stromal cells within a polymer scaffold, demonstrating that this dime-size artificial human liver tissue could grow stably for weeks in immune-compromised mice that had their own normal livers. The liver implant fused with the mouse circulatory system and received blood to perform a few liver functions. In the new work, the lab wanted to expand the size of the human liver graft beyond the 1 million cells used in the prior model. The team assembled different geometries of human primary hepatocytes, human umbilical vein endothelial cells, and fibroblasts, placed them within a degradable hydrogel, and implanted the tissue seed into a fat pad within a liver-injury mouse model.

To recapitulate liver damage, the animals are missing a key amino acid metabolism gene that results in toxic metabolite build up and progressive liver failure, which can be rescued by a drug used to treat individuals with a similar genetic disorder. The group chose this model because it they expected it to foster the liver seeds' growth. "The hypothesis is that mouse liver injury will produce factors that will travel through the blood stream and tell the human liver tissue to regenerate." The team found that the human liver tissue grew less in animals that were continuously treated with the drug compared to animals that were given intermittent cycles of the drug.

The human liver seed tissue grew best when they assembled endothelial cells into rope-like structures on top of the hepatocytes, rather than when the tissue was a spherical aggregate of all three cell types. The patterned tissue formed new structures in vivo, including ones that resembled bile ducts, and contained pockets of red blood cells, suggesting the presence of vascular structures within the tissue. The organ-like structures also produced appropriate human proteins such as albumin and transferrin.

Microglia, the immunocompetent cells of the central nervous system (CNS), act as neuropathology sensors and are neuroprotective under physiological conditions. Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production. An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation. A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions.

The retina is an extension of the brain and therefore the inflammatory response in the brain can occur in the retina. The brain and retina are affected in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and glaucoma. AD is an age-related neurodegeneration of the CNS characterized by neuronal and synaptic loss in the cerebral cortex, resulting in cognitive deficit and dementia. The extracellular deposits of beta-amyloid (Aβ) and intraneuronal accumulations of hyperphosphorylated tau protein (pTau) are the hallmarks of this disease. These deposits are also found in the retina and optic nerve. PD is a neurodegenerative locomotor disorder with the progressive loss of dopaminergic neurons in the substantia nigra. This is accompanied by Lewy body inclusion composed of α-synuclein (α-syn) aggregates. PD also involves retinal dopaminergic cell degeneration. Glaucoma is a multifactorial neurodegenerative disease of the optic nerve, characterized by retinal ganglion cell loss. In this pathology, deposition of Aβ, synuclein, and pTau has also been detected in retina.

These neurodegenerative diseases share a common pathogenic mechanism, neuroinflammation, in which microglia play an important role. Microglial activation has been reported in AD, PD, and glaucoma in relation to protein aggregates and degenerated neurons. The activated microglia can release pro-inflammatory cytokines which can aggravate and propagate neuroinflammation, thereby degenerating neurons and impairing brain as well as retinal function. The differential activation of microglial M1 or M2 phenotypes can produce a neurotoxic or neuroprotective environment, and could constitute a key in neuroinflammation regulation. In the search for a new strategy to control neuroinflammation, it might be more effective to change the M1 phenotype to the M2 phenotype than to block microglial activation completely. In the regulation of microglial activation, several cell types including, neurons, astrocytes, and T-cells are involved. When the neuroinflammatory process is triggered by protein aggregates (Aß, α-syn, pTau etc.), peripheral immune cells infiltrate CNS and prompt more activation on resident microglia, favoring neuroinflammatory processes.

Many tissues of our bodies, such as our skin, can heal because they contain stem cells that can divide and differentiate into the type of cells needed to repair damaged tissue. The cells of our retinas, however, lack this ability to regenerate. As a consequence, injury to the retina often leads to permanent vision loss. This is not the case, however, in zebrafish, which have a remarkable ability to regenerate damaged tissue, including neural tissue like the retina. This is possible because the zebrafish retina contains cells called Müller glia that harbor a gene that allows them to regenerate. When these cells sense that the retina has been injured, they turn on this gene, called Ascl1. The gene codes for a type of protein called a transcription factor. It can affect the activity of many other genes and, therefore, have a major effect on cell function. In the case of the zebrafish, activation of Ascl1 essentially reprograms the glia into stem cells that can change to become all the cell types needed to repair the retina and restore sight.

Researchers wanted see whether it was possible to use this gene to reprogram Müller glia in adult mice. The researchers hoped to prompt a regeneration that doesn't happen naturally in mammal's retina. Like humans, mice cannot repair their retinas. They created a mouse that had a version of the Ascl1 gene in its Müller glia that was turned on with an injection of the drug tamoxifen. Earlier studies by the team had shown that when they activated the gene, the Müller glia would differentiate into retinal cells known as interneurons after an injury to the retina of these mice. These cells play a vital role in sight. They receive and process signals from the retina's light-detecting cells, the rods and the cones, and transmit them to another set of cells that, in turn, transfer the information to the brain.

In their earlier research, however, the researchers found that activating the gene worked only during the first two weeks after birth. Any later, and the mice could no longer repair their retinas. The researchers determined that genes critical to the Müller glia regeneration were being blocked by molecules that bind to chromosomes. This is one way cells "lock up" genes to keep them from being activated. It is a form of epigenetic regulation - the control of how and when parts of the genome operate. In their new paper, the researchers show that by using a drug that blocks epigenetic regulation called a histone deacetylase inhibitor, activation of Ascl1 allows the Müller glia in adult mice to differentiate into functioning interneurons. The researchers demonstrated that these new interneurons integrate into the existing retina, establish connections with other retinal cells, and react normally to signals from the light-detecting retinal cells.

The infectious nature of Alzheimer's disease (AD) was revealed when spirochetes (both dental and Lyme) were shown to be present in the brains of affected patients. The dental microbes travel from the oral cavity during times of disruption of the dental plaque and subsequent bacteremia following dental procedures. Lyme borrelia travel to the brain via the blood stream during the secondary stage of that disease. The spirochetes have an affinity for neural tissue and pass through the blood-brain barrier easily. Once the spirochetes are in the brain, they attach, divide (albeit very, very slowly), and multiply. When they reach a quorum, they begin to spin out a biofilm. Because of the exceedingly slow division, it takes approximately 2 years to accumulate sufficient organisms to make one biofilm. At some point after attachment and formation of the biofilms, the innate immune system becomes activated and attempts to destroy them.

The innate immune system first responder, Toll-like receptor 2, generates both NF-κB and TNF-α which try to kill the spirochetes in the biofilm, but cannot penetrate the "slime". NF-κB is also responsible for the generation of amyloid-β (Aβ) which itself is anti-microbial. Aβ cannot penetrate the biofilm either, and its accumulation leads to destruction of the cerebral neurocircuitry. Where spirochetes have been found in the brains of Alzheimer's disease (AD), it may be considered an infectious disease. Treatment with a bactericidal antibiotic with a concomitant biofilm disperser seems most reasonable; but any neurologic damage is irreversible. It is therefore of the utmost importance to treat early in the course of this disease.

Age-related phenotypes within the hematopoietic system can be influenced by cell-extrinsic alterations, such as changes in the bone marrow (BM) microenvironment. However, in mice, ample evidence points to intrinsic alterations in the hematopoietic stem cells (HSCs) themselves as the main drivers of hematological aging. These include functional, genetic, and epigenetic modifications. In mice, HSCs increase in frequency that however is paralleled by a decreased proliferative capacity on a per-cell basis. In several reports, aged murine HSCs have been characterized by an increased myeloid-to-lymphoid output, often referred to as a myeloid bias (My-bi), although also their myeloid cell forming ability is decreased on a per cell basis when compared to younger HSCs.

These observations are presumably coupled to an age-related clonal shift within the aged HSC compartment towards increased My-bi HSC frequency at the expense of lymphoid-biased (Ly-bi) HSCs. Regardless, the lineage skewing with murine HSC aging has been linked to an upregulation of myeloid-specific genes and a downregulation of lymphoid-specific genes, although many of previous transcriptome analyses were based on a selection and manual curation of lineage-associated genes. By contrast, recent global transcriptome analysis of single HSCs based on more objectively defined lineage-affiliated transcription programs revealed a molecular and functional platelet bias, rather than a My-bi, in aged murine HSC.

Human HSC and progenitor cell aging has not been characterized as extensively as within the murine system, but several parallels suggest that aging characteristics at least to some degree might be conserved across species. For instance, HSC proliferation and clonal diversity decline between cord blood (CB) and aged bone marrow (BM). In addition, donor age affects outcome of clinical BM transplantations, although this most likely cannot be solely attributed to reduced HSC performance. More direct evaluations of the frequencies and function of aged human hematopoietic stem and progenitor cells (HSPCs) from a limited number of individuals displayed similarities to previous findings in the mouse, including an increased myeloid-to-lymphoid output ratio and decreased reconstitution potential, although this is not undisputed. In the present study we characterize age-related changes of human HPSCs and compare these to similar studies in mice. By separating the myeloid lineage into megakaryocytic/erythroid and granulocyte/macrophage lineage, we could reveal a molecular underpinning of megakaryocytic/erythroid bias in aged HSC of both humans and mice.

Downstream of human HSCs, we observed decreasing levels of common lymphoid progenitors (CLPs), and increasing frequencies of megakaryocyte/erythrocyte progenitors (MEPs) with age, which could be linked to changes in lineage-affiliated gene expression patterns in aged human HSCs. These findings were paralleled in mice. Therefore, our data support the notion that age-related changes also in human hematopoiesis involve the HSC pool, with a prominent skewing towards the megakaryocytic/erythroid lineages, and suggests conserved mechanisms underlying aging of the blood cell system.

Our results support the notion that an increased HSC frequency with age may be a compensatory mechanism to sustain sufficient blood cell replenishment. However, these compensatory mechanisms do not fully maintain optimal functions of HSCs and progenitor cells in elderly humans, as evidenced by the frequency of age-related hematological defects, including anemia and reduced immune responses. A deeper understanding of the events underlying this functional decline may support interventional approaches to prevent or ameliorate the aging hematopoietic phenotype.

Being first isolated in 1966 from bone marrow, mesenchymal stem cells (MSC) are adult stromal nonhematopoietic cells, well known for their potential to differentiate into osteoblasts and osteocytes. Although they are most known for their osteogenic differentiation potential, MSC have the ability to commit into all three lineages (osteogenic, chondrogenic, and adipogenic). MSC have been isolated and purified not only from bone marrow where they cooperate with hematopoietic stem cells (HSC) to form the niche, but also from various tissues, such as umbilical cord and umbilical cord blood, white adipose tissue, placenta, and the amniotic membrane of placenta. The capacity of MSC to differentiate into cell lineages and develop teratoma, a preserved tumor that contains normal three-germ layer tissue and organ parts, is a reason to consider them as multipotent progenitor cells suitable for regenerative therapy.

Beside their potential to differentiate into osteoblasts in the process of osteogenesis, there have been several other regenerative roles attributed to MSC. These cells can serve as pericytes wrapping around blood vessels to support their structure and stability. MSC have also shown the potential to integrate into the outer wall of the microvessels and arteries in many organs, such as spleen, liver, kidney, lung, pancreas, and brain. This led to the speculation that both bone marrow- and vascular wall-derived MSC as well as white adipose tissue-, umbilical cord blood-, and amniotic membrane-derived MSC could act as a cell source for regenerative therapy to treat various disorders such as osteoporosis, arthritis, and vessel regeneration after injury.

MSC may also be induced to differentiate into functional neurons, corneal epithelial cells, and cardiomyocytes under specific pretreatments ex vivo and in vivo that broaden the capacity of these cells in regenerative therapeutic interventions. In a previous study, umbilical cord matrix stem cells derived from human umbilical cord Wharton's Jelly were aimed to treat neurodegenerative disorders such as Parkinson's disease by transplantation into the brain of a rat model. The transplantation resulted in a significant reduction of symptoms for Parkinson's disease, thus suggesting an additional therapeutic role for umbilical cord matrix stem cells (MSC) in treating central nervous disorders. Further, MSCs exibit potent immunomodulatory and anti-inflammatory properties through cellular crosstalk and production of bioactive molecules.

These findings were enough evidence for scientists to speculate a promising role for MSC in regenerative therapy. In the past years, MSC have been used in clinical trials aiming for regeneration of tissues such as bone and cartilage as well as treatment of disorders such as spinal cord injury, multiple sclerosis (MS), Crohn's disease, and graft-versus-host disease (GvHD) due to their broad differentiation capacity and potential of hematopoietic cell recruitment. Several clinical trials are running to identify different aspects of MSC application in terms of safety and efficacy, and at the time of writing, a total number of 657 past clinical studies were found that involve mesenchymal stem cells for different clinical phases.