The Arcane
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Here I am going to ramble a little about patterns of human behavior. "Arcane" is one of those words sorely abused by generations of people involved in the most fanciful of modern pastimes, which is to say the creation of alternative magical and religious beliefs and practices, both in earnest and for fun. As a consequence it has gathered a broad wake of connotations and cultural baggage. Cut all that away and it has an unbiased, simple, and straightforward meaning, however. To be arcane is to be obscure, to be hidden, to be known only to a few.

We humans have evolved a strong urge to pattern recognition. It is a key part of our intelligence as it applies to the business of surviving the rigors of natural selection. Clearly the benefits of identifying and acting on real patterns far outweighed the disadvantages of incorrectly seeing patterns that are not real. How else to explain magical thinking, the tendency for people to fit everything they observe into simple models of cause and effect regardless of accuracy, and then search for the truth later, if at all? The world about us is so very complex that there will always be things that any given group of people cannot understand or model accurately with the resources at their disposal, but put in that situation they will build the models anyway, because that is more comfortable than acknowledging ignorance. So we have religion, magical traditions, the ridiculous marketing that emerges from the snakeoil "anti-aging" marketplace, and generations of people attaching extra saddlebags of meaning to workhorse words such as "arcane," "esoteric," and the like.

Every present culture has very deep roots, stretching back at least centuries into eras in which it was universally accepted that an arcane world lies underneath the mundane, steering it, providing the rules that make sense of what seems senseless. In search of patterns, any patterns, people looked for guidance to whomever was bold enough to claim to see into the arcane world, and since we are a hierarchical species, like our fellow primates, that form of leadership was institutionalized into power structures very early on. Thus we have a history of shamans, priesthoods, temples, the Hero's Journey, and the endless, ever more baroque theology that commenced as soon as things advanced to the point of fighting with words and concepts rather than weapons. All of that lies underneath the thin veneer of modernism, a bone mountain, the legacy of the dead.

Now, here is an interesting thing about modern science and technology: its complexity and importance has in effect created a real arcane world that lies alongside the mundane, steering its future, determining who will live and who will die, what changes and what persists, how the rules of everyday life will differ tomorrow. The present state of technology is the greatest determinant of how we live our mundane lives, and technological progress is the greatest determinant of what tomorrow will bring. Yet few people choose to undertake the work needed to peer from their daily grind into the arcana of technology, even in this age of enormously rapid change, in which the formative lives of each new generation are appreciably different from those of their parents.

Medicine and medical research, especially into aging, shape the rules that will determine the portents for the rest of our lives. How long will we live, will we suffer, what must we do to have the best odds of success? Two thousand years ago people went to priests and burned offerings. A thousand years ago they petitioned physicians who had more in common with priests than with today's practitioners. Today they go clinics and understand about as much of the underpinnings of what they are told to do, for all that it is a lot more effective. The behaviors and organizations laid down to deal with the imaginary arcana of mysticism and religion continue for the real arcana of technology. Very few people go beyond talking to researchers to lift the veil and seek to understand why medicine is the way it is, why the answers to their questions are what they are. They accept the patterns that are explained in shorthand, and are comforted by them, right or wrong. That the patterns offered are better and more effective because of the changing tides of the arcane world of medical research is almost beside the point.

It is always too easy to castigate, however. We who do look further, who place ourselves with a foot in the arcane and a foot in the mundane, drifting from day to day activities on the one hand to presenting the logical outcome of human agelessness resulting from effectively treating aging as a medical condition on the other - we can forget just how distantly removed from all this we once were, or how much of an accident it is that we are where we are today. Ponder just how little thought you gave to medicine and where it came from when you were young, immersed in the mundane: back when you thought aging was set in stone, and the sum of the world was school, shopping, relationships, the changing of the seasons, a job, a hobby. The sum of an unremarkable, unique life. That is most people, unaware of what actually sways their futures.

All of this is why you see similar patterns of human organization at the high level emerging at the boundary of medical science and the world at large as at the boundary of organized religion and the world at large. The data is vastly different, and the importance vastly different. But the same underlying incentives and facets of human nature are at work, driving the small decisions that snowball into organizations and initiatives. For preference I'd like to see this change. The arcane world of medical research, and particularly that related to ending frailty and disease in aging, cannot continue to be as arcane as it is today if we are to see the growth we need in funding and support. The scale of applied resources and pace of progress that is justified by the grand panoply of suffering caused by disease and aging is hard to sustain when no-one thinks about medicine until they are sick. Research and development of new therapies is slow, and leaving education and support for that process until it is needed is leaving it far too late to make a difference.

If we could just bootstrap medicine to much the same position in the public eye as the automobile or the personal computer, where there is some breakdown of the veil between the arcane world of progress and development and the mundane world of use, even that would be a great gain. Unfortunately doing this is an uphill battle against our own evolutionary history and evolved preferences: threatened by complexity, and worse, by the time needed to make a dent in that complexity, most people retreat and direct their limited attention elsewhere. It is a hard sell to persuade anyone to outlay their precious time to understand something that will be important a decade or two from now. In effect those of us closer to the inside of the veil of the arcane for medical research are something like reverse Cassandras: knowing that wondrous, golden futures lie ahead, if only people will listen, understand, and help. More are taking notice with each passing year, but it still far more slowly than they might. Changing the world is not easy.

A View of the Importance of Neurogenesis
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Neurogenesis is name given to the creation of new neurons in the central nervous system, and particularly the brain. Only within the last thirty years, quite recently in the grand scheme of things, have researchers proved that neurogenesis occurs at a low level in adults, that the brain is not a fixed set of long-lived and non-dividing cells, but is augmented with new arrivals on an ongoing basis. Once verified, this became a topic of considerable interest for the growing fields of regenerative medicine and stem cell research. Can the rate of neurogenesis be safely increased, and will this produce benefits for patients suffering neurodegenerative conditions, or postpone the onset of such conditions? Can investigation of neurogenesis be used to guide improvements in first generation stem cell therapies based on transplanted cells?

With more research into the biology of the brain, aided by the rapid improvement in the tools of biotechnology since the 1990s, there is an increased realization of the importance of adult neurogenesis. Few evolved processes exist without serving multiple ends, and this one is no exception in that regard. More than a mere repair and replacement mechanism, neurogenesis in adults is necessary to the correct functioning of the brain. Couple that to the discovery that rates of neurogenesis decline with age, and the processes of slow growth and change in the brain become ever more attractive as an area of medical research. It is worth noting that some of the recent work emerging from parabiosis studies, in which alterations are made to levels of some of the molecular signals in the circulatory system, have shown preliminary signs of being able to reduce the age-related decline in neurogenesis.

The article linked below is a good read, and goes some way to providing the high-level context and background to explain why research into neurogenesis is so important to those parts of the life science community focused on aging, age-related diseases of the brain, neurobiology, and regenerative medicine. Clearly there is a lot more to be done before an initial set of therapies emerge via the traditional drug development approach, and those therapies will likely be pretty marginal at the outset if history is any guide, but it is an interesting field to watch.

Brain Gain: Young Neurons in the Adult Human Brain are Likely Critical to its Function

At a lab meeting in the mid-1990s a neuroscientist told his team that he wanted to determine whether new neurons are produced in the brains of adult humans. At the time, adult neurogenesis was well established in rodents, and there had been hints that primate brains also spawned new neurons later in life. But reports of neurogenesis in the adult human brain were sparse and had not been replicated. Soon enough, a clear picture emerged: the human hippocampus, a brain area critical to learning and memory and often the first region damaged in Alzheimer's patients, showed evidence of adult neurogenesis. In November 1998, the group published its findings. "When it came out, it caught the fancy of the public as well as the scientific community. It had a big impact, because it really confirmed neurogenesis occurs in humans."

Fifteen years later, in 2013, the field got its second (and only other) documentation of new neurons being born in the adult human hippocampus - and this time learned that neurogenesis may continue for most of one's life. Neuroscientistists took advantage of nuclear bomb tests carried out during the Cold War. Atmospheric levels of carbon-14 have been declining at a known rate since such testing was banned in 1963, and researchers were able to date the birth of neurons in the brains of deceased patients by measuring the amount of carbon-14 in the cells' DNA.

In the late 1990s and early 2000s, researchers delved into the cell biology of neurogenesis, characterizing the populations of stem cells that give rise to the new neurons and the factors that dictate the differentiation of the cells. They also documented significant differences in the behavior of young and old neurons in the rodent brain. Most notably, young neurons are a lot more active than the cells of established hippocampal networks, which are largely inhibited. "For a period of about four or five weeks, while the newborn neurons are maturing, they're hyperexcitable. They'll fire at anything, because they're young, they're uninhibited, and they're integrating into the circuit."

To determine the functional role of the new, hyperactive neurons, researchers began inhibiting or promoting adult neurogenesis in rodents by various means, then testing the animals' performance in various cognitive tasks. What they found was fairly consistent: the young neurons seemed to play a role in processing new stimuli and in distinguishing them from prior experiences. This type of assessment is called pattern separation. While some researchers quibble over the term, which is borrowed from computational neuroscience, most who study hippocampal neurogenesis agree that this is a primary role of new neurons in the adult brain. The basic idea is that, because young neurons are hyperexcitable and are still establishing their connectivity, they are amenable to incorporating information about the environment. If a mouse is placed in a new cage when young neurons are still growing and making connections, they may link up with the networks that encode a memory of the environment.

While studying the function of hippocampal neurogenesis in adult humans is logistically much more difficult than studying young neurons in mice, there is reason to believe that much of the rodent work may also apply to people - namely, that adult neurogenesis plays some role in learning and memory. "Given that the dentate gyrus is so highly conserved and that the mechanisms of its function are so similar between the species - and given that neurogenesis is there in humans - I would predict that the general principle is the same." And if it's true that hippocampal neurogenesis does contribute to aspects of learning involved in the contextualization of new information - an ability that is often impaired among people with neurodegenerative diseases - it's natural to wonder whether promoting neurogenesis could affect the course of Alzheimer's disease or other human brain disorders. Epidemiological studies have shown that people who lead an active life - known from animal models to increase neurogenesis - are at a reduced risk of developing dementia, and several studies have found reduced hippocampal neurogenesis in mouse models of Alzheimer's. But researchers have yet to definitively prove whether neurogenesis, or lack thereof, plays a direct role in neurodegenerative disease progression.

Of course, the big question is whether researchers might one day be able to harness neurogenesis in a therapeutic capacity. Some scientists say yes. "I think the field is moving toward that. Neurogenesis is not something de novo that we don't have at all - that would be much harder. Here, we know it happens; we just need to enhance it."

The Long Road Ahead to Exercise Mimetics
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Today I'll point out a couple of recent research publications on the topic of the molecular mechanisms of exercise: how it might work to improve health, how it extends healthy life span but not maximum life span in animal studies, and how the response to exercise might be safely improved or otherwise manipulated. Researchers nowadays tend to comment on future directions for drug discovery based on their investigations of exercise, and in that this slice of the field is becoming much like calorie restriction research ten to fifteen years ago.

Take a moment to think about how much work and funding has gone into investigations of calorie restriction and the search for drug candidates that can mimic even just a fraction of the beneficial metabolic alterations and extension of healthy life spans that occur in response to calorie restriction: probably a few billion dollars and year after year of dedicated investigations by hundreds of scientists in the past decade alone. Yet at the end of all that, and after the collection of enormous amounts of data, there is only a small number of drug candidates, few of which are anything other than marginal in animal studies, none of which can reproduce all of the beneficial changes observed in calorie restriction, and there is still no comprehensive accounting of how calorie restriction works under the hood, just an outline of ever-growing complexity.

It has taken fifteen years to get that far. Processes like the reaction to restricted calorie intake and exercise are enormously complex. They impact near every aspect of metabolism and cellular biology, and the quest to understand them well enough to manipulate them is more or less the same thing as the quest to understand cellular biology completely. This and the past history of calorie restriction mimetic drug research is why I'm not holding my breath waiting on exercise mimetic drugs. Researchers will talk about this as a goal, just as they have talked about calorie restriction mimetic drugs, but the reality is that the inherent complexity involved makes this is a very long-term project, one that tends to produce marginal outcomes at great expense. Exercise mimetics and calorie restriction mimetics that are safe and reliable would be a pleasant thing to have around, to be sure, but it seems to me that at the present time there are better and more cost-effective approaches to the treatment of aging as a medical condition.

Exercise Pills: At the Starting Line

Excessive caloric intake and limited physical activity contribute to the current explosion of 'modern' chronic diseases such as obesity, type 2 diabetes, muscle atrophy, and cardiovascular diseases. By contrast, regular physical exercise maintains glucose homeostasis and induces physiological adaptations that effectively prevent, and often reverse, these diseases. Recognizing the human and economic burdens these diseases cause, and taking into account the health benefits of exercise, have led many exercise scientists to suggest that physical exercise may be the preferred method in the treatment and prevention of these 'modern' chronic diseases.

Unfortunately, exercise compliance levels are almost universally low, especially for people using home-based exercise programs. A variety of factors including poor physical condition, weakness, sickness, lack of time, and poor motivation contribute to low exercise compliance. The much publicized poor compliance begs the question: is there an alternative approach that both induces the health benefits of physical exercise and overcomes the problem of low compliance rate? Regular physical exercise activates a number of molecular pathways in whole organ systems and reduces the risk of developing numerous chronic diseases. Although nothing can fully substitute for physical exercise, candidate exercise pills that have emerged in recent years may be an attractive alternative.

Exercise in a bottle could become a reality

Researchers exposed a thousand molecular changes that occur in our muscles when we exercise, providing the world's first comprehensive exercise blueprint. "Exercise is the most powerful therapy for many human diseases, including type 2 diabetes, cardiovascular disease and neurological disorders. However, for many people, exercise isn't a viable treatment option. This means it is essential we find ways of developing drugs that mimic the benefits of exercise." The researchers analysed human skeletal muscle biopsies from four untrained, healthy males following 10 minutes of high intensity exercise. Using a technique known as mass spectrometry to study a process called protein phosphorylation, they discovered that short, intensive exercise triggers more than 1000 changes.

"Exercise produces an extremely complex, cascading set of responses within human muscle. It plays an essential role in controlling energy metabolism and insulin sensitivity. While scientists have long suspected that exercise causes a complicated series of changes to human muscle, this is the first time we have been able to map exactly what happens. This is a major breakthrough, as it allows scientists to use this information to design a drug that mimics the true beneficial changes caused by exercise. Most traditional drugs target individual molecules. With this exercise blueprint we have proven that any drug that mimics exercise will need to target multiple molecules and possibly even pathways, which are a combination of molecules working together. We believe this is the key to unlocking the riddle of drug treatments to mimic exercise."

Fundraising Posters: Spread the Word that We're Matching SENS Donations Dollar for Dollar
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Last week we launched the Fight Aging! fundraiser for SENS rejuvenation research programs, work on the biotechnologies needed to repair the cellular and molecular damage that causes aging and all age-related disease. Do we want to see meaningful progress towards the defeat of degenerative aging in our lifetime? Yes, yes we do. We will be matching dollar for dollar all donations to the SENS Research Foundation until either the end of the year or our $125,000 matching fund runs out - whichever happens first. Obviously we'd love to see the community hit this target, as that would mean an extra quarter of a million dollars for the best lines of early stage research into ending frailty and disease in aging. As of today, 94 donors have given $22,542 since the fundraiser launched on the 1st. A good start!

The SENS Research Foundation has a track record of producing results, as I outlined recently. The philanthropy of past years has blossomed into a first round of startups, clinical development, and greater ongoing funding: Gensight is commercializing an approach to mitochondrial repair, Oisin Biotech is working on senescent cell clearance, and Human Rejuvenation Technologies was formed to further develop the use of bacterial enzymes to remove of some of the metabolic waste compounds that contribute to atherosclerosis. The wheel is turning and now is the time for greater efforts, to remove the hurdles and fund the groundwork needed for the next round of biotechnologies for human rejuvenation.

I ran up a pair of new fundraising posters over the weekend, sticking to this year's simple motif of text and color, suitable for signs and more visible from a distance. This year's fundraiser is a stretch goal for our community, based on how we've been doing over the past couple of years. We need to get out there and wave the flag, track down new supporters and expand our corner of the world, the small community interested in actually getting something done about aging.

2015 Fundraiser #1: 4200 x 2800px

2015 Fundraiser #2: 4200 x 2800px

Panel Discussion: How Can Life Extension Become as Popular as the War on Cancer?
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Given the BioViva press release I pointed out earlier today, you may be interested in listening to a Longevity Day roundtable held yesterday, since Elizabeth Parrish of BioViva was participating, as well as Keith Comito of the Life Extension Advocacy Foundation, and a few other names you might recognize. From my perspective it is great to see so much going on that I only find out about after the fact: one of the signs of a healthy and growing community is that people are off doing things and I have no idea, since there is too much to keep track of in any reasonable amount of time.

What can be done to raise public support for the pursuit of indefinite life extension through medicine and biotechnology to the same level as currently exists for disease-specific research efforts aimed at cancers, heart disease, ALS, and similar large-scale nemeses? In this panel discussion, held on October 1, 2015 - International Longevity Day - Mr. Stolyarov asks notable life-extension supporters to provide input on this vital question and related areas relevant to accelerating the pursuit of indefinite longevity. This panel is coordinated in conjunction with MILE, the Movement for Indefinite Life Extension.

Panelists: Adam Alonzi, Sven Bulterjis, Keith Comito, Roen Horn, B. J. Murphy, and Elizabeth Parrish

A set of presentation slides was put together by Butlerjis, and is worth a few minutes of your time. In particular, one of the lessons to take away here is that big budget cancer research didn't just magically happen overnight. Rather it was the culmination of many failed attempts to create such a state of affairs over the course of half a century. Prior to the 1970s cancer research in fact looked quite similar to the situation for aging research today: little interest, little funding, large gaps in the scientific understanding of the fine details of the disease, but the clear potential to make a big difference to patients and therapies with what was known at the time.

Aging Research Needs Marketing: What Can We Learn from Cancer Research?

1910: The American Association for Cancer Research convinces president Taft to ask congress to build a national lab for cancer research: failure.

1927: Senator Matthew Neely asks congress to give 5 million USD for information that could lead to a cure for cancer: he got 50,000 USD.

1937: Neely, Senator Homer Bone and Representative Warren Magnuson : National Cancer Institute Act, success signed by president Roosevelt: NCI founded, but the war in Europe soon ended funds for the NCI.

1946-47: Neely and Senator Claude Pepper: 3rd proposal for nation wide cancer research: rejected.

Solomon Garb said in 1969: "A big obstacle in the fight against cancer is the severe an chronic lack of money, something that is not known to most people. We won't get there by repeating this. It is also necessary to explain how it will be used, what kind of projects will be financed with it, why these projects deserve our support, and where the scientists and technicians that have to execute them will come from."

Why do some diseases have a big impact only in a given era? Theory: the society couples diseases to psychological crises. For Cancer: in the '70s when the focus changed from external (USSR) to internal (cancer). For AIDS: in the '80s when the generation was obsessed with sexuality and freedom. For SARS: in the 21st century alongside the fears of globalization. But what about aging?

To conclude: cancer has a similar history to aging, we also need marketing, business people, and celebrities on our side, and aging has to be recognized as a disease.