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Fight Aging! Newsletter, April 15th 2019


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Posted 14 April 2019 - 12:43 PM


Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

This content is published under the Creative Commons Attribution 4.0 International License. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

To subscribe or unsubscribe please visit: https://www.fightaging.org/newsletter/

Contents

  • Retinal Scans to Visualize the Loss of Capillary Density in the Central Nervous System
  • The Effects of Extracellular Vesicles from Senescent Cells in Osteoarthritis
  • Growing Muscle and Strengthening Bone in Mice with a Follistatin-Like Molecule
  • Chemotherapy Accelerates Age-Related Tauopathy and Cognitive Decline in Mice
  • An Interview with Aubrey de Grey at Undoing Aging 2019
  • An Interview with Vittorio Sebastiano of Turn.bio
  • CD22 Antibodies Enhance Microglial Function and Cognitive Function in Mice
  • Upregulation of YAP or FOXD1 Reduces Cellular Senescence and Osteoarthritis in Mice
  • Aubrey de Grey on the Dawn of the Era of Human Rejuvenation
  • The Interventions Testing Program Finds Glycine Supplementation has a Tiny Effect on Mouse Life Span
  • In Rotifers, the Offspring of Older Mothers Benefit More From Calorie Restriction
  • Gum Disease Bacteria More Common in the Brains of Alzheimer's Patients
  • Calorie Restriction Reduces Inflammation via Moderate Hyperadrenocorticism
  • The Dysfunctional Immune Response in the Development of Alzheimer's Disease
  • Faltering Glial Cell Activities in the Development of Parkinson's Disease

Retinal Scans to Visualize the Loss of Capillary Density in the Central Nervous System
https://www.fightagi...nervous-system/

The angiogenesis hypothesis of aging suggests that loss of capillaries throughout the body is an important driver of age-related decline. This loss must be a downstream consequence of other forms of damage and dysfunction, issues that lead to a disruption of the balance of signals and cell capabilities needed to maintain the network of capillary blood vessels. Hundred of capillaries pass through every square millimeter of tissue, allowing the bloodstream to nourish the resident cells. If the density of that network declines, then ever lesser amounts of oxygen and nutrients are delivered to the cells that need them. This is particularly important in tissues requiring a great deal of energy, such as muscles and the brain. As for all aspects of aging, of course, there is good evidence for this process of capillary loss to be relevant, but the relative size of the effect is unknown, when comparing against other processes of aging. Only when specific aspects of age-related decline can be repaired in isolation is it possible to see the size of their contribution.

The retina is considered a part of the central nervous system, and thus the eyes can act as a window into the state of aging in the brain and major nerves. In today's open access paper, researchers report on the use of scanning technologies to visualize the decline in capillary density in the retina. This is a mark of aging, related to just how much deterioration and damage has taken place in tissues. This is why it correlates well to incidence of Alzheimer's disease, I would expect. Alzheimer's disease has many causes and disease processes, of which at least some, such as chronic inflammation in the central nervous system, can be credibly argued to disrupt the regenerative processes responsible for maintaining tissues and blood vessel networks.

Eyes reveal early Alzheimer's disease

It's known that patients with Alzheimer's have decreased retinal blood flow and vessel density but it had not been known if these changes are also present in individuals with early Alzheimer's or forgetful mild cognitive impairment who have a higher risk for progressing to dementia. Multicenter trials could be implemented using this simple technology in Alzheimer's clinics. Larger datasets will be important to validate the marker as well as find the best algorithm and combination of tests that will detect high-risk subjects. The back of the eye is optically accessible to a new type of technology (OCT angiography) that can quantify capillary changes in great detail and with unparalleled resolution, making the eye an ideal mirror for what is going on in the brain.

Researchers recruited 32 participants who had cognitive testing consistent with the forgetful type of cognitive impairment, and age-, gender- and race- matched them to subjects who tested as cognitively normal for their age. All individuals underwent the eye imaging with OCT angiography. The data were analyzed to identify whether the vascular capillaries in the back of the eye were different between the two groups of individuals. Now the team hopes to correlate these findings with other more standard (but also more invasive) types of Alzheimer's biomarkers as well as explore the longitudinal changes in the eye parameters in these subjects.

Parafoveal vessel loss and correlation between peripapillary vessel density and cognitive performance in amnestic mild cognitive impairment and early Alzheimer's Disease on optical coherence tomography angiography

Optical coherence tomography angiography (OCTA) is a non-invasive clinical tool that can capture the retinal capillary microcirculation at the micrometer resolution. Previous retinal vascular studies using retinal functional imager and laser flowmetry have shown decreased flow in the temporal retinal vein and major parafoveal arterioles and venules in Alzheimer's disease (AD) and mild cognitive impairment (MCI) individuals. However, OCTA provides a unique opportunity to investigate the microvasculature in a specific retinal vascular plexus of interest. OCTA has demonstrated that retinal neural sub-layers are supplied by distinct capillary plexuses, each reflecting the metabolic demand of a particular neuronal layer. Importantly, we know that the inner retina layer in both the macula and optic disc bears the brunt of AD pathology including the loss of ganglion cells, thinning of the retinal nerve fiber layer (RNFL), and deposition of amyloid-β plaques according to histological and OCT structural imaging studies.

Our study shows that compared to matched cognitively normal controls, participants with early cognitive impairment demonstrated significantly decreased superficial parafoveal vessel density and blood flow. In addition, we found that parafoveal and peripapillary densities were positively correlated with the Montreal Cognitive Assessment (MoCA), a measure of overall cognitive impairment. Most importantly, we demonstrated the role of OCTA in detecting early capillary changes, which may represent potentially early, non-invasive biomarkers of AD. Future directions include a larger cohort as well as longitudinal studies that examine the temporal relationship between vascular damage and pathological loss of ganglion cells, their nerve fibers, and cognitive decline.

The Effects of Extracellular Vesicles from Senescent Cells in Osteoarthritis
https://www.fightagi...osteoarthritis/

The accumulation of senescent cells in all tissues throughout the body is one of the causes of aging. These errant cells are never present in enormous numbers relative to non-senescent cells that make up the overwhelming majority of tissues even in very old people. Yet they cause significant harm. Senescent cells secrete a mix of inflammatory signals that disrupts tissue structure and function, and provokes a state of chronic inflammation that further contributes to the progression of age-related disease. Much of this signaling, as for any cell type, is carried via extracellular vesicles, membrane-bound packages of molecules that pass between cells.

In recent years, a great deal of attention has been given to the secretion of vesicles and their effects on recipient cells. One strong motivation for this work is that vesicles they are comparatively easy to harvest and use in comparison to the cells that create them. Many first generation stem cell therapies, those that produce therapeutic effects via signals delivered by the transplanted cells in the short time before they die, might be replaced with delivery of vesicles, which is logistically a much easier form of treatment.

In the case of senescent cells, researchers are investigating secreted vesicles and their contents to better understand exactly how these cells contribute to age-related disease, at the very detailed level of molecular interactions. This work is largely disconnected from efforts to destroy senescent cells via senolytic treatments, however: the development community doesn't need to understand how senescent cells cause harm in order to prevent them from causing harm. This is an important aspect of much of the present development of rejuvenation therapies, in that the mode of treatment effectively bypasses the lack of scientific knowledge regarding exactly how specific mechanisms of aging progress in detail.

Senescence cell-associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers

Osteoarthritis (OA) is an age-related and posttraumatic degenerative joint disease that is accompanied by cartilage degradation, persistent pain, and impairment of mobility. Senescent cells (SnCs) are a newly implicated factor in the development of OA. Cellular senescence is characterized by a proliferation arrest, which protects against cancer, as well as other changes that can also contribute to aging phenotypes and pathologies. SnCs accumulate with age in many tissues, including articular cartilage, where they promote pathological age-related deterioration.

These and other tissue pathologies are presumably mediated by the secretion of extracellular proteases, proinflammatory cytokines, chemokines, and growth factors, termed the senescence-associated secretory phenotype (SASP), by SnCs. The local elimination of SnCs in a murine model of posttraumatic OA (PTOA) reduced pain and increased cartilage development. Bridging these results to human cells, the selective removal of senescent chondrocytes improved the cartilage-forming ability of chondrocytes isolated from human arthritic tissue. Recent findings suggest that SnCs can transmit limited senescent phenotypes to nearby cells, termed secondary or paracrine senescence. Understanding the mechanisms of this SnC transmission may inform mechanisms of OA disease causation.

Extracellular vesicles (EVs), including exosomes and microvesicles, are small membrane-limited particles that can participate in intercellular communication. EVs mediate local tissue development and homeostasis through the transfer of cargoes, such as proteins and microRNAs (miRs). For example, the EVs present in articular cartilage and synovial fluid can contribute to mineralization of the cartilage extracellular matrix (ECM) and formation of an inflammatory joint environment. Recently, it was reported that SnCs secrete more EVs compared with their nonsenescent counterparts. These senescent-associated EVs may also induce senescence in neighboring cells. In the case of arthritis, SnCs can modulate the environment of the articular joint, increasing inflammation and ECM degradation. It is not known whether EVs secreted by SnCs in the articular joint are responsible for the progression of OA or whether they can be use as indicators of disease progression and treatment efficacy.

In this study, we found that senescent chondrocytes isolated from OA patients secrete more EVs compared with nonsenescent chondrocytes. These EVs inhibit cartilage ECM deposition by healthy chondrocytes and can induce a senescent state in nearby cells. We profiled the miR and protein content of EVs isolated from the synovial fluid of OA joints from mice with SnCs. After treatment with a molecule to remove SnCs, termed a senolytic, the composition of EV-associated miR and protein was markedly altered. The senolytic reduced OA development and enhanced chondrogenesis, and these were attributable to several specific differentially expressed miRs (miR-30c, miR-92a, miR-34a, miR-24, miR-125a, miR-150, miR-186, and miR-223) and proteins (Serpina and aggrecan). In aged animals, treatment with senolytic modulated the inflammatory response by decreasing recruitment and activation of myeloid and phagocytic cells. Collectively, these findings suggest that altered levels of synovial EV miRs and proteins are a potential mechanism by which SnCs can transfer senescence, inhibit tissue formation, and promote OA development. When isolated from synovial fluid, EVs may also be used to predict therapeutic response to senolytic therapies in the articular joint.

Growing Muscle and Strengthening Bone in Mice with a Follistatin-Like Molecule
https://www.fightagi...-like-molecule/

In today's research materials, the authors report on the use of follistatin-like molecules to enhance bone density and increase muscle mass in mice. Myostatin and follistatin are well known to control muscle growth, and are consequently among the most promising targets for near future gene therapies. Either inhibition of myostatin, which can be achieved via antibody therapies in addition to gene therapies, or upregulation of follistatin can be used to deliver increased muscle growth in mammals. There are natural myostatin loss of function mutants in many species, including a few humans, and a range of heavily muscled engineered lineages in mice, dogs, and the like. There is robust evidence for this alteration to be essentially beneficial, and it does in fact modestly increase life span in mice in addition to the direct benefits relating to muscle mass.

While additional muscle growth at any age sounds quite desirable, the main reason for considering this sort of therapy is to slow or perhaps turn back to some degree the characteristic loss of muscle mass and strength that occurs with advancing age. This happens to everyone, and is given the name sarcopenia. While targeting myostatin or follistatin seems likely to be effective to some degree, and reliably effective if the animal data is any guide, it doesn't address the underlying causes. It is a compensatory approach only, and even the highly effective compensatory approaches eventually run into the wall of ever-increasing molecular damage that overflows the mechanisms of compensation.

The interesting aspect of the line of work supporting the research noted here, which apparently dates back quite a few years, is that follistatin is just one point in a spectrum of potential molecules that can influence bone density in addition to muscle mass. The myostatin / follistatin gene therapies of the near future may turn out to deliver follisatin-like molecules into tissues rather than follistatin itself, these molecules tailored to specific outcomes in their bone or muscle development.

New medication gives mice bigger muscles

Researchers have studied a new group of medication which could prove beneficial for the elderly and the chronically ill who suffer a loss of bone- and muscle mass. They have named the group of medicinal products IASPs, Inhibitors of the Activin-receptor Signaling Pathway. IASPs inhibit a signal pathway which is found in virtually all cells. The difference between the various medications in the group is that they inhibit different routes into the pathway. The researchers have shown that it is possible to achieve an effect on different tissues such as muscle tissue, bone tissue, or blood cells depending on the IASP they used.

"We found an increased muscle mass of 19 per cent in mice after just one week. At the same time as an effect on the muscle mass, we saw that the drugs also counteracted osteoporosis." However, there is an Achilles heel. The effect on the blood cells has presented the researchers with a challenge. Thus far the drugs in the group of medicinal products have stimulated the formation of red blood cells. "This isn't bad if we're dealing with someone suffering from anaemia, low muscle mass, and osteoporosis all at once, as is the case for some. But for the majority of patients with a normal blood per cent, this increases the risk of blood clots." The researchers have therefore been working on a solution. They have succeeded in creating a molecule in the IASP group which for the first time works on bones and muscles but does not affect the blood.

A follistatin-based molecule increases muscle and bone mass without affecting the red blood cell count in mice

Inhibitors of the activin receptor signaling pathway (IASPs) have become candidate therapeutics for sarcopenia and bone remodeling disorders because of their ability to increase muscle and bone mass. However, IASPs utilizing activin type IIA and IIB receptors are also potent stimulators of erythropoiesis, a feature that may restrict their usage to anemic patients because of increased risk of venous thromboembolism. Based on the endogenous TGF-β superfamily antagonist follistatin (FST), a molecule in the IASP class, FSTΔHBS-mFc, was generated and tested in both ovariectomized and naive mice.

In ovariectomized mice, FSTΔHBS-mFc therapy dose-dependently increased cancellous bone mass up to 42% and improved bone microstructural indices. For the highest dosage of FSTΔHBS-mFc, the increase in cancellous bone mass was similar to that observed with parathyroid hormone therapy. The quadriceps femoris muscle mass dose-dependently increased up to 21% in ovariectomized mice. In both ovariectomized and naive mice, FSTΔHBS-mFc therapy did not influence red blood cell count or hematocrit or hemoglobin levels. If the results are reproduced, a human FSTΔHBS-mFc version could be applicable in patients with musculoskeletal conditions irrespective of hematocrit status.

Chemotherapy Accelerates Age-Related Tauopathy and Cognitive Decline in Mice
https://www.fightagi...ecline-in-mice/

It is fair to say that the extended chemotherapy treatment that is provided to cancer patients has the side-effect of accelerating aging. On the one hand, we can look at the epidemiological data to see the reduction in life expectancy and increased risk of age-related disease suffered by cancer survivors who underwent chemotherapy. It is also possible to look at various aging-associated biomarkers and see that they indicate an older biological age in these former patients. With the modern acceptance of senescent cell accumulation as an important cause of aging, it has become clear that the generation of excess senescent cells by chemotherapeutics is most likely the primary cause of accelerated aging in chemotherapy patients.

Lingering senescent cells build up in tissues with age, and secrete a potent mix of inflammatory signals and other harmful molecules that rouse the immune system into chronic inflammation, disrupt tissue structure and function, and cause nearby cells to change their behavior for the worse as well. When treating cancer, forcing cancer cells into senescence is beneficial: they stop replicating, and most self-destruct. Chemotherapy is fairly indiscriminate, however, and adds to the burden of senescence throughout the body. These cells then go on to speed up the development of all of the common age-related diseases via chronic inflammation, fibrosis and other disruptions of tissue regeneration, and other mechanisms. This is better than dying of cancer, but certainly worse than having fewer senescent cells.

Today's open access study is just about the opposite of work published earlier this year, in which researchers demonstrated that using senolytic therapies to clear senescent glial cells in the brain could reverse neuroinflammation and tau protein aggregation in a mouse model of Alzheimer's disease. The late stages of this condition are marked by neurofibrillary tangles of hyperphosphorylated tau protein, and it seems likely that chronic inflammation, senescence, and dysfunction of other sorts in glial cells are an important mechanism bridging the gap between early accumulation of amyloid-β and later accumulation of tau protein in the progression of Alzheimer's. In the work reported here, researchers used a chemotherapeutic to general more senescent cells in mice, and showed that this accelerated aggregation of tau protein in the brain.

Chemotherapy accelerates age-related development of tauopathy and results in loss of synaptic integrity and cognitive impairment

More than 74% of the 15.5 million cancer survivors in the United States are 60 years old or older. Various reports suggest that 35%-85% of patients treated for cancer suffer from long term reductions in cognitive function, which include attention deficits, decreased executive functioning and multitasking, and decreased memory function. Neuroimaging data obtained in patients treated for cancer indicate that cognitive deficits in these patients are associated with changes in the functional connectome and in structure of the white matter. In at least a subset of cancer survivors, there is evidence for accelerated biological aging.

Aging increases neuronal vulnerability and is associated with buildup of damaged proteins that perturb neuronal circuits. During aging, conformational changes and post-translational modifications of tau protein, such as phosphorylation, result in dissociation of tau from axonal microtubules. These changes in tau lead to missorting and clustering of the protein, a process known as age-related tauopathy. Tauopathy is associated with the synapse loss and neuroinflammation that occur during aging, and is exaggerated in human Alzheimer's disease patients and in animal models of the disease.

Most studies on chemotherapy-induced cognitive impairment have been done in patients undergoing treatment for breast cancer. However, there is accumulating evidence that patients treated with platinum-based compounds for solid tumors including testicular, lung, bladder, and head and neck cancer also frequently develop cognitive deficiencies and structural abnormalities in the brain. Preclinical studies have shown that administration of chemotherapeutic agents, including cisplatin and doxorubicin to mice increases expression of cellular senescence markers. We and others showed that treatment of young adult rats or mice with these chemotherapeutics reduces their performance in cognitive function tasks and induces structural changes in the brain.

We hypothesized that chemotherapy-induced cognitive impairment is associated with accelerated development of tau clustering in the brain as a sign of accelerated aging. We show for the first time that treatment of adult (7-8 month-old) male C57BL/6 mice with cisplatin results in reduced cognitive function and a marked increase in the number of large endogenous tau clusters in the hippocampus when assessed 4 months later. In contrast, we detected only few small tau clusters in the hippocampus of age-matched 11-12 month-old control mice. Our current findings indicate that the chemotherapeutic cisplatin accelerates development of age-related tauopathy, identifying chemotherapy as one of the possible causes for the accelerated aging in cancer patients. Further studies should include additional chemotherapeutics and also investigate ways to prevent the development of tauopathy after chemotherapy in order to mitigate accelerated brain aging in patients treated for cancer.

An Interview with Aubrey de Grey at Undoing Aging 2019
https://www.fightagi...ing-aging-2019/

The Life Extension Advocacy Foundation (LEAF) volunteers were out in force at the recent Undoing Aging conference in Berlin, networking and conducting interviews. The event was a who's who of the rejuvenation research and broader longevity science communities. These are in fact two different things: despite the growing focus on senolytics to clear senescent cells from aged tissues, work on methods of rejuvenation after the Strategies for Engineered Negligible Senescence (SENS) model of damage repair is still something of a minority concern embedded within a broader field that is much more concerned with stress response upregulation via calorie restriction mimetics and similar approaches. If the goal is an end to aging as soon as possible, then want to see more rejuvenation capable in principle of large, reliable gains in health and life expectancy, and less tinkering with metabolism that is only capable in principle of small, unreliable gains in health and life expectancy. In this context, it doesn't hurt that central, important events like Undoing Aging are organized by people with a strong rejuvenation focus.

LEAF will be publishing any number of interviews in the weeks ahead, and today's example is an interview with one of the hosts of Undoing Aging, Aubrey de Grey of the SENS Research Foundation. I feel that by now de Grey should require little introduction. For the past fifteen years or more, he has been one of the most vocal proponents of tackling aging as a medical condition, in particularly by developing therapies to repair, reverse, or work around the root causes of aging. Quite early on, de Grey assessed the literature and proposed a set of research programs that would tackle all of the forms of molecular damage and cell dysfunction that cause aging. This was an extensive work of synthesis, drawing together strands of research from throughout the life science community that had, up until that point, been given all too little attention. It has been a long road from the stage of a few voices in the wilderness to today's realization of the first actual, real, working rejuvenation therapies, in the form of senolytics. Nonethless, here we are, finally.

An Interview with Dr. Aubrey de Grey

How has SENS been progressing over the years, and what's going on right now?

The idea of comprehensive damage repair as a way to really bring aging under proper medical control and keep people useful much later in life has now become completely mainstream. It's been kind of reinvented by various groups over the past few years so that now it's kind of become the orthodox way of thinking. Moreover, the progress that's been made in the laboratory by, of course, us with our various projects, and also by other people, has got to the point where these projects have become investable. They've got to the point where people, perhaps not every investor, but at least the more visionary investors who are comfortable with high-risk, high-reward activities, are getting in there. They're seeing how to join the dots as a value proposition. The result is that we've, so far, over the past few years, been able to spin out half a dozen of our projects into startup companies and align in parallel with us. There's dozens and dozens more companies coming along literally once a week, now, it's ridiculous how rapidly, that are doing stuff that is very much rejuvenation, very much damage repair.

In terms of the seven deadly things that SENS plans to tackle, could you give us some examples of where we are specifically for each of them or some of them?

The best news at the level of SENS Research Foundation is that the most challenging, the most difficult components of SENS are now beginning to yield. We're really now seeing very significant, dramatic progress, albeit still early stage, but going much faster than it was even a couple of years ago. The ones that are slightly less hard, for example, the removal of molecular waste products inside cells, those things have gone far enough that they have become spin-off companies. We've got two companies created that way: we've got a company that's looking at the extracellular stiffening problem of restoring elasticity, and we've got a company looking at death-resistant cells, cells that are getting into a senescent state. This is all going amazingly well.

For the most difficult things, in which I will especially include mitochondrial mutations, we're now undisputedly the world leaders in these areas. These are lines of research that everyone had totally given up on to the point of being really certain that they were completely impossible and would never make progress. We just had the persistence to do enough to get there. It really is a great example of how the short term-ism that is imposed upon scientists by the system of science funding that exists worldwide has had an enormously damaging effect in stopping people from working on the most valuable work and forcing them to work on low-hanging fruit that doesn't scale.

As a final question, how do you like how the conference is going?

The main thing that I've got to say about this particular conference that blows my mind is the sheer number of people that are here. We have run conferences starting with my own conferences back in 2003. We've run lots and lots of them over the years, and they never grow; my first conference back in '03, had maybe 200, 250 people, and all the other ones that I ran, that series in Cambridge, were about the same, fluctuating by 20 or so. We were not seeing any increase in enthusiasm, and so on, resulting from the work that was being done. That was the same with the conferences that we ran in California in the period like 2014 through '17. It was also true for conferences that other people have run, they started but they're not grown.

Now, we may be just hitting that point where it's take-off time. Last year, the first time that the Berlin Conference happened, the first one in Europe in five years since my last conference in 2013 in Cambridge, and it was big. It was 300 people; that's on the high side. I thought, well, that's great, but it's probably just because I haven't done one in Europe for five years. I was thinking this year, they'll do really well to keep it at 300 people, and we sold out, which is 500 people; we literally were not allowed to bring any more people in because of the size of the venue and the fire regulations and so on.

An Interview with Vittorio Sebastiano of Turn.bio
https://www.fightagi...no-of-turn-bio/

Turn.bio is working on an interesting approach to induction of pluripotency in the tissues of living animals. They use a form of temporary reprogramming to take cells only some of the way to a pluripotent state, far enough that they issue the sort of beneficial signaling expected of induced pluripotent stem cells, and potentially also repair some of their internal damage, such as via the clearance of dysfunctional mitochondria, but not so far they they actually become induced pluripotent stem cells. The cells revert back to their original state, but with the benefit of some damage repair, and a changed signaling environment. As the company progresses, we shall see whether or not this more careful, partial approach is enough to avoid the risk of cancer that is suspected to result from inducing pluripotency in vivo.

We've already seen successful partial cellular reprogramming in living animals through OSKM induction. How does your approach differ?

Well, I think that work is absolutely the first proof of principle that some kind of cellular rejuvenation is triggered by the expression of reprogramming factors. The only caveat is that our work is significantly different from their work, in the sense that our work really demonstrates for the first time that in the naturally aged context, that's what we can also do. We looked at human samples all the way from 50 to 95 years old. We have shown this across multiple cell types; we have looked holistically and comprehensively at all the hallmarks of aging, including transcriptomic, methylation clock, physiology of aging, and stem cell homeostasis. Another fundamental difference is the fact that we're using mRNAs. Now, mRNAs are non-integrative, they are clinically translatable, and so they huge potential to bring this to the clinic.

In your experiment, you reach a four day transient expression period, using these factors. How did you reach that four-day figure?

It's not four days for all cell types; it depends on the cell type. If we differentiate cells like fibroblasts and endothelial cells, we use four days, for chondrocytes, three days, and for muscle stem cells, we use two days. This is actually part of the secret of finding the sweet spot, the empirical moment in time just before the point of no return where the cell is becoming partially reprogrammed but has not yet lost its identity. We know that during the process, it takes 12-15 days for cells to go all the way back to iPSCs. We know from previous studies that already, by day five, we can see early signs of the activation of genes that are pluripotency-associated. For fibroblasts or endothelial cells, that's the time when we see these early events, so we want to stop before that because that would potentially trigger or instigate a potential loss of cell identity.

How would we systemically treat a human in this manner if different cells need different reprogramming times?

Well, the short answer to that is that we don't know that yet, and we need to figure that out. I can tell you the way we're approaching this, particularly on the company side: there is a short-term application, which is most likely going to be the ex vivo approach. The stem cells are going to be isolated from the tissue, rejuvenated in vitro, and then transplanted back. In that type of scenario, we have a uniform population of cells for which we have found this sweet spot so that we can utilize them. Also, because it is done ex vivo, we can make sure the target cells have not changed their identity and are safe. That's one approach.

Do you think your technology has the potential to make systemic rejuvenation in humans a plausible and available prospect in, say, the next 10 to 20 years?

Yes, I strongly believe so, even though at first glance it may seem really difficult, and maybe to some extent impossible, because we naively think about getting everywhere in the body. There is another possibility: what if we could, for example, as we said before for the muscle, what if we can actually target a tissue or an organ that actually has a very dramatic systemic effect on its own? In other words, what if we could, for example, target the hypothalamus? The hypothalamus is one of the main systemic regulators of endocrine functions, and it is shown that inflammation in the hypothalamus affects the entire body. So, what if we started with the hypothalamus, or what if we started at the endothelium in the body, which is pretty much everywhere in every single vessel? The endothelial cells secrete a lot of pro-inflammatory or anti-inflammatory cytokines, so just on its own, this one tissue could actually have a dramatic, systemic effect.

CD22 Antibodies Enhance Microglial Function and Cognitive Function in Mice
https://www.fightagi...nction-in-mice/

One of the many jobs undertaken by microglia in the central nervous system is to clean up pathogens, cell debris, and other molecular waste, ingesting it and breaking it down. Microglia become less capable with age, which is at least in part attributed to the more inflammatory environment characteristic of older individuals, but there are probably other significant causes. These cells do not replicate, and so are most likely more vulnerable to the accumulation of molecular damage than most cell populations.

In particular, this and other forms of stress can lead to cellular senescence, and senescent microglia have now been implicated in the progression of Parkinson's disease and Alzheimer's disease. The advent of senolytic therapies to selectively destroy senescent cells may turn out to produce significant benefits to patients with these and other neurodegenerative conditions. Of note, cellular senescence causes issues in part because these errant cells produce inflammatory signaling that rouses and disrupts the immune system, including other microglia. Cause and effect in the brain can be quite circular and confusing.

The ingest-then-digest procedure employed by microglia and other immune cell types in the body is called phagocytosis. A new study used laboratory techniques to identify mouse genes whose activity either impairs or enhances microglial phagocytosis and whose activity levels either increase or decrease substantially with age. The investigators picked about 3,000 genes encoding proteins that they judged could be targeted by drugs or that had already been the focus of drug development. The goal was to learn how each blockade affected the ability of cultured mouse microglia to ingest small particles of latex. One at a time, they blocked each gene's ability to encode a protein. In a parallel experiment, the investigators determined which of those approximately 3,000 genes are more or less active in microglia from the hippocampi of young mice versus old mice.

Surprisingly, when the scientists compared the results of both experiments, they found just one gene that affected microglial phagocytosis and whose activity in microglia substantially changed with advancing age. Older microglia produced far more copies of this gene - a proxy for upregulated production of the protein for which the gene is a blueprint - than younger ones did, and knocking out its function greatly improved microglial phagocytosis. So they zeroed in on this gene, called CD22, which is found in both mice and humans. In a follow-on experiment, the CD22 protein turned up three times as often on the surface of older mice's microglia as on those of younger mice's microglia, confirming the gene-activity finding. These proteins could be blocked by antibodies, molecules that bind to a specific protein and can be generated in the lab. Antibodies are bulky and don't easily penetrate cells, but they're excellent for targeting cell-surface proteins.

The team injected antibodies to the CD22 protein into the hippocampus on one side of mice's brains. Along with the antibodies, the scientists administered bits of myelin. This substance coats numerous nerve cells, for which it provides insulation. But myelin debris accumulates in aging brains and has been shown to overwhelm microglia's ability to clear it away. The researchers found that, 48 hours later, the myelin bits they'd injected into the mice's hippocampi were far less prevalent on the side where they had administered CD22-blocking antibodies. The investigators conducted analogous experiments, substituting a protein called beta-amyloid, whose buildup in the brain is a hallmark of Alzheimer's disease, and alpha-synuclein, another protein similarly associated with Parkinson's disease. In both cases, microglia exposed to CD22-blocking antibodies outperformed their peers in ingesting the neurodegeneration-linked substances.

The team observed that old mice receiving these infusions outperformed control mice of the same age on two different tests of learning and memory that are commonly used to assess mice's cognitive ability. "The mice became smarter. Blocking CD22 on their microglia restored their cognitive function to the level of younger mice. CD22 is a new target we think can be exploited for treatment of neurodegenerative diseases."

Upregulation of YAP or FOXD1 Reduces Cellular Senescence and Osteoarthritis in Mice
https://www.fightagi...hritis-in-mice/

Senescent cells are now a prominent target for the development of therapies to treat aging and age-related diseases. Senescent cells accumulate with age, and are responsible for a sizable amount of the chronic inflammation that accompanies old age - as well as fibrosis, compromised regeneration, and a laundry list of other issues. While the dominant approach is selective destruction of these cells, which appears to produce rejuvenation robustly and effectively in mice, a fair number of research groups are interested in finding ways to prevent cells from becoming senescent in the first place. The investigation here into cellular senescence and osteoarthritis is an example of the type.

I'm not convinced that this is as useful a path forward. Firstly it means constantly taking the treatment over decades, rather than once every so often, as needed. Secondly, cells become senescent for a reason, usually some form of DNA damage or environmental stress. Preventing senescence may result in a higher risk of cancer or other problems in tissue due to cells that should in fact be removed from the picture. That may still be better than the alternative of more rather than fewer senescent cells, as was the case in the short term for the mice in this study, but it doesn't compare favorably with destroying these errant cells.

Mesenchymal stem cells (MSCs) are widely distributed in adult tissues and are involved in tissue repair and homeostatic maintenance. Over time, MSCs exhibit an age-associated decline in their number and function, namely, MSC senescence, which may be implicated in the loss of tissue homeostatic maintenance and leads to organ failure and degenerative diseases. Therefore, an understanding of the mechanisms underlying MSC senescence will likely reveal novel therapeutic targets for ameliorating degenerative diseases.

Osteoarthritis is a prevalent aging-associated disorder that is characterized by the progressive deterioration of articular cartilage. Previous reports have demonstrated that cells isolated from mouse and human articular cartilage express MSC markers and characteristics. Cell death induced by oxidative stress or wound occurs primarily at the surface zone of cartilage. When such cell death is inhibited by chemicals, cartilage disorganization and matrix loss are greatly reduced. Therefore, MSCs or chondrocyte progenitor cells residing in cartilage may be a critical target for the prevention of osteoarthritis. Although the transplantation of ex vivo cultures of MSCs into the osteoarthritic joint has been shown to improve the symptoms, the rejuvenation of endogenous senescent MSCs may also be a therapeutic option for osteoarthritis.

Senescent mesenchymal stem cells (MSCs) residing in the joint cartilage may be a critical target for the prevention of osteoarthritis; however, the key regulators of MSC senescence are little known, and targeting aging regulatory genes for the treatment of osteoarthritis has not yet been reported. Here, we show that Yes-associated protein (YAP), a major effector of Hippo signaling, represses human mesenchymal stem cell senescence through transcriptional up-regulation of forkhead box D1 (FOXD1). Lentiviral gene transfer of YAP or FOXD1 can rejuvenate aged hMSCs and ameliorate osteoarthritis symptoms in mouse models. We propose that the YAP-FOXD1 axis is a novel target for combating aging-associated diseases.

Aubrey de Grey on the Dawn of the Era of Human Rejuvenation
https://www.fightagi...n-rejuvenation/

In this interview, Aubrey de Grey of the SENS Research Foundation discusses the present state of rejuvenation biotechnology. The first rejuvenation therapies now exist, these being the various methods of selectively removing senescent cells that de Grey and others called for back in 2002. The world is finally catching up to the vision of rejuvenation therapies that our community has advocated for more than fifteen years. Now that we are finally here, there is, if anything, even more work to be accomplished than was the case in past years. The funding for clinical development exists, but it is still true that many lines of work relevant to rejuvenation are moving too slowly in the laboratory, or in the transition to for-profit development. There is much left to do if we are to build the means of radical life extension in our lifetimes.

Can you compare 2018 to 2017 or early years? What is changing?

2018 was a fantastic year for rejuvenation biotechnology. The main thing that made it special was the explosive growth of the private-sector side of the field - the number of startup companies, the number of investors, and the scale of investment. Two companies, AgeX Therapeutics and Unity Biotechnology, went public with nine-digit valuations, and a bunch of others are not far behind. Of course this has only been possible because of all the great progress that has been made in the actual science, but one can never predict when that slow, steady progress will reach "critical mass".

In 2017 SENS RF have received about 7 million. What has been accomplished in 2018?

We received almost all of that money right around the end of 2017, in the form of four cryptocurrency donations of 1 million or more, totalling about 6.5 million. We of course realised that this was a one-off windfall, so we didn't spend it all at once! The main things we have done are to start a major new project at Albert Einstein College of Medicine, focused on stem cell therapy for Alzheimer's, and to broaden our education initiative to include more senior people.

What breakthroughs of 2018 can you name as the most important by your choice?

On the science side, well, regarding our funded work I guess I would choose our progress in getting mitochondrial genes to work when relocated to the nucleus. We published a groundbreaking progress report at the end of 2016, but to be honest I was not at all sure that we would be able to build quickly on it. I'm delighted to say that my caution was misplaced, and that we've continued to make great advances. The details will be submitted for publication very soon.

You say that many rejuvenating therapies will work in clinical trials within five years. Do you mean first - maybe incomplete - rejuvenation panel, when you speak on early 2020?

Yes, basically. SENS is a divide-and-conquer approach, so we can view it in three overlapping phases. The first phase is to get the basic concept accepted and moving. The second phase is to get the most challenging components moving. And the third phase is to combine the components. Phase 1 is pretty much done. Phase 2 is beginning, but it's at an early stage. Phase 3 will probably not even properly begin for a few more years. That's why I still think we only have about a 50% chance of getting to longevity escape velocity by 2035 or so.

Is any progress in the OncoSENS program? Have you found any alternative lengthening of telomeres (ALT) genes? Is there any ongoing research in WILT?

No - in the end that program was not successful enough to continue with, so we stopped it. There is now more interest in ALT in other labs than there was, though, so I'm hopeful that progress will be made. But also, one reason why I felt that it was OK to stop was that cancer immunotherapy is doing so well now. I think there is a significant chance that we won't need WILT after all, because we will really truly defeat cancer using the immune system.

The Interventions Testing Program Finds Glycine Supplementation has a Tiny Effect on Mouse Life Span
https://www.fightagi...ouse-life-span/

The NIA Interventions Testing Program (ITP) is a very conservative organization. The organizers take compounds that cannot possibly do more than slightly slow aging, largely those that upregulate stress response mechanisms in a similar way to calorie restriction, and rigorously test them in large mouse studies. The results are of the best quality, and tend to demonstrate that most earlier, less rigorous studies overestimated the effects of compounds on life span. This is an expensive business, but I would say one of dubious practical value.

The practice of calorie restriction shows us the likely bounds of the possible when it comes to upregulating stress responses in humans. It is not the road to large increases in human life span; calorie restriction, while improving health noticeable, doesn't add more than a few years to life span in our species. This is despite extending mouse life span by up to 40%. Upregulation of stress responses has evolved to have a much larger effect on life span in short-lived species. So when we see results in mice on the order of 5% extension of life span in the ITP study noted here, one can expect it to have absolutely no detectable result at all in humans.

The NIA Interventions Testing Program (ITP) has to date reported on four drugs with consistent major effects on mouse lifespan in one or both sexes and found evidence for significant but less dramatic effect of four other drugs. Rapamycin, started at 9 months of age, was found to increase median lifespan by as much as 26% in females and 23% in males. Acarbose can lead to an increase of 22% in median lifespan in male mice, and to a significant, but smaller, 5% increase in female mice. A third drug, 17-α-estradiol (17aE2), a nonfeminizing congener of the well-known estrogen 17-β-estradiol, increases lifespan of male mice by 19%. Lastly, NDGA (nordihydroguaiaretic acid) has been shown to increase lifespan of male mice only, with an increase of 12% in median lifespan. Of the other agents tested so far by the ITP, four (methylene blue, aspirin, Protandim, and green tea extract [GTE]) provided some evidence for possible health benefits.

Diets low in the amino acid methionine have been shown to extend median and maximum lifespan in rats. Glycine plays a special role in methionine metabolism, serving as the only acceptor for methyl groups, through action of glycine-N-methyl transferase (GNMT), the key enzyme in the only pathway for methionine clearance in mammals. Methionine toxicity can be blocked by dietary glycine, consistent with the notion that GNMT is the principal effector of methionine clearance, at least at toxic levels. These data suggest that excess dietary glycine might depress methionine levels and thus mimic some of the benefits of a low methionine diet.

We therefore evaluated the effects of an 8% glycine diet on lifespan and pathology of genetically heterogeneous mice in the context of the Interventions Testing Program. Elevated glycine led to a small (4%-6%) but statistically significant lifespan increase, as well as an increase in maximum lifespan, in both males and females. Pooling across sex, glycine increased lifespan at each of the three independent test sites. Glycine-supplemented females were lighter than controls, but there was no effect on weight in males.

In Rotifers, the Offspring of Older Mothers Benefit More From Calorie Restriction
https://www.fightagi...ie-restriction/

An interesting discovery in the field of calorie restriction research is noted here: in a short-lived species, the offspring of older mothers benefit more from a restricted calorie intake. Now, these animals also have shorter life spans and impaired reproductive fitness. This suggests that they bear a greater load of molecular damage when born, which one might expect given what is known of both aging and the health effects observed with advanced maternal age observed in many species. Since calorie restriction upregulates cellular stress responses, leading to greater maintenance and repair activities, it may well work more effectively in those animals with more damage and dysfunction to stave off. There may well be no practical outcome in human medicine that results from this finding, but it is intriguing.

There has been evidence for well over a century, from experiments done in a wide variety of animal species and from data in humans, that offspring from older mothers have shorter lifespans and lower rates of reproduction, but it wasn't well understood how a mother's age might affect other aspects of her offspring's health or response to interventions. Using rotifers, researchers studied the effects of maternal age on offspring aging and their response to dietary changes. In their experiments, they fed mother rotifers a regular diet. They then studied the offspring from young (about three days old), middle-aged, and advanced-aged (about nine days old) mothers. The offspring were fed one of three different diets: constant high food, constant low food, or alternating between high food and fasting every other day.

"These calorie-restricted and intermittent-fasting diets are known to significantly increase lifespan in rotifers and many other species, "Our study confirmed that offspring from older mothers have shorter lifespans and lower reproductive rates than offspring of younger mothers. However, offspring of older mothers, we found, have a greater increase in lifespan in response to caloric restriction than do young-mother offspring." In the offspring born from older mothers, the decreased lifespan seemed to be due to an earlier onset of aging. This early onset was delayed when those offspring were subject to caloric restriction. Even though offspring from older mothers responded more positively to caloric restriction, it did not improve their overall fitness. In evolutionary terms, "fitness" takes into consideration both lifespan and rates of reproduction. For old-mother offspring on caloric restriction or full food diets, the window for reproduction was shortened and they had half as many offspring - only 14-15, instead of the average of 25 to 30 for young-mother offspring. Caloric restriction did not rescue reproduction.

Gum Disease Bacteria More Common in the Brains of Alzheimer's Patients
https://www.fightagi...imers-patients/

Researchers here note that the bacteria associated with gum disease are found more frequently in the brains of Alzheimer's disease patients. While looking over this research, it is worth bearing in mind that a recent large study found only a 6% increased risk of dementia in patients with periodontitis. So rather than thinking that there is a very large contribution to the disease process here, we might consider an alternative model: that people with Alzheimer's disease may be more likely to have a leaky blood-brain barrier, allowing greater traffic of normally forbidden molecules, cells, and pathogens into the brain. Vascular dysfunction is common in Alzheimer's patients, many of whom also exhibit vascular dementia in addition to the signs and symptoms of Alzheimer's disease. Thus the infiltration of bacteria into the brain may be a consequence of underlying damage rather than a cause of it, and this bacterial infiltration, while being clearly associated with disease-related mechanisms, may cause only modest additional harm over and above the more direct consequences of that damage.

The bacterium, Porphyromonas gingivalis, is the bad actor involved in periodontitis, the most serious form of gum disease. While previous researchers have noted the presence of P. gingivalis in brain samples from Alzheimer's patients, new results offer the strongest evidence to date that the bacterium may actually contribute to the development of Alzheimer's disease. The researchers compared brain samples from deceased people with and without Alzheimer's disease who were roughly the same age when they died. They found P. gingivalis was more common in samples from Alzheimer's patients, evidenced by the bacterium's DNA fingerprint and the presence of its key toxins, known as gingipains.

In studies using mice, they showed P. gingivalis can move from the mouth to the brain and that this migration can be blocked by chemicals that interact with gingipains. An experimental drug from Cortexyme that blocks gingipains, known as COR388, is currently in phase 1 clinical trials for Alzheimer's disease. Researchers are working on other compounds that block enzymes important to P. gingivalis and other gum bacteria in hopes of interrupting their role in advancing Alzheimer's and other diseases.

The researchers also report evidence on the bacterium's role in the autoimmune disease rheumatoid arthritis, as well as aspiration pneumonia, a lung infection caused by inhaling food or saliva. "P. gingivalis's main toxins, the enzymes the bacterium need to exert its devilish tasks, are good targets for potential new medical interventions to counteract a variety of diseases. The beauty of such approaches in comparison to antibiotics is that such interventions are aimed only at key pathogens, leaving alone good, commensal bacteria, which we need."

Calorie Restriction Reduces Inflammation via Moderate Hyperadrenocorticism
https://www.fightagi...drenocorticism/

The metabolic response to calorie restriction, a sustained reduction in calorie intake while maintaining optimal micronutrient intake, is sweeping and complex. It also extends life span quite dramatically in short-lived species. Near everything changes, which makes it a challenge to characterize the few important mechanisms early in the chain of cause and effect. It also makes it a very fruitful area of study from the pure science perspective, as there is always something new to be discovered, as illustrated by the research results reported here.

While calorie restriction itself is widely studied, and a good lifestyle choice in this modern world of cheap calories and their consequences, I remain unconvinced that the biochemistry of calorie restriction is the road to therapies capable of meaningful extension of the healthy human life span. The gain might be a few years, and better health along the way. This is not to be rejected if that were the outer limits of what is possible, but it is not. It is a poor strategy in a world in which we could plausibly gain decades of additional time in good health by focusing on repair of the damage that causes aging, rather than trying to pick apart the evolved responses to diet.

Calorie restriction (CR) is among the most robust ways to extend lifespan and delay age-related diseases in mammals. Considerable evidence indicates that cell nonautonomous factors, often driven by neuroendocrine signaling, play an essential role in mediating the life- and health-span enhancing effects of CR. Less is known about the specific hormone targets of these neuroendocrine factors that ultimately promote the health-enhancing CR state. CR lowers plasma concentrations of numerous anabolic hormones, including growth hormone (GH), insulin, and insulin-like growth factor 1 (IGF1), which may be contributors.

By contrast, glucocorticoids, which play a major role in responding to stressors, are elevated in CR animals, although again their roles have not be delineated. Glucocorticoids are anti-inflammatory, and attenuated inflammation is widely observed in CR animals. These observations have led to the hypothesis that the hyperadrenocorticism of CR contributes to the attenuation of inflammation in CR animals. Here, we tested this hypothesis directly using a corticotropin-releasing hormone knockout (CRHKO) mouse, which is glucocorticoid deficient and has increased inflammation following allergen exposure.

There were four control groups: CRHKO mice and wild-type (WT) littermates fed either ad libitum (AL) or CR (60% of AL food intake), and three experimental groups: (a) AL-fed CRHKO mice given corticosterone (CORT) in their drinking water titrated to match the integrated 24-hr plasma CORT levels of AL-fed WT mice, (b) CR-fed CRHKO mice given CORT to match the 24-hr CORT levels of AL-fed WT mice, and © CR-fed CHRKO mice given CORT to match the 24-hr CORT levels of CR-fed WT mice. Inflammation was measured volumetrically as footpad edema induced by carrageenan injection. As previously observed, CR attenuated footpad edema in WT mice. This attenuation was significantly blocked in CORT-deficient CR-fed CRHKO mice. Replacement of CORT in CR-fed CRHKO mice to the elevated levels observed in CR-fed WT mice, but not to the levels observed in AL-fed WT mice, restored the anti-inflammatory effect of CR. These results indicate that the hyperadrenocorticism of CR contributes to the anti-inflammatory action of CR, which may in turn contribute to its life-extending actions.

Paradoxically, hyperadrenocorticism is well known to be detrimental to health and lifespan. In humans, chronically elevated glucocorticoids are associated with insulin resistance and are the cause of Cushing's syndrome, a life-threatening disorder of glucocorticoid overproduction. Chronic elevation of CORT levels increases the risk of hypertension, hyperkalemia, diabetes, atherosclerosis, osteoporosis, glaucoma, and impairment of the immune and reproductive systems. Elevation of CORT damages hippocampal cells in rats, which in turn is associated with neurodegeneration and cognitive impairment in rodents.

However, all evidence for deleterious effects of hyperadrenocorticism occurs under conditions of ad libitum food intake. There is no evidence that the hyperadrenocorticism associated with CR is deleterious. The results of this study suggest that it may be beneficial - to the extent that resilience against inflammatory stressors is advantageous for the organism. These results not only suggest glucocorticoids are necessary for the anti-inflammatory actions of CR in mice but also buttress previous results that hyperadrenocorticism of CR may be involved in the retardation of aging by CR.

The Dysfunctional Immune Response in the Development of Alzheimer's Disease
https://www.fightagi...eimers-disease/

Alzheimer's disease progresses from the slow accumulation of amyloid-β plaques, that appear to cause comparatively mild dysfunction, to the accumulation of neurofibrillary tangles composed of altered tau protein, which cause major dysfunction and cell death in the later stages of the condition. Along the way chronic inflammation in brain tissue arises, along with dysfunctional behavior on the part of immune cells in the brain. As is the case in the open access review paper here, one can take these facts and suggest that amyloid-β deposition causes immune cell dysfunction, which in turn causes tau deposition. There is certainly evidence to support this view, such as the recent studies showing that clearance of senescent microglia turns back tau pathology and inflammation in animal models of Alzheimer's disease. This is probably just one of several lines of cause and consequence, however: Alzheimer's is a very complex condition.

Neuroinflammation is considered one of the cardinal features of Alzheimer's disease (AD). Neuritic plaques composed of amyloid β and neurofibrillary tangle-laden neurons are surrounded by reactive astrocytes and microglia. Exposure of microglia, the resident myeloid cell of the central nervous system (CNS), to amyloid β causes these cells to acquire an inflammatory phenotype. While these reactive microglia are important to contain and phagocytose amyloid plaques, their activated phenotype impacts CNS homeostasis.

In rodent models, increased neuroinflammation promoted by overexpression of proinflammatory cytokines can cause an increase in hyperphosphorylated tau and a decrease in hippocampal function. The peripheral immune system can also play a detrimental or beneficial role in CNS inflammation. Systemic inflammation can increase the risk of developing AD dementia, and chemokines released directly by microglia or indirectly by endothelial cells can attract monocytes and T lymphocytes to the CNS. These peripheral immune cells can aid in amyloid β clearance or modulate microglia responses, depending on the cell type.

The contribution of specific pro-inflammatory and anti-inflammatory factors in AD is not straightforward, especially since the evaluation of cognition, amyloid β pathology, and neurofibrillary tangles yields conflicting results in mouse models. Furthermore, translating rodent studies that have modulated expression of specific cytokines in the CNS is challenging. In addition, studies that have shown promise, such as the beneficial effects of pioglitazone in mouse models of AD, do not always prove effective in humans.

Nonetheless, the immune response is deeply tied to the development of pathology, and with advancing technologies, we are able to more fully dissect the complexity of this response and the effector cells that carry it out. Our knowledge of how microglia and peripheral immune cells interact has proved invaluable in understanding how this delicate balance goes awry in disease. Immunomodulation in AD offers multiple, promising pathways of investigation that might lead to therapeutics that can prevent or halt the development of amyloid and tau pathology and cognitive decline.

Faltering Glial Cell Activities in the Development of Parkinson's Disease
https://www.fightagi...insons-disease/

Glial cells in the brain are a class of immune cell responsible for a wide range of supporting activities necessary to brain function, a great deal more than merely tackling pathogens and cleaning up metabolic waste. It is the ingestion and breaking down of metabolic waste in the brain, a process called phagocytosis, that is the focus of this open access paper, however. Neurodegenerative conditions, such as Parkinson's disease in this case, are largely characterized by the presence of solid deposits of misfolded or otherwise altered proteins. The capacity of glial cells to carry out phagocytosis of these protein aggregates is disrupted with advancing age, particularly by rising levels of chronic inflammation. It is suspected that this loss of function is a significant contribution to the progression of neurodegeneration. Recent studies showing that clearance of senescent glial cells produces significant benefits in animal models of neurodegeneration supports this line of thinking, but there is still much work to be accomplished in this area of study.

The clinical symptoms of Parkinson's disease (PD) reflect the underlying systemic neurodegeneration and protein deposition. A common denominator of both inherited and sporadic forms of PD is the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta projecting to the putamen that control voluntary movements. Additionally, proteinaceous inclusions mainly composed by the protein α-synuclein (α-syn) are located in the perikarya (Lewy Bodies, LBs) and within the cell processes (Lewy neurites, LNs) of the surviving nerve cells.

Although less often discussed than neuronal pathology, α-syn-containing inclusions in astrocytes have been repeatedly detected in the substantia nigra, cerebral cortex and other brain regions in idiopathic PD samples. The density of α-syn immunoreactive astrocytes parallels the occurrence of LNs and LBs in neurons. Neuronal loss and the presence of cytoplasmic inclusions in neuronal and non-neuronal cells are also accompanied by reactive changes of astrocytes and microglia referred to as gliosis. Microglia as well as astrocytes are inflammatory cells that express immune-associated molecules including the major histocompatibility complex (MHC) class II, pro-inflammatory cytokines, and inducible oxide synthase (iNOS). Moreover, astrocytes become hypertrophic and accumulate the intermediate filament protein, glial fibrillary acidic protein (GFAP).

Although reactive glial cells and the upregulation of cytokines was found in the brains and cerebrospinal fluid of patients with PD, the role of neuroinflammation in the pathogenesis of PD is still undetermined. Neuroinflammation in PD has long been considered a downstream response to neuronal damage. However, alteration of glial physiological functions are emerging as causally linked to brain diseases. In the healthy brain, astrocytes maintain ion homeostasis of the microenvironment, provide structural and metabolic support, regulate synaptic transmission, water transport, and blood flow. Additionally, microglia continuously extend and retract their process to interact with neurons and other types of glial cells, including astrocytes.

Microglial phagocytosis (alongside other mechanisms, such as synaptic stripping and "trogocytosis") plays an important role in the engulfment of synaptic elements. Recent studies also revealed that astrocytes contribute to phagocytic clearance in a similar manner during normal physiological conditions and there is abundant evidence that microglia and astrocytes communicate with each other. It was further proposed that astrocytes can ingest aggregated proteins from the extracellular environment, suggesting that astrocytes keep, in coordination with microglia, the brain clean. Since the elimination of unwanted and potentially harmful matter is crucial for central nervous system (CNS) function, dysregulation of glial phagocytosis and degradation might have a key role in PD pathogenesis.


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