Fight Aging! Newsletter, July 23rd 2018 – Fight Aging!
A few recent papers have, collectively, added evidence for persistent viral infection to be a significant contributing cause of Alzheimer's disease. A number of viruses in the herpesvirus family are prevalent in the population but cause few obvious symptoms, such as HSV-1 and cytomegalovirus (CMV). Some of these, particularly CMV, are already under suspicion as being the cause of long-term dysfunction in the immune system. Viral infection is an attractive way to explain why only some of the people who exhibit all of the known risk factors for Alzheimer's disease actually go on to develop the full clinical manifestation of the condition. The proportion of the population with latent infection is high, but not too high: other candidate differentiating factors are a lot less convincing because either the population size is too small, or near everyone has it.
How can viral infections contribute to the development of Alzheimer's disease? The amyloid cascade hypothesis tells us that, in the first early stages of Alzheimer's disease, amyloid-β accumulates in the brain, producing only comparatively minor symptoms of degeneration. In later life, this accumulation reaches a critical point that causes tau protein to alter and form solid neurofibrillary tangles in significant amounts. It is this tau aggregation that causes the lion's share of the damage in the later stages of the condition - though a high enough level of amyloid-β can still be harmful in and of itself. Infection is important because amyloid generation is an innate immune mechanism that evolved to respond to viral infection. Thus infection speeds up the production and aggregation of amyloid-β in the brain, pushing things ever closer to the tipping point into pathology.
Authors have recently reported that infection with a different herpes virus, herpes simplex virus type 1 (HSV1), leads to a similarly increased risk of later developing senile dementia (SD). Further, when the authors looked at patients treated aggressively with antiherpetic medications at the time, the relative risk of SD was reduced by a factor of 10. It should be stressed that no investigations were made on subjects already suffering from SD, and that those treated were the few rare cases severely affected by HSV. Nonetheless, antiherpetic medication prevented later SD development in 90% of their study group. These articles provide the first population evidence for a causal link between herpes virus infection and senile dementia.
Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer's disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism.
Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Aβ is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aβ antimicrobial activities. Thus, infection can seed and dramatically accelerate β-amyloid deposition. Here, we show Aβ oligomers bind herpesvirus surface glycoproteins, accelerating β-amyloid deposition and leading to protective viral entrapment activity in mouse and human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce β-amyloidosis in brain. These data support the notion that Aβ might play a protective role in central nervous system innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Aβ amyloidosis.
Oisin Biotechnologies is the company working on what is, to my eyes, the best of the best when it comes to the current crop of senolytic technologies, approaches capable of selectively destroying senescent cells in old tissues. Adding senescent cells to young mice has been shown to produce pathologies of aging, and removal of senescent cells can reverse those pathologies, and also extend life span. It is a very robust and reliable approach, with these observations repeated by numerous different groups using numerous different methodologies of senescent cell destruction.
Most of the current senolytic development programs focus on small molecules, peptides, and the like. These are expensive to adjust, and will be tissue specific in ways that are probably challenging and expensive to alter, where such alteration is possible at all. In comparison, Oisin Biotechnologies builds their treatments atop a programmable suicide gene therapy; they can kill cells based on the presence of any arbitrary protein expressed within those cells. Right now the company is focused on p53 and p16, as these are noteworthy markers of cancerous and senescent cells. As further investigation of cellular senescence improves the understanding of senescent biochemistry, Oisin staff could quickly adapt their approach to target any other potential signal of senescence - or of any other type of cell that is best destroyed rather than left alone. Adaptability is a very valuable characteristic.
The Oisin Biotechnologies staff are currently more than six months in to a long-term mouse life span study, using cohorts in which the gene therapy is deployed against either p16, p53, or both p16 and p53, plus a control group injected with phosphate buffered saline (PBS). The study commenced more than six months ago with mice that were at the time two years (104 weeks) old. When running a life span study, there is a lot to be said for starting with mice that are already old; it saves a lot of time and effort. The mice were randomly put into one of the four treatment groups, and then dosed once a month. As it turns out, the mice in which both p16 and p53 expressing cells are destroyed are doing very well indeed so far, in comparison to their peers. This is quite impressive data, even given the fact that the trial is nowhere near done yet.
The image of study data presented in this post is taken from the Oisin Biotechnologies PDF that accompanies a presentation given at the recent ICSA meeting in Montreal. We should certainly hope to see more of this sort of thing in the years ahead as senolytic technologies improve.
Hematopoietic stem and progenitor cell populations are responsible for generating immune cells. Their decline is one of the causes of immune failure with age, as the pace at which new immune cells are created falters. There are other equally important issues in immune aging, such as the atrophy of the thymus, where T cells of the adaptive immune system mature, and the accumulation of malfunctioning immune cells in older individuals, but we'll put those to one side for this discussion.
Stem cell decline with aging is a complicated business with many contributing causes, and the relative importance of those causes seems to differ between populations and tissues. Few stem cell populations are very well studied when it comes to asking why exactly it is that they decline in activity with age. Those that are, such as muscle, hematopoietic, and neural populations all seem to be quite different. Muscle stem cells decline in activity but, given the right signals, appear quite ready to go back to work with minimal signs that they are greatly impacted by damage. Hematopoietic stem cells do appear to be more damage-limited, however.
In this open access paper, the authors look at the detrimental impact of cellular senescence on hematopoietic cells, and thus on the immune cells that they produce. Cellular senescence is a reaction to damage or excessive replication; senescent cells cease to replicate, and most such cells self-destruct or are destroyed by the immune system. Some linger, however, and the harmful, inflammatory mix of signals that they generate are implicated as a cause of degenerative aging. Studies in mice show that removing senescent cells improves health and extends life span. There are also populations of cells that show some of the markers and behaviors of senescence, but have yet to be definitively classified as senescent - nothing is simple when it comes to cellular biology. This pseudo-senescence or maybe-senesence may be the case here; more research will determine whether or not this is the case.
Aging is associated with an increased prevalence of multiple comorbidities, including infectious and malignant diseases. Many of these disorders are thought to stem from old-age-related immune decline. Increasing efforts to characterize the immune system of elderly people in recent years have revealed that most immunocompetent cell compartments present profound quantitative as well as qualitative impairments. The cause of these impairments can vary, and is often related to the exhaustion of the cells or their functions over time in inflammatory settings.
The majority of mature blood cell compartments need, therefore, to be continuously replenished or replaced, which is the role of hematopoietic progenitor cells (HPCs) and, ultimately, hematopoietic stem cells (HSCs). While the self-renewal and differentiation potential of stem cells, along with their blood cell reconstitution capacity, have long been considered as infinite, increasing evidence indicates that this is not the case. Under conditions of stress, HSCs eventually exhibit several functional defects, including a diminished regenerative and self-renewal potential. Loss of stem cell activity is therefore a likely mechanism of impairment common to many mature cell types, thus representing a central cause of immune-competence decline.
Most studies on HSC aging have been carried out in mouse models, and have highlighted extrinsic and intrinsic factors affecting the function of HSCs. A recent study reveals that loss of autophagy in most HSCs from aged mice causes an activated metabolic state, which is associated with accelerated myeloid differentiation, and impairs HSC self-renewal activity and regenerative potential. In humans, much less information is available on the aged HSCs, due to the limited and challenging access to bone marrow samples of elderly humans, the niche of HSCs. Reduced transplantation success in patients receiving HSCs isolated from older (45 years and above) donor bone marrows indicates that human HSC regenerative capacity also declines with aging.
We performed here a comprehensive study of blood HPCs, as an alternative to bone marrow HSCs, to overcome the constraint of sample availability from elderly adults. Based on phenotypic analyses, in vitro T lymphocyte differentiation assays, and gene expression profiling of circulating HPCs from aged subjects, we demonstrate impaired lymphopoiesis and active cell cycling of HPCs with aging, and provide insights into their functional impairments. Our findings reveal that, while mobilized, elderly HPCs present evidence of cellular senescence and increased cell death by pyroptosis. Reduced telomere length and telomerase activity in old HPCs may affect the properties of their progeny, such as mature T lymphocytes. This pre-senescent profile is characteristic of the multiple intrinsic and extrinsic factors affecting HPCs in elderly individuals and represents a major obstacle in terms of immune reconstitution and efficacy with advanced age.
I made the pilgrimage to storied Manhattan last week for the first conference organized by the Life Extension Advocacy Foundation (LEAF), titled Ending Age-Related Diseases. It was well organized, all in all a very professional effort. Congratulations are due to the volunteers who set it all up and kept everything moving smoothly. The attendees were a mix of researchers, entrepreneurs, advocates, interested members of the public, and investors of various stripes - a good mix, one that in the present excitable market environment provoked a great deal of useful networking.
The presentations were recorded and will start to appear online as the LEAF volunteers process them. You should make a point of taking a look when they turn up, particularly the view from the investor side of the house. Investors who are personally interested in the success of a field are very different beasts from the run of the mill individual who mechanically seeks returns. They usually have an interesting perspective on the real world challenges inherent in turning a promising technology into a therapy, and that was the case here. The Fight Aging! audience is perhaps more familiar with the science, and so may find considerations of the business side of the house novel and interesting.
While attending the conference, I had a chance to meet in person a sizable number of people who I have only talked to via email over the past decade or more. I apologize to the apparently equally sizable number of people I didn't have the chance to talk to during the breaks between presentations. Keith Comito of LEAF announced that the organization will be making this a yearly event, so I will endeavor to do better next year. Hopefully at that time I will have more interesting things to say about progress towards rejuvenation therapies at Repair Biotechnologies, and the state of the industry as a whole.
As I see things, this sort of mix of participants is very much needed in order to keep progress underway in our rejuvenation research community. We need a regular stirring up of the everyday patient advocates, the entrepreneurs and employees who build therapies, the scientists who discover new opportunities, and the investors who fund those tasks. Communication and building bridges are hard tasks, and there is ever a tendency to form camps and forget how to travel between them. There is a vast chasm between academia and commercial medical development, and all too many promising foundations for therapy fall in and are never seen again.
Is this because scientists are not doing enough to reach out to entrepreneurs and investors? Is it because there are too few entrepreneurs? That the universities make it too hard to license technologies developed in academia, discouraging investment across the field? That investors and their funds are sitting around waiting to be handed opportunities in a nice, neat package, rather than doing more legwork? I'm inclined to put more blame on the investor community simply because they have the resources to do better and more interesting things. They could work more systematically when it comes to reaching back into the research community to pick up promising work and assemble companies to develop it. Doing so in a robust, organized way will help all parties.
While at the conference, I buttonholed a number of people to espouse what we shall call the Dasatinib Empire concept. At this point in time, I think there is more than sufficient evidence to consider that dasatinib and quercetin in combination is most likely a useful, cheap senolytic treatment - a legitimate rejuvenation therapy that partially clears out the senescent cells that cause age-related disease and dysfunction. A single dose is in the 100 to 200 range, less if one shops cleverly, and one treatment every few years is likely close to the optimal dosage. Human trials, such as that ongoing at Betterhumans, will prove the benefits over the next few years, but it looks very compelling even right now. Dasatinib has side-effects that are very well categorized thanks to the past fifteen years of studies as a cancer therapeutic, and they appear neither onerous nor life-threatening in the senolytic scenario of a single dose once every few years, rather than the sustained dosing of cancer treatment.
Given this, and that dasatinib is a generic pharmaceutical, out of patent protection, why can't someone build a serious non-profit or for-profit effort to deliver dasatinib and quercetin at scale to the tens of millions of older people who would benefit significantly from it? An initiative could finalize the human data currently in progress, and then it would be as much a matter of delivering information as delivering pharmaceuticals: anyone can set forth and obtain dasatinib if they only know how to do it. Doing this at scale would probably entail driving a very large truck through the loophole of off-label use of a generic drug, working to help as many older people as possible, as rapidly as possible, and then weaponizing favorable public opinion to fend off the inevitable attention of the FDA. Indeed, this could be a path to change the regulatory landscape, to force regulators to accept the treatment of aging as a fait accompli. I'd say this is a better, more aggressive, more plausible way to do it than the slow approach of trying to change the FDA from within.
It is the case that FDA officials, as a rule, are strongly opposed to the prospect of widespread off-label use, meaning the physician-ordered use of a treatment for something other than the purposes the FDA has approved. They see their role as protecting the population, and off-label use, while completely legal, is viewed as an end-run around their shield. However, and as I have argued in the past, the FDA is too much of a barrier, too strongly opposed to any and all risk, too unwilling to grant patients any choice in their own lives. The cost of that barrier is higher than the benefit. Why should so many millions of people suffer when the evidence strongly suggests that their suffering could be alleviated to some degree at low cost and little risk? Shouldn't it be their choice?
Manhattan is a wealthy enclave. There are any number of individuals resident in that small section of New York real estate with the wealth, connections, and acumen to make something like the Dasatinib Empire a reality, were they to turn their attention to it for the years it would require. At some point it will become obvious to even those who have not watched the development of our longevity science community that the benefits of early senolytics are large, the costs are low, and there is thus much that might be accomplished in the world by joining up these dots. So I'll keep mentioning this to people. Sooner or later it will happen.
Over at the Life Extension Advocacy Foundation (LEAF), an argument is made that we shouldn't be overly concerned about the current unwillingness of the FDA and similar regulatory bodies to recognize the treatment of aging and its causes as a valid indication. What is an indication? The outcome of the present overly burdensome regulatory process is formal approval of the use of a specific medical technology for a specific defined condition or set of symptoms. That condition or set of symptoms is known as an indication. Aging is not currently in the list of recognized conditions. The argument made by LEAF is that there are defined paths for rejuvenation therapies to be approved as treatments for specific age-related diseases. Thus treatments can be developed in principle, and from there the concept of off-label use applies.
Aging is a variety of distinct processes, damages, and errors; therefore, simply treating aging in clinical terms is not a viable endpoint. For a clinical trial to be conducted, it requires a verifiable indication, and aging is too general for the FDA and EMA to classify it as a disease. However, the majority of damage repair therapies, if not all, could be developed as therapies for diseases with accepted indications and verifiable endpoints, which should satisfy bodies such as the FDA and EMA. Therefore, whether regulatory agencies perceive aging as a disease or not is of no consequence to the development of rejuvenation biotechnologies that address the aging processes.
Even though classifying aging as a disease is unnecessary, significant reform in the regulatory system is still needed in order to encourage investors and companies to put the time and money into researching and developing rejuvenation therapies. One area in need of reform is the establishment of aging biomarkers, which indicate the repair or removal of age-related damage, as acceptable endpoints for rejuvenation therapies. Studies that use these biomarkers would also need to include long-term follow-up studies to ascertain the effects of a therapy over a longer period of time. Another area where regulatory bodies have struggled is keeping up with the rapid march of technology and medicine. Technologies such as gene therapies have struggled to gain traction due to an antiquated regulatory framework struggling to cope with them. Thankfully, this is also being acknowledged.
Aging not being classified as a disease by the FDA, EMA, etc. is not a major issue; the real need is for policy changes that make developing drugs and therapies that target the aging processes easier and more financially viable. It is good that changes are being made to current frameworks and that progress will almost certainly continue in these areas. Meanwhile, we can continue to support the development of repair-based approaches to aging knowing that such therapies, if they work, will be approved even in the current regulatory landscape.
The counterargument to this proposition is that off-label use at scale is not a given - it is by no means certain that a rejuvenation therapy can be approved for, say, arthritis patients, and then the floodgates immediately open for everyone and anyone to use it for any plausibly connected medical condition. Yes, off-label use, as written into law, says that physicians can prescribe approved therapies for unapproved uses. It is estimated that 20% of medical usage in the US is off-label, but this is something that has arisen slowly and organically over time. There are few good analogues in recent medical history for anything as broadly effective as a rejuvenation therapy, something that can beneficially treat hundreds of named conditions.
Why is this a problem? FDA staff see themselves as the shield that stands between unrestricted use of therapies and the public at large. They are opposed to widespread off-label use, as they see this as an end-run around their shield. This is the justification for preventing patient choice - the usual authoritarian assumption that people have no agency and are not qualified to make their own decisions or order their own affairs. When potential therapies and potential indications are first put in front of the FDA, minimizing the likelihood for off-label use is a topic that will come up. If you, for example, propose to treat only a fraction of the population of patients who have a specific condition, based on some biomarker that might be used to segregate the patient population into smaller groups than is presently the case, then the fact that this will tend to lead to significant off-label use in the rest of the patient population is one of the reasons why such designs can be rejected.
When off-label use rises to a significant level in some other way, the FDA may step in. But this is not a given. There are no hard and fast rules here. It is a political anarchy: FDA bureaucrats want to shut down that off-label use and force more clinical trials on their own terms, one named disease at a time, but there is always too much to do in any given day. On the other side of this are developers, patient advocates, and public opinion. People involved in providing therapies when the FDA has decided that they want to step in risk prosecution, fines, and jail time for their principles if the FDA decides to take a hard line. This is the case whether or not it is accepted by the letter of the law to offer these technologies off-label: the FDA will squeeze the manufacturers and the distributors, not the physicians. Fighting this sort of intervention may will be ruinously expensive, a long-running legal battle with a government agency with far greater resources than any of the other players in the space.
The bottom line is that when senolytics or other early rejuvenation therapies are narrowly approved for specific age-related conditions, that will likely roll right into a sizable battle over off-label use. It seems inevitable that people will try - and why shouldn't they? Does the law serve humanity, or does humanity serve the law? Should we all lie down and die because FDA staff are prissy about their rules? Because of the incentives and the parties involved, it just isn't the case that approval for the first few age-related diseases will immediately enable widespread use, unless the political and public opinion battle immediately goes very poorly for the FDA. Sadly, I don't see why it would: the leadership at the FDA has successfully shut down or held back numerous other avenues for off-label delivery of beneficial treatments over the past decades, over the objections of many well-supported advocacy organizations and the voices of suffering patients.
The Ichor Therapeutics contingent present at the Ending Age-Related Diseases conference in New York last week were quite pleased that the timing worked out to allow them to announce during the conference a 10 million investment from Juvenescence into a joint venture with their portfolio company Antoxerene. Antoxerene started as a protein biotechnology infrastructure company, but the staff are now turning that infrastructure to the discovery and development of senolytic compounds, those capable of selective destruction of senescent cells. Antoxerene joins a number of existing companies working on various approaches to this goal: this diversity bodes well for our future health and wellbeing, given that senescent cells are thought to be one of the root causes of aging.
Antoxerene, Inc., a portfolio company of Ichor Therapeutics, Inc., focused on small molecule drug discovery for pathways of aging, announced today the launch of a joint venture with Juvenescence Limited. The joint venture, called FoxBio, Inc., will develop Antoxerene's collection of small molecules that target senescent cells. Juvenescence will provide the initiative 10 million in equity financing and drug development expertise.
Researchers appear to have found a novel way to sabotage fibrosis, the condition in which regenerative processes run awry with age and cells begin building scar-like structures that disrupt normal tissue function. The approach involves blocking TLR4 signaling. Fibrosis is a feature of the decline of many organs; liver, lung, kidney, heart, and so forth. If it can be turned off comparatively simply, that would produce noteworthy gains for the health of older individuals, even when the underlying causes of regenerative disarray are not addressed. The question is always whether or not there is a good way to interfere without also altering other important cellular processes, of course.
An interesting broader context for this TLR4 signaling inhibition is the growing evidence that suggests senescent cells to be a significant contributing cause of fibrosis. Senescent cells secrete a great many disruptive, inflammatory signal molecules, and that changes the behavior of surrounding cells, usually for the worse when that signaling persists for a long time. It may or may not be the case that senescent cells directly cause increased TLR4 signaling, but it is worthy of note that TLR4 deficient mice exhibit a reduced level of cellular senescence than their peers. There are some dots yet to be joined here.
Fibrosis, the hallmark of systemic sclerosis (SSc), is characterized by excessive production and persistent accumulation of collagens and other extracellular matrix (ECM) molecules in skin, lungs, and other internal organs. The process underlies a large number of fibrotic diseases that, in aggregate, account for a considerable proportion of deaths worldwide. With no effective therapy to date, fibrosis therefore represents a significant unmet global health need.
TLRs and related pattern-recognition receptors represent the first line of host defense against microbial pathogens. Cell surface receptors such as TLR4 and endosomal receptors such as TLR3 recognize extrinsic pathogen-associated molecule patterns (PAMPs) such as LPS and virus-derived nucleic acids. Significantly, TLRs also recognize damage-associated molecule patterns (DAMPs) that arise endogenously during various forms of noninfectious tissue injury. Regulated PAMP sensing by TLR4 has a unique requirement of myeloid differentiation 2 (MD2), an accessory receptor that interacts with TLR4 to form the signaling-competent receptor. The requirement for MD2 as an accessory pattern-recognition receptor for PAMPs appears to be unique for TLR4.
We recently demonstrated that particular DAMPs are markedly upregulated in fibrotic skin and lungs in patients with SSc and largely colocalize with TLR4-expressing myofibroblasts. In mice, genetic ablation of either of two DAMPs prominently associated with SSc resulted in markedly attenuated skin and lung fibrosis and enhanced fibrosis resolution, suggesting a fundamental pathogenic role for DAMP-TLR4 signaling in driving persistent organ fibrosis.
We developed a small molecule that selectively blocks MD2, which is uniquely required for TLR4 signaling. Targeting MD2/TLR4 abrogated inducible and constitutive myofibroblast transformation and matrix remodeling in fibroblast monolayers, as well as in 3-D scleroderma skin equivalents and human skin explants. Moreover, the selective TLR4 inhibitor prevented organ fibrosis in several preclinical disease models and mouse strains, and it reversed preexisting fibrosis.
Researchers here report on a single gene alteration in fruit flies, increased levels of vinculin, that improves cardiovascular function in later life and increases life span. Effect sizes in flies are much larger than those in humans, where is is possible to directly compare interventions. Short-lived species have evolved to exhibit a far greater plasticity of longevity in response to environmental and genetic changes, at least in those methodologies tested to date. It remains to be seen as to whether the initial hypothesis on the important mechanisms linking vinculin levels to improved health turn out to be correct. Vinculin is involved in common cellular processes that in turn influence many aspects of tissue function. This is frequently the case in studies of slowed aging - finding out exactly how and why it works is a long and arduous process.
Our cells tend to lose their shape as we grow older, contributing to many of the effects we experience as aging. This poses particular problems for the heart, where aging can disrupt the protein network within muscle cells that move blood around the body. Researchers discovered that maintaining high levels of the protein vinculin - which sticks heart muscle cells to one another - confers health benefits to fruit flies. Their work shows that fruit flies bred to produce 50 percent more vinculin enjoyed better cardiovascular health and lived a third of their average life span longer.
Vinculin works at the intercalated disks that glue together heart muscle cells, called cardiomyocytes. As we age, cardiomyocytes make less vinculin. Vinculin organizes the heart's contractile proteins, so as vinculin levels fall our heartbeats become disorganized and less efficient. By breeding flies with complementary genes, researchers created a genetic switch that turned on extra copies of the vinculin-coding gene. To ensure that only cardiomyocytes were producing the protein, the group used the same activation machinery as a heart development gene called Tinman.
While typical fruit flies live for roughly six weeks, flies that made more vinculin survived up to nine weeks. Additionally, flies with a vinculin boost were more active and able to climb the walls of their enclosures, a test of fruit fly athletic ability. Researchers were surprised how much improving cardiac function also helped the flies maintain a healthier metabolism. To measure this improvement, researchers fed the flies a special form of glucose and detected how the flies modified and used the sugar. Flies with more vinculin broke down more glucose than their counterparts. The team concluded higher vinculin levels in the flies' hearts enabled other organs to efficiently get the nutrients they needed in the breakdown process.
Clearance of metabolic waste from the brain via fluid drainage pathways is becoming an important topic in the context of age-related neurodegeneration, as is noted by the authors of this open access review paper. There is good evidence to suggest that drainage of cerebrospinal fluid is a significant path for the removal of wastes, such as the protein aggregates associated with dementia, and that the relevant fluid channels atrophy and fail with age. That decline may well be an important contribution to the development of neurodegenerative disease in later life, and the first efforts to do something about it are now underway. Restoring drainage is the goal of Leucadia Therapeutics, for example, a company that will probably be joined by similar initiatives in the years ahead.
Waste removal from the central nervous system is essential for maintaining brain homeostasis across the lifespan. Two interconnected, dynamic networks were recently uncovered, which may provide new information concerning the conundrum of how the brain manages waste removal in the absence of authentic lymphatic vessels (LVs). The glymphatic system serves as the brain's "front end" waste drainage pathway that includes a perivascular network for cerebrospinal fluid (CSF) transport, which is connected to a downstream authentic lymphatic network associated with the meninges, cranial nerves, and large vessels exiting the skull. The anatomical and functional components of the two systems are complex, and the processes by which they physically interconnect are only partly understood.
The first pioneering studies documented that soluble amyloid beta (Aβ) protein and tau oligomers - metabolic waste products whose buildup is associated with Alzheimer's disease (AD) - were transported from the interstitial fluid (ISF) space and out of the brain via the glymphatic system. This information was followed by another hallmark study reporting that slow wave sleep enhanced glymphatic Aβ clearance from brain when compared to wakefulness. Collectively, this information was met with excitement in the neuroscience and clinical communities because maintaining efficient brain waste drainage across the lifespan - possibly by preserving normal sleep architecture - emerged as a novel therapeutic target for preventing cognitive dysfunction and decline.
The idea of maximizing brain "waste drainage" as a new preventive or therapeutic target for neurodegenerative disease states was further strengthened by animal studies providing evidence of declining glymphatic transport efficiency in healthy aging, AD models, traumatic brain injury, cerebral hemorrhage, and stroke. Considering the novelty of the glymphatic system concept, along with the rapidly emerging literature associating key physiological processes (e.g., vascular pulsatility, and sleep) with glymphatic transport function and waste solute outflow from brain, we decided it was timely to review this information cohesively. Hence, the goal of this mini-review is to provide a broad overview of the current data, controversies, and gaps in knowledge of the glymphatic system and waste drainage from the brain, while addressing potential consequences of aging as well as critically reviewing evidence for its existence in the human brain.
The Life Extension Advocacy Foundation volunteers recently published a long and interesting interview with Peter de Keizer, the researcher who led development of the FOXO4-p53 approach to selective destruction of senescent cells. As senescence cells cause aging and age-related disease, there is considerable interest in developing means to remove them, and thus produce rejuvenation. The FOXO4-DRI used in de Keizer's study is probably the best of the current crop of senolytic compounds, as while the degree to which it kills senescent cells is broadly similar to the others, the evidence to date suggests that it produces insignificant side-effects; its method of action is much more localized to senescent cells. A company, Cleara Biotech, has been funded to develop this research into a commercial therapy.
It doesn't seem like as many people in Europe talk about aging as in the U.S. Is being in Europe instead of the U.S. better or worse for your research?
As usual, the U.S. innovates, China imitates, and Europe hesitates. I returned to Europe for personal reasons, but I have been talking to American investors who want to explore Europe a bit more, and there are possibilities. People here do acknowledge aging as a problem, and the Undoing Aging conference in Berlin was a success. The downside with Silicon Valley is that there are big budgets and a great spirit, but we also need a style of research, which is, in every city, a little bit different. In Europe, the focus is very much molecular. I would like to combine the great vision and budget of Silicon Valley with European quality and maybe a bit of skepticism. We never publish anything unless we are really convinced. In that sense, I like Europe because people are interested in aging here; you just have to talk to the right people, and many people are skeptical. When I talk to scientists about what we do, they also get excited.
Are the regulations regarding trials more stringent than in the U.S.?
Yes, that's true, especially for animal work. There's a lot of societal pressure not to do animal work. We have to deal with these hurdles, but there's good money in science here, certainly in Western Europe, and we can make do quite well. This is generalizing, but we tend to talk less and do more.
Would you say that a potential side effect of the drug, if not used at the proper dose, could be excessive lysis?
The honest answer is "We don't know." I've seen in mice that you can go too far; if you look at the cell data, it's tenfold more potent against senescent cells. That sounds like a lot, but if you want to treat relatively healthy people with this, if one in ten cells that will be destroyed is basically a healthy cell, I find it very risky. So, you need to have a perfect dose or a perfect range.
With mice, we could scale it and we could say if it's too much or not, but for humans, it's more difficult. What we're doing now is trying to optimize this to make it tenfold more selective. This is version 4, and the published paper is on version 3; the first two were generated in the US in 2012, and they were not so effective. The first step was very short and had a very poor solubility, the second step lasted much longer, and the third peptide we made in D-amino acid is the one we published now. Now, we're making the fourth one because we know where the critical amino acids and the non-important and important ones are in the interaction domain of the two proteins, FOXO4 and p53. We plan on giving number 4 to a team of drug development experts to get it to a hundredfold selectivity, and then it should be much safer for use.
How long would you say it's going to be for this safe version four to be optimal?
That's the fun part. It took me ten years to come to this third version because in academia, we always have 20 other things that are also interesting. Now, we actually teamed up with a company, Cleara, that we founded just recently. The team has 20 people, with 10 structural experts, and they're going crazy on this. Every week, we have a meeting at which they have made some more progress, and it is super fast. We gave ourselves four months for a library screen on the first version, and then it's another ten rounds of optimizations. Once we have a lead candidate, we will start doing all the things that academia never wants to look at, like a liver update and all the stuff that scientists aren't interested in but is important to have. I want to do ten rounds of that, and it's three weeks per round, then we'll know roughly where the weak spots are in our current version, and we can go back and add heavy metal toxicity, etc. We gave ourselves a year for optimization, but I hope sooner.
How well does this treatment compare to other treatment options, such as fasting?
With fasting, you don't kill, you just delay the secretions from senescent cells. It's like rapamycin and aspirin; it just blocks the secretion profile. Fasting offers a transient benefit for sure, but a week later, you eat again, and they're just there again. It's just making them dormant. We have not seen evidence that senescent cells are removed by fasting, in mice or in cells.
Have you looked at other senolytics?
We tried a lot, and the BCL inhibitors look the most promising. What we saw when comparing them to FOXO4-DRI is that they are toxic at low levels and should not be given to healthy people. That's the downside of these drugs. In vitro, if you do low-level navitoclax on healthy cells, you get 10, 20 percent cell death. That's relatively stable. That's a decrease in viability because you're affecting some cells that are apparently sensitive to BCL inhibition. We did not see that with FOXO4, and that's what's reported in our paper. As for quercetin and dasatinib, I'm absolutely not a fan of those. We've tried a couple of experiments; we've never seen a good result.
How often do you think people would need senolytic treatments, will they be for older or younger people?
In mice, over a year; we did it once a month. It seemed to be enough, and I think we can actually reduce that frequency. But, I still have to do the experiment. If we do it once in a while, once every three months, once every half a year in mice, it might actually be sufficient. I don't think they accumulate that fast. Maybe later in life, you'll do it a bit faster. Early in life, there's really no reason to do it so often. It's like a car. If it's only a couple of years old, you don't go to the mechanic as often.
The open access study noted here is one of many to show that greater levels of physical activity correlate well with a reduced risk of age-related disease. It isn't possibly to reliably live to extreme old age on the back of a good exercise program, but that physical activity does reliably improve the odds of experiencing better rather than worse health in later life. Even small benefits can be worth chasing when they cost little and are reliably obtained, so long as that pursuit doesn't distract from far more important initiatives. Exercise is beneficial, but it is no substitute for the rejuvenation therapies presently under development.
Successful aging has been defined as not suffering from chronic diseases, having optimal social engagement and mental health, and a lack of physical disability. Numerous studies have found that physical activity decreases the risk of many chronic diseases and increases longevity. However, the association between physical activity and successful aging has shown heterogeneity across studies. Some studies have shown either a lack of or a weak independent association between physical activity and successful aging; however, other cohort studies as well as systematic reviews have shown that higher levels of physical activity was associated with aging successfully.
Therefore, in our cohort study of 1,584 adults aged 49+ years at baseline we aimed to investigate whether total physical activity is independently associated with successful aging, which was defined as not experiencing disability and chronic disease (coronary artery disease, stroke, diabetes, cancer), having good mental health and functional independence, and reporting optimal physical, respiratory, and cognitive function during 10 years of follow-up. Participants provided information on the performance of moderate or vigorous activities and walking exercise and this was used to determine total metabolic equivalents (METs) minutes of activity per week.
Of the cohort, 249 (15.7%) participants had aged successfully 10 years later. Older adults in the highest level of total physical activity (more than 5000 MET minutes/week; n = 71) compared to those in the lowest level of total physical activity (less than 1000 MET minutes/week; n = 934) had 2-fold greater odds of aging successfully than normal aging. Our finding of a positive association between physical activity levels and successful aging is in agreement with the existing literature showing that physical activity might be an important parameter in enabling people to age successfully. Moreover, a systematic review found that the effect sizes for the association of successful or healthy aging with high levels of physical activity ranged from 1.27 to 3.09, which is in line with our observed estimate.
Many methods demonstrated to slow aging in short-lived species, such as the nematode worm Caenorhabditis elegans, involve hormesis. This is the induction of mild cellular stress and damage, through heat, or lack of nutrients, or raised levels of oxidative molecules generated by mitochondria, that leads to an enhanced cellular maintenance response. The net result is a gain in health and tissue function. The open access paper here discusses some of the known hormetic mechanisms in nematodes, those involving alterations in mitochondrial function, and illustrates one of many methods of triggering mitochondrial hormesis in that species. The degree to which longevity is enhanced in this case is not large at all when considering the plasticity of life span in nematodes; life spans in this species have been extended by a factor of ten by some research groups. Sadly, we know that these approaches have nowhere near the same outcome in mammals.
Alterations in microRNA (miRNA) processing have been previously linked to aging. Here we used the small molecule enoxacin to pharmacologically interfere with miRNA biogenesis and study how it affects aging in C. elegans. Enoxacin extended worm lifespan and promoted survival under normal and oxidative stress conditions. Enoxacin-induced longevity required the transcription factor SKN-1/Nrf2 and was blunted by the antioxidant N-acetyl-cysteine, suggesting a prooxidant-mediated mitohormetic response. The longevity effects of enoxacin were also dependent on the miRNA pathway, consistent with changes in miRNA expression elicited by the drug. Among these differentially expressed miRNAs, the widely conserved miR-34-5p was found to play an important role in enoxacin-mediated longevity.
And how does miR-34-5p down-regulation affect lifespan? Mir-34 has been previously associated with lifespan and the onset of age-related diseases in model organisms, but the directionality and the mechanisms underlying its effects have been a matter of debate. A previous study demonstrated that mir-34 loss-of-function significantly extends lifespan through activation of autophagy, but other studies did not see an effect on survival or even found the opposite. Here we show that both enoxacin and mir-34 loss-of-function extend lifespan via a mechanism that requires a prooxidative effect. Different types of food (e.g., dead bacteria here versus live bacteria in the previous studies) and slightly different experimental conditions could have created different thresholds of sensitivity to prooxidant agents or a different redox balance which in turn could explain the apparent discrepancies in reports associating mir-34 with longevity.
Sub-lethal levels of mitochondrial reactive oxygen species (ROS) are usually associated with beneficial effects and lifespan extension, while elevated ROS can be toxic - a phenomenon often referred to as mitohormesis. Mitochondrial ROS requires the transcription factor SKN-1/Nrf2 to increase lifespan and confer their beneficial effects, and so does enoxacin. Together, these results indicate that enoxacin promotes non-toxic levels of ROS through inhibition of miR-34-5p, which in turn activates stress response pathways mediated by SKN-1 and autophagy. In addition to its beneficial outcomes, there is a toxic effect caused by enoxacin treatment. Consistent with this notion, enoxacin-mediated miR-34-5p inhibition confers a lesser lifespan extension than deletion of the mir-34 gene.


Join the Washington DC Sunday Night Film Club this Sunday, Nov 15th at 4:00pm for Spectre at the AMC Loews Uptown 1 . Look for Brian F. wearing a white & blue-striped shirt in the theatre lobby about 15 minutes before the film. As always, after the film we will descend on a local establishment for dinner/drinks/discussion.


Hello from my studio. This table is mostly being used by Johan when he's working from home (not often) and by me when I put on make up (two minutes a day). Will clean it up soon and start using it more.
Hello from my hallway. That arrow is left since Johan made a surprise for me last month.
Hello from my kitchen. Kristina gave me these for my birthday four weeks ago, time to say bye.
Hello from my kitchen again. A shelf with tea (most of them from you lovely blog readers) and the fridge shows good memories and things to look forward to. Yesterday I started making plans for rebuilding the kitchen (the positive side of being sick).
Thank you for your thoughtfulness on yesterday's post.
You helped me feel better.
This is a lovely house you got there! Love the light in here!
I hope you feel better soon. Drink lots of tea!
Hi Sandra, this is my first visit to your blog and I love it already! Such a beautiful place.
The first and the last photo made me smile as they make me think of my own house.
Lovely to see all these sorts of tea: I do have plenty myself from my blog readers and other beloved ones.
Happy weekend to you and hoping you'll feel better soon!
PS: And now I realize I have been here before, because I remember your Berlin photos. It's great to be back and I'll start to follow you from now in as this place is so warm and inspiring!
I love the desk !
love the cozyness (or cozyiness...how do you write that?!) of your place!!
tea collection is pretty impressive btw!


1 Ophelia: The Nazis have stolen the Crown Jewels? That never happened!
1 Student: Are you calling me a liar?
2 Student: It just came over the wireless from London!
3 Ophelia: I mean the Nazis never even planned to steal the Crown Jewels.
3 Student: You're privy to Nazi plans?!
4 Student: Spies! They're spies!!
4 Shakespeare: Oh well done, Ophelia.
"Wireless" always carries an aura of old-timey antiqueness.
Or at least it did before it started being used for newfangled gadgetry like Bluetooth and Wi-fi.
Last Modified: Thursday, 3 March 2011; 02:11:01 PST.


text:
var child_process = require('child_process');
var fs = require('fs');

var configLocation = JSON.parse(fs.readFileSync('/home/git/Gitorade/gitorade.location', 'utf8'));
var config = JSON.parse(fs.readFileSync(configLocation.location, 'utf8'));

function filelog(text) {
	text = text.toString();
	var now = new Date();
	var timestamp =
		now.getFullYear() + '.' +
		(now.getMonth()+1) + '.' +
		now.getDate() + '-' +
		(now.getHours()+1) + ":" +
		(now.getMinutes()+1) + ":" +
		(now.getSeconds()+1);

	text = timestamp + " - " + text;
	console.log(text);
	//console.log(gitoradeLogLocation);
	fs.appendFileSync(gitoradeLogLocation, text + '\n');
}

child_process.exec("kill " + process.env.SERVERPID, function (){
	child_process.exec('screen -d -m -L node ' + config.gitoradeServerLocation, function(){
		filelog('Finished restarting');
	});
})

redpajama_set_name: RedPajamaGithub


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Sport Court of Southern California: Before, During, and After.. Transform Your Space!
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text:
is a male badminton player from Japan.

Yamada played badminton at the 2000 Summer Olympics and 2004 Summer Olympics in men's singles, losing in the round of 32 to Taufik Hidayat of Indonesia in both times.

Link
2004 Japanese Olympic Committee

1976 births
Living people
Japanese male badminton players
Olympic badminton players of Japan
Badminton players at the 2004 Summer Olympics
Badminton players at the 2002 Asian Games
Badminton players at the 1998 Asian Games
Badminton players at the 2000 Summer Olympics
Asian Games competitors for Japan
21st-century Japanese people

redpajama_set_name: RedPajamaWikipedia


Because I care, but, research for yourselves too.
Do research to find water that doesn't contain fluoride. I use Crystal Springs brand of Spring Water. Each state has their own name branded from the same company. Get the information on your state here. www.water.com One can also install a whole house filter that would help in showering as well, this is best option if one can afford to do so.
Throw away the poisonous white table salt if you're still using it. The minerals and nutrients have been stripped causing it to be sodium chloride which the body recognizes as a poison without the nutrients adhered to it. Go with Celtic or Himalayan Pink Salt.
Black Lights put negative ions in the air and can be used to clean the air.
Get an Air Filter for cleaning the inside air of your living space. I use Surround Air as it has 6 filters and one filter can be cleaned with water. It also uses a black light feature for ion in the air.
When one goes to their Western Medical Doctor and asks for a cancer test, a specimen will be taken and sprinkled with sugar, left for some hours and then observed to see if anything grew. If there is a large amount of growth, there is cancer. You see, cancers grow with sugar. Every human has a certain amount of cancer cells, but, it's when one consumes a lot of sugar and acidic foods as well that those cancer cells multiply and get out of hand. So maybe this information will help you choose foods that will aid in avoiding cancers. I hope so.
Now for toxins we hear about this that can remove this or what about that one that can remove that. Well how about one that removes all of it including radiation and nano particles? Then that would be Liquid Zeolite.
On the subject of vaccines... I would advise everyone not to get injected. I often ask "What's you favorite ingredients in vaccines?" This usually stumps a lot of people. Who really knows what they are allowing in their body via vaccine? Not many. Truth is there's a lot of ingredients one wouldn't want in their body, example: fetal aborted cells are often used in vaccines.


text:
Q: The AlertDialog is invisible when the Activity back to foreground I write a program support download file. When in this download activity, I start a progress bar and then run a thread to do the download things. This thread send message to UI thread to notify how many has been downloaded frequently. In the main(UI) thread, I update the progress bar display when receive the message. If any problem happen in download progress, it will send another message. When main thread receive the message, it stop the progress bar and pop up a new AlertDialog to show the error reason.
Here is a special test for it. When downloading, switch the program to settings. Turn off the WIFI/GPRS to make the network off.
When I back to my program, it should display the background ui and a pop up AlertDialog to show the reason as I wish. But it only display the background ui(which means the main activity) and with a half-light of backlight just as the popup windows still there. When I press back for first time, nothing happens except the backlight is bright just like I have close a pop up window.
I think maybe it is because when I start the AlertDialog my activity is not in foreground.
I tried to use:
ActivityManager am = (ActivityManager)Update.this.getSystemService(Context.ACTIVITY_SERVICE);
ComponentName cn = am.getRunningTasks(1).get(0).topActivity;

to judge whether the top activity is mine. But I want to show the dialog. If the activity isn't being seen by the user, when he gets back to my activity, I want it to show the dialog.

A: Indeed the dialog already shown but not visible to the user and it would become visible if you rotate the device.
There seemed a refresh/drawing issue if dismiss a progress dialog and show another new dialog immediately when the activity is not in foreground.
During my testing, such issue not happen if wait for the dismiss action finished for the progress dialog and then show the new dialog.
So one solution is that show the AlertDialog first and then dismiss the ProgressDialog. That worked for my application.

A: I think, there is some king of bug in Dialog. I have the same situation, and only solution was dismiss curent dialog by dialogDismiss(id) and show it again by showDialog(id).

redpajama_set_name: RedPajamaStackExchange


text:
Nobody's Fool: Movie Review
November 2, 2018 / Leave a comment
Directed by – Tyler Perry
Produced by – Tyler Perry, Mark E. Swinton, Will Areu
Starring – Tiffany Haddish, Tika Sumpter, Omari Hardwick, Mehcad Brooks, Amber Riley, Whoopi Goldberg
Two things emerged toward the start of this film. To start with, the Lionsgate logo that typically presents Perry's work had been supplanted by the "Paramount Players" logo. Second, I could have sworn the credit did exclude the now-standard expressions of proprietorship "Tyler Perry's" before the title. I can be pardoned on the off chance that I missed them, in light of the fact that in the meantime the title shows up, Perry is indiscriminately filling the screen with forward and backward content air pockets. (more…)
The Nutcracker and the Four Realms: Movie Review
Directed by – Lasse Hallström, Joe Johnston
Produced by – Mark Gordon, Larry Franco
Starring – Keira Knightley, Mackenzie Foy, Eugenio Derbez, Matthew Macfadyen, Richard E. Grant, Misty Copeland, Helen Mirren, Morgan Freeman
Disney's interpretation of the occasion great is kinda the story you know, and it's kinda Tim Burton's "Alice in Wonderland," or, in other words a suggestion. It has bits of Tchaikovsky's music and some artful dance, cordiality of hotshots Misty Copeland and Sergei Polunin, yet not sufficiently about. And while the film's folklore is thick, it's likewise greatly dull. (more…)
Bohemian Rhapsody: Movie Review
Directed by – Bryan Singer
Produced by – Graham King, Jim Beach
Starring – Rami Malek, Lucy Boynton, Gwilym Lee, Ben Hardy, Joseph Mazzello, Aidan Gillen, Tom Hollander, Mike Myers
Opening and shutting with Queen's triumphant execution at Live Aid in 1985, the film appears (kind of) the change of bashful buck-toothed Farrokh Bulsara, the closeted child of Parsis guardians, into the swaggering Freddie Mercury. Freddie is indicated moving toward a band he enjoys backstage at a club in London. They simply lost their lead vocalist, and Mercury has composed a melody he needs to demonstrate them. (more…)
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redpajama_set_name: RedPajamaCommonCrawl


It's great to have a nonprofit's name in the form of a question. It is a good way of having the conversation with the community already having begun before you open your mouth. In the case of Why Hunger? this conversation has been going on for 35 years, ever since singer and activist Harry Chapin first posed the question and then even better, got together with founding (and current) Executive Director Bill Ayres to do something about it.
The organization is a grassroots support organization that tries to build the movement against hunger and poverty by amplifying the voices of innovators who we think come from the grassroots.
At the recent Feeding America national summit, I met with Harry Chapin's daughter Jen Chapin, who is a wonderful singer-songwriter, who some in the western region may remember from her address and performance at a conference in Tucson last year hosted by the Community Food Bank of Southern Arizona.
Jen Chapin, Board Member of Why Hunger?
I also had a chance to speak with Jessica Powers, director of the National Hunger Clearinghouse at Why Hunger? Below are excerpts of my discussion with her.
Jessica Powers, Director of the National Hunger Clearing House, Why Hunger?
The organization has been working on an essential new resource for those running nutrition programs which has just been made available.
So tell me a little bit about the types of support that Why Hunger? provides.
We do training and technical assistance. We do capacity building through some small grant programs, and we also use the vehicle of storytelling a lot. We try and find out about innovative approaches that people are using, and we try to amplify those voices to a wider audience in order to inspire people about things they could try in their own communities.
Can you give me an example of what you are working on?
Sure. Through our grassroots action network, we currentlyhave 3 food desert projects that we're working on. The technical title is 'building community power to eliminate food deserts', and we're working in Southwest Arizona, in the Mississippi Delta, and in Central Coast California.
And what we do is we bring together different stake holders who are working on food systems issues who may not be talking to each other currently, so that might include ranchers, people from public health, people from the school system and food bankers. And then through a facilitative process, we talk about the history of that area, how they got to the current situation that they're in and what their vision for the future is. Our role is really to facilitate moving that forward that we actually think the community should determine for themselves what is the best solution for them, but that our role is to help move that forward by being sort of a consistent presence and helping with any challenges that arise in moving the work forward.
The National Hunger Clearinghouse works on capacity building for emergency food providers, and we focus mainly on food pantries and smaller agencies. Through that program, we had a lot of conversations with people, and they kept saying that there was a lot of innovation happening in food sourcing and nutrition education, and it was really hard to find out what was going on and to find a place which could be a hub for that information.
We did research and created program profiles on a host of organizations that are working on those 2 different issues. And so we organized them sort of by strengths. So in the nutrition education guide, we're looking at programs that maybe are better at working with diverse communities. Some are better at evaluation. And the idea is that people can then tailor it to the program that works for them in their area.
Self-Promotion – Promoting someone you're committed to spending the rest of your life with.
Yes, in many ways, that is our mission. We have a Food Security Learning Center on our website which is an encyclopedia of food system issues. Everything from water to community food assessments to race in the food system, youth in the food system etc. We have a particular lens, which is that we want to see healthy nutritious food available to people. So the articles are definitely written with that lens. But I guess the big thing that we do is try to disseminate information and try to share stories with a wider audience.
Damn, I remember my college days when wearing a button could solve the most intractable of human problems. What happened to the world??!!
What do you think food banks could do or be involved in that they are not currently as a whole involved in?
I think that we all acknowledge that the root cause of hunger is poverty, and if we're not talking about poverty and solutions to that, then we're spinning our wheels. So I would challenge food banks to do more of that, to talk more about wage disparity, to talk more about living wages and healthcare and things like that, that are forcing people into the position where they need emergency food assistance.
This came up in the speech by Matt Habash, last year's winner of the John Van Hengel Award (Prestigious food banking award), and he was encouraging people to make that link to poverty. But in subsequent sessions that I attended, people from other food banks were saying, "Oh my god, I can't go near that because it's a political hot potato, and it's outside our wheelhouse, etc." Are there other things that they could do?
It is not only a case of the food bank using its own voice. They could be sharing more information and insights with the agencies that they work with, and helping them build their advocacy skill set. They can also use State Associations as more of the political voice.
I think it is a question of framing. It has to be about opportunity. The whole childhood hunger piece, when you talk about children having an equal opportunity to become leaders, to become educated. I think that's something most people can agree on regardless of their party politics. And I don't think that people talk about that enough.
So are you suggesting that food banks take more of a leadership role in putting together coalitions and becoming the backbone organization for a wider variety of community organizations?
Yes. Increasingly we're seeing that there is a political movement that wants to privatize charity. That means putting the burden onto the food banks, so I think food banks need to stand up to this. When you look at the total pie of food distribution, food banks are still a relatively small piece in this country and so they can't be expected to take on such an increasing burden, and I think they need to be more vocal about that. I think when we have discussions that are based solely on poundage or distribution or logistics or supply chain, then it sort of takes away from our ability to say, "Hey, wait a minute, this is supposed to be an emergency response, not a long-term solution," right?
Thanks, Jessica, and thank you for your work in putting together such a great guide.


The first consideration is financing. Can you afford the buy-in and associated monthly fees? If necessary, a senior is allowed to convert home equity and other assets into their initial expenditure to join a CCRC however, the vast majority of seniors who choose to reside in a CCRC have the personal financial resources to fund the stay out-of-pocket. All facilities and contracts are different. Each state has an agency that regulates CCRCs, and the government entities offer listings and a consumer guide about the CCRCs available in your state. There is also an independent nonprofit organization called CARF International, which provides accreditation for CCRCs and their services.
Overall, you will not be able to use Medicare to cover the cost of a CCRC because Medicare Services do not cover long-term care. The exception for Medicare coverage is if you use skilled nursing services while in your CCRC facility; Medicare will cover up to 100 days of that service. Because these CCRC contracts are similar to a "long-term insurance plan" it is tax-deductible because the IRS considers it a prepaid medical expense. The financial picture is different for every individual and every facility so get with your financial planner and elder law attorney to carefully review the contract and its terms before committing to anything.
While every CCRC is different, there is some standardization in the three types of contracts that are typically offered. The first is an all-inclusive, fixed price contract. While it is the most expensive contract, it provides unlimited access to all of the assisted living, medical care, or skilled nursing care at no additional charge. This contract is best for someone entering the facility while still healthy and independently able. The second option is a modified contract that provides services for a set length of time which is a gamble. In the event you outlive the contractual timeline the additional services required are likely to expose you to a higher monthly fee. The third type of contract is a fee for service which means you only pay for the services you use. Fee service contracts typically lowers your entry cost into the community, but you will pay market rate for assisted living or skilled nursing care if you need those services.
The best time to make a move into a CCRC is when you are healthy and able to take advantage of all the facilities have to offer. Being in a community that provides health and wellness strategies above and beyond medical care can allow you to age more successfully and with fewer health incidents. Moving into a CCRC is not a decision to be made in desperation because of an urgent health care need. The complexity and range of the CCRC contracts and pricing options need your careful thought and review with professional guidance to optimize your aging experience. Seniors with a spouse find a CCRC living choice particularly gratifying because partners will need different medical help at different rates. Even if the couple is not living in the same unit due to medical conditions they are at least on the same campus.
The social and activity amenities offered in CCRCs are very interactive and keep residents engaged. However, if the location of the campus is remote from urban environments, you might feel isolated and disconnected from the world at large. Some CCRCs are popping up in downtown locations and even on college campuses around the country. So be certain when considering a move to a CCRC you ask yourself if the site appeals to you for the long term. Also, find out how far removed it might be from family members you want to visit with often.
There are many questions to ask when contemplating a move into a continuing care retirement community. Visit the property and bring a family member or legal counsel to ensure the proper inquiries are made and that answers are complete. Ask to spend a week at the facility to experience it first hand and avoid buyer's remorse. You are deciding whether to reside at a property for the rest of your life and must be sure that the facility is a fit for you. Because there have been bankruptcies in the CCRC business sector, you must review the facility's financial sustainability. You do not want an unsuccessful CCRC to force you into a relocation process late in life that can be financially, physically, and emotionally draining.
If we can assist you in identifying and choosing a CCRC as part of your overall long term care plan, please don't hesitate to contact us at (406) 549-0306.


You are here: Home / Blog / Dimensional Lettering / Are Foam Letter Signs A Good Choice In Irvine CA?
Are Foam Letter Signs A Good Choice In Irvine CA?
One of the most affordable, versatile, and environmentally-friendly signage solutions on the market today is sign foam. Also referred to as high-density urethane, sign foam is used for a wide variety of signage applications both inside and out. It can be used for sign panels as well as letters. Today, we will help you determine whether exterior foam letters for Irvine, CA are right for your organization.
WHAT MAKES FOAM LETTERS GREAT?
Additionally, sign foam is ideally suited for routing, carving, and sandblasting. Plus, wood is not the only material it can mimic. It can be made to look just like any other materials as well.
HOW ARE SIGN FOAM LETTERS USED?
When you want to give a monument sign, dimensional letter sign, or any other marker a dimensional appearance, foam letters are the way to go. When you choose a dimensional letter sign, the foam letters are typically applied to an aluminum composite panel. The letters can then be printed on with a digital printer, painted, or covered with a laminate, such as metal or acrylic.
Foam is used in the construction of many of the large monument signs you see next to the entrances of parking lots for many buildings and complexes. You probably didn't even realize they were made using foam. This is because they are often made to look like other materials. You get nearly the same level of durability at a fraction of the price of the materials they are made to mimic. As a matter of fact, foam letters can usually withstand high wind speeds or repeated blows from a hammer.
WHY SHOULD YOU USE FOAM?
You should consider foam letters for their versatility even if you are not concerned about being green. There is a virtually limitless variety of custom touches we can give your foam sign. It can take the look of stucco, masonry, or wood. And, there are marvelous signs we can craft when using foam in conjunction with acrylic and aluminum.
You should contact Caliber Signs & Imaging for exterior foam letters for Irvine, CA if you are interested in saving trees and money with your new signs. From design to installation and maintenance, we handle every part of the sign-making process. Even if you are unsure about what you want, we can make recommendations based on your vision, goals, and budget. Contact us for a free estimate today!
https://www.calibersi.com/wp-content/uploads/2016/06/WHY-SHOULD-YOU-USE-FOAM.jpg 227 343 Martin Neil https://www.calibersi.com/wp-content/uploads/2016/11/webmail4-1.jpg Martin Neil2015-12-15 13:37:012018-10-29 09:05:08Are Foam Letter Signs A Good Choice In Irvine CA?
Custom Signs For Your Irvine CA Business 10 Tips For Great Sign Design, Including Vehicle Wraps!


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David Richards, the former Benetton and BAR boss, is considering a return to Formula One as Honda's saviour - a move which would place a question mark against Jenson Button's future.
Richards has been contacted by two parties interested in buying the for-sale team and running it with his expertise.
That would help save some of the 750 workforce at Honda's factory in Brackley, Northamptonshire, but Button, their 28-year-old British driver, could be among those surplus to requirements given that he and Richards parted on bad terms when Honda took over BAR in 2004.
However, dispensing with Button could be complicated as he recently signed a new three-year deal worth £8million a year.
Richards declined to confirm whether the approaches were from the Arab consortium, Dubai Investment Capital, or Formula Three's Trevor Carlin.
Richards, 56, is the owner of Prodrive, who run the Subaru entry in the World Rally Championship, and head of Aston Martin.
He wanted to put Prodrive on the F1 grid in 2008, but pulled out, blaming a dispute over whether he could use McLaren chassis and engines as so-called 'customer cars'.
The Formula One Teams' Association, meanwhile, have called for a greater share of the sport's profits to complement cost-cutting measures.
Max Mosley, the head of the ruling FIA, agrees with the thrust of FOTA's demands, indicating that the teams should take 'at least £30m' per year from profits, which are centred on TV revenue.


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Hong Kong Officials Quarantined After Covid-19 Case at Tapas Birthday Party
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That's the headline on my newest story, out Friday. It begins:
HONG KONG—As Hong Kong officials were warning citizens to exercise caution after the city's first Omicron cases emerged last week, senior civil servants joined dozens of other partygoers at a tapas restaurant Monday evening to celebrate the birthday of a China lawmaker.
Now some of them are in a government quarantine center after being classified as close contacts of a party guest who later tested positive for Covid-19. Among them are the city's home affairs secretary, the director of immigration and some legislators.
Images of the event — held in honor of Witman Hung, a local representative to China's national legislature — emerged shortly before tough new restrictions on nightlife and other venues across the city came into effect Friday, drawing angry comments from some residents on social media.
Hong Kong has some of the world's strictest testing and quarantine regimens, and tough border controls had kept the city free of community cases for months. That bubble was punctured last week after an aircrew worker, who was later found to have Omicron, broke home quarantine conditions to eat lunch at a restaurant. Several other diners in the venue later tested positive, and health officials have warned that there are now invisible transmission chains in the city, although recorded cases of Covid-19 transmitted in the community have remained just a few.
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Facebook Ends Ban on Posts Asserting Covid-19 Was Man-Made
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That's the headline on a story I wrote that ran Thursday. It begins:
Facebook Inc. has ended its ban on posts asserting Covid-19 was man-made or manufactured, a policy shift that reflects a deepening debate over the origins of the pandemic that was first identified in Wuhan, China, almost 18 months ago.
The Wall Street Journal reported Sunday that three researchers from China's Wuhan Institute of Virology became sick enough in November 2019 that they sought hospital care, according to a previously undisclosed U.S. intelligence report.
"In light of ongoing investigations into the origin of COVID-19 and in consultation with public health experts, we will no longer remove the claim that COVID-19 is man-made or manufactured from our apps," Facebook said in a statement on its website Wednesday.
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Book Notes: 'Pandemics: A Very Short Introduction,' by Christian McMillen
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From time to time I share notes about the books I've been reading, or have revisited recently after many years.
These posts are meant to help me remember what I've learned, and to point out titles I think are worth consulting.
They're neither formal book reviews nor comprehensive book summaries, but I hope you find them useful. For previous postings, see my Book Notes category.
Pandemics: A Very Short Introduction
When it comes to pandemics – including Covid–19 – there's nothing new under the sun.
My Three Key Takeaways
I read this short (153-page) book, by University of Virginia historian Christian McMillen, earlier this year, as Covid–19 began spreading across the globe.
My major takeaway: pandemics have long ravaged human populations, of course, and Covid–19 has several historical parallels.
When cholera hit Europe in the 19th century, merchants rebelled against about trade restrictions. (See the conflict today between those who want to reopen economies and those who think strict lockdowns must continue for public health.)
When the 1918 influenza swept through nations, authorities in the U.S. and U.K. downplayed its severity. (See how some world leaders this year reacted to Covid–19.)
Whether it's cholera, HIV, malaria or tuberculosis, poorer people and poorer countries are usually hit hardest. It makes sense: richer people can quarantine themselves and have access to the best medical care.
(The coronavirus hasn't run its full course anywhere, really, it seems. But news from places like Brazil and India – not to mention the U.S., the world's richest nation – is worrying.)
We have been largely complacent when faced with the possibility of another global pandemic, McMillen writes.
Some notable quotations (all emphasis mine)
From the end of the chapter on influenza:
"The 1918 influenza was an event. Unlike malaria and tuberculosis – the perpetual pandemics – influenza comes and goes. In this way it is more like smallpox or plague. Of course these two diseases are no longer major global threats. Influenza is. When H5N1 appeared in humans in 1997 and the novel strain of H1N1 turned up in 2009, the world was reminded of the possibility of another 1918. It has not happened yet. We do not know when it will."
From the epilogue, in discussing the WHO's "lackluster response" to Ebola:
"…the WHO is, for better or worse, representative of a way of seeing things in the world of global health, and the leadership's statement on lessons learned allows me to make a point: every single lesson it learned (or in one instance relearned) could have been gleaned from a look at the past. These lessons are not new; the history of epidemics and pandemics has been teaching them for centuries."
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Yesterday, we highlighted the QuakeMap maxim of "No report is left unclosed!" – meaning we are determined to see that all reports on QuakeMap get fully addressed. However, closing all 1800 reports takes time and resources. Thanks to Professional Development and Research Center (PDRC), we have an additional set of volunteers who just joined us.
We have seven new volunteers, five of them from PDRC, who joined QuakeMap volunteers' roster. Antoine Merci (a long time QuakeMap volunteer and also our featured Volunteer of the Day today) introduced our new volunteers to the QuakeMap process and trained them on placing calls and verifying reports – tasks that they will be doing in the upcoming days at QuakeMap.
To make sure that our new volunteers are thoroughly acquainted with the QuakeMap verification process, we conducted drills in which they placed several mock calls within the QuakeMap team. Sometimes, they would place calls as QuakeMap verifiers and other times, they would be receiving calls as Earthquake survivors/victims. After they were comfortable with the process, our new volunteers then took charge and started dialing in at real people on the ground.
We have setup a crowdfunding campaign for raising US $ 50,000 to help us continue our works at QuakeMap.org and QuakeRelief.info. As of now, we are 18% funded and have received donations from 69 people. Please help us sustain our vital activities to coordinate post-earthquake relief efforts.
Meet Antoine Merci from Canada. He has been dispensing his invaluable voluntary efforts at QuakeMap for several weeks now. He joined the QuakeMap team as a dispatcher – matching 'needs' in the QuakeMap reports to the relief efforts being provided by different organizations. He also keeps a tab on our report status; and most recently, he has also been training our newest batch of volunteers at QuakeMap. Let's hear it from Antoine himself.
– I was introduced to Neil Horning.
I found a contract to return to Nepal on April 28th. The quake happened at around 2 am in East Canada. My mother woke me up a little before 5 am as Nepal was all over the news. I spent the first part of the day trying to contact all my loved ones there, but I could not get any news from my life partner. I quickly got a call to inform me that my contract was cancelled, as the program was put on hold due to the unknown risk level. One friend and I booked our plane tickets, and we reached TIA on April 28th at night. Meanwhile, I was able to get in touch with most of the people I know in Nepal. We assisted some quick distributions on the first weeks thanks to generous involvement from our friends and families, and the coordination of courageous partners here.
I was actively searching an edible coffee one morning after our distributions were done, when I met Neil again. After exchanging news, I asked if I could help in any way. He told me to be back two hours later. That was in front of Buzz Café. I was able to commit full time as I knew my loved ones were safe, and have been here since.
I quickly realized the enormous potential of the quakemap tool, and I find every hour contributed has a significant chance of helping someone who is going through the most difficult event of her or his life. Being still unable to contact the people on the field in their first language, my role has been to translate what we learn from the field into an exact report page. I trust that the information that we provide can help responders to assist the needs timely. Constant awareness of the enormous urgent needs is both a great source of motivation and an unbearable sadness. I am looking forward to contribute the most I can.


Tool Design Checker: Tool drawing checker Examines tool drawings prepared by TOOL DESIGNER (professional industry) 007.061-026 for inaccuracies of detail and evaluates overall tool design for fit, form, and function, utilizing knowledge of engineering principles, tool design methods, and manufacturing processes: Measures drawing dimensions, and compares figures with dimensions on original layout, specifications, or sample part to verify measurements conform to scale. Marks verified or out-of-scale dimensions on drawings. Inspects lines and figures on drawings for clarity. Evaluates overall tool design for functionality, conformance to drawing standards and design specifications, and manufacturing feasibility. Reviews material requirements for standardization and conformance to industry specification manuals. Discusses design, manufacturing, and related issues with engineering, production, or other personnel. Approves or rejects design. May also operate computer to examine and evaluate computer-generated tool designs.


Ian Balina, respected cryptocurrency investor and YouTube influencer have stated on his social media pages that he has been hacked over $1 Million. While Balina remains uncertain about the actual cause of the hack, he stated that the only clue he has was that he's requested to change his college email after receiving notification that it was compromised.
Ian said he kept text versions of his private keys in his Evernote as encrypted text files with passwords, he however stated that his email and Evernote were hacked through the college email.
While lamenting on the loss, Ian averred he was not moved, but he's seeking to arrest the notorious hacker, and possibly bring him to book. In in this wise, he gave the details of the hacker seeking that the crypto community be on the look out to apprehend the evil perpetrator.
Experts have weighed in on the situation. One of them is the CEO of Tradelize, Anton Zapolskyi, who proffered long-lasting solution to hacking.
"There are some doubts when it comes to wallet security. Although it's easier to keep funds in a singular wallet with 2-FA, this shouldn't be the singular method of security," Anton counsels.
Hacking is becoming a normal activity in the cryptocurrency space. Notable influencers have been hacked and stripped off their hard-earned wealth in the past. Exchange platforms and even cryptocurrency platforms were robbed as well. One very callous hacking that the cryptocurrency community will never forget is the Coincheck $530 million cryptocurrency heist, which encapsulated first enormous cryptocurrency hacking estimated to be $400 million in bitcoin stolen from Mt Gox in 2014.
Hacking is a punishable offense under the computer status, however, hackers remain unmoved despite stiff penalties placed on the illegal act.