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In the vicissitudes of life, our recent and living generations moved from the hard times of a hundred years ago to the exponential good times of today. Now a few hundred key pioneers have positioned the world in front of the opportunities of Transhumanism and its main tenet, indefinite life extension. Will we unite the world on these issues and capitalize or waste it and let the weeds reclaim our “wheel”, the magnum opus of our generations? I challenge all would-be leaders and followers to honor our ancestors’ long tradition of pioneering the next stages of our future. Everything about you was crafted and honed for this and there is no other time. Find the blazers of our emerging values and paths, your philosophers of the future, out there at the forefronts on this epic new transhuman voyage of freedoms and discoveries and follow them. All leaders who haven’t already, I implore you to fully embrace your roles, triple down and raise your flags even higher. Friedrich Nietzsche wrote a book preluding this philosophy of the future, which serves as the structure for this paper and is quoted here throughout.

“[Conditioning to hard times] is thus established, unaffected by the vicissitudes of generations; the constant struggle with uniform unfavourable conditions is, as already remarked, the cause of a type becoming stable and hard. Finally, however, a happy state of things results, the enormous tension is relaxed; there are perhaps no more enemies among the neighbouring peoples, and the means of life, even of the enjoyment of life, are present in superabundance. With one stroke the bond and constraint of the old discipline severs: it is no longer regarded as necessary, as a condition of existence—if it would continue, it can only do so as a form of luxury, as an archaizing taste. Variations, whether they be deviations (into the higher, finer, and rarer), or deteriorations and monstrosities, appear suddenly on the scene in the greatest exuberance and splendour; the individual dares to be individual and detach himself. At this turning-point of history there manifest themselves, side by side, and often mixed and entangled together, a magnificent, manifold, virgin-forest-like up-growth and up-striving, a kind of tropical tempo in the rivalry of growth, and an extraordinary decay and self-destruction, owing to the savagely opposing and seemingly exploding aptitudes, which strive with one another ‘for sun and light,’ and can no longer assign any limit, restraint, or forbearance for themselves by means of the hitherto existing morality. It was this morality itself which piled up the strength so enormously, which bent the bow in so threatening a manner:—it is now ‘out of date,’ it is getting ‘out of date.’ ” – Friedrich Nietzsche, Beyond Good and Evil: Prelude to a Philosophy of the Future

Our elders came from the great depression and world war. Then they had to watch what they called “morals”, but which were actually just coping mechanisms particular to their vicissitude of time, as Nietzsche gets at in various places, become increasingly disregarded. That happened faster than ever because, little did they know, the bell curve of exponential advancements in fields across the board were upon them. The variations of excellence and monstrosities proliferated like no other time and were supercharged for an abundant harvest by the buds of enlightenment and technology that had been poking their heads out of the fertile intellectual fields of civilization from the smatterings of good times they were able to come upon throughout the century. A lot of it was stored as compounding action potential. It went off like rifles in the 50s and 60s, with so much force that the bullets are still flying today, and the shots of individual aptitude have been firing ever since. Like he is saying, it’s a jungle of individual morals competing in the survival of the fittest, so you must find ways, that hard times naturally make, to get all these independent construction workers of the best ideas behind the same projects in order to tap that energy for the big stages and human potentials.

This is our window in time here, as I often say, to get projects like life extension, transhumanism, space exploration, and some other things done. The people of the past didn’t have this opportunity and the chance here isn’t available forever because death will close us off from it or bad times will set back in. A great gate in Plato’s cave has opened, the eternal guard lions of death have left their posts and we don’t know how long until they come back or the gate closes. It is devastating watching those who have been hypnotized by the cave, by the death trance, sitting there with a wide-open door and the clock ticking down. The climb must be made, now is the time, there is no other. Team up and follow the leaders on these new emerging circumstances and moral imperatives or everyone will die as the marvels of space and boundless technology tumble from our hands. We rouse them to action slowly but surely, though all as one, more gets done.

It is not difficult for Transhumanists or the masses to mistake increased privileges, like so many of the industrialized world have these decades, as chance to secure leisure, pride building, keeping up with the Joneses and so forth. When people start to make good money, do they generally harness all the opportunities they seethed about missing out on when they were poor — the recording studio, the seminars, the investments in life extension that I have heard countless people say they would be back to make when their worldly careers were secured? Many times, we just eat more expensive food, wear more expensive clothes, drive a better car and take more extravagant vacations, wasting the capital gains that were there or dreamed about.

Do hard times need to come back again to allow us to see how incredible the opportunities of this generation and the next “were”, so we can spend our time mourning instead of capitalizing? Or as is happening at present, do we need to let the existential voids gut the bulk of an increasing number of the masses around us until the despair is so great that it forces us back into the undistinguished moral frameworks of the intellectually deflated and delicate, those abasements of our character that grow among the fields of new excellence like weeds?

You see it emerging everywhere, lots of people want it to be a trend not to talk about noble ambitions because it infringes on peoples sacred opinion bubbles, as though open discourse isn’t integral to the human condition and as if those opinion bubbles weren’t arrived at by forms of discourse themselves. Nihilisms everywhere try not only to discourage people from leaving the void but to take up residence in it and work to enrich themselves with absurdity. New kinds of spirituality insist upon random arbitrariness and make it a trend to taboo all dissent. Some in science work to turn what is a mode of investigation into a mechanical way of life. Religion looms there always ready to take advantage of the lost and reclaim its full-time hymn hummers. Television turns gossip and trivialities into an art and trains people in it. Since the world doesn’t have enough leadership yet, or rather, doesn’t recognize enough of it yet, most of the rest of television is reserved for pounding general politics uninspired aimlessness into people’s heads so a few can covertly jockey for power, just to waste that power on screaming into the void from atop piles of gold.

As Nietzsche refers to when talking about politics, and it applies in some ways to the rest of these competing frameworks for wasting time,

”Supposing a statesman were to bring his people into the position of being obliged henceforth to practise ‘high politics,’ for which they were by nature badly endowed and prepared, so that they would have to sacrifice their old and reliable virtues, out of love to a new and doubtful mediocrity;—supposing a statesman were to condemn his people generally to ‘practise politics,’ when they have hitherto had something better to do and think about, and when in the depths of their souls they have been unable to free themselves from a prudent loathing of the restlessness, emptiness, and noisy wranglings of the essentially politics-practising nations;—supposing such a statesman were to stimulate the slumbering passions and avidities of his people, were to make a stigma out of their former diffidence and delight in aloofness, an offence out of their exoticism and hidden permanency, were to depreciate their most radical proclivities, subvert their consciences, make their minds narrow, and their tastes ‘national’—what! a statesman who should do all this, which his people would have to do penance for throughout their whole future, if they had a future, such a statesman would be great, would he?”

The brevity of the portal of opportunity itself must become the crisis. That, along with the worst crisis of all that has always been here ready to propel us to ascending, unifying action if the masses hadn’t tucked tail and ran to hide among rationalizations and excuses, trying vainly to escape it: the 100-year lifespan. More of us must lead on the issue and follow the lead on the issue of the enormous opportunity cost of death and the horrific tragedy of it. People are rightly held to account for excusing death away, but the blame is also ours for not keeping the injustices of death pronounced so that the excuse makers don’t have such a cush and comfortable time construing them. When pro-death culture is rebutted the messages start soaking in for everyone who hears them, and the people who are still forming their worldviews then have the chance to take in substantive versions of all sides of the story. Many people take a side that’s not conducive to life extension simply by default.

Leaders are needed to start the processions of masses on their courses of history, but there are leaders. So, what it is that’s needed is people to start following them. It’s like they say in movements, the first follower is the first leader because they inspire the next 2 to follow, which inspires the next 4 to follow and so forth. What is lacking is enough people courageous enough to set the example and become the first followers.

These are my leaders and they should be yours too: Aubrey de Grey, Michael West, Dave Kekich, Bill Faloon, Kevin Perrott, Joao Pedro de Magalhaes, Natasha Vita-More, Max More, Zoltan Istvan, Keith Comito, Paul Sandford Mcglothin, Ben Goertzel, Bill Andrews, Dave Gobel, Dave Pizer, Michael Rose, Cynthia Kenyon, Gennady Stolyarov, Nikola Danaylov , Brian Kennedy, David Wood, Hank Pellissier, Eric Klien, David Kelley, Ilia Stambler, Roen Horn, Maria Konovalenko, Mikhail Batin, Michael Greve, Steve Hill, Elena Milova, James Hughes, Reason, Velerija Pride, Peter Rothman, Sven Bulterijs, Adam Ford, Nick Bostrom, Ray Kurzweil and at least a hundred others. Every small action taker is a priceless leader as well and every follower leads by example.

We need the media to start portraying our leaders until they can be recognized as such from a distance, when they have large enough crowds of followers clamoring around them. Media: make the people named here regular pundits and guests on the major news networks around the world. Do that and the people will follow, they will create the demands that get these jobs done. Aubrey will go to the head of the NIA and Kennedy to the head of the NIH, Faloon will go to the head of the FDA, Comito will become the Executive Director of CNN, Reason will have a top rated show on ABC, Danaylov on CNN and Al Jazeera, and Wood on the BBC, Magalhaes will become the Director General of the World Health Organization, Kurzweil will become President. A bunch of them will become unofficial advisors and golf buddies of billionaires. They will fill out more of the roles in pop culture from movies and songs to celebrity personalities and cultural references. Many will become Governors and join Congress, become Deans and Chancellors and the world will be ripe for indefinite life extension and all the rest that follows from it. All of us transhumanists must continue manually building these followings until the media fixes better sight of the growing stories that are leading up to things like those and catches up.

Humanity engineers cells, does more of it and gets better at it every year. With enough resources and focus, we will become master mechanics and precision engineers of the biological clock. Let’s ALL act like we aren’t suicidal and do these things that it takes to get the bustling world industry that supports this built.

In those good times where people’s individual aptitudes increasingly show, Nietzsche says that then,

”Danger is again present, the mother of morality, great danger; this time shifted into the individual, into the neighbour and friend, into the street, into their own child, into their own heart, into all the most personal and secret recesses of their desires and volitions. What will the moral philosophers who appear at this time have to preach? They discover, these sharp onlookers and loafers, that the end is quickly approaching, that everything around them decays and produces decay, that nothing will endure until the day after tomorrow, except one species of man, the incurably mediocre. The mediocre alone have a prospect of continuing and propagating themselves—they will be the men of the future, the sole survivors; ‘ be like them! become mediocre!’ is now the only morality which has still a significance, which still obtains a hearing.—But it is difficult to preach this morality of mediocrity! it can never avow what it is and what it desires! it has to talk of moderation and dignity and duty and brotherly love—it will have difficulty in concealing its irony!”

Nietzsche talks at length about the clever moralists of mediocrity weaving webs of stagnancy. These leaders of mediocrity, the loafers and chicken littles are out there drawing crowds right now. Are you going to let them develop large followings that assimilate the masses to the standpatisms, aimless conventionalities and the evolutionarily flightless bird-like destinations of life that absorb so many now, or are Life Extension and the overall frontier expanding trajectories of Transhumanism the competing evolutionary principles that will win? Will we unite and build the vast armies of pioneers who blaze open the frontiers of Sapiens potential? As Natasha Vita-More writes, “We need a worldwide league of activists and experts to help spread positive news, reliable information, and a well-thought-out socio-political stance.” More heads of life extension organizations and initiatives: take up administration positions at the movement for indefinite life extension page facebook.com/movementforindefinitelifeextension, there are many now and we need you all. Post important things related to life extension there and refer people back to it when the opportunities arise. By getting people to join there, they all join the whole, create solidarity, and a larger show of force, which is crucial in grabbing large-scale attention. We involve increasing percentages of these grassroots supporters from there.

A quarter of a billion people of the world can make these transhuman goals happen and a quarter billion are there to follow if we want them to. Our stance is established in themes and concepts that are written about in papers and books around the cause. I’m writing a key book on the fundamental imperative of indefinite life extension that I have condensed and worked out over the years and suggest that all who join as administrators of the movement for indefinite life extension contribute to a series of books to be called The Movement for Indefinite Life Extension. The admins will meet to develop a list of all foundational stances that we will seek to have covered and make the final decisions on what goes into the series for philosophy, politics, sociology, ethics, history, psychology and so forth. We will also develop one coordinated mass movement for indefinite life extension event to involve the participation of no less than 1,000 people, designed to drive world spotlight to the cause and drive up these “likes’/defacto petition signatures, with no time frame yet set.

When other people try to get transhumanism’s would-be followers to play Duck Duck Goose instead of cosmic chess, they are coming for your future, destiny, place in the history books, all of our lives, your holodeck, our tickets to vacations on other planets and chance to live in a world of superabundance. Things like 3d printing and cheap energy sources can make the entire population of the world richer than the richest Forbes List billionaires of today like the middle class among us today are richer than the richest Kings and Queens of a thousand years ago. Your golden geese circle daffy ducks while the windows close. We can get more people to show up for this than they can for that. Beat them, play to win, you are the alpha thinkers, step into the role, claim your destiny. Who among us is seriously going to follow through with letting these people stomp out the purpose of all our lives? Those are our followers but what is happening is that by leaving them to their own devices, and idle to what’s important, we foster the very conditions that slow us down.

The unique position of this generation, the last and the next is in front of this window of the opportunities of all time and space. Technology can develop far enough and get enough done in time for us. Self-actualization and beyond are ours if we’ll only expedite these goals, if we’ll speed up the process of generating awareness and participation. We know where we’re going, why, and how to get there. Lead by leading or lead by setting the example and following, it’s the same difference, it all gets us there.

“They determine first the Whither and the Why of mankind, and thereby set aside the previous labour of all philosophical workers, and all subjugators of the past—they grasp at the future with a creative hand, and whatever is and was, becomes for them thereby a means, an instrument, and a hammer. Their “knowing” is CREATING, their creating is a law-giving, their will to truth is—WILL TO POWER.—Are there at present such philosophers? Have there ever been such philosophers? MUST there not be such philosophers some day?”

Let’s keep the mediocre at bay by engaging our ethic of the tradition of progress. Stand behind the United Nations Universal Declaration of Human Rights http://www.un.org/en/universal-declaration-human-rights/, the Transhuman Declaration https://humanityplus.org/philosophy/transhumanist-declaration/, the Transhumanist Bill of Rights https://transhumanist-party.org/tbr-2/, and the Technoprogressive Declaration https://transvision-conference.org/tpdec2017/ to make sure there is enough support to signal to the world that this is where we all need to be. Otherwise, the scales of supernaturalism, nihilism, consumerism or some other thing could tip us too far into the abysses of lost potential.

The United Nations Universal Declaration of Human Rights says, for example:

Article 27: “Everyone has the right freely to participate in the cultural life of the community, to enjoy the arts and to share in scientific advancement and its benefits.”

Article 28: “Everyone is entitled to a social and international order in which the rights and freedoms set forth in this Declaration can be fully realized.”

In other words, the world’s goals are no longer to figure out ways to free ourselves from the worst of the struggles, tediums and grunt laboring — now our goals are to make sure everyone does what it takes to implement the achievements that have unlocked those limitations and enable the right of everyone to stand before the fertile fields of our aptitude.

The spirit of that declaration and centuries of progress and evolving mindset that built up to it have helped establish a foundation for transhumanism to gain its footing and flourish, and those are two of its articles that sum up the angle that the Transhuman Declaration, Transhumanist Bill of Rights, and Technoprogressive Declaration expand on. As they outline, the time to focus on adding to our overall condition, or as we call it, “Humanity+”, is here.

Another line in the UN declaration suggests that these conditions and our morality naturally prescribe this transhuman expansion and direction.

Article 29: “Everyone has duties to the community in which alone the free and full development of his personality is possible.”

Developing our species is the overarching reason why you exist, the nature of your reality. We must know what is going on in order to know what we need and want, and that cannot be known until we develop enough to have the chance to do so. New technologies and extended lengths of lifespan are imperative.

The Transhumanist Declaration, the Transhumanist Bill of Rights and the Technoprogressive Declaration declare these kinds of fundamentals of our condition in various ways.

In the Transhumanist Declaration:

“Reduction of existential risks, and development of means for the preservation of life and health, the alleviation of grave suffering, and the improvement of human foresight and wisdom should be pursued as urgent priorities, and heavily funded.”

In the Transhumanist Bill of Rights:

Article IV. “Sentient entities are entitled to universal rights of ending involuntary suffering, making personhood improvements, and achieving an indefinite lifespan via science and technology.”

Article VIII. “Sentient entities are entitled to the freedom to conduct research, experiment, and explore life, science, technology, medicine, and extraterrestrial realms to overcome biological limitations of humanity.”

In the Technoprogressive Declaration:

“Our vision is a sustainable abundance of: clean energy, healthy food, shelter, affordable healthcare, all-round intelligence, mental well-being, and time for creativity, enabled by application of converging technologies, with no one left behind.”

Did the people of 1,000 years ago have opportunities like these? Most of the opportunities they go over weren’t even conceived of yet, not even 100 years ago. Only some of the seeds were then growing deep in the forests of daily awareness. Now the fruits are falling off the trees in groves as far as the eye can see. There has never been a time like this before. Anyone who is considering getting in on this movement, do it now before it’s too late. Just message me and I will personally pitch you indisputable reasoning why you ought to join. Stay tuned to the movement for indefinite life extension post feed for a steady stream of the news, reasoning, philosophy, sociological insights, declarations, opportunities for involvement, updates and everything else.

”The problem of those who wait.—Happy chances are necessary, and many incalculable elements, in order that a higher man in whom the solution of a problem is dormant, may yet take action, or ‘break forth,’ as one might say—at the right moment. On an average it does not happen; and in all corners of the earth there are waiting ones sitting who hardly know to what extent they are waiting, and still less that they wait in vain. Occasionally, too, the waking call comes too late—the chance which gives ‘permission’ to take action—when their best youth, and strength for action have been used up in sitting still; and how many a one, just as he ‘sprang up,’ has found with horror that his limbs are benumbed and his spirits are now too heavy! ‘It is too late,’ he has said to himself—and has become self-distrustful and henceforth forever useless.—In the domain of genius, may not the ‘Raphael without hands’ (taking the expression in its widest sense) perhaps not be the exception, but the rule?—Perhaps genius is by no means so rare: but rather the five hundred hands which it requires in order to tyrannize over the kairos, ‘the right time’—in order to take chance by the forelock!”

We all ride the same orb through the galaxy here, products of the same glorious struggle for survival, progeny of the same springs if ingenuity and imagination, the accomplishments of many triumphant generations worth of “a better tomorrow for our grandchildren”. Life extension, space travel and all the rest aren’t just goals for some particular culture or two, this is for all of us, this is for continuing the tradition of the evolution of our species and the universe.

The Roman Empire never did conquer the North East. Communication was harder back then but let’s say that they had a signup sheet and a newsletter that went out to the whole empire within a minute. Do you think they would have been able to drum up enough support and unity to get it done then? Of course, it would have been simple then. They would have conquered the world. That’s what a Facebook page does for us. It SEEMS too simplistic, but it’s not. If you don’t want the window to close, then just “like” the movement for indefinite life extension page and add and direct people to like the page like your life depends on it. Every aspect of the cause goes out to those “likers”, those defacto petition signers, and increased percentages of them are actively sent off to fitting projects and organizations and involved by us, one on one, via notices and others methods from there. One, solid, unified showing of numbers, social proof, is the only thing standing between you and the train ride to the future.

“the most divergent, the man beyond good and evil, the master of his virtues, and of super-abundance of will; precisely this shall be called GREATNESS: as diversified as can be entire, as ample as can be full.”

Now, on through the window and into the mysteries, in pursuit of the homunculus, to the edges of infinity, through the wonders of imagination, down into the atoms, in search of the purpose of life we go!

A new study on adult neurogenesis and Alzheimer’s disease.


According to a study led by scientists at Massachusetts General Hospital, exercise-induced neurogenesis improves cognition in a mouse model of Alzheimer’s disease, yielding more benefits than drug-induced adult neurogenesis. The scientists were able to figure out the difference between the two types of induced neurogenesis and pharmacologically reproduce the same benefits provided by exercise [1].

Study abstract

Adult hippocampal neurogenesis (AHN) is impaired before the onset of Alzheimer’s disease (AD) pathology. We found that exercise provided cognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN and elevating levels of brain-derived neurotrophic factor (BDNF). Neither stimulation of AHN alone, nor exercise, in the absence of increased AHN, ameliorated cognition. We successfully mimicked the beneficial effects of exercise on AD mice by genetically and pharmacologically inducing AHN in combination with elevating BDNF levels. Suppressing AHN later led to worsened cognitive performance and loss of preexisting dentate neurons. Thus, pharmacological mimetics of exercise, enhancing AHN and elevating BDNF levels, may improve cognition in AD. Furthermore, applied at early stages of AD, these mimetics may protect against subsequent neuronal cell death.

An incurable affliction that gradually destroys a person’s ability to walk, speak, and eventually breathe can also deteriorate the mind, new research suggests. People with amyotrophic lateral sclerosis (ALS) are more likely to have other mental and behavioral health problems than people without the condition, the study found.

ALS, also called Lou Gehrig’s disease, is a progressive neurologic condition that affects some 20,000 Americans at any one time. In ALS, a person’s motor neurons throughout their body and brain steadily die off. These neurons are responsible for helping us carry out voluntary movement.

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Today, we want to let you know that the documentary Paywall: The Business of Scholarship is now available in both English and Russian. This is a documentary exploring the crisis in scientific journal publication and the excessive fees that some publishers charge to access knowledge.

Holding scientific knowledge to ransom

Around 70% of scientific publications are hidden behind paywalls, restricting access to knowledge and holding back progress. We believe that this is unfair and that putting profit before the health of others is unacceptable, and this is one reason why we support the concept of open science here at LEAF.

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Utilizing new mobile application technology, researchers at The University of New Mexico found that medical cannabis provides immediate symptom relief across dozens of health symptoms with relatively minimal negative side effects.

In two recent studies titled, “Patient-Reported Symptom Relief Following Medical Cannabis Consumption,” and “Effectiveness of Raw, Natural Medical Cannabis Flower for Treating Insomnia under Naturalistic Conditions” published in the journals, Frontiers in Pharmacology and Medicines, respectively, UNM Department of Psychology Associate Professor Jacob Miguel Vigil and UNM Department of Economics Assistant Professor Sarah See Stith, document that patients experienced statistically and clinically significant therapeutic benefits when they used cannabis for symptoms ranging from chronic pain to insomnia.

These studies analyzed data collected with the Releaf App, developed by co-authors Franco Brockelman, Keenan Keeling and Branden Hall and currently, the largest repository of user-entered information on the consumption and effects of cannabis use in the United States with nearly 100,000 recorded user sessions.

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On any given day, Zoubaida Salman instructs a classroom of 15-year-olds at the Sur Baher Girls School in East Jerusalem, where she has served as the science teacher and Environment and Health Coordinator for the past 22 years. One of the most important lessons comes from their backyard: water is scarce and precious in this region.

Water shortages can lead to major sanitation issues at schools, so students have to play an active role in managing it. At Sur Baher, the most significant use of is for flushing toilets, which stop working if there is not enough water. If the water runs out, school administrators must buy it from the city. In other regions, the schools even close because of .

A team of scientists with the NASA DEVELOP program is helping address these water shortages by collaborating with a nonprofit called Water Resources Action Project(WRAP). WRAP designs and constructs systems for schools in the Middle East to capture rainfall during the five-month rainy season for use later. Selecting a geographically promising area is time-consuming and tedious work though for the small, volunteer-based team. The NASA DEVELOP team is using to help WRAP more easily identify suitable locations for the rainwater harvesting systems.

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Researchers don’t know much about whether people who aren’t diabetic should avoid having glucose spikes after meals, or whether, by contrast, average glucose levels are more important — things that need to be studied, he said.

“They’re right to be asking it. I don’t have data to give guidance on how to interpret it,” Bergenstal said. “I think they’re right to say it can’t be bad if I keep my blood sugars more stable. It’s a reasonable assumption, but we don’t have the data for it.”

It’s generally accepted that non-diabetics are better able to regulate their glucose levels. A higher than normal level, meanwhile, indicates prediabetes. But a new study out of Stanford University in late July that used CGMs on 57 participants, including diabetics and non-diabetics, had a surprising finding.

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The Alzheimer’s Hypothesis

Introduction

Alzheimer’s disease was first discovered in 1907 in a 51 year old woman by the German physician A. Alzheimer. One of the first changes noticed was an eruption of jealous feelings towards her husband. It wasn’t long before symptoms of rapid memory impairment were observed. The impairments prevented her from finding her way out of her home, She hid herself, she would drag objects to and fro, and occasionally screamed because she believed people were out to kill her.

When she was institutionalized her gestures would show a complete helplessness. As common in most Alzheimer’s patients, she was disoriented as to time and place. At times she would state that she didn’t understand anything, felt confused, and totally lost. When the doctor came in to see her she would consider it as an official visit and would apologize for not having finished her work. Other times she would be terrified and start to yell that the doctor wanted to operate on her. Other times she would send him away in complete indignation uttering phrases indicating that she was afraid that the doctor wanted to damage her woman’s honor. At times she would become completely delirious , dragging her blankets and to and fro, calling for her husband and daughter, and seeming to experience auditory hallucinations. She would often scream for hours and hours in a horrible voice. Mental regression advanced quite steadily. After four and a half years of illness the patient finally died.

Alzheimer performed a postmortem examination of the woman’s brain. He paid special attention to changes in the “neurofibrils,” fibers in the cytoplasm of a nerve axon — elements of the cytoskeleton that can be stained by a silver solution.

The Bielschowsky silver preparation showed very characteristic changes in the neurofibrils. Looking inside an apparently normal-looking cell, however, one or more single fibers became observably prominent through their striking thickness and specific impregnability. At a more advanced stage many many fibers arranged in parallel showed the same changes. Over time they formed dense bundles and gradually advanced to the surface of the cell. The cell and nucleus would eventually disappear, leaving only a tangled bindle of fibrils where the neuron once was.

Since these fibrils can be readily stained with certain dyes, a chemical transformation of the fibril substance must have taken place. This might be why the fibrils survived the destruction of the cell. The transformation of the fibrils seems to go hand in hand with the storage of an as-of-yet not closely investigated pathological byproduct of neuronal metabolism. Such alterations were found in about one-quarter to one-third of all the neurons in the cerebral cortex. Numerous neurons, especially in the upper cell layers, had completely disappeared.

The number and distribution of neurofibrillary tangles, what are commonly known as the “tombstones” of dead and dying neurons, are correlated with the severity of the symptoms in Alzheimer’s disease.

Phase1

What is the purpose of beta-amyloid?

Alzheimer’s disease causes impairment with memory, thinking, and behavior. Alzheimer’s affects 5.5 million people age 65 and older and approximately 200,000 individuals under the age 65. Alzheimer’s disease is the 5th leading cause of death in the United States. The root cause of Alzheimer’s is still unknown. There are several hypothesis that attempt to explain it. This article focuses on the research being done in a joint effort between a team from Harvard University being led by Rudolf Tanzi and Robert Moir at Boston Massachusetts General Hospital.

Tanzi and Moir investigated the development of Alzheimer’s disease in animals and found the development of amyloid plaques is not unique to humans. 70 percent of vertebrates share certain sequences of particular amino acids in human beta-amyloid. Moir believes because this sequence is shared so widely and has not changed over time that it must be doing something very important. Moir discovered that the antimicrobial peptide LL37 acts as one of the brain’s defenses against microbes alongside beta-amyloid.

In order to test this hypothesis, the team injected the brains of mice that were bred to develop Alzheimer’s plaques comparable to the way humans do with bacteria. Overnight, the mice produced plaques. Tanzi discovered that each plaque had a single bacterium in it. A single bacterium can induce an entire plaque.

25 May 2016

New Scientist

Science Translational Medicine 25 May 2016:

Vol. 8, Issue 340, pp. 340ra72

DOI: 10.1126/scitranslmed.aaf1059

Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease

Full Abstract

Phase 2

The Role of Sleep on the Brian’s Filtration System

Lulu Xie and team recently uncovered one of the key functions of sleep. The team compared 2 arousal states in the mouse, sleeping and awake, using state-of-the-art in vivo two-photon imaging. The researchers found that metabolic waste products of neural activity were cleared out of the sleeping brain at a faster rate than during the awake state. Like the accumulation of beta amyloid plaques, sleep is a cross-species phenomenon.

The study by Xie et. al reports that the critical function of metabolic homeostasis is dependant on sleep. The team utilized real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice. The experiment found a 60 percent increase in the interstitial space in association of natural sleep or anesthesia. This resulted in a noticeable convective exchange of cerebrospinal fluid and interstitial fluid, which are found in the spaces between the blood vessels and surrounding cells.

Thus as a result convective fluxes the rate of β-amyloid clearance during sleep. Hence, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate during our waking hours.

Sleep Drives Metabolite Clearance from the Adult Brain

Science 18 Oct 2013:

Vol. 342, Issue 6156, pp. 373–377

DOI: 10.1126/science.1241224

Full Abstract

In a separate study Ehsan Shokri-Kojori and team published a study on April 9 2018 showing that just 1 night of sleep deprivation builds β-Amyloid within the brain.

PNAS April 24, 2018 115 (17) 4483–4488

Full Abstract

On September 5th of this year The Sleep Research Society came out with a report that collaborates with the data suggesting just how important the role of sleep is to prevent Alzheimer’s disease. The Baltimore Longitudinal Study of Aging, conducted by Adam P Spira et al showed that those who experienced excessive sleepiness during normal waking hours were nearly three times more likely to have brain deposits of beta amyloid than those who didn’t.

PET scan of a human brain with Alzheimer’s disease

Sleep, zsy152

Published: 05 September 2018

Full Abstract

The accumulated evidence above shows that Beta-Amyloid are part of the brain’s ancient immune system . The evidence also indicates that the buildup of Beta-amyloid plaques occurs when it’s not flushed out. Many researchers, including Rudolf Tanzi and Robert Moir believe that it is the plaques that cause the damage to the brain.

Phase 3

The fIltration System of the Brain

The re-discovery of cellular membranes around the brain known as meningers has a network of lymphatic vessels that drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes in mice. This lymphatic system was first discovered in 1787 (Mascagni, P. Vasorum lymphaticorum corporis humani historia et ichnographia) and was rediscovered by Da Mesquita et al.

Their research showed that meningeal lymphatics play a central role in brain health and disease by helping to maintaining both cognitive function and proteostasis.

The purpose of the lymphatic system in the body is to drain tissue of interstitial fluid that houses cellular debris and toxic chemicals. A rich protein-fluid called lymph is formed by interstitial fluids which circulates through the lymphatic system before returning to the blood. Lymph is filtered through the lymph nodes. Lymph nodes are responsible for initiating immune responses when foreign particles are detected.

Because the brain does not have its own lymphatic vessels it utilizes the interstitial fluid (ISF) along the walls of blood vessels to transport waste and proteins from the parenchyma to reach the cerebrospinal fluid that circulates through the meninges. The transvascular process is the process in which metabolic waste products, proteins, and other molecules in these fluids are removed from the brain by being transported along the walls of blood vessels, which crosses the blood-brain barrier. To what extent, if any, the meningeal lymphatic vessels were also involved in waste clearance is still unknown.

To verify the critical role of the meningeal lymphatic vessels Da Mesquite et. al injected a drug designed to damage the vessels into one of the three principal openings in the subarachnoid space between the arachnoid and pia mater layers of the meninges surrounding the brain, collectively referred to as the cisterna magna. In order to track the CSF they injected a fluorescent tracer molecule. This provided insight as to where the fluid goes in mice lacking meningeal lymphatic vessels. Da Mesquite et. al noted that the the tracer did not travel deep into the cervical lymph nodes in mice lacking meningeal lymphatic vessels. Injecting high concentrations of a tracer into the CSF can cause the diffusion of a tracer into the brain along blood vessels as shown by previous work — but this too was also reduced. The researchers used different tracers, surgically closing off drainage to the deep cervical lymph nodes; and examined mice with impaired lymphatic vessel development . The authors were able to confirm through these various methods the results by doing so.

The authors also noted that deficits within spatial orientation and memory were a result of meningeal lymphatic destruction.

Another interesting finding by the researchers was a change in gene expression within the hippocampus, a substructure crucial to memory and spatial orientation.

The gene expression resembled those previously observed in neurodegenerative disorders. The accumulated evidence by these experiments suggests collectively that the drainage of brain ISF and CSF by meningeal lymphatics is critical to proper function of cognition within the brain.

These findings present an interesting question: where exactly did the tracers go? One study (https://onlinelibrary.wiley.com/doi/abs/10.1038/icb.1951.30) suggests that tracers injected into the cisterna magna are transported primarily in the blood and that the lymphatic system is only secondary. To reveal whether the impairment of meningeal lymphatics can lead to a shift in the pathways responsible for controlling brain proteostasis the simultaneous measurements of tracers movements meningeal lymphatics, other lymphatic vessels, (for example the neck) and the blood may give insights into whether there’s an increase in the transvascular removal of waste products across the blood-brain barrier and/or their drainage into the venous system in the meninges.

The next observation by Da Mesquita’s team was a decrease in the diameter and coverage of meningeal lymphatic vessels through induced aging. The researchers also observed a decrease in drainage of tracers from the ISF and CSF into deep cervical lymph nodes. The signaling of the pathway involving vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR3 promotes lymphatic vessel growth in mice. Likewise when the pathway involving endothelial growth was damaged it caused a loss of meningeal lymphatic vessels. Moreover the authors showed that there was an increase diameter of meningeal lymphatic vessels by providing treatment VEGF-C, improving lymphatic drainage as a result. Consistent with the accumulated research, Da Mesquita et al. showed that the drainage of CSF tracer could be restored into deep cervical lymph nodes by the local delivery of the vegf-c into the cisterna of old mice with a viral vector . This resulted in the restoration of spatial orientation.

The accumulation of amyloid-β protein within the brain, a hallmark of Alzheimer’s disease, causes age related impairments in the transvascular clearance of waste. The effects of of ablating the meningeal lymphatics in two mouse models of Alzheimer’s disease, in which amyloid-β protein is produced in neurons and secreted into the ISF was investigated by Da Mesquita and team. The results showed that ablation led to the accumulation of amyloid-β protein in the meningenges. The authors also noted to the potential relevance for humans by showing that amyloid-β had accumulated in meningenges of people who had Alzheimer’s disease as well.

When amyloid-β protein deposition in the brain parenchyma first became apparent, Da Mesquita and colleagues discovered that the two mouse models did not exhibit any apparent structural or functional changes in the meningeal lymphatics at the time. Cognitive impairment could not be prevented in either model using viral delivery vegf-c, which points to another disruption in another clearance pathway the early amyloid-β deposition and cognitive impairments in these two models-most likely the transvascular clearance. More than likely an increased burden is placed upon meningeal lymphatic system due to the gradual deterioration of transvascular-clearance routes through aging. Faulty lymphatic drainage of amyloid-β and other proteins from the ISF and CSF may be caused when the capacity of the lymphatic system is reached. This gives strong evidence to suggest that there is a very delicate relationship between meningeal lymphatics and blood vessels in the regulation of proteostasis in the brain.

In order to open new directions for research into cognition, neurodegeneration, and Alzheimer’s disease, the improvement of our understanding of waste clearance pathways from the brain, how the ISF and the CSF drain into the meningeal lymphatics, and how these lymphatic vessels interact with the blood vessels at the blood-brain barrier is vital. The potential of improving clearance with meningeal lymphatics to rebuild brain proteostasis, and may lessen amyloid-β protein deposition have been shown by Da Mesquita et al. to rely upon the local growth of lymphatic vessels. Whether or not the improvement of the impaired function of blood vessels due to aging, and whether enhancing clearance at the blood-brain barrier can improve lymphatic drainage function, remains to be to determined.

Nature 25 July 2018

A lymphatic-waste disposal system implicated in Alzheimer’s Disease

Naturevolume 560, pages185–191 (2018

Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease

Full Abstract

The accumulated evidence shows that Beta-amyloid may prove to be beneficial in killing off microbes, but also that proper rest is needed to activate the filtration system of the brain to consistently flush out these neurotoxins before they cause impairment or disease . Further research into the prevention of age-related damage to the brain’s lymphatic system may offer clues as to how we can prevent cognitive decline of age-related diseases. Ideally this will be done with protective mechanisms the brain already has in place.

Journal of Alzheimer’s Disease — Volume Pre-press, issue Pre-press, vol. 65, no. 2, pp. 659–682, 2018

Accepted 5 July 2018

Published: 21 August 2018

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

Full Abstract

Further analysis of these key factors could pave the road to ending Alzheimer’s and other age-related diseases.

Nicholi Avery, [email protected]

Adam Alonzi, [email protected]