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Review of “Death is Wrong” by Adam Alonzi

Review of “Death is Wrong” by Adam Alonzi

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The New Renaissance Hat
Adam Alonzi
April 7, 2014
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Death is wrong, and it can be defeated. Gennady Stolyarov’s new book, Death is Wrong, makes this powerful  idea accessible to everyone. Now that you have seen the phrase in print, it should not seem odd to you; the vincible visage of the Grim Reaper should seem less frightening. It is a primitive spectre, a monster to be unmasked in the venerable tradition of Scooby Doo. There is no more reason to believe in its inevitability than there is to believe in the Easter Bunny. This strange, wonderful and intoxicating idea should begin to sink into our brains, not because it is pleasant, but because it is true. Please support his Indiegogo campaign here.

Death can be cured. Let this sink into your brain, not because it is comforting, but because it is true. Even obvious truths will not gain acceptance unless we vigorously campaign against the falsehoods Death is not something to embrace, and it is not something to ignore. To turn it into a matter of metaphysics or “bioethics” is insulting to those who, by no fault of their own, are burdened by the ailments of old age. There are many extraordinary men and women who could go on working for hundreds of years if their stars were not designed to dim so soon.

What do you want to do with your life? This is the question Mr. Stolyarov poses to his readers. Whatever you wish to do is restricted by the time you have on this earth. This is restricted largely by your genes, even if you do all you can to mitigate the hand chance and meiosis have dealt you. The fountain of youth now is not far off. We no longer need to deceive ourselves with lofty philosophical discourses of dreams of a world after this one. Conventional “wear and tear” theories claim the body has a finite amount of repair resources, yet if this was true, exercise should greatly decrease one’s lifespan. As far as we can tell, moderate exercise fights aging as well as or better than anything in our still inadequate arsenal.

If the process is the result of unavoidable changes we should not expect to find animals which undergo negligible senescence. We should also expect animals of the same basic shape, type and size to age at approximately the same rates. American crows normally die before their eigth birthday; Kakapo parrots can live well into their nineties. Post-reproductive suicide may be viewed as a peculiarity of some species, but it also graphically illustrates the control genes have over the aging process. The goal of the Transhumanist movement now should be to convince as many people as possible of the viability of this research. Arcane mathematical tidbits from evolutionary biology, although more cogent, are less convincing than masses of salmon carcasses floating downstream or lowly tortoises who, for no obvious reason, live for centuries.

Knowing our quality of life is doomed to decay with each passing year, we do not always take full advantage of the opportunities available to us. Why play the guitar? Some people have been playing it since they were 12. It would be impossible to schedule it in between shifts at the lab and carting the kids around. An ambition is forsaken for lack of time. It is often irrational, as late is better than never, but humans are not always rational animals. The creeping fear of time is partially justified. Anger is more than justified. There is no reason we should not have more quality time to fulfill our aspirations. Paradoxically, coming to terms with the shortness of life can be more paralyzing than invigorating. Like so many falsehoods, carpe diem stems from deep but forgivable denial.

People, including history’s greatest minds, have tried to find ways in which they or their creations were eternal. These efforts amount mostly to confabulations. As much as this statement will be contested, I must make it: death makes life meaningless. If you cannot agree with this, at least concede that aging can make life intolerable. Before you dismiss this, keep in mind it is easy to pontificate about the value of old age when one is young. Creaking joints and failing organs may change your views. Our finest moments are when we feel eternal, yet feeling eternal is quite different from being eternal. Freud called it the oceanic sensation; the expansion of the self into the wider world. When someone knows with certainly they may live hundreds or thousands of years, these otherwise momentary delusions find firm ground on which to stand.

Death is Wrong - by Gennady Stolyarov II, Illustrated by Wendy Stolyarov

In the end our efforts are all for naught. From a cosmic perspective this may be so, and a pugnacious devil’s advocate may ask if there is such a thing as a “good” age to die, but one can forcefully and effectively argue that 75 is too young. 35 is far too young to begin losing one’s faculties, as many professions today require years of training. A man in the prime of his career should also be in the prime of his life. 20 is universally considered too young to die. So are 30, 40, and 50. Before we can even begin to enjoy the fruits of our labors, we are already declining. Before we can begin to understand a portion of the world’s treasures, we are growing old and tired. What a sad state of affairs! We desire lasting rewards, yet we cannot have them. The productions of an entire lifetime do not last, because the enjoyer of those productions and the accolades they have won eventually perishes. With his body, presumably, his consciousness also disappears into nothingness. Deadlines tend to force a person to work in a state of fear. Death is the ultimate deadline.

What of knowledge and talents? Why acquire knowledge when it can only be imperfectly transmitted to the next generation? Preserved in books, but there are already so many books. Immortality may not be necessary for society’s continued progress now, but with the constant expansion of information and the sprawling interconnectedness of different disciplines, it is reasonable to wonder if hyperspecialization is our salvation. Immortality and intelligence amplification will allow us all, to some extent, to become generalists capable of making sane and sound decisions for ourselves and society. Why invest in higher pleasures when the lower ones deliver immediate gratification?

Living for each day devolves into hedonistic stupidity. Why should we care about the consequences of our actions when, regardless of what happens to us, our stories all end in the same way? What was once a psychological necessity is now a hindrance to the greater good. What was once a rational position is now an effrontery to a sane approach to medicine. This is not say that research efforts dedicated to the cell cycle or the precipitating factors involved in autoimmune disorders are worthless – far from it! Rather it means that life extension in its own right ought to be a major area of inquiry. The totem must be smashed and the taboo crushed.

Yet whose decree are we following and why? Disease is our oldest foe. We are not complacent about hereditary illnesses that will only be cured after the perfection of in vivo gene therapy. Yet a lifespan of less than a century is blindly accepted as a physical limit by, according to polls taken by Theodore Goldsmith, a shocking number of scientists and laymen alike. Death is literally our mortal foe, but the amount of energy we have spent fighting it directly would not lead one to this conclusion. The biochemical changes associated with aging are the primary risk factors for diabetes, atherosclerosis, arthritis, and cancer. Yet, in spite of the undeniable correlation between aging and these diseases, research effort is directed mostly at treating them individually instead of addressing their underlying cause.

This is rooted not in a scientific sentiment, but in the unfounded assumption that death is inevitable. This stems less from skepticism towards modern medicine and more from historical superstitions that allowed our ancestors to cope with the mysterious and inhospitable universe in which they found themselves. Worse, there are throngs of secular and religious nihilists alike who actively spread the gospel of death. They erect altars to petty Molochs to distract themselves from their own worst enemy. It will be difficult to battle the most entrenched notion of all, but nothing worth having is easy to obtain. The end of suffering is the highest ideal. Why should we worship false idols any longer?

Should Transhumanism take precedence over the fight against Creationism? The answer seems painfully obvious. I do not care if a pig farmer in Alabama believes the Neolithic era was populated by dinosaurs. His ignorance has no dreadful ramifications for humankind. As an academic and popular movement, anti-aging should be the first and foremost topic of scientific discussion. The secular and sane world accepts Darwinism. There is no reason to suppose converting the remaining holdouts will benefit society in the least. The sane and secular world, however, is still largely unaware of the strides science is making toward biological immortality. Moreover, a small bit about intelligent design in a science textbook, while objectionable on moral grounds, will not do much more damage to an already broken school system.

Mentioning intelligent design in passing will do nothing to dumb down an already doltish student body. Advocates of evolution would be more helpful if they turned their energies to spreading numeracy and basic literacy. Both are in short supply. To spend a lifetime fighting against hopeless ignoramuses makes one an imbecile of the highest order. Let the ignorant tend to their own business while we welcome the age of wonders. Let this be a call to arms. Let this be a call to awaken and accept the foolishness of how humanity uses its resources. Rage against the dying of the light. Do not go gentle into that good night.

Adam Alonzi is the author of Praying for Death and A Plank in Reason. He is also a futurist, inventor, DIY enthusiast, biotechnologist, programmer, molecular gastronomist, consummate dilletante and columnist at The Indian Economist. Read his blog Cool Flickers.

To Accept Aging and Death is to Choose Aging and Death – Article by Reason

To Accept Aging and Death is to Choose Aging and Death – Article by Reason

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The New Renaissance Hat
Reason
April 1, 2014
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It is in the nature of things for people to become more accepting of the imperfect state of the world and the flawed human condition with advancing age, to lose that youthful indignation and urge to change all that causes suffering and injustice. We can blame a range of things for this, but I suspect that it has a lot to do with the growth in wealth and connections that occurs over the years for most individuals. Whatever your starting level, on average the 50-year-old you will be in a better place than the 20-year-old you. The gains you have amassed merge with nostalgia in a slow erosion of the desire to tear down walls and shake up your neighbors: things are better for you, and isn’t that a good thing? Not everyone is this way, of course, but it is a dynamic to be aware of in your relationship with the world. It is human nature to measure today against yesterday, and feel good about gains that are relatively large but absolutely small.

Acceptance of death and aging is the mindset I am thinking in particular here. The unpleasant ends of life are dim and distant myths when you are young and vigorous in your search for world-changing causes. It is the rare young individual who is willing to devote his or her life in preparation for a time half a century down the road. The older folk who feel the pressures of time and encroaching frailty are those who have become more accepting, however. To fight aging and work on rejuvenation treatments is an intrinsically hard sell in comparison to many other ventures. The youth think they have time to focus on other matters first, and the old have come to terms.

Nonetheless, with rapid progress in biotechnology year after year the number of people needed to get the job done is falling rapidly. Ten million supporters willing to put in a little time or money (rather than just a wave and a good word) and the careers of a few thousand scientists and biotechnicians is probably more than is needed at this point, a level of support that lies in a similar ballpark to that of the cancer or stem-cell research communities. We are not there yet, though support for scientific, medical approaches to the treatment and prevention of aging has grown in a very encouraging fashion over the past decade. At any time in the next year or so you might see mainstream press articles in noted publications favorably mention the SENS Research Foundation, regenerative medicine, Google’s Calico initiative, and progress in genetic science all in the same few paragraphs.

We are here, where we are, precisely because numerous people retained a youthful fire and verve, and indignation and horror of aging and death. Despite the ever-present opposition from a mainstream that once mocked aging research, these iconoclasts put in the work that has raised funds, created organizations, and changed minds: all seeds for tomorrow’s grand rejuvenation research community. This is a work in progress. But let us take a moment to admire some of the fire from those driving things along at the grassroots level:

Those Critical of Indefinite Life Extension Fear Life

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Accepting death is in fact choosing it. In the face of recent discoveries and progress in science, medicine, technology – it is a matter of choice. Pretending to be fearless in the face of death isn’t some form of heroism. It isn’t reasonable or courageous. It is quite the opposite. It is taking the easy way out. Let’s repeat it – death really is the easy way out. You fall asleep; you get a bullet; cancer kills you; some choose suicide; some accept aging and its effects as an inexorable given. The hard truth here that we should be prepared to acknowledge is: accepting death is the true cowardice, no matter the circumstances. Fighting it and choosing life is the true courage.

Critics of indefinite life extension, don’t put on a snide, condescending face and tell me that you aren’t afraid of death, because you are, too.

By your own knee-jerk flippancy, reactionary admission, you are also afraid of life. You’re afraid of death, and you’re afraid of life. You say, right to us, all the time, that you don’t want to bear to deal with the drastic changes, you don’t want to live without all your friends and family around, you don’t want to live with war still being a reality anywhere. You can’t stand all the jerks and the dangerous people, and rich people, or tyrants, controlling you for one decade longer than a traditional lifespan. The thought of it makes you want to jump into your grave right now to get away from this big, bad, scary life.

You, my friend, are afraid of life. Living scares you. You think of life and you cower. You see the challenges of life and you’re too scared to face them. You wouldn’t dare form and join teams and initiatives to meet those challenges on the intellectual combat fields of dialectics and action. You don’t have what it takes. Life isn’t for you. It’s not your thing. So love your death, fear your life. Do that if that’s what you want.

I am afraid of death. It scares me to think of losing my life. I value my life. I have no shame in that. That is the reasonable thing to do. What I have shame for is that anybody would think that being afraid of death might possibly be something to mock.

You mock us for being afraid of death. We are afraid of death; it’s a logical and positive thing to be afraid in the face of it. It reminds a person to take action against danger. It’s your being afraid of life that is to be mocked. So stand up and tell us how afraid you are of living. We promise not to look upon you with too much shame, and we promise to lend you a hand if you need help crossing over to the land of reason.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 

This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

Theorizing That Some Change in the Aging Brain is Optimization, Not Degeneration – Article by Reason

Theorizing That Some Change in the Aging Brain is Optimization, Not Degeneration – Article by Reason

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The New Renaissance Hat
Reason
February 9, 2014
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The nature of neural networks is perhaps better understood by more people nowadays than used to the be the case. Forms of neural network are used for a range of computational purposes, where they have proved useful as a way to economically discover solutions to difficult problems in pattern recognition, optimization, and other fields. How a particular solution works isn’t always clear, especially when using larger networks, but if it can be proven to work well then why worry?

We ourselves are neural networks: the complex adaptive phenomena that we choose to call the self arises from comparatively simple exchanges between many, many neurons. The machine is the connections and the state of its neurons, constantly altering itself in response to circumstances and its own operation.

The brain, like all tissues, suffers due to the accumulation of cellular and molecular damage that drives aging. But which of the characteristic differences between a young brain and an old brain are aging, and which are the expected operation of the neural network as it processes and reprocesses the data gathered throughout life? In some cases the classification is obvious: broken blood vessels and white matter hyperintensities are damage, as is the amyloid that accumulates in Alzheimer’s disease. We would be better off without them, and they harm us by destroying physical structures needed for operation of the brain. Once researchers start looking at the structure of neural connections, or activity in response to stimulus, or gene expression maps in various portions of the brain things become a little less clear, however:

The Brain Ages Optimally to Model Its Environment: Evidence from Sensory Learning over the Adult Lifespan

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The aging brain shows a progressive loss of neuropil, which is accompanied by subtle changes in neuronal plasticity, sensory learning and memory. Neurophysiologically, aging attenuates evoked responses – including the mismatch negativity (MMN). This is accompanied by a shift in cortical responsivity from sensory (posterior) regions to executive (anterior) regions, which has been interpreted as a compensatory response for cognitive decline.

Theoretical neurobiology offers a simpler explanation for all of these effects – from a Bayesian perspective, as the brain is progressively optimized to model its world, its complexity will decrease. A corollary of this complexity reduction is an attenuation of Bayesian updating or sensory learning.

Here we confirmed this hypothesis using magnetoencephalographic recordings of the mismatch negativity elicited in a large cohort of human subjects, in their third to ninth decade. Employing dynamic causal modeling to assay the synaptic mechanisms underlying these non-invasive recordings, we found a selective age-related attenuation of synaptic connectivity changes that underpin rapid sensory learning. In contrast, baseline synaptic connectivity strengths were consistently strong over the decades. Our findings suggest that the lifetime accrual of sensory experience optimizes functional brain architectures to enable efficient and generalizable predictions of the world.

My suspicion is that it would be faster to implement rejuvenation biotechnologies and then assess what happens to an aging brain that remains physiologically young than to fully pick apart and understand present contributions to changes over time in the brain.

This line of research is of interest because of a potential threat to extreme longevity, past the present limits of human life span, once we have build the necessary medical technologies. The threat is this: it is possible that the brain is like the immune system, in that it is poorly structured for long term use, and will fail for reasons inherent to that structure, even in the absence of damage. We have no reason to suspect that this is the case, but equally there is no good reason to rule this out – the scientific community simply doesn’t understand enough about the detailed operation of the brain to say either way with confidence.

On the plus side, this is a comparatively remote potential threat, something that lies decades past all the other fatal forms of damage and age-related disease that we have to deal with. Old people with little physical damage to their brains are sharp and on the ball, to the degree allowed by their failing bodies and decades of increasing caution required in their interaction with the world. Further, by the time we are at the point of worrying about this, biotechnology will be far more advanced. So it is, I think, worth considering, but not worth panicking over.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 

This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

Weak Evidence Against a Significant Role for Nuclear DNA Damage in Aging – Article by Reason

Weak Evidence Against a Significant Role for Nuclear DNA Damage in Aging – Article by Reason

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The New Renaissance Hat
Reason
February 2, 2014
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The nuclear DNA in our cells is surrounded by a panoply of exceedingly efficient quality control and repair machinery, but nonetheless damage occurs: individual cells suffer all sorts of mutations over time as molecules react with DNA or pieces are lost or reshuffled during replication. This is more pronounced in long-lived cells, such as those in the central nervous system, or the stem cell populations that support specific tissues.

Cancer spawns from nuclear DNA damage, and the risk of cancer grows greatly with age – not just because of growing damage to nuclear DNA, but also due to the decline of the immune system’s watchdogs and other related consequences of aging. But aside from cancer, does the accumulation of various forms of nuclear DNA damage scattered across our cells contribute meaningfully to dysfunction and decline? There is some debate on this topic, and while the consensus position is more or less “yes, of course,” there is at this point no experiment by which one can conclusively demonstrate that this is the case.

Today I’ll point you to an open-access study in which researchers compare DNA sequencing data from the blood of a pair of 40-year-old twins and a pair of 100-year old twins. Blood cells cycle into and out of circulation on a timescale of a few months, but we might take nuclear DNA damage in blood cells as being representative of the damage present in the population of hematopoietic stem cells that generated those blood cells.

Aging as Accelerated Accumulation of Somatic Variants: Whole-Genome Sequencing of Centenarian and Middle-Aged Monozygotic Twin Pairs

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It has been postulated that aging is the consequence of an accelerated accumulation of somatic DNA mutations and that subsequent errors in the primary structure of proteins ultimately reach levels sufficient to affect organismal functions. The technical limitations of detecting somatic changes and the lack of insight about the minimum level of erroneous proteins to cause an error catastrophe hampered any firm conclusions on these theories.In this study, we sequenced the whole genome of DNA in whole blood of two pairs of monozygotic (MZ) twins, 40 and 100 years old, by two independent next-generation sequencing (NGS) platforms (Illumina and Complete Genomics). Potentially discordant single-base substitutions supported by both platforms were validated extensively by Sanger, Roche 454, and Ion Torrent sequencing.

We demonstrate that the genomes of the two twin pairs are germ-line identical between co-twins, and that the genomes of the 100-year-old MZ twins are discerned by eight confirmed somatic single-base substitutions, five of which are within nucleotide substitutions can be detected, and that a century of life did not result in a large number of detectable somatic mutations in blood.

I would have expected more differences and larger differences to turn up, but, as the researchers note, it is impossible to detect mutations that have not spread to at least some degree. (In this case, that means spreading through the population of hematopoietic stem cells.) A next step might be a survey of whole-genome sequencing by tissue types in old twins, especially those with longer-lived cells, to see whether this low level of exhibited mutational damage is peculiar to blood or typical for most or all tissues.

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The number of somatic variants may be substantially larger but those present in smaller fractions of cells go undetected. Consistent, detectable somatic variation likely includes somatic mosaicism in blood generated during development or clonal expansion of mutations generated at any point during the lifetime. The frequency of these variants is limited in blood even after 100 years of life. In summary, this study shows that the number of detectable somatic variants in blood by using NGS is very low and that accumulation of somatic mutations is not necessarily a consequence of a century of life. Stochastic somatic variation occurring in less than 20% of cells will go undetected, however.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 

This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

More Recent Coverage of SENS Research – Article by Reason

More Recent Coverage of SENS Research – Article by Reason

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The New Renaissance Hat
Reason
January 31, 2014
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SENS stands for the Strategies for Engineered Negligible Senescence, a research and development plan first assembled more than a decade ago by biomedical gerontologist Aubrey de Grey. This was a work of vision and synthesis: taking decades of research results from many diverse fields of medical research whose scientists had comparatively little contact with one another, and little interest in working on ways to treat aging, and pulling these results together into a convincing argument as to (a) which forms of cellular and molecular damage cause aging, and (b) how to go about developing the means of repair for this damage.

Aging is damage, and repair is rejuvenation. Sufficiently comprehensive implementations of SENS should not only prevent aging and age-related disease, but also reverse the effects of aging in the old. This isn’t a matter of hand-waving: the capabilities in molecular biology and research plans to build therapies are outlined in considerable detail at the SENS Research Foundation website and in related scientific papers. You should take a look if you haven’t recently. The estimated cost of developing this to the point of demonstration in mice is on a par with the total cost of development of a single drug: perhaps $1-2 billion over 10-20 years.

It is pleasing to chart the changing character of press coverage over the years for SENS rejuvenation research and its figurehead advocate and organizer Aubrey de Grey. In the past ten years of increasing support within the scientific community and an influx of millions of dollars in philanthropic funding for research, it has become ever harder for journalists to stick their heads in the sand and pretend that SENS is either fringe or not real science. The gatekeepers of the establishment are never kind to any form of change or progress in the early days.

Measured by budget the SENS Research Foundation is a presently a tenth of the size of the well-established and mainstream Buck Institute for Aging Research. This is still larger than a good many labs in the field, and funding for SENS research has grown considerably over the past few years. Skilled molecular biologists in numerous laboratories are working on aspects of the SENS program of development for rejuvenation therapies. This work is still at the level of building tools and foundations for later progress, but it is very much real, tangible medical research. This is a new and upcoming field, the future of medical science and aging.

Aubrey de Grey: Out to Defy Death

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Spend a moment asking yourself, “What is the world’s worst problem?”

Biomedical gerontologist Aubrey de Grey, Ph.D., has an answer that may be radically different from yours. For him, it’s aging, and he not only makes a convincing case for why this is so, but he’s devoting his life to doing something about it. Dr. de Grey is the founder of SENS, a research foundation that aims to help build the regenerative medicine industry, an industry that arguably has the best chance for curing the diseases of aging. Surprisingly, he’s having more success than the people who were calling him a maverick and a heretic five years ago ever imagined.

First they ignore you, then they laugh at you, then they fight you, then you win. To my eyes, things have made it to the early stages of the winning part of that saying these days, certainly insofar as the scientific community is concerned. (Much more remains to be done in order to sell the public on the idea that radical life extension is a real possibility and that the relevant research is important and should be supported.) SENS is far more than Aubrey de Grey nowadays: it’s his vision, but has grown to be shared quite widely. There are dozens of influential allied scientists and laboratories, a number of high-net-worth philanthropists providing support, many advocates, a SENS Research Foundation staff, fundraisers, and, of course, the numerous researchers working to build the tools needed for future rejuvenation treatments.

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The SENS Foundation is a public charity based in California, and its purpose is to fill a niche in the research funding chain. Private sector research, particularly in the drug industry, has funds to drive important research, but only after it’s clear that the odds of success are good, the time frame is reasonably short, and the potential for profit large. At the other end of the research spectrum, public sector research funding is available for basic research that doesn’t have an immediate commercial purpose.

However, in Dr. de Grey’s view, and his colleagues’ as well, there’s a midway point between the private sector funding and the public sector, and this midpoint is often neglected. Research that may yield incalculable commercial success (and public benefit as well), may be at such an early stage of development that it doesn’t yet attract commercial funders. “We exist to make sure that this kind of intermediate research is not neglected,” he says.

People no longer refer to Aubrey de Grey as a “maverick” or “heretic.” “These days, I’m more often called ‘controversial,'” he says, sounding pleased with this new characterization.

“Controversial,” after all can be translated as, “might be right.”

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 

This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

A Simpler Path to Creating Pluripotent Stem Cells – Article by Reason

A Simpler Path to Creating Pluripotent Stem Cells – Article by Reason

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The New Renaissance Hat
Reason
January 31, 2014
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An improvement on current methods of creating pluripotent stem cells has been in the news the past few days. It involves stressing cells with simple mechanisms, and is straightforward enough that I hear numerous laboratories and individual researchers have started in on trying it out immediately, as well as revisiting other variants of stressing cells to see what the outcome might be. The methodology is something that DIYbio enthusiasts could carry out as a weekend project with minimal cost and equipment, which is a great improvement over prior standard methods involving delivery of genes or similar operations.

As with all such potential infrastructure improvements, one pillar of importance is the reduction in cost and difficulty of research. When someone figures out a much cheaper way of achieving any particular goal, all further work that builds on that goal moves more rapidly: existing groups can do more, and new groups that previously couldn’t afford to join in now start work. Cell pluripotency is near the base of regenerative medicine and tissue engineering: ways to better achieve it accelerate the whole field.

As you can see, there are also other ramifications, however, such as for persistent reports of pluripotent stem cells isolated from adult tissues – VSELs and others – and the debate over difficulties in replicating that research.

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In 2006, Japanese researchers reported a technique for creating cells that have the embryonic ability to turn into almost any cell type in the mammalian body – the now-famous induced pluripotent stem (iPS) cells. In papers published this week, another Japanese team says that it has come up with a surprisingly simple method – exposure to stress, including a low pH – that can make cells that are even more malleable than iPS cells, and do it faster and more efficiently.

“It’s amazing. I would have never thought external stress could have this effect,” says Yoshiki Sasai. It took Haruko Obokata, a young stem-cell biologist at the same centre, five years to develop the method and persuade Sasai and others that it works. “Everyone said it was an artefact – there were some really hard days.”

The results could fuel a long-running debate. For years, various groups of scientists have reported finding pluripotent cells in the mammalian body. But others have had difficulty reproducing such findings. Obokata started the current project by looking at cells thought to be pluripotent cells isolated from the body. But her results suggested a different explanation: that pluripotent cells are created when the body’s cells endure physical stress.

Obokata has already reprogrammed a dozen cell types, including those from the brain, skin, lung and liver, hinting that the method will work with most, if not all, cell types. On average, she says, 25% of the cells survive the stress and 30% of those convert to pluripotent cells – already a higher proportion than the roughly 1% conversion rate of iPS cells.

Link: http://www.nature.com/news/acid-bath-offers-easy-path-to-stem-cells-1.14600

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 

This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

Why Prioritize SENS Research for Human Longevity? – Article by Reason

Why Prioritize SENS Research for Human Longevity? – Article by Reason

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The New Renaissance Hat
Reason
December 29, 2013
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Why do I vocally support rejuvenation research based on the Strategies for Engineered Negligible Senescence (SENS) over other forms of longevity science? Why do I hold the view that SENS and SENS-like research should be prioritized and massively funded? The short answer to this question is that SENS-derived medical biotechnology has a much greater expected utility – it will most likely produce far better outcomes, and at a lower cost – than other presently ongoing lines of research into creating greater human longevity.

What is SENS?

But firstly, what is SENS? It is more an umbrella collection of categories than a specific program, though it is the case that narrowly focused SENS research initiatives run under the auspices of the SENS Research Foundation. On the science side of the house, SENS is a synthesis of existing knowledge from the broad mainstream position regarding aging and the diseases of aging: that aging is caused by a stochastic accumulation of damage at the level of cells and protein machinery in and around these cells. SENS is a proposal, based on recent decades of research, as to which of the identified forms of damage and change in old tissues are fundamental – i.e. which are direct byproducts of metabolic operation rather than cascading effects of other fundamental damage. On the development side of the house, SENS pulls together work from many subfields of medical research to show that there are clear and well-defined ways to produce therapies that can repair, reverse, or make irrelevant these fundamental forms of biological damage associated with aging.

(You can read about the various forms of low-level damage that cause aging at the SENS Research Foundation website and elsewhere. This list includes: mitochondrial DNA mutations; buildup of resilient waste products inside and around cells; growing numbers of senescent and other malfunctioning cells; loss of stem cells; and a few others).

Present arguments within the mainstream of aging research are largely over the relative importance of damage type A versus damage type B, and how exactly the extremely complex interaction of damage with metabolism progresses – but not what that damage actually is. A large fraction of modern funding for aging research goes towards building a greater understanding this progression; certainly more than goes towards actually doing anything about it. Here is the thing, however: while understanding the dynamics of damage in aging is very much a work in progress, the damage itself is well known. The research community can accurately enumerate the differences between old tissue and young tissue, or an old cell and a young cell – and it has been a good number of years since anything new was added to that list.

If you can repair the cellular damage that causes aging, it doesn’t matter how it happens or how it affects the organism when it’s there. This is the important realization for SENS – that much of the ongoing work of the aging research community is largely irrelevant if the goal is to get to human rejuvenation as rapidly as possible. Enough is already known of the likely causes of aging to have a reasonable expectation of being able to produce laboratory demonstrations of rejuvenation in animal models within a decade or two, given large-scale funding.

Comparing Expected Values

Expected value drives human endeavor. What path ahead do we expect to produce the greatest gain? In longevity science the investment is concretely measured in money and time, and we might think of the expected value in terms of years of healthy life added by the resulting therapies. The cost of these therapies really isn’t much of a factor – all major medical procedures and other therapies tend to converge to similar costs over time, based on their category: consider a surgery versus an infusion versus a course of pills, for example, where it’s fairly obvious that the pricing derives from how much skilled labor is involved and how much care the patient requires as a direct result of the process.

On the input side, there are estimates for the cost in time and money to implement SENS therapies for laboratory mice. For the sake of keeping things simple, I’ll note that these oscillate around the figures of a billion dollars and ten years for the crash program of fully-funded research. A billion dollars is about the yearly budget of the NIA these days, give or take, which might be a third of all research funding directed towards aging – by some estimates, anyway, though this is a very hard figure to verify in any way. It’s by no means certain the that the general one-third/two-thirds split between government and private research funding extends to aging research.

On the output side, early SENS implementations would be expected to take an old mouse and double its remaining life expectancy – e.g. produce actual rejuvenation, actual repair, and reversal of the low-level damage that causes aging, with repeated applications at intervals producing diminishing but still measurable further gains. This is the thing about a rejuvenation therapy that works; you can keep on applying it to sweep up newly accruing damage.

So what other longevity science do we have to compare against? The only large running programs are those that have grown out of the search for calorie-restriction mimetic drugs. So there is the past decade or so of research into sirtuins, and there is growing interest in mTOR and rapamycin analogs that looks to be more of the same, but slightly better (though that is a low bar to clear).

In the case of sirtuins, money has certainly flowed. Sirtris itself sold for ~$700 million, and it’s probably not unreasonable to suggest that a billion dollars have gone into broader sirtuin-related research and development over the past decade. What does the research community have to show for that? Basically nothing other than an increased understanding of some aspects of metabolism relating to calorie restriction and other adaptations that alter lifespan in response to environmental circumstances. Certainly no mice living longer in widely replicated studies as is the case for mTOR and rapamycin – the sirtuin results and underlying science are still much debated, much in dispute.

The historical ratio of dollars to results for any sort of way to manipulate our metabolism to slow aging is exceedingly poor. The thing is, this ratio shouldn’t be expected to get all that much better. Even if marvelously successful, the best possible realistic end result of a drug that slows aging based on what is known today – say something that extracts the best side of mTOR manipulation with none of the side-effects of rapamycin – is a very modest gain in human longevity. It can’t greatly repair or reverse existing damage, it can’t much help those who are already old become less damaged, it will likely not even be as effective as actual, old-fashioned calorie restriction. The current consensus is that calorie restriction itself is not going to add more than a few years to a human life – though it certainly has impressive health benefits.

(A sidebar: we can hope that one thing that ultimately emerges from all this research is an explanation as to how humans can enjoy such large health benefits from calorie restriction, commensurate with those seen in animals such as mice, without also gaining longer lives to match. But if just eating fewer calories while obtaining good nutrition could make humans reliably live 40% longer, I think that would have been noted at some point in the last few thousand years, or at least certainly in the last few hundred).

From this perspective, traditional drug research turned into longevity science looks like a long, slow slog to nowhere. It keeps people working, but to what end? Not producing significant results in extending human longevity, that’s for sure.

Ergo…

The cost of demonstrating that SENS is the right path or the wrong path – i.e. that aging is simply an accumulation of damage, and the many disparate research results making up the SENS vision are largely correct about which forms of change in aged tissue are the fundamental forms of damage that cause aging – is tiny compared to the cost of trying to safely eke out modest reductions in the pace of aging by manipulating metabolism via sirtuins or mTOR.

The end result of implementing SENS is true rejuvenation if aging is caused by damage: actual repair, actual reversal of aging. The end result of spending the same money and time on trying to manipulate metabolism to slow aging can already be observed in sirtuin research, and can reasonably be expected to be much the same the next time around the block with mTOR – it produces new knowledge and little else of concrete use, and even when it does eventually produce a drug candidate, it will likely be the case that you could do better yourself by simply practicing calorie restriction.

The expectation value of SENS is much greater than that of trying to slow aging via the traditional drug-discovery and development industry. Ergo the research and development community should be implementing SENS. It conforms to the consensus position on what causes aging, it costs far less than all other proposed interventions into the aging process, and the potential payoff is much greater.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 

This work is reproduced here in accord with a Creative Commons Attribution license.  It was originally published on FightAging.org.

A Brace of Papers from the Longevity Genetics Community – Article by Reason

A Brace of Papers from the Longevity Genetics Community – Article by Reason

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The New Renaissance Hat
Reason
December 29, 2013
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You’ll find quite a few papers on longevity and genetics in the preprint queue of Current Vascular Phamacology at the moment. This is a portion of the output of that part of the research community focused on developing a full understanding of the molecular biology of how aging progresses and varies between individuals and species. Biology is fantastically complex, and obtaining that full understanding will be a much, much more challenging endeavor than merely successfully treating or reversing aging.

Treating and even curing aging are goals that might be achieved without a full understanding of exactly how aging progresses. Consider this: you don’t need anything even close to a full molecular model of the progression of rust to greatly extend the life of metal equipment through scrubbing and protective coating. Exactly the same argument about knowledge and action can be applied to biology and medicine. Knowing what the damage is and having a complete understanding of how that damage progresses to cause the visible symptoms of aging are two very different things, the latter much more complex than the former, and only the former actually needed to produce useful therapies.

Nonetheless, most of the present work and funding in the aging science community is focused on developing an understanding of how degenerative aging progresses, not on damage repair and treatment of aging. So most of the output of the research community looks much along the lines of these first few papers I’m going to point out today.

The Challenges in Moving from Ageing to Successful Longevity

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During the last decades survival has significantly improved and centenarians are becoming a fast-growing group of the population. Genetic factors contribute to the variation of human life span by around 25%, which is believed to be more profound after 85 years of age. It is likely that multiple factors influence life span and we need answers to questions such as: 1) What does it take to reach 100?, 2) Do centenarians have better health during their lifespan compared with contemporaries who died at a younger age?, 3) Do centenarians have protective modifications of body composition, fat distribution and energy expenditure, maintain high physical and cognitive function, and sustained engagement in social and productive activities?, 4) Do centenarians have genes which contribute to longevity?, 5) Do centenarians benefit from epigenetic phenomena?, 6). Is it possible to influence the transgenerational epigenetic inheritance (epigenetic memory) which leads to longevity?, 7) Is the influence of nutrigenomics important for longevity?, 8) Do centenarians benefit more from drug treatment, particularly in primary prevention?, and, 9) Are there any potential goals for drug research?

Genes Of Human Longevity: An Endless Quest?

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Human longevity is a complex trait which genetics, epigenetics, environmental and stochasticity differently contribute to. To disentangle the complexity, our studies on genetics of longevity were, at the beginning, mainly focused on the extreme phenotypes, i.e. centenarians who escaped the major age-related diseases compared with cross sectional cohorts.

In association studies on candidate genes many SNPs, positively or negatively correlated with longevity have been identified. On the other hand, the identification of longevity-related genes does not explain the mechanisms of healthy aging and longevity, but it opens a huge amount of questions on epigenetic contribution, gene regulation and the interactions with essential genomes, i.e. mitochondrial DNA and microbiota.

Centenarian Offspring: a model for Understanding Longevity

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A main objective of current medical research is the improving of life quality of elderly people as priority of the continuous increase of ageing population. Accordingly, the research interest is focused on understanding the biological mechanisms involved in determining the positive ageing phenotype, i.e. the centenarian phenotype. Centenarians have been used as an optimal model for successful ageing. However, it is characterized by several limitations, i.e. the selection of appropriate controls for centenarians and the use itself of the centenarians as a suitable model for healthy ageing. Thus, the interest has been centered on centenarian offspring, healthy elderly people. They may represent a model for understanding exceptional longevity for the following reasons: to exhibit a protective genetic background, cardiovascular and immunological profile as well as a reduced rate of cognitive decline than age-matched people without centenarian relatives.

Phenotypes and Genotypes of High Density Lipoprotein Cholesterol in Exceptional Longevity

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A change in the lipoprotein profile is a metabolic hallmark of aging and has been the target for modern medical developments. Although pharmaceutical interventions aimed at lipid lowering substantially decrease the risk of cardiovascular disease, they have much less impact on mortality and longevity. Moreover, they have not affected death from other age-related diseases.

In this review we focus on high density lipoprotein (HDL) cholesterol, the levels of which are either elevated or do not decrease as would be expected with aging in centenarians, and which are associated with lower prevalence of numerous age-related diseases; thereby, suggesting a potential HDL-mediated mechanism for extended survival. We also provide an update on the progress of identifying longevity-mediating lipid genes, describe approaches to discover longevity genes, and discuss possible limitations. Implicating lipid genes in exceptional longevity may lead to drug therapies that prevent several age-related diseases, with such efforts already on the way.

It has to be said, however, that some areas of research are close enough to the development of actual rejuvenation treatments – those addressing at least some of the root cause damage of aging rather than downstream consequences – that even the scientific mainstream is coming around to the idea. The impact of cellular senescence on aging is one such field, as several obvious and existing applications of medical technology may aid in removal of the senescent cells that accumulate with age, and early work in mice confirms that such treatments should prove helpful:

Cellular Senescence in Ageing, Age-Related Disease and Longevity

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Cellular senescence is the state of permanent inhibition of cell proliferation. There is mounting evidence that senescent cells contribute to ageing and age-related disease by generating a low grade inflammation state (senescence-associated secretory phenotype-SASP). Even though cellular senescence is a barrier for cancer it can, paradoxically, stimulate development of cancer via proinflammatory cytokines. There is evidence that senescent vascular cells, both endothelial and smooth muscle cells, participate in atherosclerosis and senescent preadipocytes and adipocytes have been shown to lead to insulin resistance.

Thus, modulation of cellular senescence is considered as a potential pro-longevity strategy. It can be achieved in several ways like: elimination of selected senescent cells, epigenetic reprogramming of senescent cells, preventing cellular senescence or influencing the secretory phenotype. Some pharmacological interventions have already been shown to have promising activity in this field.

 

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 

This work is reproduced here in accord with a Creative Commons Attribution license.  It was originally published on FightAging.org.

Free Will and Self-Causation – Article by Leonid Fainberg

Free Will and Self-Causation – Article by Leonid Fainberg

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The New Renaissance Hat
Leonid Fainberg
August 26, 2013
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Homo liber nulla de re minus quam de morte cogitat; et ejus sapientia non mortis sed vitae meditatio est.

~ SPINOZA’S Ethics, Pt. IV, Prop. 67

(There is nothing over which a free man ponders less than death; his wisdom is, to meditate not on death but on life.)

Reductionism and its corollary, Determinism, are deeply enrooted in the fabric of the modern mainstream philosophy. These are leftovers of the Cartesian mind-body dichotomy. Instead of rejecting this notion altogether, Reductionists simply choose the other, bodily side of this loaded coin. Now they have reached a blind alley in their attempts to explain life in terms of lifelessness. As Hans Jonas observed:

“Vitalistic monism is replaced by mechanistic monism, in whose rules of evidence the standard of life is exchanged for that of death.” (The Phenomenon of Life, pg. 11).

Since Mind and Free Will are biological phenomena which cannot be explained in terms of non-life, Reductionists are necessarily Determinists. Hard Determinists reject the notion of Free Will (and therefore Mind) completely; soft Determinists and Compatibilists are still trying to find explanation of Free Will in the indeterminate realm of Quantum mechanics, in stochastic rules of Chaos theory, or in the mystical realm of Tao. I maintain that Free Will is a manifestation on the conceptual level of the very essential property of life itself, which is biological self-causation.

“Freedom must denote an objectively discernible mode of being, i.e., a manner of executing existence, distinctive of the organic per se.” (Ibid, pg. 3).

The Law of Causality is the Law of Identity applied to action (Ayn Rand). Since biological action is a self-generated, goal-orientated response (SIGOR) to environmental challenges, such an action cannot be predetermined by any antecedent cause. On the contrary, any antecedent or proximate action could be only detrimental to the healthy living process.

As Rosen put it:

“[I]t is perfectly respectable to talk about a category of final causation and to a component as the effect of its final cause… In this sense, then, a component is entailed by its function… a material system is an organism if and only if it is closed to efficient causation.” (Life Itself, pg. 135).

In other words the process of biological causation is a process in which a final cause (a goal), becomes its efficient cause.  Traditionally, the notion of the final cause associated with Aristotle’s primary mover, some divine, supernatural source.  However, this is not a case of mysticism, far from it.

Life emerged as a result of self-organization of abiotic elements. How that happened we don’t know yet. However, some researchers think that this is a thermodynamically inevitable event.

“Life is universally understood to require a source of free energy and mechanisms with which to harness it. Remarkably, the converse may also be true: the continuous generation of sources of free energy by abiotic processes may have forced life into existence as a means to alleviate the buildup of free energy stresses….” (Energy Flow and the Organization of Life. Harold Morowitz and Eric Smith, 2006).

But does this mean that life is a determined process? I don’t think so. Life is an emergent phenomenon, and as such it possesses new properties which its precursors don’t have. In their book Biological Self-organization Camazine et al. (2001: 8) define self-organization “as a process in which pattern at the global level of a system emerges solely from numerous interactions among the lower-level components of the system. The system has properties that are emergent, if they are not intrinsically found within any of the parts, and exist only at a higher level of description….’’

From this definition it follows that (1) a process of self-organization doesn’t have an antecedent cause; and (2) emergent properties of such a system are different from the properties of its components and therefore cannot be explained by means of reductionism. In other words, properties of such a system are not defined by antecedent cause. Life is a self-organizing, self-regulated material structure which is able to produce self-generated, goal-orientated action when the goal is preservation and betterment of itself. This new emergent identity which applied to biotic action defines new type of causation: self-causation.

Harry Binswanger observed that “All levels of living action, from a cell’s protein-synthesis to a scientist’s investigations, are goal-directed. In vegetative action, past instances of the ‘final cause’ act as ‘efficient cause.’” (1992).

This is the mechanism of self-causation. Now it is clear why any action imposed on the organism and driven by antecedent cause could be only detrimental: it inevitably would interfere with the self-generated action of the organism. Each and every organism is its own primary mover. In the low organisms the degree of freedom of action is limited by their genetic setup. However, even low organisms, like fungi for example, able to overcome this genetic determinism.

“During a critical period, variability is generated by the fact that a system becomes conditioned by all the factors influencing the spontaneous emergence of a symmetry-breaking event. In such a context variability does not reflect an environmental perturbation in expression of a pre-existing (genetic) program of development…It is expression of a process of individuation.” (Trewavas, 1999)

SIGOR is limited by an organism’s perceptual ability and capacity to process the sensory input. The process of evolution is a process of development of these qualities, since the organism’s survival depends on them. More freedom of action means better chances of survival. The end product of such a process is Free Will and self-awareness – that is, human mind. Free Will therefore is an expression of self-causation on conceptual level.

As Rodrigues observed: “Cerebral representations result from self-emergence of networks of interactions between modules of neurons stimulated by sensorial perception.” (Rodriguez at al., 1999)

The human abilities to choose goals consciously and to act rationally in order to achieve them lead us from biology to ethics. But the origin of these abilities lies in the very fundamental property of any living being. This property is self-generated, goal-orientated action driven by self-causation. Any attempt to reduce this property to the set of biochemical reactions or to undetermined behavior of subatomic particles is doomed to fail. Ayn Rand profoundly summarized the meaning of life in We, The Living: “I know what I want, and to know HOW TO WANT – isn’t it life itself?”

Leonid Fainberg is an Objectivist philosopher and contributor to The Rational Argumentator.

Indefinite Life Extension is Achievable – Video by G. Stolyarov II

Indefinite Life Extension is Achievable – Video by G. Stolyarov II

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Mr. Stolyarov summarizes why indefinite life extension is achievable in our lifetimes, given enough effort, funding, and moral support. He encourages your support for the Movement for Indefinite Life Extension (MILE), which has the goal of increasing awareness of indefinite life extension by an order of magnitude each year.

References
– The Movement for Indefinite Life Extension (MILE) Facebook Page: http://themile.info or https://www.facebook.com/pages/MILE-Movement-for-Indefinite-Life-Extension/197250433628807
– SENS Research Foundation: http://sens.org
– Resources on Indefinite Life Extension (RILE): http://rationalargumentator.com/RILE.html