This is an excerpt from the conclusion section of, “…NASA’s Managerial and Leadership Methodology, Now Unveiled!..!” by Mr. Andres Agostini, that discusses some management theories and practices. To read the entire piece, just click the link at the end of this illustrated article and presentation:
In addition to being aware and adaptable and resilient before the driving forces reshaping the current present and the as-of-now future, there are some extra management suggestions that I concurrently practice:
1. Given the vast amount of insidious risks, futures, challenges, principles, processes, contents, practices, tools, techniques, benefits and opportunities, there needs to be a full-bodied practical and applicable methodology (methodologies are utilized and implemented to solve complex problems and to facilitate the decision-making and anticipatory process).
The manager must always address issues with a Panoramic View and must also exercise the envisioning of both the Whole and the Granularity of Details, along with the embedded (corresponding) interrelationships and dynamics (that is, [i] interrelationships and dynamics of the subtle, [ii] interrelationships and dynamics of the overt and [iii] interrelationships and dynamics of the covert).
Both dynamic complexity and detail complexity, along with fuzzy logic, must be pervasively considered, as well.
To this end, it is wisely argued, “…You can’t understand the knot without understanding the strands, but in the future, the strands need not remain tied up in the same way as they are today…”
For instance, disparate skills, talents, dexterities and expertise won’t suffice ever. A cohesive and congruent, yet proven methodology (see the one above) must be optimally implemented.
Subsequently, the Chinese proverb indicates, “…Don’t look at the waves but the currents underneath…”
2. One must always be futurewise and technologically fluent. Don’t fight these extreme forces, just use them! One must use counter-intuitiveness (geometrically non-linearly so), insight, hindsight, foresight and far-sight in every day of the present and future (all of this in the most staggeringly exponential mode). To shed some light, I will share two quotes.
The Panchatantra (body of Eastern philosophical knowledge) establishes, “…Knowledge is the true organ of sight, not the eyes.…” And Antonio Machado argues, “… An eye is not an eye because you see it; an eye is an eye because it sees you …”
Managers always need a clear, knowledgeable vision. Did you already connect the dots stemming from the Panchatantra and Machado? Did you already integrate those dots into your big-picture vista?
As side effect, British Prime Minister W. E. Gladstone considered, “…You cannot fight against the future…”
3. In all the Manager does, he / she must observe and apply, at all times, a sine qua non maxim, “…everything is related to everything else…”
4. Always manage as if it were a “project.” Use, at all times, the “…Project Management…” approach.
5. Always use the systems methodology with the applied omniscience perspective.
In this case, David, I mean to assert: The term “Science” equates to about a 90% of “…Exact Sciences…” and to about 10% of “…Social Sciences…” All science must be instituted with the engineering view.
6. Always institute beyond-insurance risk management as you boldly integrate it with your futuring skill / expertise.
7. In my firmest opinion, the following must be complied this way (verbatim): the corporate strategic planning and execution (performing) are a function of a grander application of beyond-insurance risk management. It will never work well the other way around. Transformative and Integrative Risk Management (TAIRM) is the optimal mode to do advanced strategic planning and execution (performing).
TAIRM is not only focused on terminating, mitigating and modulating risks (expenses of treasure and losses of life), but also concentrated on bringing under control fiscally-sound, sustainable organizations and initiatives.
TAIRM underpins sensible business prosperity and sustainable growth and progress.
8. I also believe that we must pragmatically apply the scientific method in all we manage to the best of our capacities.
If we are “…MANAGERS…” in a Knowledge Economy and Knowledge Era (not a knowledge-driven eon because of superficial and hollow caprices of the follies and simpletons), we must do therefore extensive and intensive learning and un-learning for Life if we want to succeed and be sustainable.
As a consequence, Dr. Noel M. Tichy, PhD. argues, “…Today, intellectual assets trump physical assets in nearly every industry…”
Consequently, Alvin Toffler indicates, “…In the world of the future, THE NEW ILLITERATE WILL BE THE PERSON WHO HAS NOT LEARNED TO LEARN…”
We don’t need to be scientists to learn some basic principles of advanced science.
Accordingly, Dr. Carl Sagan, PhD. expressed, “…We live in a society exquisitely dependent on science and technology, in which hardly anyone knows about science and technology…” And Edward Teller stated, “…The science of today is the technology of tomorrow …”
And it is also crucial this quotation by Winston Churchill, “…If we are to bring the broad masses of the people in every land to the table of abundance, IT CAN ONLY BE BY THE TIRELESS IMPROVEMENT OF ALL OF OUR MEANS OF TECHNICAL PRODUCTION…”
I am not a scientist but I tirelessly support responsible scientists and science. I like scientific and technological knowledge and methodologies a great deal.
Chiefly, I am a college autodidact made by his own self and engaged into extreme practical and theoretical world-class learning for Life.
9. In any management undertaking, and given the universal volatility and rampant and uninterrupted rate of change, one must think and operate in a fluid womb-to-tomb mode.
The manager must think and operate holistically (both systematically and systemically) at all times.
The manager must also be: i) Multidimensional, ii) Interdisciplinary, iii) Multifaceted, iv) Cross-functional, and v) Multitasking.
That is, the manager must now be an expert state-of-the-art generalist and erudite. ERGO, THIS IS THE NEWEST SPECIALIST AND SPECIALIZATION.
Managers must never manage elements, components or subsystems separately or disparately (that is, they mustn’t ever manage in series).
Managers must always manage all of the entire system at the time (that is, managing in parallel or simultaneously the totality of the whole at once).
10. In any profession, beginning with management, one must always and cleverly upgrade his / her learning and education until the last exhale.
An African proverb argues, “…Tomorrow belongs to the people who prepare for it…” And Winston Churchill established, “…The empires of the future are the empires of the mind…” And an ancient Chinese Proverb: “…It is not our feet that move us along — it is our minds…” And Malcolm X observed, “…The future belongs to those who prepare for it today…” And Leonard I. Sweet considered, “…The future is not something we enter. The future is something we create…”
And finally, James Thomson argued, “…Great trials seem to be a necessary preparation for great duties …”
Consequently, Dr. Gary Hamel, PhD. indicates, “…What distinguishes our age from every other is not the world-flattening impact of communications, not the economic ascendance of China and India, not the degradation of our climate, and not the resurgence of ancient religious animosities. RATHER, IT IS A FRANTICALLY ACCELERATING PACE OF CHANGE…”
Men who are unemployed for more than two years show signs of faster ageing in their DNA, according to a study published today in the journal PLOS ONE.
Researchers at the University of Oulu, Finland and Imperial College, London arrived at this conclusion by studying blood samples collected from 5,620 men and women born in Northern Finland in 1966. The researchers measured the lengths of telomeres in their white blood cells, and compared them with the participants’ employment history for the prior three years, and found that extended unemployment (more than 500 days in three years) was associated with shorter telomere length.
Telomeres are repetitive DNA sequences at the ends of chromosomes, which protect the chromosomes from degrading. With every cell division, it appears that these telomeres get shorter. And the result of each shortening is that these cells degrade and age.
When cells are grown in a lab, their telomeres do indeed shorten each time the cells divide. This process can be used to find a cell’s “expiry date”, a prediction of when that cell will run out of telomeres and stop dividing. However, this does not seem to relate to the actual health of the cells.
In the new study, the researchers found that that on average, men who had been unemployed for more than two of the preceding three years were more than twice as likely to have short telomeres compared to men who were continuously employed. In women, there was no association between unemployment status and telomere length.
The researchers accounted for telomere length differences resulting from medical conditions, obesity, socio-economic status and early childhood environment.
Previous studies, noted by the study authors, have found a correlation between shorter telomeres and higher rates of age-related diseases like Type 2 diabetes and heart disease. The authors conclude that the reduction in these men’s telomeres may have been the result from the stress of long-term unemployment, adding to evidence of a direct connection between prolonged unemployment and poor health.
An abstract concept
Employment is something very abstract; an employed and unemployed body are apparently more or less the same. So it might seem surprising that such an abstract thing as employment can affect a body on the cellular level. But the same is true for how stimuli affect our brains: remote objects trigger electrochemical cascades in our visual system – and when we learn new things, gene expression in the brain changes. We are interactive creatures, with innumerable stimuli that are constantly shaping multiple processes in our bodies. In this sense, the hypothesis that employment experience has cellular effects is not surprising.
This was an association study, which means than under certain set of circumstances two variables are statistically linked. This study is therefore incapable of genuinely predicting whether unemployment is the cause, and short telomeres the effect. Perhaps the opposite is true: maybe people whose cells lose their telomeres also lose their jobs. More likely, an outside factor that shortens telomeres could have a limiting effect on success in the labour market. For example, such a factor might somehow contribute towards illness or pessimism.
Additionally, because the study was conducted in an isolated and genetically quite homogeneous population, the results of the study may be due to their genetic make-up as well as (or instead of) environmental effects.
In the end, we do not need a genetic study to know long-term unemployment is bad for people socially, medically and psychologically; there is plenty of evidence for that. Additionally, the bio-gerontology community (those who study the biological processes of ageing) recognises telomere attrition as one of the nine causes of the disease of ageing, including Type 2 diabetes and cardiovascular diseases.
Where this study does make a significant contribution is in recognising long-term, low-level stress as a major problem. In momentarily stressful situations, the instant fight-or-flight response stimulates us; but being under pressure for a long time with no relief wears us down. Prolonged stress is bad for memory and health, and could quite conceivably shorten telomeres – making an unemployed person significantly more unhealthy, with the effects persisting even after they get a job.
In the long run, what we really need to learn to slow or stop the ageing process is how to reduce or repair the damage done by stress.
The authors do not work for, consult to, own shares in or receive funding from any company or organisation that would benefit from this article. They also have no relevant affiliations.
Containing more than 160 essays from over 40 contributors, this edited volume of essays on the science, philosophy and politics of longevity considers the project of ending aging and abolishing involuntary death-by-disease from a variety of viewpoints: scientific, technological, philosophical, pragmatic, artistic. In it you will find not only information on the ways in which science and medicine are bringing about the potential to reverse aging and defeat death within many of our own lifetimes, as well as the ways that you can increase your own longevity today in order to be there for tomorrow’s promise, but also a glimpse at the art, philosophy and politics of longevity as well – areas that will become increasingly important as we realize that advocacy, lobbying and activism can play as large a part in the hastening of progress in indefinite lifespans as science and technology can.
The collection is edited by Franco Cortese. Its contributing authors include William H. Andrews, Ph.D., Rachel Armstrong, Ph.D., Jonathan Betchtel, Yaniv Chen, Clyde DeSouza, Freija van Diujne, Ph.D., John Ellis, Ph.D., Linda Gamble, Roen Horn, the International Longevity Alliance (ILA), Zoltan Istvan, David Kekich (President & C.E.O of Maximum Life Foundation), Randal A. Koene, Ph.D., Maria Konovalenko, M.Sc. (Program Coordinator for the Science for Life Extension Foundation), Marios Kyriazis, MD, M.Sc MIBiol, CBiol (Founder of the ELPIs Foundation for Indefinite Lifespans and the medical advisor for the British Longevity Society), John R. Leonard (Director of Japan Longevity Alliance), Alex Lightman, Movement for Indefinite Life Extension (MILE), Josh Mitteldorf, Ph.D., Tom Mooney (Executive Director of the Coalition to Extend Life), Max More, Ph.D. , B.J. Murphy, Joern Pallensen, Dick Pelletier, Hank Pellissier (Founder of Brighter Brains Institute), Giulio Prisco, Marc Ransford, Jameson Rohrer, Martine Rothblatt, Ph.D., MBA, JD., Peter Rothman (editor-in-chief of H+ Magazine), Giovanni Santostasi, Ph.D (Director of Immortal Life Magazine, Eric Schulke, Jason Silva , R.U. Sirius, Ilia Stambler, Ph.D (activist at the International Longevity Alliance), G. Stolyarov II (editor-in-chief of The Rational Argumentator), Winslow Strong, Jason Sussberg, Violetta Karkucinska, David Westmorland, Peter Wicks, Ph.D, and Jason Xu (director of Longevity Party China and Longevity Party Taiwan).
Through my writings I have tried to communicate ideas related to how unique our intelligence is and how it is continuing to evolve. Intelligence is the most bizarre of biological adaptations. It appears to be an adaptation of infinite reach. Whereas organisms can only be so fast and efficient when it comes to running, swimming, flying, or any other evolved skill; it appears as though the same finite limits are not applicable to intelligence.
What does this mean for our lives in the 21st century?
First, we must be prepared to accept that the 21st century will not be anything like the 20th. All too often I encounter people who extrapolate expected change for the 21st century that mirrors the pace of change humanity experienced in the 20th. This will simply not be the case. Just as cosmologists are well aware of the bizarre increased acceleration of the expansion of the universe; so evolutionary theorists are well aware of the increased pace of techno-cultural change. This acceleration shows no signs of slowing down; and few models that incorporate technological evolution predict that it will.
The result of this increased pace of change will likely not just be quantitative. The change will be qualitative as well. This means that communication and transportation capabilities will not just become faster. They will become meaningfully different in a way that would be difficult for contemporary humans to understand. And it is in the strange world of qualitative evolutionary change that I will focus on two major processes currently predicted to occur by most futurists.
Qualitative evolutionary change produces interesting differences in experience. Often times this change is referred to as a “metasystem transition”. A metasystem transition occurs when a group of subsystems coordinate their goals and intents in order to solve more problems than the constituent systems. There have been a few notable metasystem transitions in the history of biological evolution:
Transition from single-celled life to multi-celled life
Transition from decentralized nervous system to centralized brains
Transition from communication to complex language and self-awareness
All these transitions share the characteristics described of subsystems coordinating to form a larger system that solve more problems than they could do individually. All transitions increased the rate of change in the universe (i.e., reduction of entropy production). The qualitative nature of the change is important to understand, and may best be explored through a thought experiment.
Imagine you are a single-celled organism on the early Earth. You exist within a planetary network of single-celled life of considerable variety, all adapted to different primordial chemical niches. This has been the nature of the planet for well over 2 billion years. Then, some single-cells start to accumulate in denser and denser agglomerations. One of the cells comes up to you and says:
I think we are merging together. I think the remainder of our days will be spent in some larger system that we can’t really conceive. We will each become adapted for a different specific purpose to aid the new higher collective.
Surely that cell would be seen as deranged. Yet, as the agglomerations of single-cells became denser, formerly autonomous individual cells start to rely more and more on each other to exploit previously unattainable resources. As the process accelerates this integrated network forms something novel, and more complex than had previously ever existed: the first multicellular organisms.
The difference between living as an autonomous single-cell is not just quantitative (i.e., being able to exploit more resources) but also qualitative (i.e., shift from complete autonomy to being one small part of an integrated whole). Such a shift is difficult to conceive of before it actually becomes a new normative layer of complexity within the universe.
Another example of such a transition that may require less imagination is the transition to complex language and self-awareness. Language is certainly the most important phenomena that separates our species from the rest of the biosphere. It allows us to engage in a new evolution, technocultural evolution, which is essentially a new normative layer of complexity in the universe as well. For this transition, the qualitative leap is also important to understand. If you were an australopithecine, your mode of communication would not necessarily be that much more efficient than that of any modern day great ape. Like all other organisms, your mind would be essentially isolated. Your deepest thoughts, feelings, and emotions could not fully be expressed and understood by other minds within your species. Furthermore, an entire range of thought would be completely unimaginable to you. Anything abstract would not be communicable. You could communicate that you were hungry; but you could not communicate about what you thought of particular foods (for example). Language changed all that; it unleashed a new thought frontier. Not only was it now possible to exchange ideas at a faster rate, but the range of ideas that could be thought of, also increased.
And so after that digression we come to the main point: the metasystem transition of the 21st century. What will it be? There are two dominant, non-mutually exclusive, frameworks for imagining this transition: technological singularity and the global brain.
The technological singularity is essentially a point in time when the actual agent of techno-cultural change; itself changes. At the moment the modern human mind is the agent of change. But artificial intelligence is likely to emerge this century. And building a truly artificial intelligence may be the last machine we (i.e., biological humans) invent.
The second framework is the global brain. The global brain is the idea that a collective planetary intelligence is emerging from the Internet, created by increasingly dense information pathways. This would essentially give the Earth an actual sensing centralized nervous system, and its evolution would mirror, in a sense, the evolution of the brain in organisms, and the development of higher-level consciousness in modern humans.
In a sense, both processes could be seen as the phenomena that will continue to enable trends identified by global brain theorist Francis Heylighen:
The flows of matter, energy, and information that circulate across the globe become ever larger, faster and broader in reach, thanks to increasingly powerful technologies for transport and communication, which open up ever-larger markets and forums for the exchange of goods and services.
Some view the technological singularity and global brain as competing futurist hypotheses. However, I see them as deeply symbiotic phenomena. If the metaphor of a global brain is apt, at the moment the internet forms a type of primitive and passive intelligence. However, as the internet starts to form an ever greater role in human life, and as all human minds gravitate towards communicating and interacting in this medium, the internet should start to become an intelligent mediator of human interaction. Heylighen explains how this should be achieved:
the intelligent web draws on the experience and knowledge of its users collectively, as externalized in the “trace” of preferences that they leave on the paths they have traveled.
This is essentially how the brain organizes itself, by recognizing the shapes, emotions, and movements of individual neurons, and then connecting them to communicate a “global picture”, or an individual consciousness.
The technological singularity naturally fits within this evolution. The biological human brain can only connect so deeply with the Internet. We must externalize our experience with the Internet in (increasingly small) devices like laptops, smart phones, etc. However, artificial intelligence and biological intelligence enhanced with nanotechnology could form quite a deeper connection with the Internet. Such a development could, in theory, create an all-encompassing information processing system. Our minds (largely “artificial”) would form the neurons of the system, but a decentralized order would emerge from these dynamic interactions. This would be quite analogous to the way higher-level complexity has emerged in the past.
So what does this mean for you? Well many futurists debate the likely timing of this transition, but there is currently a median convergence prediction of between 2040–2050. As we approach this era we should suspect many fundamental things about our current institutions to change profoundly. There will also be several new ethical issues that arise, including issues of individual privacy, and government and corporate control. All issues that deserve a separate post.
Fundamentally this also means that your consciousness and your nature will change considerably throughout this century. The thought my sound bizarre and even frightening, but only if you believe that human intelligence and nature are static and unchanging. The reality is that human intelligence and nature are an ever evolving process. The only difference in this transition is that you will actually be conscious of the evolution itself.
Consciousness has never experienced a metasystem transition (since the last metasystem transition was towards higher-level consciousness!). So in a sense, a post-human world can still include your consciousness. It will just be a new and different consciousness. I think it is best to think about it as the emergence of something new and more complex, as opposed to the death or end of something. For the first time, evolution will have woken up.
Aging destroys fitness. How could aging have evolved? Below is my answer to this question. This is mainstream science from peer-reviewed journals [Ref 1, Ref 2, Ref 3] , but it is my science, and as Richard Feynman warned us*, I’m the last one who can be objective about the merits of this theory. — Josh Mitteldorf
Too fit for its own good
In 1874, a swarm of Rocky Mountain Locusts descended on the American midwest. They covered the sky and shadowed the earth underneath for hundreds of miles. A single cloud was larger than the state of California. Once on the ground, they ate everything that was green, leaving behind a dust bowl. The earth was thick with egg masses, ready to renew the plague the following year.
Laura Ingalls Wilder wrote in her childhood memoir (in the third person)
Huge brown grasshoppers were hitting the ground all around her, hitting her head and her face and her arms. They came thudding down like hail. The cloud was hailing grasshoppers. The cloud was grasshoppers. Their bodies hid the sun and made darkness. Their thin, large wings gleamed and glittered. The rasping, whirring of their wings filled the whole air and they hit the ground and the house with the noise of a hailstorm. Laura tried to beat them off. Their claws clung to her skin and her dress. They looked at her with bulging eyes, turning their heads this way and that. Mary ran screaming into the house. Grasshoppers covered the ground, there was not one bare bit to step on. Laura had to step on grasshoppers and they smashed squirming and slimy under her feet.
The locusts returned in several more seasons, but the last reported sighting of a Rocky Mountain locust was in 1902. There are preserved specimens in museums and laboratories today, but no living locusts. Entomologists interested in the locust’s rise and fall travel to the glaciers of Wyoming, mining hundred-year-old ice for carcasses that they might study.
Where did they go? The Rocky Mountain Locust drove itself to extinction by overshooting its sustainable population.
Every animal species is part of a food web, and depends on an ecosystem to survive. If the ecosystem collapse, it takes down every species and every individual with it. Because of their mobility, the locusts were able to devastate many ecosystems, denuding one landscape, then flying hundreds of miles to deposit their children in a fresh location. Animals that can’t fly become victims of their own greed much more quickly than the locust. If the lions killed every gazelle on the Serengeti, how long would it be before the lions were gone, too?
Evolution of Individuals and Groups
How would an evolutionary biologist describe this situation? Were the locusts too fit for their own good? To capture this story, you have to distinguish between individual fitness and collective fitness. Individually, these locusts were super-competitors. Collectively, they were a circular firing squad. The science of individual fitness and collective fitness is called Multi-level Selection Theory, and it has been spearheaded by David S Wilson of Binghamton University, based on theoretical foundations by George Price. MLS is regarded with suspicion by most evolutionary biologists, but embraced by a minority as sound science.
Selfish organisms that consume as much of the available food species as possible may thrive for a time. They may crowd out other individuals of the same species that compete less aggressively. But as soon as their kind grows to be the majority, they are doomed – they wipe out the food source on which their children depend.
Animals are evolved to be “prudent predators”†. Species that have exploited their food sources too aggressively, or that have reproduced too fast have become extinct in a series of local population crashes. These extinctions have been a potent force of natural selection, counterbalancing the better-known selective pressure toward ever faster and more prolific reproduction.
How did Evolutionary Theory go Wrong?
This is an idea that has common-sense appeal to anyone who thinks logically and practically about evolutionary science. In order not to to appreciate this idea, you need years of training in the mathematical science of evolutionary genetics. Evolutionary genetics is an axiomatic framework, built up logically from postulates that sound reasonable, but the conclusions to which they lead are deeply at odds with the biological world we see. This is the “selfish gene” theory that says all cooperation in nature is a sort of illusion, based on a gene’s tendency to encourage behaviors that promote the welfare of other copies of the same gene in closely-related individuals.
The “selfish gene” is an idea that should have been rejected long ago, as absurd on its face. Yes, there is plenty of selfishness and aggression in nature. But nature is also rich with examples of cooperation between unrelated individuals, and even cooperation across species lines, which is called “co-evolution”. Species become intimately adapted to depend on tiny details of the other’s shape or habits or chemistry. Examples of this are everywhere, from the bacteria in your gut to the flowers and the honeybees. In the same way, predators and their prey (I’m using this word to include plant as well as animal food sources) adapt to be able to co-exist for the long haul. It is obvious to every naturalist that there is a temperance in nature’s communities, that when ecosystems are out of balance they don’t last very long.
It makes good scientific sense that extinctions from overpopulation are a powerful evolutionary force, and it is part of Darwin’s legacy as well. Natural selection is more than merely a race among individuals to reproduce the fastest. The very word “fitness” came from an ability to fit well into the life of the local community.
But beginning some forty years after Darwin’s death, mathematical thinking has led the evolutionary theorists astray. They have forgotten the first principle of science, which is that every theory must be validated by comparing predictions from the theory to the world we see around us. Predictions of the selfish gene theory work well in the genetics lab, but as a description of nature, they fail spectacularly.
Understanding Aging based on Multi-level Selection
If we are willing to look past the “selfish gene” and embrace the science of multi-level selection, we can understand aging as a tribute paid by the individual in support of the ecosystem. If it weren’t for aging, the only way that individuals would die would be by starvation, by diseases, and by predation. All three of these tend to be “clumpy” – that is to say that either no one is dying or everyone is dying at once. Until food species are exhausted, there is no starvation; but then there is a famine, and everyone dies at once. If a disease strikes a community in which everyone is at the peak of their immunological fitness, then either everyone can fend it off, or else everyone dies in an epidemic. And without aging, even death by predation would be very clumpy. Many large predators are just fast enough to catch the aging, crippled prey individuals. If this were not so, then either all the prey would be vulnerable to predators, or none of them would be. There could be no lasting balance between predators and prey.
Aging helps to level the death rate in good times and bad. Without aging, horde dynamics would prevail, as deaths would occur primarily in famines and epidemics. Population would swing wildly up and down. With aging comes the possibility of predictable life spans and death rates that don’t alternately soar and plummet. Ecosystems can have some stability and some persistence.
Aging is plastic, providing further support for ecosystem stability
This would be true even if aging operated on a fixed schedule; but natural selection has created an adaptive aging clock, which further enhances the stabilizing effect. When there is a famine and many animals are dying of starvation, the death rate from old age is down, because of the Caloric Restriction effect. In times of famine and other environmental stress, the death rate from aging actually takes a vacation, because animals become hardier and age more slowly.
When we ask “Why does an animal live longer when it is starving?” the answer is, of course, that the ability to last out a famine and re-seed the population when food once again becomes plentiful provides a great selective advantage. This may sound like it is an adaptation for individual survival, consistent with the selfish gene. But we might ask the same question conversely: “Why does an animal have a shorter life span when there is plenty to eat?” When we look at it this way, it is clear that tying aging to food cannot be explained in terms of the selfish gene. In order to be able to live longer under conditions of starvation, animals must be genetically programmed to hold some fitness in reserve when they have plenty to eat, and this offers an advantage only to the community, not to the individual.
Hormesis is an important clue concerning the evolutionary meaning of aging. This word refers to the fact that when an individual is in a challenging environment, its metabolism doesn’t just compensate to mitigate the damage, but it overcompensates. It becomes so much stronger that it lives longer with challenge than without. The best-known example is that people (and animals) live longer when they’re underfed than when they’re overfed. We also know that exercise tends to increase our life expectancy, despite the fact that exercise generates copious free radicals (ROS) that ought to be pro-aging in their effect.
Without aging, it is difficult for nature to put together a stable ecosystem. Populations are either rising exponentially or collapsing to zero. With aging, it becomes possible to balance birth and death rates, and population growth and subsequent crashes are tamed sufficiently that ecosystems may persist. This is the evolutionary meaning of aging: Aging is a group-selected adaptation for the purpose of damping the wild swings in death rate to which natural populations are prone. Aging helps to make possible stable ecosystems.
___________
“ The first principle is that you must not fool yourself, and you are the easiest person to fool.” — R P Feynman (from the Galileo Symposium, 1964)
† Here “predator” can mean herbivore as well as carnivore. This is the common usage in ecology.
Immortal Life has complied an edited volume of essays, arguments, and debates about Immortalism titled Human Destiny is to Eliminate Death from many esteemed ImmortalLife.info Authors (a good number of whom are also Lifeboat Foundation Advisory Board members as well), such as Martine Rothblatt (Ph.D, MBA, J.D.), Marios Kyriazis (MD, MS.c, MI.Biol, C.Biol.), Maria Konovalenko (M.Sc.), Mike Perry (Ph.D), Dick Pelletier, Khannea Suntzu, David Kekich (Founder & CEO of MaxLife Foundation), Hank Pellissier (Founder of Immortal Life), Eric Schulke & Franco Cortese (the previous Managing Directors of Immortal Life), Gennady Stolyarov II, Jason Xu (Director of Longevity Party China and Longevity Party Taiwan), Teresa Belcher, Joern Pallensen and more. The anthology was edited by Immortal Life Founder & Senior Editor, Hank Pellissier.
This one-of-a-kind collection features ten debates that originated at ImmortalLife.info, plus 36 articles, essays and diatribes by many of IL’s contributors, on topics from nutrition to mind-filing, from teleomeres to “Deathism”, from libertarian life-extending suggestions to religion’s role in RLE to immortalism as a human rights issue.
The book is illustrated with famous paintings on the subject of aging and death, by artists such as Goya, Picasso, Cezanne, Dali, and numerous others.
The book was designed by Wendy Stolyarov; edited by Hank Pellissier; published by the Center for Transhumanity. This edited volume is the first in a series of quarterly anthologies planned by Immortal Life
This Immortal Life Anthology includes essays, articles, rants and debates by and between some of the leading voices in Immortalism, Radical Life-Extension, Superlongevity and Anti-Aging Medicine.
A (Partial) List of the Debaters & Essay Contributors:
Martine Rothblatt Ph.D, MBA, J.D. — inventor of satellite radio, founder of Sirius XM and founder of the Terasem Movement, which promotes technological immortality. Dr. Rothblatt is the author of books on gender freedom (Apartheid of Sex, 1995), genomics (Unzipped Genes, 1997) and xenotransplantation (Your Life or Mine, 2003).
Marios Kyriazis MD, MSc, MIBiol, CBiol. founded the British Longevity Society, was the first to address the free-radical theory of aging in a formal mainstream UK medical journal, has authored dozens of books on life-extension and has discussed indefinite longevity in 700 articles, lectures and media appearances globally.
Maria Konovalenko is a molecular biophysicist and the program coordinator for the Science for Life Extension Foundation. She earned her M.Sc. degree in Molecular Biological Physics at the Moscow Institute of Physics and Technology. She is a co-founder of the International Longevity Alliance.
Jason Xu is the director of Longevity Party China and Longevity Party Taiwan, and he was an intern at SENS.
Mike Perry, PhD. has worked for Alcor since 1989 as Care Services Manager. He has authored or contributed to the automated cooldown and perfusion modeling programs. He is a regular contributor to Alcor newsletters. He has been a member of Alcor since 1984.
David A. Kekich, Founder, President & C.E.O Maximum Life Extension Foundation, works to raise funds for life-extension research. He serves as a Board Member of the American Aging Association, Life Extension Buyers’ Club and Alcor Life Extension Foundation Patient Care Trust Fund. He authored Smart, Strong and Sexy at 100?, a how-to book for extreme life extension.
Eric Schulke is the founder of the Movement for Indefinite Life Extension (MILE). He was a Director, Teams Coordinator and ran Marketing & Outreach at the Immortality Institute, now known as Longecity, for 4 years. He is the Co-Managing Director of Immortal Life.
Hank Pellissier is the Founder & Senior Editor of ImmortaLife.info. Previously, he was the founder/director of Transhumanity.net. Before that, he was Managing Director of the Institute for Ethics and Emerging Technology (ieet.org). He’s written over 120 futurist articles for IEET, Hplusmagazine.com, Transhumanity.net, ImmortalLife.info and the World Future Society.
Franco Cortese is on the Advisory Board for Lifeboat Foundation on their Scientific Advisory Board (Life-Extension Sub-Board) and their Futurism Board. He is the Co-Managing Director alongside of Immortal Life and a Staff Editor for Transhumanity. He has written over 40 futurist articles and essays for H+ Magazine, The Institute for Ethics & Emerging Technologies, Immortal Life, Transhumanity and The Rational Argumentator.
Gennady Stolyarov II is a Staff Editor for Transhumanity, Contributor to Enter Stage Right, Le Quebecois Libre, Rebirth of Reason, Ludwig von Mises Institute, Senior Writer for The Liberal Institute, and Editor-in-Chief of The Rational Argumentator.
Brandon King is Co-Director of the United States Longevity Party.
Khannea Suntzu is a transhumanist and virtual activist, and has been covered in articles in Le Monde, CGW and Forbes.
Teresa Belcher is an author, blogger, Buddhist, consultant for anti-aging, life extension, healthy life style and happiness, and owner of Anti-Aging Insights.
Dick Pelletier is a weekly columnist who writes about future science and technologies for numerous publications.
Joern Pallensen has written articles for Transhumanity and the Institute for Ethics and Emerging Technologies.
CONTENTS:
Editor’s Introduction
DEBATES
1. In The Future, With Immortality, Will There Still Be Children?
2. Will Religions promising “Heaven” just Vanish, when Immortality on Earth is attained?
3. In the Future when Humans are Immortal — what will happen to Marriage?
4. Will Immortality Change Prison Sentences? Will Execution and Life-Behind-Bars be… Too Sadistic?
5. Will Government Funding End Death, or will it be Attained by Private Investment?
6. Will “Meatbag” Bodies ever be Immortal? Is “Cyborgization” the only Logical Path?
7. When Immortality is Attained, will People be More — or Less — Interested in Sex?
8. Should Foes of Immortality be Ridiculed as “Deathists” and “Suicidalists”?
9. What’s the Best Strategy to Achieve Indefinite Life Extension?
ESSAYS
1. Maria Konovalenko:
I am an “Aging Fighter” Because Life is the Main Human Right, Demand, and Desire
2. Mike Perry:
Deconstructing Deathism — Answering Objections to Immortality
3. David A. Kekich:
How Old Are You Now?
4. David A. Kekich:
Live Long… and the World Prospers
5. David A. Kekich:
107,000,000,000 — what does this number signify?
6. Franco Cortese:
Religion vs. Radical Longevity: Belief in Heaven is the Biggest Barrier to Eternal Life?!
7. Dick Pelletier:
Stem Cells and Bioprinters Take Aim at Heart Disease, Cancer, Aging
8. Dick Pelletier:
Nanotech to Eliminate Disease, Old Age; Even Poverty
9. Dick Pelletier:
Indefinite Lifespan Possible in 20 Years, Expert Predicts
10. Dick Pelletier:
End of Aging: Life in a World where People no longer Grow Old and Die
11. Eric Schulke:
We Owe Pursuit of Indefinite Life Extension to Our Ancestors
12. Eric Schulke:
Radical Life Extension and the Spirit at the core of a Human Rights Movement
13. Eric Schulke:
MILE: Guide to the Movement for Indefinite Life Extension
14. Gennady Stolyarov II:
The Real War and Why Inter-Human Wars Are a Distraction
15. Gennady Stolyarov II:
The Breakthrough Prize in Life Sciences — turning the tide for life extension
16. Gennady Stolyarov II:
Six Libertarian Reforms to Accelerate Life Extension
17. Hank Pellissier:
Wake Up, Deathists! — You DO Want to LIVE for 10,000 Years!
18. Hank Pellissier:
Top 12 Towns for a Healthy Long Life
19. Hank Pellissier:
This list of 30 Billionaires — Which One Will End Aging and Death?
20. Hank Pellissier:
People Who Don’t Want to Live Forever are Just “Suicidal”
LongeCity has been doing advocacy and research for indefinite life extension since 2002. With the Methuselah Foundation and the M-Prize’s rise in prominence and public popularity over the past few years, it is sometimes easy to forget the smaller-scale research initiatives implemented by other organizations.
LongeCity seeks to conquer the involuntary blight of death through advocacy and research. They award small grants to promising small-scale research initiatives focused on longevity. The time to be doing this is now, with the increasing popularity and public awareness of Citizen Science growing. The 2020 H+ Conference’s theme was The Rise of the Citizen Scientist. Open –Source and Bottom-Up organization have been hallmarks of the H+ and TechProg communities for a while now, and the rise of citizen science parallels this trend.
Anyone can have a great idea, and there are many low-hanging fruits that can provide immense value and reward to the field of life extension without necessitating large-scale research initiatives, expensive and highly-trained staff or costly laboratory equipment. These low-hanging fruit can provide just as much benefit as large scale ones – and, indeed, even have the potential to provide more benefit per unit of funding than large-scale ones. They don’t call them low-hanging fruit for nothing – they are, after all, potentially quite fruitful.
In the past LongeCity has raised funding by matching donations made by the community to fund a research project that used lasers to ablate (i.e. remove) cellular lipofuscin. LongeCity raised $8,000 dollars by the community which was then matched by up to $16,000 by SENS Founation. A video describing the process can be found here. In the end they raised over $18,000 towards this research! Recall that one of Aubrey’s strategies of SENS is to remove cellular lipofuscin via genetically engineered bacteria. Another small-scale research project funded by LongeCity involved mitochondrial uncoupling in nematodes. To see more about this research success, see here.
LongeCity’s 3rd success was their project on Microglia Stem Cells in 2010. The full proposal can be found here, and more information on this second successful LongeCity research initiative can be found here.
These are real projects with real benefits that LongeCity is funding. Even if you’re not a research scientist, you can have an impact on the righteous plight to end the involuntary blight of death, by applying for a small-scale research grant from LongeCity. What have you got to lose? Really? Because it seems to me that you have just about everything to gain.
LongeCity has also contributed toward larger scale research and development initiatives in the past as well. They have sponsored projects by Alcor, SENS Foundation and Methuselah Foundation. They crowdsourced a longevity-targeted multivitamin supplement called VIMMORTAL based on bottom-up-style community suggestion and deliberation (one of the main benefits of crowdsourcing).
So? Are you interested in impacting the movement toward indefinite life extension? Then please take a look at the various types of projects listed below that LongeCity might be interested in funding.
— — — — — — — — —
The following types of projects can be supported:
• Science support: contribution to a scientific experiment that can be carried out in a short period of time with limited resources. The experiment should be distinguishable from the research that is already funded by other sources. This could be a side-experiment in an existing programme, a pilot experiment to establish feasibility, or resources for an undergrad or high-school student.
• Chapters support: organizing a local meeting with other LongeCity members or potential members. LongeCity could contribute to the room hire, the expenses of inviting a guest speaker or even the bar tab.
• Travel support: attendance at conferences, science fairs etc. where you are presenting on a topic relevant to LongeCity. Generally this will involve some promotion of the mission and/or a report on the then conference to be shared with our Members
• Grant writing:
Bring together a team of scientists and help them write a successful grant application to a public or private funding body. Depending on the project, the award will be a success premium or sometimes can cover the costs of grant preparation itself.
• Micro matching fundraiser:
If you manage to raise funds on a mission-relevant topic, LongeCity will match the funds raised. (In order to initiate one of these initiatives LongeCity usually also requires that the fundraiser spends at least 500 ‘ThankYou points’ but this requirement can be waived in specific circumstances.)
• Outreach:
Support for a specific initiative raising public awareness of the mission or of a topic relevant to our mission. This could be a local event, a specific, organized direct marketing initiative or a media feature.
• Articles:
Write a featured article for the LongeCity website on a topic of interest to our members or visitors. LongeCity is mainly looking for articles on scientific topics, but well-researched contributions on a relevant topic in policy, law, or philosophy are also welcome.
Grant Size:
‘micro grants’ — up to $180
‘small grants’ — up to $500
Grant applications exceeding $500 can be received, but will not be evaluated conclusively under the small grants scheme. Instead, LongeCity will review the application as draft and may invite a full application afterward.
Decisions as part of the small grants programme are usually pretty quick and straightforward. However please contact LongeCity with a proposal ahead of time, as they will not normally consider applications where the money has already been spent!
Proposals can be as short or elaborate as necessary, but normally should be about half a page long.
Only LongeCity Members can apply, but any Member is free to apply on behalf of someone else — thus, non-Members are welcome to find a Member to ‘sponsor’ their application.
You can also use the ideas forum to prepare the proposal. For general questions, or to discuss the proposal informally, feel free to contact LongeCity at the above email.
In this essay I argue that technologies and techniques used and developed in the fields of Synthetic Ion Channels and Ion Channel Reconstitution, which have emerged from the fields of supramolecular chemistry and bio-organic chemistry throughout the past 4 decades, can be applied towards the purpose of gradual cellular (and particularly neuronal) replacement to create a new interdisciplinary field that applies such techniques and technologies towards the goal of the indefinite functional restoration of cellular mechanisms and systems, as opposed to their current proposed use of aiding in the elucidation of cellular mechanisms and their underlying principles, and as biosensors.
In earlier essays (see here and here) I identified approaches to the synthesis of non-biological functional equivalents of neuronal components (i.e. ion-channels ion-pumps and membrane sections) and their sectional integration with the existing biological neuron — a sort of “physical” emulation if you will. It has only recently come to my attention that there is an existing field emerging from supramolecular and bio-organic chemistry centered around the design, synthesis, and incorporation/integration of both synthetic/artificial ion channels and artificial bilipid membranes (i.e. lipid bilayer). The potential uses for such channels commonly listed in the literature have nothing to do with life-extension however, and the field is to my knowledge yet to envision the use of replacing our existing neuronal components as they degrade (or before they are able to), rather seeing such uses as aiding in the elucidation of cellular operations and mechanisms and as biosensors. I argue here that the very technologies and techniques that constitute the field (Synthetic Ion-Channels & Ion-Channel/Membrane Reconstitution) can be used towards the purpose of the indefinite-longevity and life-extension through the iterative replacement of cellular constituents (particularly the components comprising our neurons – ion-channels, ion-pumps, sections of bi-lipid membrane, etc.) so as to negate the molecular degradation they would have otherwise eventually undergone.
While I envisioned an electro-mechanical-systems approach in my earlier essays, the field of Synthetic Ion-Channels from the start in the early 70’s applied a molecular approach to the problem of designing molecular systems that produce certain functions according to their chemical composition or structure. Note that this approach corresponds to (or can be categorized under) the passive-physicalist sub-approach of the physicalist-functionalist approach (the broad approach overlying all varieties of physically-embodied, “prosthetic” neuronal functional replication) identified in an earlier essay.
The field of synthetic ion channels is also referred to as ion-channel reconstitution, which designates “the solubilization of the membrane, the isolation of the channel protein from the other membrane constituents and the reintroduction of that protein into some form of artificial membrane system that facilitates the measurement of channel function,” and more broadly denotes “the [general] study of ion channel function and can be used to describe the incorporation of intact membrane vesicles, including the protein of interest, into artificial membrane systems that allow the properties of the channel to be investigated” [1]. The field has been active since the 1970s, with experimental successes in the incorporation of functioning synthetic ion channels into biological bilipid membranes and artificial membranes dissimilar in molecular composition and structure to biological analogues underlying supramolecular interactions, ion selectivity and permeability throughout the 1980’s, 1990’s and 2000’s. The relevant literature suggests that their proposed use has thus far been limited to the elucidation of ion-channel function and operation, the investigation of their functional and biophysical properties, and in lesser degree for the purpose of “in-vitro sensing devices to detect the presence of physiologically-active substances including antiseptics, antibiotics, neurotransmitters, and others” through the “… transduction of bioelectrical and biochemical events into measurable electrical signals” [2].
Thus my proposal of gradually integrating artificial ion-channels and/or artificial membrane sections for the purpse of indefinite longevity (that is, their use in replacing existing biological neurons towards the aim of gradual substrate replacement, or indeed even in the alternative use of constructing artificial neurons to, rather than replace existing biological neurons, become integrated with existing biological neural networks towards the aim of intelligence amplification and augmentation while assuming functional and experiential continuity with our existing biological nervous system) appears to be novel, while the notion of artificial ion-channels and neuronal membrane systems ion general had already been conceived (and successfully created/experimentally-verified, though presumably not integrated in-vivo).
The field of Functionally-Restorative Medicine (and the orphan sub-field of whole-brain-gradual-substrate-replacement, or “physically-embodied” brain-emulation if you like) can take advantage of the decades of experimental progress in this field, incorporating both the technological and methodological infrastructures used in and underlying the field of Ion-Channel Reconstitution and Synthetic/Artificial Ion Channels & Membrane-Systems (and the technologies and methodologies underlying their corresponding experimental-verification and incorporation techniques) for the purpose of indefinite functional restoration via the gradual and iterative replacement of neuronal components (including sections of bilipid membrane, ion channels and ion pumps) by MEMS (micro-electrocal-mechanical-systems) or more likely NEMS (nano-electro-mechanical systems).
The technological and methodological infrastructure underlying this field can be utilized for both the creation of artificial neurons and for the artificial synthesis of normative biological neurons. Much work in the field required artificially synthesizing cellular components (e.g. bilipid membranes) with structural and functional properties as similar to normative biological cells as possible, so that the alternative designs (i.e. dissimilar to the normal structural and functional modalities of biological cells or cellular components) and how they affect and elucidate cellular properties, could be effectively tested. The iterative replacement of either single neurons, or the sectional replacement of neurons with synthesized cellular components (including sections of the bi-lipid membrane, voltage-dependent ion-channels, ligand-dependent ion channels, ion pumps, etc.) is made possible by the large body of work already done in the field. Consequently the technological, methodological and experimental infrastructures developed for the fields of Synthetic
Ion-Channels and Ion-Channel/Artificial-Membrane-Reconstitution can be utilized for the purpose of a.) iterative replacement and cellular upkeep via biological analogues (or not differing significantly in structure or functional & operational modality to their normal biological counterparts) and/or b.) iterative replacement with non-biological analogues of alternate structural and/or functional modalities.
Rather than sensing when a given component degrades and then replacing it with an artificially-synthesized biological or non-biological analogue, it appears to be much more efficient to determine the projected time it takes for a given component to degrade or otherwise lose functionality, and simply automate the iterative replacement in this fashion, without providing in-vivo systems for detecting molecular or structural degradation. This would allow us to achieve both experimental and pragmatic success in such cellular-prosthesis sooner, because it doesn’t rely on the complex technological and methodological infrastructure underlying in-vivo sensing, especially on the scale of single neuron components like ion-channels, and without causing operational or functional distortion to the components being sensed.
A survey of progress in the field [3] lists several broad design motifs. I will first list the deign motifs falling within the scope of the survey, and the examples it provides. Selections from both papers are meant to show the depth and breadth of the field, rather than to elucidate the specific chemical or kinetic operations under the purview of each design-variety.
For a much more comprehensive, interactive bibliography of papers falling within the field of Synthetic Ion-Channels or constituting the historical foundations of the field, see Jon Chui’s online biography here, which charts the developments in this field up until 2011.
First Survey
Unimolecular ion channels:
Examples include a.) synthetic ion channels with oligocrown ionophores, [5] b.) using a-helical peptide scaffolds and rigid push–pull p-octiphenyl scaffolds for the recognition of polarized membranes, [6] and c.) modified varieties of the b-helical scaffold of gramicidin A [7]
Barrel-stave supramolecules:
Examples of this general class falling include avoltage-gated synthetic ion channels formed by macrocyclic bolaamphiphiles and rigidrod p-octiphenyl polyols [8].
Macrocyclic, branched and linear non-peptide bolaamphiphiles as staves:
Examples of this sub-class include synthetic ion channels formed by a.) macrocyclic, branched and linear bolaamphiphiles and dimeric steroids, [9] and by b.) non-peptide macrocycles, acyclic analogs and peptide macrocycles [respectively] containing abiotic amino acids [10].
Dimeric steroid staves:
Examples of this sub-class include channels using polydroxylated norcholentriol dimer [11].
pOligophenyls as staves in rigid rod b barrels:
Examples of this sub-class include “cylindrical self-assembly of rigid-rod b-barrel pores preorganized by the nonplanarity of p-octiphenyl staves in octapeptide-p-octiphenyl monomers” [12].
Synthetic Polymers:
Examples of this sub-class include synthetic ion channels and pores comprised of a.) polyalanine, b.) polyisocyanates, c.) polyacrylates, [13] formed by i.) ionophoric, ii.) ‘smart’ and iii.) cationic polymers [14]; d.) surface-attached poly(vinyl-n-alkylpyridinium) [15]; e.) cationic oligo-polymers [16] and f.) poly(m-phenylene ethylenes) [17].
Helical b-peptides (used as staves in barrel-stave method):
Examples of this class include: a.) cationic b-peptides with antibiotic activity, presumably acting as amphiphilic helices that form micellar pores in anionic bilayer membranes [18].
Monomeric steroids:
Examples of this sub-class falling include synthetic carriers, channels and pores formed by monomeric steroids [19], synthetic cationic steroid antibiotics [that] may act by forming micellar pores in anionic membranes [20], neutral steroids as anion carriers [21] and supramolecular ion channels [22].
Complex minimalist systems:
Examples of this sub-class falling within the scope of this survey include ‘minimalist’ amphiphiles as synthetic ion channels and pores [23], membrane-active ‘smart’ double-chain amphiphiles, expected to form ‘micellar pores’ or self-assemble into ion channels in response to acid or light [24], and double-chain amphiphiles that may form ‘micellar pores’ at the boundary between photopolymerized and host bilayer domains and representative peptide conjugates that may self assemble into supramolecular pores or exhibit antibiotic activity [25].
Non-peptide macrocycles as hoops:
Examples of this sub-class falling within the scope of this survey include synthetic ion channels formed by non-peptide macrocycles acyclic analogs [26] and peptide macrocycles containing abiotic amino acids [27].
Peptide macrocycles as hoops and staves:
Examples of this sub-class include a.) synthetic ion channels formed by self-assembly of macrocyclic peptides into genuine barrel-hoop motifs that mimic the b-helix of gramicidin A with cyclic b-sheets. The macrocycles are designed to bind on top of channels and cationic antibiotics (and several analogs) are proposed to form micellar pores in anionic membranes [28]; b.) synthetic carriers, antibiotics (and analogs) and pores (and analogs) formed by macrocyclic peptides with non-natural subunits. [Certain] macrocycles may act as b-sheets, possibly as staves of b-barrel-like pores [29]; c.) bioengineered pores as sensors. Covalent capturing and fragmentations [have been] observed on the single-molecule level within engineered a-hemolysin pore containing an internal reactive thiol [30].
Summary
Thus even without knowledge of supramolecular or organic chemistry, one can see that a variety of alternate approaches to the creation of synthetic ion channels, and several sub-approaches within each larger ‘design motif’ or broad-approach, not only exist but have been experimentally verified, varietized and refined.
Second Survey
The following selections [31] illustrate the chemical, structural and functional varieties of synthetic ions categorized according to whether they are cation-conducting or anion-conducting, respectively. These examples are used to further emphasize the extent of the field, and the number of alternative approaches to synthetic ion-channel design, implementation, integration and experimental-verification already existent. Permission to use all the following selections and figures were obtained from the author of the source.
There are 6 classical design-motifs for synthetic ion-channels, categorized by structure, that are identified within the paper:
“The first non-peptidic artificial ion channel was reported by Kobuke et al. in 1992” [33].
“The channel contained “an amphiphilic ion pair consisting of oligoether-carboxylates and mono- (or di-) octadecylammoniumcations. The carboxylates formed the channel core and the cations formed the hydrophobic outer wall, which was embedded in the bilipid membrane with a channel length of about 24 to 30 Å. The resultant ion channel, formed from molecular self-assembly, is cation selective and voltage-dependent” [34].
“Later, Kokube et al. synthesized another channel comprising of resorcinol based cyclic tetramer as the building block. The resorcin-[4]-arenemonomer consisted of four long alkyl chains which aggregated to forma dimeric supramolecular structure resembling that of Gramicidin A” [35]. “Gokel et al. had studied [a set of] simple yet fully functional ion channels known as “hydraphiles” [39].
“An example (channel 3) is shown in Figure 1.6, consisting of diaza-18-crown-6 crown ether groups and alkyl chain as side arms and spacers. Channel 3 is capable of transporting protons across the bilayer membrane” [40].
“A covalently bonded macrotetracycle4 (Figure 1.8) had shown to be about three times more active than Gokel’s ‘hydraphile’ channel, and its amide-containing analogue also showed enhanced activity” [44].
“Inorganic derivative using crown ethers have also been synthesized. Hall et. al synthesized an ion channel consisting of a ferrocene and 4 diaza-18-crown-6 linked by 2 dodecyl chains (Figure 1.9). The ion channel was redox-active as oxidation of the ferrocene caused the compound to switch to an inactive form” [45]
B STAVES:
“These are more difficult to synthesize [in comparison to unimolecular varieties] because the channel formation usually involves self-assembly via non-covalent interactions” [47].“A cyclic peptide composed of even number of alternating D- and L-amino acids (Figure 1.10) was suggested to form barrel-hoop structure through backbone-backbone hydrogen bonds by De Santis” [49].
“A tubular nanotube synthesized by Ghadiri et al. consisting of cyclic D and L peptide subunits form a flat, ring-shaped conformation that stack through an extensive anti-parallel β-sheet-like hydrogen bonding interaction (Figure 1.11)” [51].
“Experimental results have shown that the channel can transport sodium and potassium ions. The channel can also be constructed by the use of direct covalent bonding between the sheets so as to increase the thermodynamic and kinetic stability” [52].
“By attaching peptides to the octiphenyl scaffold, a β-barrel can be formed via self-assembly through the formation of β-sheet structures between the peptide chains (Figure 1.13)” [53].
“The same scaffold was used by Matile etal. to mimic the structure of macrolide antibiotic amphotericin B. The channel synthesized was shown to transport cations across the membrane” [54].
“Attaching the electron-poor naphthalenediimide (NDIs) to the same octiphenyl scaffold led to the hoop-stave mismatch during self-assembly that results in a twisted and closed channel conformation (Figure 1.14). Adding the compleentary dialkoxynaphthalene (DAN) donor led to the cooperative interactions between NDI and DAN that favors the formation of barrel-stave ion channel.” [57].
MICELLAR
“These aggregate channels are formed by amphotericin involving both sterols and antibiotics arranged in two half-channel sections within the membrane” [58].
“An active form of the compound is the bolaamphiphiles (two-headed amphiphiles). (Figure 1.15) shows an example that forms an active channel structure through dimerization or trimerization within the bilayer membrane. Electrochemical studies had shown that the monomer is inactive and the active form involves dimer or larger aggregates” [60].
ANION CONDUCTING CHANNELS:
“A highly active, anion selective, monomeric cyclodextrin-based ion channel was designed by Madhavan et al (Figure 1.16). Oligoether chains were attached to the primary face of the β-cyclodextrin head group via amide bonds. The hydrophobic oligoether chains were chosen because they are long enough to span the entire lipid bilayer. The channel was able to select “anions over cations” and “discriminate among halide anions in the order I-> Br-> Cl- (following Hofmeister series)” [61].
“The anion selectivity occurred via the ring of ammonium cations being positioned just beside the cyclodextrin head group, which helped to facilitate anion selectivity. Iodide ions were transported the fastest because the activation barrier to enter the hydrophobic channel core is lower for I- compared to either Br- or Cl-“ [62]. “A more specific artificial anion selective ion channel was the chloride selective ion channel synthesized by Gokel. The building block involved a heptapeptide with Proline incorporated (Figure 1.17)” [63].
Cellular Prosthesis: Inklings of a New Interdisciplinary Approach
The paper cites “nanoreactors for catalysis and chemical or biological sensors” and “interdisciplinary uses as nano –filtration membrane, drug or gene delivery vehicles/transporters as well as channel-based antibiotics that may kill bacterial cells preferentially over mammalian cells” as some of the main applications of synthetic ion-channels [65], other than their normative use in elucidating cellular function and operation.
However, I argue that a whole interdisciplinary field and heretofore-unrecognized new approach or sub-field of Functionally-Restorative Medicine is possible through taking the technologies and techniques involved in in constructing, integrating, and experimentally-verifying either a.) non-biological analogues of ion-channels & ion-pumps (thus trans-membrane membrane proteins in general, also sometimes referred to as transport proteins or integral membrane proteins) and membranes (which include normative bilipid membranes, non-lipid membranes and chemically-augmented bilipid membranes), and b.) the artificial synthesis of biological analogues of ion-channels, ion-pumps and membranes, which are structurally and chemically equivalent to naturally-occurring biological components but which are synthesized artificially – and applying such technologies and techniques toward the purpose the gradual replacement of our existing biological neurons constituting our nervous systems – or at least those neuron-populations that comprise the neo- and prefrontal-cortex, and through iterative procedures of gradual replacement thereby achieving indefinite-longevity. There is still work to be done in determining the comparative advantages and disadvantages of various structural and functional (i.e. design) motifs, and in the logistics of implanting the iterative replacement or reconstitution of ion-channels, ion-pumps and sections of neuronal membrane in-vivo.
The conceptual schemes outlined in Concepts for Functional Replication of Biological Neurons [66], Gradual Neuron Replacement for the Preservation of Subjective-Continuity [67] and Wireless Synapses, Artificial Plasticity, and Neuromodulation [68] would constitute variations on the basic approach underlying this proposed, embryonic interdisciplinary field. Certain approaches within the fields of nanomedicine itself, particularly those approaches that constitute the functional emulation of existing cell-types, such as but not limited to Robert Freitas’s conceptual designs for the functional emulation of the red blood cell (a.k.a. erythrocytes, haematids) [69], i.e. the Resperocyte, itself should be seen as falling under the purview of this new approach, although not all approaches to Nanomedicine (diagnostics, drug-delivery and neuroelectronic interfacing) constitute the physical (i.e. electromechanical, kinetic and/or molecular physically-embodied) and functional emulation of biological cells.
The field of functionally-restorative medicine in general (and of nanomedicine in particular) and the field of supramolecular and organic chemistry converge here, where these technological, methodological, and experimental infrastructures developed in field of Synthetic Ion-Channels and Ion Channel Reconstitution can be employed to develop a new interdisciplinary approach that applies the logic of prosthesis to the cellular and cellular-component (i.e. sub-cellular) scale; same tools, new use. These techniques could be used to iteratively replace the components of our neurons as they degrade, or to replace them with more robust systems that are less susceptible to molecular degradation. Instead of repairing the cellular DNA, RNA and protein transcription and synthesis machinery, we bypass it completely by configuring and integrating the neuronal components (ion-channels, ion-pumps and sections of bilipid membrane) directly.
Thus I suggest that theoreticians of nanomedicine look to the large quantity of literature already developed in the emerging fields of synthetic ion-channels and membrane-reconstitution, towards the objective of adapting and applying existing technologies and methodologies to the new purpose of iterative maintenance, upkeep and/or replacement of cellular (and particularly neuronal) constituents with either non-biological analogues or artificially-synthesized-but-chemically/structurally-equivalent biological analogues.
This new sub-field of Synthetic Biology needs a name to differentiate it from the other approaches to Functionally-Restorative Medicine. I suggest the designation ‘cellular prosthesis’.
References:
[1] Williams (1994)., An introduction to the methods available for ion channel reconstitution. in D.C Ogden Microelectrode techniques, The Plymouth workshop edition, CambridgeCompany of Biologists.
[2] Tomich, J., Montal, M. (1996). U.S Patent No. 5,16,890. Washington, DC: U.S. Patent and Trademark Office.
[69] Freitas Jr., R., (1998). “Exploratory Design in Medical Nanotechnology: A Mechanical Artificial Red Cell”. Artificial Cells, Blood Substitutes, and Immobil. Biotech. (26): 411–430. Access: http://www.ncbi.nlm.nih.gov/pubmed/9663339
In rich countries, more than 80% of the population today will survive past the age of 70. About 150 years ago, only 20% did. In all this while, though, only one person lived beyond the age of 120. This has led experts to believe that there may be a limit to how long humans can live.
Animals display an astounding variety of maximum lifespan ranging from mayflies and gastrotrichs, which live for 2 to 3 days, to giant tortoises and bowhead whales, which can live to 200 years. The record for the longest living animal belongs to the quahog clam, which can live for more than 400 years.
If we look beyond the animal kingdom, among plants the giant sequoia lives past 3000 years, and bristlecone pines reach 5000 years. The record for the longest living plant belongs to the Mediterranean tapeweed, which has been found in a flourishing colony estimated at 100,000 years old.
This jellyfish never dies. Michael W. May
Some animals like the hydra and a species of jellyfish may have found ways to cheat death, but further research is needed to validate this.
The natural laws of physics may dictate that most things must die. But that does not mean we cannot use nature’s templates to extend healthy human lifespan beyond 120 years.
Putting a lid on the can
Gerontologist Leonard Hayflick at the University of California thinks that humans have a definite expiry date. In 1961, he showed that human skin cells grown under laboratory conditions tend to divide approximately 50 times before becoming senescent, which means no longer able to divide. This phenomenon that any cell can multiply only a limited number of times is called the Hayflick limit.
Since then, Hayflick and others have successfully documented the Hayflick limits of cells from animals with varied life spans, including the long-lived Galapagos turtle (200 years) and the relatively short-lived laboratory mouse (3 years). The cells of a Galapagos turtle divide approximately 110 times before senescing, whereas mice cells become senescent within 15 divisions.
The Hayflick limit gained more support when Elizabeth Blackburn and colleagues discovered the ticking clock of the cell in the form of telomeres. Telomeres are repetitive DNA sequence at the end of chromosomes which protects the chromosomes from degrading. With every cell division, it seemed these telomeres get shorter. The result of each shortening was that these cells were more likely to become senescent.
Other scientists used census data and complex modelling methods to come to the same conclusion: that maximum human lifespan may be around 120 years. But no one has yet determined whether we can change the human Hayflick limit to become more like long-lived organisms such as the bowhead whales or the giant tortoise.
What gives more hope is that no one has actually proved that the Hayflick limit actually limits the lifespan of an organism. Correlation is not causation. For instance, despite having a very small Hayflick limit, mouse cells typically divide indefinitely when grown in standard laboratory conditions. They behave as if they have no Hayflick limit at all when grown in the concentration of oxygen that they experience in the living animal (3–5% versus 20%). They make enough telomerase, an enzyme that replaces degraded telomeres with new ones. So it might be that currently the Hayflick “limit” is more a the Hayflick “clock”, giving readout of the age of the cell rather than driving the cell to death.
The trouble with limits
Happy last few days? It doesn’t have to end this way. ptimat
The Hayflick limit may represent an organism’s maximal lifespan, but what is it that actually kills us in the end? To test the Hayflick limit’s ability to predict our mortality we can take cell samples from young and old people and grow them in the lab. If the Hayflick limit is the culprit, a 60-year-old person’s cells should divide far fewer times than a 20-year-old’s cells.
But this experiment fails time after time. The 60-year-old’s skin cells still divide approximately 50 times – just as many as the young person’s cells. But what about the telomeres: aren’t they the inbuilt biological clock? Well, it’s complicated.
When cells are grown in a lab their telomeres do indeed shorten with every cell division and can be used to find the cell’s “expiry date”. Unfortunately, this does not seem to relate to actual health of the cells.
It is true that as we get older our telomeres shorten, but only for certain cells and only during certain time. Most importantly, trusty lab mice have telomeres that are five times longer than ours but their lives are 40 times shorter. That is why the relationship between telomere length and lifespan is unclear.
Apparently using the Hayflick limit and telomere length to judge maximum human lifespan is akin to understanding the demise of the Roman empire by studying the material properties of the Colosseum. Rome did not fall because the Colosseum degraded; quite the opposite in fact, the Colosseum degraded because the Roman Empire fell.
Within the human body, most cells do not simply senesce. They are repaired, cleaned or replaced by stem cells. Your skin degrades as you age because your body cannot carry out its normal functions of repair and regeneration.
To infinity and beyond
If we could maintain our body’s ability to repair and regenerate itself, could we substantially increase our lifespans? This question is, unfortunately, vastly under-researched for us to be able to answer confidently. Most institutes on ageing promote research that delays onset of the diseases of ageing and not research that targets human life extension.
Those that look at extension study how diets like calorie restriction affect human health or the health impacts of molecules like resveratrol derived from red wine. Other research tries to understand the mechanisms underlying the beneficial effects of certain diets and foods with hopes of synthesising drugs that do the same. The tacit understanding in the field of gerontology seems to be that, if we can keep a person healthy longer, we may be able to modestly improve lifespan.
Living long and having good health are not mutually exclusive. On the contrary, you cannot have a long life without good health. Currently most ageing research is concentrated on improving “health”, not lifespan. If we are going to live substantially longer, we need to engineer our way out of the current 120-year-barrier.
Avi Roy does not work for, consult to, own shares in or receive funding from any company or organisation that would benefit from this article, and has no relevant affiliations.
The following article was originally published by Immortal Life
When asked what the biggest bottleneck for Radical or Indefinite Longevity is, most thinkers say funding. Some say the biggest bottleneck is breakthroughs and others say it’s our way of approaching the problem (i.e. that we’re seeking healthy life extension whereas we should be seeking more comprehensive methods of indefinite life-extension), but the majority seem to feel that what is really needed is adequate funding to plug away at developing and experimentally-verifying the various, sometimes mutually-exclusive technologies and methodologies that have already been proposed. I claim that Radical Longevity’s biggest bottleneck is not funding, but advocacy.
This is because the final objective of increased funding for Radical Longevity and Life Extension research can be more effectively and efficiently achieved through public advocacy for Radical Life Extension than it can by direct funding or direct research, per unit of time or effort. Research and development obviously still need to be done, but an increase in researchers needs an increase in funding, and an increase in funding needs an increase in the public perception of RLE’s feasibility and desirability.
There is no definitive timespan that it will take to achieve indefinitely-extended life. How long it takes to achieve Radical Longevity is determined by how hard we work at it and how much effort we put into it. More effort means that it will be achieved sooner. And by and large, an increase in effort can be best achieved by an increase in funding, and an increase in funding can be best achieved by an increase in public advocacy. You will likely accelerate the development of Indefinitely-Extended Life, per unit of time or effort, by advocating the desirability, ethicacy and technical feasibility of longer life than you will by doing direct research, or by working towards the objective of directly contributing funds to RLE projects and research initiatives. Continue reading “Longevity’s Bottleneck May Be Funding, But Funding’s Bottleneck is Advocacy & Activism” | >
Both dynamic complexity and detail complexity, along with fuzzy logic, must be pervasively considered, as well.
9. In any management undertaking, and given the universal volatility and rampant and uninterrupted rate of change, one must think and operate in a fluid womb-to-tomb mode.
