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Fight Aging! Newsletter, March 28th 2016
March 28th 2016
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.
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- NASA and New Organ Develop the Vascular Tissue Challenge
- Anders Sandberg on Working Towards Radical Life Extension
- Arguing a Primary Role for Astrocytes in Neurodegeneration
- Remember that Professional Ethicists Justify their Wages by Inventing Problems
- The Reasonable Wager of Cryonics
- Latest Headlines from Fight Aging!
- Supplying the Aging Brain with More Energy
- Dopamine Receptor Level Influences Mouse Lifespan via Behavioral Changes
- Increased Generation of Mitochondrial Reactive Oxygen Species Tends to Slow Aging in Laboratory Species
- Cardiovascular Health Correlates with Brain Health
- Preserved Embryonic Kidney Tissue Grows into New Kidneys in Adult Animals
- A Correlation Between Periodontitis and Cognitive Decline in Alzheimer's Disease
- A New Method for Early Detection of Amyloid in Aging Tissues
- Physical Activity Associates with Improved Brain Health
- Arguing for Intestinal Dysfunction as an Important Component in Degenerative Aging
- On Rejuvenation of Muscle Stem Cell Function
The news for today is that NASA's Centennial Challenges Program and the Methuselah Foundation's tissue engineering initiative New Organ have joined forces to develop the Vascular Tissue Challenge, which is currently public in a draft form as an RFI. The intent is to divide a 500,000 purse between up to three teams who can advance the state of the art in tissue engineering by reliably producing thick sections of vascularized living tissue.
I'm sure you've all seen the announcements roll in over the past few years as research groups have built small organoids that function correctly for their organ type: slivers of pancreatic tissue, thymus tissue, kidney tissue, and so forth. It has, I think, been amply demonstrated that the research community has the development of methodologies needed to build complex, functional tissue well in hand. There is a great deal that can be done with even such tiny slices of tissue, ranging from integration into tools that speed research to use as matched tissue patches for patients with damaged organs. A little bit of a pancreas or a liver - or a dozen little bits, or more - is actually quite useful in the context of diseases, age-related and otherwise, that cause progressive damage to those organs.
However, not all is roses and rainbows in the field. Growing much larger sections of tissue from the starting point of cells and entirely artificial scaffolds, with the goal of creating whole organs to order, as needed, and matched to the recipient patient, remains to be accomplished. The proliferation of organoids can be contrasted with the absence of larger solid structures. The challenge here, and this has been the blocking issue for a decade, is that the research community cannot yet reliably create tissue that is equipped with the network of tiny blood vessels needed to keep the cells alive and provisioned with nutrients. Thinner tissues can get by without blood vessels, as fluids will diffuse through their structure, but the blood vessels are absolutely required by any tissue much thicker than a centimeter or so.
This is why decellularization of donor organs has taken off: stripping out the cells is is a way to obtain a scaffold, the natural extracellular matrix, that has the intricate blood vessels and the chemical cues to guide newly introduced cell populations to repopulate and rebuild the correct structures. This cannot yet be done for artificial scaffold materials, such as those turned out by 3-D printers, or at least not in anything more than a very early and limited way. Once microvasculature can be produced in engineered tissue in a robust fashion, however, the gate is flung open and the creation of organs in a variety of ways will happen just a few years later at most. Given all of this, vascularization of tissue is an important goal, and a good place to add incentives into the research process.
Draft Vascular Tissue Challenge
The Vascular Tissue Challenge is a 500,000 prize purse to be divided among the first three teams who can successfully create thick, human vascularized organ tissue in an in-vitro environment while maintaining metabolic functionality similar to their in vivo native cells throughout a 30-day survival period. NASA's Centennial Challenges Program is sponsoring this prize to help advance research on human physiology, fundamental space biology, and medicine taking place both on the Earth and the ISS National Laboratory. Specifically, innovations may enable the growth of de novo tissues and organs on orbit which may address the risks related to traumatic bodily injury, improve general crew health, and enhance crew performance on future, long-duration missions.
The Vascular Tissue Challenge rules are currently open for public comment. If interested in this challenge, please provide your feedback.
National Aeronautics and Space Administration (NASA) - Centennial Challenges Program - Vascular Tissue Challenge - Request for Information (RFI)
The Centennial Challenges program is seeking input on a Vascular Tissue challenge being considered for start in 2016. The challenge would require competitors to create a thick tissue with fully functioning vascular systems, similar to the tissue found in the heart, lungs, liver or kidney. This RFI is seeking feedback from potential challengers. Comments must be submitted in electronic form no later than 5:00 pm EDT, April 15, 2016.
The ability to provide oxygen and nutrients to thick human tissue by adequate vascularization of layers of cells to ensure metabolic functions similar to native in-vivo tissues has not been reliably demonstrated. Developing this capability will enable new research initiatives that may bring real solutions to organ disease, skin burns and other medical concerns. NASA's objective for this challenge is to produce viable thick-tissue assays above and beyond the current state of the art technology.
Competitors will be asked to produce an in-vitro vascularized tissue that is more than 1 centimeter in thickness in all dimensions at the launch of the trial and maintains greater than 85% survival of the required parenchymal cells throughout a 30-day period. Tissues must provide adequate blood perfusion without uncontrolled leakage into the bulk tissue to maintain metabolic functionality similar to their in-vivo native cells. Histological measurement of the quality and amount of functional performance will be required to determine survival of parenchymal tissue. Teams must demonstrate 3 successful trials with at least a 75% trial success rate to win an award. In addition to the in-vitro trials, teams must also submit a Spaceflight Experiment Concept that details how they would further advance some aspect of their tissue vascularization research through a microgravity experiment that could be conducted in the U.S. National Laboratory (ISS-NL) onboard the International Space Station.
If you happen to know anyone in the tissue engineering community, please do direct their attention towards this initiative.
Anders Sandberg is one of the earlier participants in the modern transhumanist movement, perhaps better thought of as a distributed and shifting set of overlapping interest and advocacy groups rather than a movement per se. The core of the transhumanist ideal is the overcoming of limits, the use of technology to expand the choices available within the human condition. The diverse membership of these groups has spread and prospered over the past twenty years, taking influential roles in biotechnology, aging research, cryonics, artificial intelligence, and other related fields. In a sense it is the ideas that matter: the defeat of aging and age-related disease so as to indefinitely extend healthy life; engineering away all of the other causes of pain and suffering; expanding our intelligence; building intelligence; seeking to be far more than we are today. Those of us who propagate these ideas and work towards their realization are in a way water carriers, passing the value along. The more people who do this, the greater the support for transhumanist goals such as achieving effective medical control over aging, the better the prospects become for all of our futures.
Like many of the other futurists who used the early years of the internet to find one another and form a community to talk about the practicality of their visions for a golden future, Anders Sandberg engineered a career from an interest in transcending the limits of the human condition through technological progress. These days he works with the Future of Humanity Institute, itself an outgrowth of a portion of the transhumanist community. This is in large part an advocacy initiative, clothed as academia, seeking to put forward a vision - with supporting evidence - for a far better future to a public that hasn't really given the topic much thought. To the world at large, tomorrow is anticipated to be much the same as today. It is strange that this is the case in a time of such rapid progress in science and technology, but most people expect to live in a future that looks much the same as the present, barring small changes in fashion and culture. The possibilities are so much greater than that, however. For one, we stand on the verge of being able to treat the causes of aging, and many people alive today will as a consequence live for long enough to see aging entirely defeated, rejuvenation robustly achieved, and their lives and healthspans made unlimited in length. That shortly beyond that lies an explosion of intelligence and culture out into the universe, of a size and scope to make our present world seem the smallest mote by comparison, is almost by the by.
Below find a link to the PDF version of a radio essay by Sandberg presented at BBC Radio 3, one portion of a much broader effort to make more people pay attention to what could be done to make the world a better place, and our lives radically different and less limited as a result.
Desperately seeking eternity (PDF)
People have tried to extend their lives since time immemorial. The oldest great work of literature, the epic of Gilgamesh is partially about the king's search for the herb of immortality. Up until recently we did not have any deep understanding of what ageing truly is, so doing anything about it was hard. That has changed radically in recent decades. We now understand why we age, and can in the lab even slow it down in test animals. Some treatments can prolong animal lifespans by up to 40 per cent whether by removing senescent cells, reducing caloric intake, or influencing certain metabolic pathways. While none of the methods are likely to carry over straight to humans, the fact that we have gone from ageing being an immutable fact to something that can be manipulated is already revolutionary.
Even if the first clinical methods for slowing ageing arrive a few decades ahead, that is still good news for the majority of people living today. Especially since slowed ageing gives you more years of medical progress. While nothing is certain, it looks like in the long run ageing may become just another treatable chronic disease. Some would argue that slowing ageing is all about achieving immortality. But treating ageing directly makes sense simply in terms of health: ageing is a direct contributor to heart disease, diabetes, weakened immune system, Alzheimer's and many other maladies. Life extension cannot give us eternal life: besides ageing, we are killed by diseases, accidents and violence. And if we fix those, we are still finite beings in a universe ruled by probability. Sooner or later we will be unlucky and perish. But we can maybe make this probability so low that it does not matter much in practice. The real issue might be what we would do if we had indefinite lifespans.
Every time someone dies, a library burns. The experiences, skills, and relationships painstakingly built across a lifetime disappear forever. We cannot prevent any particular library from eventually having a fire, but we can make sure the fires are rare. Humans are precious, and that is why we should not wish them to age. Some might say we need a change of generations to keep our culture youthful. Yet, to continue the library metaphor, few people think the way of maintaining a successful culture is to burn the archives and art museums. There are better ways of changing things than killing the old guard. The physicist Max Planck said that science advances one funeral at a time, but in practice many radical new ideas do sweep the scientific world faster than scientists are being replaced. In the social arena we have seen struggles to extend human rights succeeding faster and faster, despite people living longer: compare the time it took for female suffrage to go from academic idea to political practice with the time it took gay rights to make the leap from unthinkable to orthodox. At any rate, if long lives actually do slow social changes there are still better ways of speeding it up than letting people die prematurely. We have term limits in politics: maybe we should have them for professors and CEOs too.
I have met 18 year olds claiming they do not want to live beyond 20 because they will be old and decrepit, while my 105 year old grandmother still potters on since dying is simply not done. Some people find new meaning again and again, others feel suicidal about Sunday afternoons. It is not uncommon to envision one's life as a book, and then assume it must have a beginning, a middle and an end. This is reasonable since we tend to construct our identities as narratives: we often tell stories about who we are, what we have done, and where we are going, so thinking of a life this way comes naturally to us. But a book can be a short pamphlet, a thick epic, or maybe a never-ending fantasy series ... which one would we want to be like?
Many people who wish for radical life extension are afraid of dying. This is a bad motivation: sooner or later they will run out of time anyway, and living just to avoid something is a diminished way of life. They are not hoping for something of value, merely the avoidance of loss. The problem with death is not just that it can be painful, but that it also irreversibly prevents any more experience, any more action. Our social bonds are broken. Pain can be dealt with, but these other factors point at what makes life worth living. We should seek to live longer because we love life. We should wish to experience good things, gain wisdom, and interact with people in important ways. A long and healthy life is quite useful for this.
In the open access paper I'll point out today, the authors provide a high level overview of the evidence that suggests immune cells called astrocytes play a primary role in the progression of age-related neurodegenerative conditions. The immune system of the brain is quite different, somewhat more intricate, and more specialized than its equivalents elsewhere in the body, and those systems are themselves very complex and only partially mapped. The brain is shielded from the sort of haphazard exposure to toxins and pathogens that other tissues must face by the existence of the blood-brain barrier, a shield lining the blood vessels that pass through the brain. The portfolio of tasks carried out by the immune system within that barrier has shifted accordingly. In the brain specialized types of immune cell, neuroglia such as microglia and the aforementioned astrocytes, undertake a very broad range of activities beyond simply sweeping up waste and destroying pathogens, and are tightly integrated into the core functions of the brain. They participate in some of the most important and fundamental neural processes, such as the formation and alteration of connections between neurons, for example.
Most of the common diseases of aging have an inflammatory component. Pathology and degeneration is accelerated by the decline of the immune system into a state of ineffective, constant inflammation. The causes of that decline are discussed elsewhere, and include a sort of misconfiguration perhaps brought on by exposure to persistent pathogens such as cytomegalovirus, and the slow and falling rate of generation of replacement immune cells in adults. Effectively addressing these causes seems a very plausible task for the next couple of decades, based on promising studies in animals from the past few years. In the brain, things are going to be much the same at the high level, but different in the details. A lot of research from recent years points to microglia as the agents of neural inflammation, but the authors here suggest that there is just as much evidence for astrocytes to be involved in the generation of a harmful inflammatory state:
Astrocytes As the Main Players in Primary Degenerative Disorders of the Human Central Nervous System
Since the beginning of the 20th century relentlessly progressive neurological diseases have classically been attributed to a primary neuronal dysfunction. This affirmation applies to Parkinson disease (PD), Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), among others. Therefore, most investigations have been carried out under this belief, leading to the coining of the term "neurodegeneration." In the 90s, a new era began that considered the possibility of a more important role of the so far neglected neuroglia. This led to different findings opposed to the belief of the astrocytes sole function being neuronal structural support.
Astrocytes have been found to have a much more active role that the one predicted by the earlier guessers. Particularly, they are involved in the ions exchange with neurons, they are organized as a syncytium that allows them to interchange information with other astrocytes residing in a defined net through different types of Ca+++ signals while regulating the release of signaling molecules involved in the production of trophic factors, transmitters and transporters that when released to the extracellular medium will modulate the synaptic activity synchronizing the neuronal functions. Also they are involved in the extracellular K+ uptake, in synaptogenesis and gene expression; adapting, at the same time, the permeability of the blood-brain barrier to the neuronal and synaptic needs.
Slowly but relentlessly, the results of several studies have confirmed the existence of an active role played not only by the astrocytes but also by microglia. Mounting evidence suggests that astrocytes modulate microglial response, through the establishment of a complex cross-talk between both types of cells mediated by the production of different chemokines and cytokines. Therefore, we think that the broader term primary degenerative disorders of the central nervous system (PDD CNS) alludes to the complex pathology of these diseases (in contrast to the classic term neurodegeneration). An early astrocytic dysfunction in the PDDs of the CNS has been broadly observed. We advocate that these observations obtained from different degenerative pathologies, but mostly from experimental animal studies, may be the trees from a forest characterized by primary astrocytic dysfunction as the main process starting them.
To my eyes professional ethics is a self-defeating field, in that it appears to corrode the ethics of those who participate. The basic problem here is one of incentives, an age-old story. The funding and standing for a professional ethicist depends upon finding a continual supply of ethical issues that can be used to justify the continued employment and budget of said ethicist. When it comes to medicine, however, and for most other fields of human endeavor, there is no such supply. All of the true ethical problems in medicine and medical science were solved long ago and the solutions finessed in great detail across centuries of thought and writing. These ethical problems in medicine are few in number and basically boil down to what to do in limited resource triage situations (the best you can), whether or not to harm people deliberately (no), and whether or not to work towards better medicine (yes). Thus a gainfully employed professional ethicist must invent new, not-actually-real problems pretty much from the get-go, or give up and admit that the job is pointless. Natural selection then ensures that we only see those who prefer the money over the integrity.
We can measure the decay in the ethics of professional ethicists by the degree to which they can contort themselves to produce different answers to those I provided for the few legitimate ethical challenges in medicine above. If you spend any time at all following the progression of aging research and efforts to extend healthy human lives, then you will see a great many ethicists demonstrating the decay of their personal ethics in just this fashion. There are any number of salaried ethicists willing to throw their newly invented logs in front of the wheels of progress in this field, and tell us just how terrible it would be to cure age-related disease and lengthen productive and healthy human lives. The processes of aging and the age-related disease it produces are the greatest cause of pain, suffering, and death in the world by a very large margin. The way to remove all of this pain, suffering, and death is to build therapies that can repair the causes of aging, therefore preventing all resulting disease and disability. That will also extend life, because healthy, youthful people have a very low mortality rate. Yet the cadre of professional ethicists weigh their present position against the lives and livelihoods of billions and go right ahead with their flimsy objections.
That this whole situation exists, that institutions responsible for providing and improving technologies have increasingly indulged a parasitical arm that siphons off funding in order to obstruct the processes of improvement, is yet another sign that the world we live in is far from perfect. It also suggests that human nature leaves much room for improvement in the years to come, once such an engineering project becomes possible. In this article we see an example of the type of "ethics" I find so objectionable, though it isn't as though one has to try hard to find other examples:
The Tricky Ethics of Living Longer
Tortoises typically live well past 100 and might be able to survive even longer. In 2006, a giant tortoise thought to be 255 years old died at India's Calcutta Zoo. We humans have yearned throughout history for longevity and even immortality. Science has already helped us live much longer than our ancestors did, by improving hygiene and protecting us from infectious diseases through antibiotics and vaccines. But current research into extending our lives presents an interesting twist. It also raises ethical questions.
I spoke to experts who foresee a coming revolution in medicine, where we treat age instead of disease. To do this, they are trying to figure out how aging works at the molecular level. The goal isn't exactly immortality. Instead, these scientists have noticed that a variety of diseases, from cancers to Alzheimer's, share aging as a major risk factor. Rather than spending a lot of money to treat each disease individually, why not tackle the root cause? What if there was a pill that slowed how our cells age, letting us avoid age-related illnesses - and also likely extending our lives? It's a safe bet that when most of us contemplate the gaping abyss of mortality, we decide we'd like to postpone that fate as long as possible, while remaining mobile, independent, and mentally sharp. If we must die, let us go peacefully in our sleep, at home, when we're at least 100.
But how might such a revolution ripple across society? Life expectancy already varies greatly. It's tied to education, wealth, and even where you live. According to Alexander Capron, an expert in health policy and ethics at the University of Southern California Gould School of Law, life-extending therapies could exacerbate these differences. For example, if these treatments are expensive, or aren't covered by affordable health care plans, only people with disposable cash will have access. This means people with money and resources will have the choice to live longer. Those who don't, won't.
"We can't cherry-pick the costs or savings to focus on," says Patrick Lin, director of the Ethics + Emerging Sciences Group at California Polytechnic State University. Instead, he says,to fairly examine the ethics involved, we should consider impacts both on the individual and society level. "Yes, healthier people may mean lower health costs and more productivity, but that's a partial picture at best. We'd also have to consider the impact of extended lives on, say, Social Security, pensions, job openings given fewer retirements, crime from unemployment, natural resources, urban density, copyright durations, prison sentences, and many, many other effects."
Another effect to consider is how families pass on their legacies, says Nigel Cameron, president of the Center for Policy on Emerging Technologies. Life extension would mean more time with extended family. But it will also mean that inheritance and property will transfer later and less often, which could put more pressure on younger generations to acquire property independently. Lifespan extension could also influence politics and social change, with different age groups pushing for different policies. "There are big generational differences in economic and social interests," Cameron says. "The whole thing becomes much more extended if people live longer, much more competitive."
Still, the research that could lead to life extension is happening, so the conversation about its implications should, too. "Personally, I'm cautiously optimistic about life extension research, but we need to be careful to manage the hype and not ignore the risks," says Lin. "Will we ever become immortal? I don't know, and no one else can see that far, either. But even extending our lives another 20-100 years or more, to start with, is a game-changer."
Cryonics has been in the press and the broader online media seemingly more often than not of late. Perhaps it is the season for it. As is the case for many other areas of science and technology in this era of rapid progress, matters in the cryonics industry are on the verge of moving from reasonable but unproven hypothesis to self-evident extrapolation of the uses of a new technology.
The reasonable but unproven hypothesis has been that suitable methods of low-temperature preservation, vitrification being the present standard, will maintain the fine structure of neurons and neural connections sufficiently well that the data of the mind is also preserved. Thus people can be preserved at death, and given the chance at a new life in a future in which restoration becomes technologically feasible. So long as the data is preserved, that restoration remains a possibility. That this data is overwhelmingly static, in the form of encoded structures, is demonstrated by the survival and recovery of cold water drowning victims, among other evidence. The core cryonics hypothesis has held up very well in the face of the past few decades of progress in our understanding of the mechanisms of memory, and progress towards being able to mount initial demonstrations of preserved structure in neural tissue and preserved memory in lower animals.
The phase in which cryonics moves to being an obvious extrapolation of a new medical technology starts when reversible vitrification is used to preserve donor organs indefinitely, removing many of the logistical issues in that industry. When organs are grown from cells to order rather than donated, again reversible vitrification will make the logistics of that tissue engineering a lot easier. This is actually pretty close to realization in the grand scheme of things. Experiments have been carried out in animals with some degree of success, and more researchers are now interested in fixing up the last set of issues in vitrification and thawing protocols that make reversible vitrification hard at present. In a world in which organs are regularly vitrified for storage, then used for transplant years later, it will become pretty obvious to the public at large that storing the brain or the body as a whole is similarly viable.
People who pay more attention to the state of technology still under development are already at that point, of course. If organized well, end of life cryopreservation is a very reasonable wager on the course of the future for someone who will age to death before the advent of sufficiently effective rejuvenation treatments. Few people realize this, unfortunately, and so near all of humanity let themselves fall into oblivion, thinking there is no alternative.
Why Cryonics Makes Sense
We think of the divide between life and death as a distinct boundary, and we believe that at any given point, a person is either definitively alive or definitively dead. Today, dead means the heart has been stopped for 4-6 minutes, because that's how long the brain can go without oxygen before brain death occurs. The brain 'dies' after several minutes without oxygen not because it is immediately destroyed, but because of a cascade of processes that commit it to destruction in the hours that follow restoration of warm blood circulation. Restoring circulation with cool blood instead of warm blood, reopening blocked vessels with high pressure, avoiding excessive oxygenation, and blocking cell death with drugs can prevent this destruction. With new experimental treatments, more than 10 minutes of warm cardiac arrest can now be survived without brain injury. Future technologies for molecular repair may extend the frontiers of resuscitation beyond 60 minutes or more, making today's beliefs about when death occurs obsolete.
In other words, what we think of as "dead" actually means "doomed, under the current circumstances." Someone fifty years ago who suffered from cardiac arrest wasn't dead, they were doomed to die because the medical technology at the time couldn't save them. Today, that person wouldn't be considered dead yet because they wouldn't be doomed yet. Instead, someone today "dies" 4-6 minutes after cardiac arrest, because that happens to be how long someone can currently go before modern technology can no longer help them. Cryonicists view death not as a singular event, but as a process - one that starts when the heart stops beating and ends later at a point called "the information-theoretic criterion for death" when the brain has become so damaged that no amount of present or future technology could restore it to its original state or have any way to retrieve its information.
Here's an interesting way to think about it: Imagine a patient arriving in an ambulance to Hospital A, a typical modern hospital. The patient's heart stopped 15 minutes before the EMTs arrived and he is immediately pronounced dead at the hospital. What if, though, the doctors at Hospital A learned that Hospital B across the street had developed a radical new technology that could revive a patient anytime within 60 minutes after cardiac arrest with no long-term damage? What would the people at Hospital A do? Of course, they would rush the patient across the street to Hospital B to save him. If Hospital B did save the patient, then by definition the patient wouldn't actually have been dead in Hospital A, just pronounced dead because Hospital A viewed him as entirely and without exception doomed.
What cryonicists suggest is that in many cases where today a patient is pronounced dead, they're not dead but rather doomed, and that there is a Hospital B that can save the day - but instead of being in a different place, it's in a different time. It's in the future. That's why cryonicists adamantly assert that cryonics does not deal with dead people - it deals with living people who simply need to be transferred to a future hospital to be saved.
Cryonics and the shifting goal posts of death
The statement "a dead person cannot be revived" seems so obvious that it is hardly worth writing down, but when you look a little deeper, it is not so clear cut. A few decades ago, someone who suffered a cardiac arrest was considered irreversibly dead. Move forward to today, and we routinely bring those people back from the brink. So, in some regards, our definition of what constitutes "dead" has shifted. It is this kind of stance that cryonics researchers often take when faced with dissenters. Their argument, whether you are prepared to run with it or not, is that death has already had its goal posts moved, so who is to say that they cannot be moved again?
Today, brain death, rather than cardiac death, is considered the stamp of finality. But even this, it might be argued, is not entirely infallible. For instance, in 1955, James Lovelock cooled a rat to just above 0°C. Its brain completely stopped its normal business. However, Lovelock managed to reanimate the rodent by warming it back up. Even in a real life situation - cold water drowning - similar findings have been described. A young girl was resuscitated after an astonishing 66 minutes of total submersion in freezing water. After an hour under water, most people would consider the individual irreversibly dead. We now know this is not always the case. Importantly, her memories and personality were still intact. This is not the only case of people "surviving clinical death." Cases like these have spawned a saying in some emergency rooms: "Nobody is dead until warm and dead."
Monday, March 21, 2016
A growing dysfunction in energy metabolism, such as might be caused by higher levels of mitochondrial damage in cells, has been implicated in the progression of age-related neurodegenerative conditions. The neurons of the brain collectively require a lot of energy to operate, and thus it is reasonable to consider that disruptions in the processes that provide that energy are significant. Such disruptions are not the root causes of neurodegeneration, however, but rather secondary or later effects of an accumulation of the fundamental cell and tissue damage that causes aging. One possible compensatory approach to therapy, a treatment that doesn't address the root causes but instead tries to modestly slow down their consequences, would involve delivering more energy stores to neurons. The researchers here report on a fairly simple proof of concept in mice:
The human brain has a prodigious demand for energy - 20 to 30% of the body's energy budget. In the course of normal aging, in people with neurodegenerative diseases or mental disorders, or in periods of physiological stress, the supply of sugars to the brain may be reduced. This leads to a reduction in the brain's energy reserves, which in turn can lead to cognitive decline and loss of memory. But new research on mice shows that the brain's energy reserves can be increased with a daily dose of pyruvate, a small energy-rich molecule that sits at the hub of most of the energy pathways inside the cell. These results need to be replicated in human subjects, but could ultimately lead to clinical applications.
"In our new study, we show that long-term dietary supplementation with pyruvate increases the energy reserves in the brain, at least in mice, in the form of the molecules glycogen, creatine, and lactate. The mice became more energetic and increased their explorative activity. It appears that these behavioral changes are directly due to the effect of pyruvate on brain function, since we didn't find that these mice had developed greater muscle force or endurance. For example, chronic supplementation with pyruvate facilitated the spatial learning of middle-aged (6- to 12-months-old) mice, made them more interested in the odor of unfamiliar mice, and stimulated them to perform so-called "rearing", an exploratory behavior where mice stand on their hind legs and investigate their surroundings. The dose necessary to achieve these effects was about 800 mg pyruvate per day - which corresponds to about 10 g per day in humans - given to the mice in normal chow over a period of 2.5 to 6 months. A single large dose of pyruvate injected directly into the blood stream had no detectable effect.
Monday, March 21, 2016
An interesting study here shows that lower levels of dopamine D2 receptor (D2R) achieved via genetic engineering in mice lead to a modestly reduced life span. This result appears to be mediated by behavioral changes, such as lesser physical activity, greater food intake, and consequently higher body mass, rather than by any other mechanism.
Dopamine (DA) is known to be implicated in a variety of functions including reward and physical mobility. The DA system has been known to be vulnerable to the effects of aging. Human imaging studies have shown that the rate of D2R loss during aging occurs at approximately 10% per decade. While it is apparent that D2R decreases in both human and rodent brains as a result of physiological deterioration following senescence, the functional consequences of this decline on behavior and lifespan are not fully understood. The D2R ability to modulate reward seeking behavior, motivation, and expectation of a reward, influences feeding behavior. Alterations in the DA reward system can lead to abnormal eating behavior; the down regulation of D2R receptor signaling is thought to reduce sensitivity to reward, providing an incentive to overeat.
An enriched environment (EE) is characterized by sensory, motor and social stimulation relative to standard housing conditions. The incorporation of exercise is an important component of an EE and its benefits have been shown to be a powerful mediator of brain function and behaviour. To determine whether the D2R gene is involved in the mechanism of environmental enrichment, different housing conditions were examined in mice. This study hypothesized that the D2 gene, in the presence of an EE, significantly influenced lifespan, body weight, and locomotor activity.
Results supported the hypothesis. Male and female wild-type (Drd2 +/+), heterozygous (Drd2 +/-) and knockout (Drd2 -/-) mice were reared post-weaning in either an enriched environment (EE) or a deprived environment (DE). Over the course of their lifespan, body weight and locomotor activity was assessed. While an EE was generally found to be correlated with longer lifespan, these increases were only found in mice with normal or decreased expression of the D2 gene. Drd2 +/+ EE mice lived nearly 16% longer than their DE counterparts. Drd2 +/+ and Drd2 +/- EE mice lived 22% and 21% longer than Drd2 -/- EE mice, respectively. Moreover, both body weight and locomotor activity were moderated by environmental factors. In addition, EE mice show greater behavioral variability between genotypes compared to DE mice with respect to body weight and locomotor activity.
These data provide the first evidence of the role of D2R gene on lifespan in mammals. Mice with normal or reduced expression of the D2 gene and housed in an EE showed significant increases in lifespan. However, mice deficient in D2 failed to benefit from an EE. The D2 gene function appears to be a critical mediator linked to the behavior and lifespan effects associated with an EE. D2's mediating role, however is environment-dependent and was not observed in mice raised in DE conditions. The anti-aging and neuroprotective factors associated with exercise may be the key factor as to why Drd2 +/+ and Drd2 +/- EE mice showed increased lifespan in comparison to their DE cohorts.
Tuesday, March 22, 2016
The interactions between molecular damage in cells, repair system activity, the generation of reactive oxygen species (ROS) in mitochondria capable of causing damage, and individual or species longevity are far from simple. The free radical theory of aging and its variants were early and in hindsight overly simplistic views based on the observation that the presence of ROS and their signs of their damage increase with age. However, numerous methods of slowing aging in short-lived animals involve increases in the rate at which mitochondria produce reactive oxygen species. These molecules are signals as well as sources of damage, and an increase can cause repair systems to overcompensate, producing a net gain in cellular maintenance and reduction in overall levels of damage. It isn't just repair: many of the benefits of exercise are also keyed to temporary increases in ROS levels.
Testing the predictions of the Mitochondrial Free Radical Theory of Ageing (MFRTA) has provided a deep understanding of the role of reactive oxygen species (ROS) and mitochondria in the ageing process. However those data, which support MFRTA are in the majority correlative (e.g. increasing oxidative damage with age). In contrast the majority of direct experimental data contradict MFRTA (e.g. changes in ROS levels do not alter longevity as expected). Unfortunately, in the past, ROS measurements have mainly been performed using isolated mitochondria, a method which is prone to experimental artefacts and does not reflect the complexity of the in vivo process. New technology to study different ROS (e.g. superoxide or hydrogen peroxide) in vivo is now available; these new methods combined with state-of-the-art genetic engineering technology will allow a deeper interrogation of, where, when and how free radicals affect ageing and pathological processes. In fact data that combine these new approaches, indicate that boosting mitochondrial ROS in lower animals is a way to extend both healthy and maximum lifespan.
A topic highly debated in the field is the role that mitochondrial ROS play in age related and non-age related pathological processes with a mitochondrial component. Are ROS a cause or a consequence of mitochondrial dysfunction? This is a very important question, which needs to be addressed, since it will affect the treatment of those pathologies. Considering all the available evidence, it is plausible to suggest that ROS can have both positive and negative roles depending on the type of the ROS, when, where and how much is produced. Therefore, we can talk about "Good" and "Bad" ROS. "Good" ROS being low reactivity ROS (i.e. superoxide or hydrogen peroxide) produced at specific places, at specific times and in moderate amounts and "Bad" ROS being highly reactive ROS (or low reactive ROS as hydrogen peroxide or superoxide produced at high concentrations) generated continuously and unspecifically. Experimental evidence suggests that boosting ROS production can contribute to the maintenance of cellular homeostasis and positively affect lifespan when induced correctly, whereas if produced in excess or in an unspecific way, they shorten survival and accelerate the onset of age-related disease.
Tuesday, March 22, 2016
Aging is a global phenomenon in the body, so measures of its progression in different organs tend to correlate well. In some cases this is because there is direct causation involved rather than it being a matter of independent processes that spring from the same root causes. The health of the cardiovascular system is demonstrably connected to the health of the brain. For example, the structural failure of small blood vessels in the brain, driven by increased blood pressure and the processes of stiffening in blood vessel walls, destroys small areas of brain tissue on an ongoing basis. The more such destruction, the worse off the individual, and the greater the age-related loss of mental capacity.
Researchers studied a racially diverse group of older adults and found that having more ideal cardiovascular health factors was associated with better brain processing speed at the study's start and less cognitive decline approximately six years later. At the beginning of the study, 1,033 participants in the Northern Manhattan Study (average age 72; 65 percent Hispanic, 19 percent black and 16 percent white), were tested for memory, thinking and brain processing speed. Brain processing speed measures how quickly a person is able to perform tasks that require focused attention. Approximately six years later, 722 participants repeated the cognitive testing, which allowed researchers to measure performance over time.
The researchers found that having more ideal cardiovascular health factors was associated with better brain processing speed at the initial assessment. The association was strongest for being a non-smoker, having ideal fasting glucose and ideal weight. Having more cardiovascular health factors was associated with less decline over time in processing speed, memory and executive functioning. Executive function in the brain is associated with focusing, time management and other cognitive skills. While this study suggests achieving ideal cardiovascular health measures is beneficial to brain function, future studies are needed to determine the value of routinely assessing and treating risk factors, such as high blood pressure, in order to reduce brain function decline.
Wednesday, March 23, 2016
This is an interesting approach to organ transplant and regrowth, demonstrated initially in rabbits. The researchers believe it may also provide the basis for xenotransplantation between species, but that remains to be seen:
Researchers have discovered a way of freezing embryonic animal kidneys so that they can later be warmed up and grown into full-size organs without the risk of rejection by their recipient. The team found that when precursor kidney tissue from 16-day-old rabbit embryos is implanted in adult rabbits, it develops into an adult kidney, connecting itself to the host's own blood supply. The host doesn't recognise the organ as strange, and permits it to connect to the blood system. The adult rabbits did not reject the foreign kidneys because the embryonic tissue was transplanted before it had started producing the protein that would alert a host's immune system to foreign cells. Researchers believe that when the protein is eventually produced, it matches that of the host instead.
The team then investigated whether it might be possible to create a biobank of potential organs for transplant. Large organs cannot be frozen to prevent decay because water in them turns to ice as they freeze, destroying delicate call structures. But the embryonic precursor kidneys are much smaller, enabling them to use a cryopreservation process called vitrification that can prevent ice formation by pumping antifreeze into an organ before cooling it to -196 °C. This technique is normally only used to freeze small tissues such as human eggs because it is difficult to get the antifreeze around larger, more complicated organs. The team managed to successfully vitrify and store the precursor kidneys for three months in liquid nitrogen. They then warmed the tissue and transplanted it into adult rabbits. Some 25 per cent of the transplants grew into healthy adult organs in the host - not as high as the 50 per cent success rate they achieved with fresh embryonic tissue, but still good.
The results suggest we may one day be able to create a long-term biobank of animal kidneys that provides an unlimited source of organs for transplanting in people. The team is now trialing a similar experiment between rabbits and goats. More than one kidney could potentially be transplanted into larger animals to make up the mass needed for them to act as a native kidney.
Wednesday, March 23, 2016
Periodontitis, an inflammatory condition of the gums, can spread the effects of chronic inflammation elsewhere in the body via the circulatory system. It is associated with the progression of a number of common age-related conditions that have an inflammatory component, such as cardiovascular disease. Thus it is worth keeping an eye on progress towards therapies capable of effectively treating inflammatory gum disease. Researchers here add more evidence for the association of Alzheimer's disease progression with periodontitis:
A new study has found a link between gum disease and greater rates of cognitive decline in people with early stages of Alzheimer's disease. Periodontitis or gum disease is common in older people and may become more common in Alzheimer's disease because of a reduced ability to take care of oral hygiene as the disease progresses. Higher levels of antibodies to periodontal bacteria are associated with an increase in levels of inflammatory molecules elsewhere in the body, which in turn has been linked to greater rates of cognitive decline in Alzheimer's disease in previous studies.
In the observational study, 59 participants with mild to moderate Alzheimer's disease were cognitively assessed and a blood sample was taken to measure inflammatory markers in their blood. The majority of participants were followed-up at six months when all assessments were repeated. The presence of gum disease at baseline was associated with a six-fold increase in the rate of cognitive decline in participants over the six-month follow-up period of the study. Periodontitis at baseline was also associated with a relative increase in the pro-inflammatory state over the six-month follow-up period. The authors conclude that gum disease is associated with an increase in cognitive decline in Alzheimer's disease, possibly via mechanisms linked to the body's inflammatory response.
Growing evidence from a number of studies links the body's inflammatory response to increased rates of cognitive decline, suggesting that it would be worth exploring whether the treatment of gum disease might also benefit the treatment of dementia and Alzheimer's disease. In the UK in 2009, around 80% of adults over 55 had evidence of gum disease, whilst 40% of adults aged over 65-74 (and 60% of those aged over 75) had less than 21 of their original 32 teeth, with half of them reporting gum disease before they lost teeth. "A number of studies have shown that having few teeth, possibly as a consequence of earlier gum disease, is associated with a greater risk of developing dementia. We also believe, based on various research findings, that the presence of teeth with active gum disease results in higher body-wide levels of the sorts of inflammatory molecules which have also been associated with an elevated risk of other outcomes such as cognitive decline or cardiovascular disease."
Thursday, March 24, 2016
Better methods of detecting the various forms of amyloid as it builds up in tissues with age should result in greater support for development and availability of the means to remove this unwanted form of metabolic waste. Amyloids are present in every individual to some degree, that presence increasing with age, and are known to cause or be associated with numerous age-related diseases. This is one of the fundamental forms of damage that causes aging, yet amyloid levels are rarely assessed in healthy individuals, or even for patients with diseases that are relevant but something other than full-blown amyloidosis. Ideally everyone, healthy or not, should undergo amyloid clearance therapies - like that developed and trialed by Pentraxin for transthyretin amyloid - every few years starting in middle age or earlier.
Researchers have developed a molecular probe that can detect an array of different amyloid deposits in several human tissues. This new probe is extremely sensitive and was used at very low concentrations to correctly identify every positive amyloidosis sample when compared to the traditional clinical tests. The probe also picked up some amyloidosis signals that the traditional methods were unable to detect. This result means that the new probe could be used to detect amyloidosis before symptoms present, leading to faster and hence more effective treatment.
Aggregates of amyloid proteins form and deposit in different tissues which can affect the normal function. As the disease progresses and amyloid deposits grow, tissues become irreversibly damaged. Amyloid deposits can be found in many different organs leading to a wide range of possible symptoms and making diagnosis challenging. To date, the primary mode of diagnosis for amyloidosis has been the Congo red stain. However, evidence from the team shows that their new probe is much more sensitive, being able to detect small amyloid deposits in samples that were previously determined to be amyloid-free.
According to the U.S. Office of Rare Diseases (ORD) amyloidosis is a rare disease, affecting less than 200,000 people in the U.S.. However, the Amyloidosis Foundation suspects that the figures are underreported and that amyloidosis is not that rare - just rarely diagnosed. A more sensitive diagnostic method would help to uncover the reality of the situation. "Given the sensitivity of the probe, we think this would make an excellent complement to traditional methods and could eventually be a replacement. It could also be used to identify new types of amyloids and presymptomatic patients who are at risk of developing the disease."
Thursday, March 24, 2016
Here is another example of recent data on the relationship between levels of physical activity in later life and the health of the brain. With the advent of low-cost accelerometers and more accurate data on activity, it is becoming clear that even the very modest exercise involved in activities such as cleaning or walking shows correlations with health. To to the degree that this relationship involves causation, the important mechanisms likely relate to the status of the vascular system, the rate at which tiny blood vessels suffer structural failure and destroy small portions of brain tissue. That is driven by the pace of arterial stiffening, progression of hypertension, and other factors that are slowed by regular exercise and sped up by the consequences of a sedentary life style, such as higher levels of chronic inflammation caused by visceral fat tissue.
A new study shows that a variety of physical activities from walking to gardening and dancing can improve brain volume and cut the risk of Alzheimer's disease by 50%. The researchers studied a long-term cohort of patients in the 30-year Cardiovascular Health Study, 876 in all, across four research sites in the United States. These participants had longitudinal memory follow up, which also included standard questionnaires about their physical activity habits. The research participants, age 78 on average, also had MRI scans of the brain analyzed by advanced computer algorithms to measure the volumes of brain structures including those implicated in memory and Alzheimer's such as the hippocampus. The physical activities performed by the participants were correlated to the brain volumes and spanned a wide variety of interests from gardening and dancing to riding an exercise cycle at the gym. Weekly caloric output from these activities was summarized.
The results of the analysis showed that increasing physical activity was correlated with larger brain volumes in the frontal, temporal, and parietal lobes including the hippocampus. Individuals experiencing this brain benefit from increasing their physical activity experienced a 50% reduction in their risk of Alzheimer's dementia. Of the roughly 25% in the sample who had mild cognitive impairment associated with Alzheimer's, increasing physical activity also benefitted their brain volumes.
Friday, March 25, 2016
Researchers investigating aging in flies have found that loss of intestinal function is a very strong determinant of degeneration and mortality in that species. Interventions that slow that decline, such as by manipulating intestinal stem cell activity or improving intestinal tissue quality control, also reduce mortality and extend life. There has been some discussion over whether this importance of intestinal function in aging is a characteristic unique to flies, and here the authors of this open access paper argue that it is not, and that there should be more targeted investigation in mammals:
A dramatic increase of intestinal permeability occurs in Drosophila melanogaster during aging in normal condition. The assay presented in this article uses a blue food dye to detect increased intestinal permeability in vivo. A blue coloration throughout the body marked the positive individuals, which were referred to as 'smurfs' from then on. Interestingly, the authors showed that genetic or physiological interventions increasing lifespan in flies significantly decreases the proportion of Smurfs compared to the control population at any given chronological age. This apparent link between the age-related increase of intestinal permeability and lifespan led them to more thoroughly analyze the Smurf phenotype. This phenotype allows the identification of individuals that are about to die of natural death amongst a population of synchronized Drosophila melanogaster individuals and those individuals show numerous other hallmarks of aging. Such a stereotyped way to die is unexpected; this could indicate a physiological phenomenon crucial during normal aging. Here we propose to test the hypothesis that such an important phenomenon should be evolutionarily conserved.
We chose to search for such a 'Smurf transition' in two other Drosophila species, Drosophila mojavensis and Drosophila virilis whose last common ancestor with Drosophila melanogaster existed approximately 50 million years ago, the nematode Caenorhabditis elegans whose divergence time with D. melanogaster is around 750 million years, and finally the vertebrate zebrafish Danio rerio, which diverged from D. melanogaster around 850-950 million years ago. We investigated whether Smurf-like animals could be observed in individuals from populations of these evolutionarily distant organisms. For each tested species, we could identify individuals showing extended dye coloration throughout their bodies. Moreover, we observed heterogeneity in a given population with only a fraction of the individuals exhibiting increased dye level outside the intestine. Thus, at least in old animals, it is possible to identify individuals with increased intestinal permeability.
One of the most striking characteristic of Smurf individuals previously described in Drosophila is the high risk of impending death they exhibit compared to their age-matched counterparts in a given population. So we decided to verify whether Smurf individuals were also committed to die in the other organisms we studied in this article. We showed that the proportion of individuals showing increased intestinal permeability grows linearly - or quasi-linearly - as a function of chronological age in these different organisms as it was previously reported in Drosophila melanogaster. Finally, we validated that, similar to what has been shown in D. melanogaster, the Smurf phenotype is a strong indicator of physiological age since it is a harbinger of natural death occurring during normal aging.
Intestinal dysfunction, as measured by the smurf assay in different species, associated to sharp transitions in gene expression and behavior appears to be a conserved hallmark of impending death. If this phase of aging is as broadly present in living organisms as our present study suggests, highly stereotyped molecularly and physiologically as well as sufficient to explain longevity curves, then we think that identifying the very events responsible for entering into this phase or those characterizing the high risk of impending death associated with that phase could answer fundamental questions about aging and lead to treatments able to significantly improve lifespan/healthspan across a broad range of species.
Friday, March 25, 2016
This review looks at a range of investigations into the effects of aging on stem cell populations supporting muscle tissue, and various attempts to restore those populations to active duty. Stem cell populations decline with age, becoming less active and more damaged. In recent years, researchers have demonstrated that a variety of approaches can be used to instruct dormant stem cells to be more active: stem cell transplants, altered GDF11 signaling, and so forth.
Elderly humans gradually lose strength and the capacity to repair skeletal muscle. Skeletal muscle repair requires functional skeletal muscle stem (satellite) and progenitor cells (SMSCs). Diminished stem cell numbers and increased dysfunction correlate with the observed gradual loss of strength during aging. Recent reports attribute the loss of stem cell numbers and function to either increased entry into a pre-senescent state or the loss of self-renewal capacity due to an inability to maintain quiescence resulting in stem cell exhaustion.
Earlier work has shown that exposure to factors from blood of young animals and other treatments could restore SMSC function. However, cells in the pre-senescent state are refractory to the beneficial effects of being transplanted into a young environment. Entry into the pre-senescent state results from loss of autophagy, leading to increased reactive oxygen species (ROS) and epigenetic modification at the CDKN2A locus due to decreased H2Aub, up-regulating cell senescence biomarker p16ink4a. However, the pre-senescent SMSCs can be rejuvenated by agents that stimulate autophagy, such as the mTOR inhibitor rapamycin. Autophagy plays a critical role in SMSC homeostasis. These results have implications for the development of senolytic therapies that attempt to destroy p16ink4a expressing cells, since such therapies would also destroy a reservoir of potentially rescuable regenerative stem cells.
Other work suggests that in humans loss of SMSC self-renewal capacity is primarily due to decreased expression of sprouty1. DNA hypomethylation at the SPRY1 gene locus down regulates sprouty1, causing inability to maintain quiescence and eventual exhaustion of the stem cell population. A unifying hypothesis posits that in aging humans, first loss of quiescence occurs, depleting the stem cell population, but that remaining SMSCs are increasingly subject to pre-senescence in the very old.


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Basic settings
Each app's basic settings can be set using the App Settings box in the Project Map. Click on the App Settings box and the Basic Settings menu will open on the right-hand side of the screen. Basic settings are broken down into two categories, App Settings and App Styles.
App Settings
The App Settings allows us to set up the basic information for our app such as the app's name, icon and the start screen.
Screen Formats
Select the size of devices the app will support (phones, tablets or both) in the Screen formats section . Additionally, we can set which screen orientations the app supports. To enable support for a device size or a screen orientation, click on the button. Blue text indicates that the device size or screen orientation is supported.
Each app in ApiOmat Studio also has a base format. The base format is the default screen size for your app, so it's wise to select the most popular device among your targeted app users. Additional screen sizes are automatically supported, and you can also create individual overrides for each device. Overrides allow you to make specific design changes to a screen or an element for other screen sizes.
Publishing Settings
You will need to fill out the fields in this area if you plan to publish your app in the App Store.
App Styles
The App Styles tab provides you with the tools to set the colors and fonts throughout your app. Click on the color boxes to open up a color picker tool which provides a number of tools for finding the right color. You can also use the eye dropper to get an exact color from any images you have uploaded and save colors to the color palette.
The Text Styles allow you to set the font for standard text that appears through out the app. Click on the Base text, Headline, Action or Nav bar title to select a font below. You can use the standard system fonts for iOS and Android, or click other fonts to use a font to suit your app.


text: The House of Friendship Foundation provides merit and/or need-based academic scholarships for deserving students. Our goal is to empower our scholarship recipients by covering their tuition, thereby allowing them to focus on their studies and obtain an undergraduate or vocational degree in their chosen field. Upon graduating and obtaining a secure profession, we encourage our scholarship recipients to "pay it forward" by lifting up and supporting other less fortunate individuals in their respective communities.


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Just thought I would toss this out there for you but under language approved 19 to 10 by a House committee, the firm that sells you Internet access would be required to track all of your internet activity and save it for 18 months, along with your name, the address where you live, your bank account numbers, credit card numbers, and IP address you have been assigned...
Ha ha. Yeah.. this is The Protecting Children from Internet Porn Act of 2011 They might as well call it the "This law does a good thing and if you don't support it, you must be a terrorist act of 2011" Because really.. god fucking damn.
Someone should introduce a bill to nationalize all the industries and call it the "Celebrating American Moms act". Because who would dare not vote for that?
The sad part of all this is that it will easily get 300 votes. But it just goes to show you that we're doomed. It doesn't even make sense. Why would there be a bank account number and credit card numbers to an internet account?
Why yes, let's put all of the bank account and credit card numbers in one government database. Those things never get hacked... Nope sir, never.
Maybe I'm just being over cautious. Surely they wouldn't be required to give that information to the government... but let's be real, of course they would. You think your identity is safe in the hands of the internet service provider when they get a letter from someone threatening to sue? HA!
In short, Death to America. Oh, my bad. I mean.. 9/11 Nevar forget! Fightin' 4 are freedoms!
Friday, September 16, 2011
Protecting Children From Internet Porn Act of 2011
Posted by Booster Gold / Javier J. at 2:32 PM
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I had no idea that it was World Toilet Day when I did an author performance at my old school. Among other things I talked about the Swenglish project and what it was like travelling around, staying with 15 people in England and 15 people in Sweden.
In Sweden a lot of people think it's very unhygienic that there are carpets in some English bathrooms and it's often one of the things they mention when talking about England. (Perhaps people in Sweden are a bit too hygiene obsessed or what do you think ...?)
I've seen a fair share of carpets myself, but none of the 15 people I stayed with in England had carpets in their toilets. (But one person's mum had one and I also saw a carpet in a pub toilet during the project!)


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Investor relations' publications
Investor Relations publications are for those who would like to understand Snam, and keep updated on the stock markets, the natural gas business and Corporate Social Responsibility matters. It is written in a clear lanuage and addressed to shareholders, sector players, and those who might be interested in investing.
Fact Book
The Fact Book is compiled annually as a summary of facts, numbers and results which are useful for understanding the Company and its businesses.
The Fact Book's material is comprehensive: it spans from the evolution of the European gas market to its regulation in Italy, from the company's investment plan to international development, from earnings data to sustainability. It concludes with an analysis of the natural gas business that the Group operates in.
25 July 2019 - 15:21 CEST


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August 2, 2019
Top Road Trip Tips To Make Your Mini Break
There is nothing quite like a road trip. It doesn't even have to be a long one - weekends are the perfect length for exploration. You can find adventures, relaxation time and fun all on the same trip. You can discover new things about yourself as well as the new areas you're visiting. Road trips can be daunting and hard to plan at times, but with the right help, hacks, and travel tips, you can make your weekend road trip the best time you've ever had. Let's take a look at some of the hacks that you need to make your dream road trip an easy one to have.
It's so important that you are entertained when you are driving for hours, and you can't always guarantee that you are going to pick up a radio signal. So, you need to think about getting your phone ready and filled with as many playlists as possible. You can always have back up phone chargers in the car to cover you in case you run out of battery before you get to your destination.
. It's highly unlikely you're road tripping alone, so if you're not, take advantage of your mates and get one person reading the maps while you drive. Have someone else on cooking duties with a camper stove and a bag of groceries. It's all about sharing.
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Maximum plate pressure on the GAB material was 50 psi.
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Think you got what it takes to write for Cracked.com? Then submit an article or some other pieces of content.
I wish I could just do stupid jokes again.
We're coming to the Windless City for C2E2.
I'm thankful for my education and everything that happened to get me where I am today, but there still some things I wished I had learned.
To do over again, sure, I probably wouldn't have helped Donald Trump run for president.
I think I can go ahead and call this another entry in the 'Long Cons That Didn't Pay Off' file.
As Cracked's foremost 'Space Jam' Authority and Occasional Wearer Of Shoes, I obviously have a lot of issues here.
Fun fact: If your coworkers catch you watching a bunch of sex scenes at work over and over again, you better have a good cover.
I thought I owed it to movies to talk about some behind-the-scenes moments that make things better.
You can still probably find them by Googling 'Hello, I'm kind of a terrible person, give me something that does not legally belong to me as quickly as possible.'


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Home » Wellness
Category Archives: Wellness
Finally–a Free Wellness ROI Tool That Isn't Made Up
We are pleased to present a free wellness ROI estimation model, as we promised about 3 months ago. This is the only tool of its kind in the industry. (Wellsteps has one, but let's just say the good news is that NASA employees don't have to worry about job security, because these people aren't rocket scientists. If you zero out inflation, no matter what other variables you enter, the Wellsteps model always shows savings of $1359.)
You can also use this to compare two wellness programs, to determine whether your vendor is lying (they are — and we are happy to help you get your money back from them), and to pressure-test Quizzify.
Eureka! We got criticized! An entire blogful of harsh words
Please visit Michael Prager's blog. Ironically, I don't think we would take issue at all with his main point which appears to be that wellness should be done for employees instead of to them. (He is in the business of doing wellness for employees, not to them.) And, in fact, if he were actually thinking clearly about his own business success, he'd be pointing that out and trying to figure out ways to work together.
Second, note that our math and facts are never, ever criticized, even by our most virulent critics. What he criticizes is that we "mock critics who say that calling people ignorant is bullying." Well, we call them the "ignorati," not ignorant. "Ignorati" means they ignore facts, which is a brilliant strategy.
Third, he is breaking ranks with the ignorati, by not ignoring us. This creates a problem because he doesn't actually point out a single thing we say that is wrong. Indecorous, perhaps, but wrong, no.
Michael, have at it: find a mistake in our math or a lie that we told about your integrity-challenged colleagues and we'll apologize to it and link people to it. Go ahead, make our day. Because right now the fact that you, having shown that you are willing to criticize us, can't find anything to actually criticize us about (other than our "bullying" observations that people who can't do arithmetic shouldn't be doing arithmetic), makes our case much better than we ever could.
Addendum: his is actually a very interesting blog on its own merits. He does do wellness for employees instead of to them ∞
Ron Goetzel reports on Graco, the company with the country's most expensive spouses
Talk about "burying the lead."
Ron Goetzel just reported on a company called Graco, where employees were subjected to a "pry-poke-prod-and-punish" wellness program. These are line employees in an "old economy" company–exactly the type of company where healthcare spending would be high. And it is high. According to the article, Graco spent $29,000,000 on healthcare for 2600 employees. That's about $11,100 apiece, roughly what you'd expect. This estimate is with or without a wellness program, since as Ron's recent HERO report noted, wellness programs have no positive impact on spending.
Yet later on in the article he writes:
In the immortal words of the great philosopher Rick Perry, oops.
$190 per member per month (and we assume that he meant just for employees, not members) is $2280/year/employee. Here are the possibilities:
(1) Graco has the country's mot expensive spouses, costing about $18,000/year (to bring the average spend to $11,000 per employee contractholder per year) but hasn't noticed
(2) Graco has some magical special sauce that kept costs way below average even before the wellness program started that Ron failed to tell us about (hence "buried the lead")
(3) Ron Goetzel made yet another rookie mistake in his math, thus invalidating the entire study, just like most of his Koop Awards.
You can rule out that this $190 had anything to do with the wellness program. Smoking rates (the only thing that really affects spending) remained unchanged, and obesity only fell a few points. And a company can't save money by overscreening people, paying for their drugs, and making them get unnecessary checkups. In any event, it wasn't $190/month. It was $11,100/year.
$2280 vs. $11,100… We look forward to Mr. Goetzel's explanation of how both these figures could be true, since it appears they are completely at odds with each other. In the immortal words of the great philosophers Dire Straits, if two men say they're Jesus, one of them must be wrong.
And once again, the mantra of Surviving Workplace Wellness holds true: In wellness, you don't have to challenge the data to invalidate it. You simply have to read the data. It will invalidate itself.
We will no doubt be accused of "bullying" him for invalidating this study, which he obviously spent a lot of well-compensated time on. So just to show our good intentions, we will offer him our course and certification in Critical Outcomes Report Analysis gratis. It seems he could learn a lot from it and we look forward to announcing his successful completion.
Update: Ron apparently "forgot" to include the actual data in his writeup, which showed that, um, how to put this tactfully, his entire conclusion is wrong. Looks like kids (who had no access to wellness) trended better than the adults who did have access. We added this as the second installment.
Measuring Wellness-Sensitive Medical Events: The Grand Finale of the HERO Analysis
The eighth in the series deconstructing the HERO Outcomes Guidelines, covering Page 14. The full series can be found here. This installment in particular should be read in conjunction with installment #4 This Grand Finale will be presented in 3 parts…with a downloadable tool to help you calculated your wellness program savings as part 3.
In the stock market, no one is as valuable as the person who's always right, except the person who's always wrong. Therefore, until now we have greatly appreciated the opportunity HERO's report has created for us to explain how to measure outcomes correctly.
So imagine our disappointment when one of their methodologies, the sixth of the seven listed, turned out to actually be valid. No surprise — this is the methodology I invented. Also no surprise given the industry's standards for integrity, they didn't acknowledge that particular factoid anywhere in their 88 pages. (And yet they accuse us of being impolite.) Here is the screen shot.
The philosophy of #6 is quite straightforward. If you were introducing a flu vaccine program, you'd measure the reduction in number of people who got the flu. If you offered a new program for conservative treatment of meniscal tears, you'd measure the reduction in the number of people who had meniscal surgery. That's the way experimentation works. You hypothesize an outcome that the intervention should create…and then you measure that outcome to see if the experiment worked.
Except, of course, in population health, where any improvement in anything (cost, trend, utilzation) gets attributed to any wellness program that happened to be in place. The masters of this would be Mercer. Mercer once "found" massive, mathematically impossible, savings for North Carolina Medicaid's medical home in a cohort that, as luck would have it, wasn't even eligible for the medical home. And one wellness industry stalwart, Larry Chapman, says the simple act of completing a health risk assessment can reduce total healthcare spending by 50%, even when the information in the HRA is wrong, as is often the case.
And did you ever notice that when a company switches to a high-deductible health plan and adds some needle-poking, they attribute the reduction in spending to the needle-poking, not the fact that everyone in their company suddenly gets socked with a bigger annual deductible?
Enter wellness-sensitive medical event rates (WSMEs). This is the only methodology that tallies hospitalizations for conditions targeted by a wellness program – statistically avoided heart attacks etc. This is the only one of the seven HERO methodologies that would be acceptable to legitimate researchers. Hence, its use both in Health Affairs and by the GE-Intel Validation Institute. The former is the most respected health policy publication and the latter is the most (the only) respected outcomes evaluation organization. Further evidence of its validity is that there is no mention of it in the leading wellness promotional publication, the American Journal of Health Promotion, perhaps because – as HERO has attested – it doesn't show savings.
History of event rate-based plausibility testing
Even though it isn't attributed to me in the HERO guidebook, I invented this methodology in 2007. This is incontrovertible. No one else had anything remotely close to it. Unlike the automobile, TV, the computer, etc., this was not one of a series of incremental improvements to or the amalgamation of existing technologies.
And none of the other invention clichés apply either. The Chinese didn't invent it in 1000 BC. Leonardo DaVinci didn't sketch it in 1541. The Germans and the Allies weren't racing to develop it at the end of World War II. By contrast, I've been presenting on it and using it for validation since then (meaning 2007). It figured prominently in Why Nobody Believes the Numbers too, before being highlighted in Health Affairs and the Validation Institute. For a modest fee, the detailed how-to can be downloaded from our website, though a Reader's Digest version appears below.
While a number of employers and health plans use it now, several health plans – more than coincidentally three of the highest-rated in the country (Harvard Pilgrim, Blue Cross of Massachusetts, and Providence Health Plans) – have been measuring hospitalizations for conditions targeted by wellness/DM programs since the methodology's inception.
So needless to say I was surprised and totally flattered that the 88-page HERO Report contained no attribution to me as the inventor of the WSME plausibility test. As mentioned previously, the strategy of the Wellness Ignorati is to ignore facts (hence their moniker), especially including my very existence. That strategy reduces the likelihood that one of their customers might click through to the site. They aren't much for our recommending that companies learn our helpful insights, which they call "bullying."
The wellness industry has had a love-hate flip-flopping relationship with WSME measurement.
First, until 2013, the entire Wellness Ignorati, quite in character, ignored this methodology, which is a powerful testament to its validity.
Then, in 2013, that strategy took a body blow: the exact methodology was used in Health Affairs. You may recall the same thing happened with another epiphany of ours — the expose of the invalid Koop Award-winning Health Fitness Corporation fabricated results. The Wellness Ignorati completely ignored our whistle-blowing expose until it appeared in Health Affairs, when they were forced to admit we were right and the whole thing was made up, or to use Ron Goetzel's phrase in the passive voice, "was unfortunately mislabeled" for four years.
Just as Ron Goetzel — the leader of the Wellness Ignorati — caved when the Health Affairs light was shined on the Koop-HFC debacle, he caved on WSMEs when the Health Affairs light was shined on them. In this case, "caving" was acknowledging the fact that this methodology existed. He reviewed the aforementioned Health Affairs article that specifically analyzed WSMEs — hospitalizations for conditions targeted by the wellness program. In September 2014, he wrote:
But then he un-caved. Once the Health Affairs storm had passed, he invoked the Sergeant Schultz defense. In December 2014 he said: ,
He may have just forgotten in December that he reviewed them in September. But in March he and his colleagues re-remembered wellness-sensitive event rates, and put them right in the HERO report, for which we are immensely grateful.
Hopefully they won't re-forget in June. (Their memory appears to be correspond with the change of seasons.) Hopefully instead, to paraphrase the immortal words of the great philosopher George Gershwin, our methodology is here to stay.
How do I feel about HERO rewriting history so that I am no longer the inventor of this methodology? Honestly, having firmly staked out a niche in the small but growing "integrity segment" of the wellness industry, I prefer them staying out of that niche as long as possible. So I'm glad they show no interest in facts.
In part two, which we will post in a few days, we will explain how we do WSME plausibility testing and why it's the essential method for assessing the impact of your wellness and disease management efforts.
Greatest Hits Collection: Staywell
Occasionally we have to attend to our Day Jobs and can't post regularly. Fortunately, we have access to a bolus of posts from mid-2014, the posts that went up on this site initially. There were too many stories to highlight, so we decided to inventory them, in order to fill in gaps when we didn't have time for new posts.
High on that list would be Staywell. First was their collaboration with Mercer, in which they agreed to tell British Petroleum that they found $17,000/person savings. They knew those savings were mathematically impossible since the average person only spends $6000/year. They also forgot that they themselves had said it was only possible to save $100/person.
Following on the heels of that was a collaboration with the American Heart Association to create screening guidelines that (surprise) call for much more screening than the United States Preventive Services Task Force recommends.
In both cases, we welcomed — and in the latter case offered $1000 honorarium for — responses to our questions, but our good-faith offer was met with silence.
Also, in both articles Staywell continued to cite Katherine Baicker's study that she herself no longer defends, with the added wrinkle of referring to it as "recent" in the hopes that no one looks at the endnotes and sees that it was submitted for publication in 2009 and covered studies from a decade before that. With any luck they'll have enough integrity to stop citing that study now that RAND has invalidated it. A good rule of thumb is that anyone who cites Baicker's study without noting that no one (including Professor Baicker) believes that 3.27-to-1 ROI any more is prima facie deliberately misleading people. It is no longer credible to say one doesn't know that her study has been shown to be hooey and that she is no longer defending it (and actually says she has no more interest in wellness).
We recommend click-throughs to both studies. Each raises questions that Staywell refused to answer, after initial conversations which confirmed they knew about these issues. You'll also see how the American Heart Association was shocked, shocked, that anyone would question their integrity (perhaps they haven't read The Big Fat Surprise) but then let it go, rather than create a news cycle.
Staywell also helped give British Petroleum a Koop Award. Nice to be on the award committee AND be an award sponsor–makes it easy to give your customers awards. With one or two exceptions, we can't remember the last time the Koop Award went to a company with no connection to a sponsor or committee member. Perhaps someone could let us know?
Dan Ariely on how the Wellness Industry Crowdsources Reality
We recommend that everyone listen to Dan Ariely's interview on NPR and TED talk "Why We Lie." It explains exactly why the Wellness Ignorati could decide to collectively self-publish an entire guidebook full of misinformation and disinformation designed specifically to increase the revenues of wellness vendors.
Here are our take-aways from Professor Ariely's TED Talk.
Like Walter White in Breaking Bad, the Ignorati started out honest. They genuinely believed that wellness saved money and that they were doing good. It was very counter-intuitive to believe otherwise. If you look at page 201 of Why Nobody Believes the Numbers, you'll see I even mildly supported biometric screens. I hadn't done the math. I just assumed early detection was a good thing and that Ron Goetzel and others was telling the truth, for which on page 83 I professed my admiration. As another example, ShapeUp's CEO Rajiv Kumar would never have attacked us (largely for refusing to believe Kate Baicker, who even RAND now dismisses and who herself no longer appears to believe her own claim) if he had realized his own outcomes claims were false.
Like Walter White, it was easy to justify the first transgressions. Since the Wellness Ignorati genuinely believed in what they were doing, when the numbers didn't add up, they either justified to themselves that it was OK to fudge them (like ShapeUp's now-retracted claims about Highmark) or ignored glaring invalidating mistakes. The best example of the latter: Ron Goetzel finally recanting Health Fitness Corporation's infamous participants-vs-non-participants self-immolation after years of ignoring it.
Or wellness vendors create a parallel universe where numbers don't have to add up (like Keas), or completely misquote industry experts saying the opposite (like Vitality).
Like Walter White, they don't actually believe they are bad people. Ariely calls this a "personal fudge factor." With the possible exception of Wellsteps' Steve Aldana (who may be honest but simply unable to recognize that no matter what numbers you enter into his model you get the same answer), they really think what they are doing is OK—even though the math clearly dictates otherwise.
Also like Walter White, they kept getting drawn deeper in. The more they lied, the more they have to keep lying. They needed to continue to defend what was looking increasingly indefensible. After giving Nebraska's program a much-publicized and ironically named C. Everett Koop Award, it's hard for Ron Goetzel and his committee to say "We goofed—we need to take it back because they made up the data and defrauded the state" even after the vendor, Health Fitness Corporation, admitted it.
Like Walter White, the Wellness Ignorati "suspend reality" (to use Ariely's term) and "buy into a new reality." Essentially the Ignorati crowdsource reality. They peer-review one another's work, give themselves awards, and decide (to use Michael O'Donnell's term) that anyone who challenges them lacks the "credentials" to do so. Or, as Ariely says: "If you were getting well-paid by Enron, wouldn't you want to see reality as they present it?"
Avoiding the media is an excellent strategy. Once again, like Walter White, the Wellness Ignorati want to keep a low profile. Exposure is bad if the facts all go the other way. That explains Ron Goetzel's refusal to debate, ever, and the Ignorati's characterization of us as name-calling bullies when all we do is ask questions.
Yep, you can read this site up, down and sideways. The fact is no names are called other than the "Wellness Ignorati." We've offered them the opportunity to propose a different name for their practice of denying facts, which they've declined. We do use the term "pretzel" to describe the very impressive twists and turns that Mr. Goetzel uses to wriggle out when he's been caught calling failed or fraudulent programs "best practies" because they are run by friends, sponsors or clients. The alternative word for what one would be called when all your claims are made up is less flattering, and we've never used it with respect to Ron.
This explains why the Ignorati steadfastly refused to answer questions for a $1000 honorarium. Once again, like Walter White, they have so much as stake that $1000 is chicken feed. At Enron, if you questioned Ken Lay at an analyst conference, he would accuse you or not understanding their business, and cut you off from future meetings, rather than answer the question. We of course were not invited to participate in or even listen to the "discussion" about the HERO report.
Like Walter White, at some point the Wellness Ignorati needed to commit to their chosen path. The Wellness Ignorati have gone too far in their insistence that wellness saves money. There is no turning back. The existence of this site makes turning back even harder because retracting their lies means acknowledging them. And as soon as they do that, we do what we do best other than invalidate the Ignorati's misstatements, which is: gloat.
Like Walter White, they are now doubling down. Examples: Ron Goetzel calling Nebraska a best practice after they admitted lying about saving the lives of cancer victims, in order to justify his original award to them. Steve Aldana can't create a real ROI model now without admitting that his original model was not "based on every ROI study ever published" as he has maintained, but rather always yields a savings of $1359/employee no matter what inflation-adjusted figures you enter.
As the house of cards collapses, people on the fringes who were sucked in (in this case HR and some brokers and consultants) wake up and ask: "How could I have believed what these people were saying?" Many major and mid-level figures connected with Enron did exactly this. We see this every week in wellness, as people come to us and say: "I get it. I can't believe I fell for this."
So thank you to Dan Ariely. In one 8-minute TED talk, he explained the entire alternative crowdsourced reality of the Wellness Ignorati – without once even mentioning them by name. But I'm sure the Ignorati nonetheless think he bullied them.
As a hot-off-the-presses example of what Professor Ariely is talking about, Wellsteps just updated their model so that now instead of saving $1359 per person in 2019, they save $1359 per person in 2020. As with previous iterations of their model, the success of the wellness program is irrelevant to the outcome of the model. Just enter a 0% inflation rate and "1" for covered people ("1" so you can see the $1359 reveal itself without having to do division) — and then whatever figures you want to enter for spending, obesity and smoking.
Here you started out with astronomical healthcare costs and got a 99% reduction in smoking and obesity…and saved $1359
Here you save $1359 without changing smoking or obesity at all:
And here you saved $1359 even though there was nothing to save. The costs are as low as the model will allow you to enter (until they got caught, you could enter figures low enough that they model would calculate negative costs), and there was no smoking or obesity to reduce:
Naturally, Wellsteps is prominent both on the Koop Award Committee and the HERO Report Committee. Wellsteps' "back story" is here.


text:
Championship chess is a thrilling world, filled with larger than life personalities, intrigues, and fast paced action. Who knew that watching hyper-intelligent people think could be so interesting? Mix chess with the dynamics of take-no-prisoners international diplomacy, crossed with complicated interpersonal entanglements, and you have the basis of a compelling story. The story of these various attempts at manipulation come together compellingly in Tim Rice, Benny Anderson, and Bjorn Ulvaeus's musical Chess.
Why this play? This play has been tried in different forms between the West End and Broadway. It has been pretty commonly understood in the industry that neither form worked perfectly. Tim Rice, whose idea this play was, invites a director to continue the work of shaping the telling of this story, its character development, and the interplay of those different worlds. That alone was a compelling reason to work on this material. ABBA's score is well known and well loved, and Tim Rice's lyrics give fuel to the world. It was an exciting prospect for me to dissect this wonderful story, script, and score, and to reimagine the intersections of the characters in order to make their journey touch us across the footlights.
Why now? Current Russian–American sparring cannot help but remind us of the deadly diplomatic tensions of the Cold War. How do we relate to each other as nations and as individuals? How do we know what the other side really wants, really means? How we really function productively?
We in the Chess company have a tremendous respect and admiration for the amazing minds that compete in chess at the championship level. We've come to understand the dominance of Russia in the game and the support they have given their most skilled players. The obsession and focus required to participate at this level attracts minds that just don't turn off. Unfortunately, minds that ignore other aspects of life are easily mis-used. We hope that you will love these characters and their story in this rarified world as much as we have loved creating it all for you.
The collaborative nature of theatre requires that artistry and co-operation from many specialists come together. Our team has been especially brilliant. We have an amazingly talented cast. Musical Director Alex Marshall's orchestration underscores the drama with passion. Halee Rasmussen's tilted, raked chess board is a constant tweak to the predicatable. Cole Adams's inspired lighting keeps us on edge and guessing at what will happen next. Adam Day masterfully brings the voices front while still letting us feel the band in the room. Brenda Van der Wiel created our edgy, surprising costumes. Amanda French wig's and make-up have added to the off kilter nature of the characters. Amber Lewandowski and her skilled stage management team have kept us focused and on schedule. The Musical Theatre Ensemble supports and broadens the score allowing us to expand the sound.
We have been so blessed with a team that has bonded, and who serve the show with definitive focus and unique sensitivity and talent.
We hope you enjoy the show!
--Denny Berry Director and Choreographer of Chess The Musical
Musical Theatre Program Head


text: Zendesk, joined by guest speakers from Forrester and Prosper, reveal how support organizations are winning the battle against the stigma of being cost centers. By leveraging multichannel support with the Zendesk family of products, companies like Prosper are untapping positive ROI through increased efficiency of agents and deflection of tickets to lower-cost channels. \r\n\r\nIn fact, the Total Economic ImpactTM (TEI) of Zendesk, a Forrester study released in May 2017, reports Zendesk customers who implemented Zendesk experience a payback period of less than 3 months and 390% ROI on average.\r\n\r\nIn this 30 min webinar, you will:\r\n\r\nHear actionable insights on the digital transformation of customer service from Ian Jacobs, a Principal Analyst at Forrester.\r\nLearn how innovative companies like Prosper are using Zendesk to exceed consumer expectations. \r\nGain access to Forrester's ROI tool that calculates an estimate of the economic benefits you can gain by implementing Zendesk.\r\n\r\nDon\u2019t miss this discussion, Watch now!\r\n