The Best of the SENS AMA – Article by Steve Hill and Aubrey de Grey

The Best of the SENS AMA – Article by Steve Hill and Aubrey de Grey

Steve Hill

Dr. Aubrey de Grey


Editor’s Note: In this article, Steve Hill highlights the Ask Me Anything on Reddit held on December 7th by Dr. Aubrey de Grey.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, December 13, 2017

 

Dr. Aubrey de Grey from the SENS Research Foundation (SRF) did an Ask Me Anything on Reddit on December 7th, and there were many great questions and answers; we thought it would be a great time to summarize some of the best ones and offer a little commentary.

What do you think were the biggest wins of the last couple of years in SENS-relevant advocacy, research, and development? What has moved the needle?

There have been lots. On the research, I would highlight our paper in Science two years ago, which shows how to synthesize glucosepane, and our paper in Nucleic Acids Research one year ago, which shows simultaneous allotopic expression of two of the 13 mitochondrial genes. Both of those projects have been greatly accelerated in the meantime as a result of those key enabling breakthroughs; watch this space.

On advocacy, I think the main win has been the arrival of private capital; I would especially highlight Jim Mellon and his Juvenescence initiative because he is not only a successful, energetic and visionary investor, he is also a highly vocal giver of investment advice.

We are pleased to have been involved with the second project mentioned here, as we hosted the MitoSENS project at Lifespan.io, where it raised 153% of its initial fundraising goal. Less than a year later, after raising this money, it went on to publish the groundbreaking study showing that backup copies of mitochondrial genes could indeed be created in the nucleus. Dr. de Grey originally proposed the idea over a decade ago amid much scepticism; it is really good to see that years later he has been vindicated. This is the power of crowdfunding and how we as a community can make big changes in science by working together.

How do you feel about the impact of groups like LEAF advocating and reporting on rejuvenation biotech? Has the advocacy and reporting of these groups made your life any easier?

Massively! A huge thing that I say all the time is that advocacy absolutely relies upon the diversity of its messengers. Different people listen to different forms of words, different styles of messaging, etc. The more, the better.

It’s good to know that our work is appreciated and helping. Working together as a community is essential for progress, so it was nice to see this question and response from someone we respect a great deal.

We have said many times before effective advocacy efforts are just as important as the research itself. Professional advocacy has the potential to increase public support and funding, paving the way for the arrival of rejuvenation biotechnology. In the past decade or so, advocacy has mostly been left to volunteers and people such as Dr. de Grey.

Popular causes attract celebrities, public support, funding and investment; if we want a revolution in medicine and how we treat aging, then we must popularize the movement. There has been a serious shortage of full-time and organized advocacy; therefore, we decided to create LEAF to support groups like the SRF, advocate to popularize the cause, and help to raise much-needed funds for research efforts. We are only able to do this thanks to the support of the community, and we are extremely grateful to our Lifespan Heroes for helping us to do the work we do.

Aside from funding, what do you consider to be a burden or delay for your type of research?

Nothing. Seriously, nothing at all. We have the plan, and we have the people. It’s all about enabling those people by giving them the resources to get on with the job.

Indeed, funding for research is one of the four major bottlenecks slowing down the development of therapies that address the aging processes. The more funding the field gets, the more projects can be launched, the sooner breakthroughs can potentially happen, and the greater the benefits will likely be for all of us.

Is there anything new you are able to say about the breaking of cross-links in the extracellular matrix?

Absolutely. Short story, we now have a bunch of glucosepane-breaking enzymes, and we are within a few months of spinning the work out into a startup.

A suspected cause of degenerative aging is the accumulation of sugary metabolic wastes known as advanced glycation end-products (AGEs). These are wastes that are, in some cases, hard for our metabolism to break down fast enough or even at all. Some types, such as glucosepane, can form cross-links, gumming together important proteins such as those making up the supporting extracellular matrix scaffold.

The properties of elastic tissues (skin and the blood vessel walls) derive from the particular structure of the extracellular matrix, and cross-links degrade that structure, preventing it from functioning correctly. AGEs’ presence contributes to blood vessel stiffening with age, and it is implicated in hypertension and diabetes.

That SRF now has candidate enzymes is very significant because it means that there are now potential ways to remove these crosslinks from our tissues. There are many types of crosslinks, and we already know of compounds and drugs that can break other kind of crosslinks; the major problem is glucosepane, as it lasts a very long time, and, so far, nothing is known to remove it. Given that other types of crosslinks can be removed, Dr. de Grey rightly thought that there must be ways to remove (cleave) glucosepane from tissues; now, it seems that we are a step closer to that potentially becoming a reality.

If the SRF is successful in finding ways to break glucosepane crosslinks, this has huge implications for diabetes, hypertension and aging. It is great to hear that the organization is now reaching the point at which it is almost time to develop this as a therapy by creating a startup company.

It seems likely that artificial intelligence will be a necessary tool in order to reach longevity escape velocity. I was wondering how much of a role does artificial intelligence play in your research? Is this something you devote many resources to?

We don’t, but that is because other major players in this field (and good friends of mine), such as Alex Zhavoronkov and Kristen Fortney, are doing it so well already (with Insilico Med and BioAge, respectively). Check out the BioData West conference that will occur in SF a couple of days before our Undoing Aging conference in Berlin; I will be chairing a session on this.

We believe that the application of AI and, in particular, machine learning will prove to be a very valuable tool for research in the coming years. Such systems are ideally suited for high-throughput, laborious tasks that also require high attention to detail and would take humans a long time to do. Drug discovery, image analysis and many more tasks in the lab could potentially be automated, saving time and freeing up researchers to work on other critical tasks.

We are proud to have hosted the MouseAge project this year, which is an AI-based visual aging biomarker application that helps researchers determine the age of mice without the use of harmful tests. In a few months, researchers will be able to use the MouseAge application in the lab to help speed research progress up. This is just one example of how AI can be used in aging research and how the community helped to make it happen.

Given current funding, how far away from robust mouse rejuvenation do you think you are?

My estimate is 5-7 years, but that’s not quite “given current funding”. My overoptimism in saying “10 years” 13 years ago consisted entirely of overoptimism about funding – the science itself has not thrown up any nasty surprises whatsoever – but, nonetheless, I am quite optimistic as of now about funding, simply because the progress we have made has led to a whole new world of startups (including spinoffs from the SENS Research Foundation) and investors, so it’s not only philanthropy anymore. Plus, the increase in overall credibility of the approach is also helping to nurture the philanthropic side. We are still struggling, that’s for sure, but I’m feeling a lot surer that the funding drought’s days are numbered than I felt even two or three years ago.

Robust mouse rejuvenation (RMR) has long been a goal for the SENS Research Foundation, going back to when the SENS approach was initially proposed. RMR was originally outlined as being able to demonstrate and replicate SENS to double the remaining life expectancy of an already aged mouse. This would not mean the first RMR would be a total implementation of all the SENS approaches or that rejuvenation would need to be absolute; it would be a first pass to demonstrate the viability of multiple SENS approaches combined to produce robust results.

Being able to achieve a first-pass RMR could do much to convince academia that the repair approach to aging is plausible and attract more funding and interest in the approach. While RMR working in mice may not sound that exciting, it has huge implications for the field and potentially the rate of funding and progress.

How confident are you still in your previous prediction that humans will be able to control aging by 2029?

I think we’ve slipped a few years, entirely because of lack of funding. The tipping point will be when results in mice convince a critical mass of my curmudgeonly, reputation-protecting expert colleagues that rejuvenation will eventually work, such that they start to feel able to say so publicly. I think that’s on the order of five years away.

We think that the tipping point could well be if senolytics have the same result in humans as they have in mice. Enhanced tissue repair and regeneration in older people would be a very strong case for the repair approach to aging and almost certain to convince the academics sitting on the fence.

Certainly, if AGE breakers could be demonstrated to work in humans, this would also go a long way towards not only convincing academia but also grabbing public interest. Removing AGEs from the skin may potentially reverse wrinkles, for example, and restore skin elasticity, offering a very visual demonstration of repair being plausible.

There is almost certainly going to be a tipping point at which the bulk of academic and public support swings in favour of a repair approach to aging; the only question is when? Well, the sooner the basic science can be done and moved to translational research, the sooner we can all potentially benefit from these technologies. This makes supporting both the research and advocacy of rejuvenation biotechnology very important for progress.

 

About Dr. Aubrey de Grey

Dr. Aubrey de Grey is a biomedical gerontologist based in Cambridge, UK and Mountain View, California, USA, and is the Chief Science Officer of SENS Research Foundation, a California-based 501(c)(3) charity dedicated to combating the aging process. He is also Editor-in-Chief of Rejuvenation Research, the world’s highest-impact peer-reviewed journal focused on intervention in aging. He received his BA and Ph.D. from the University of Cambridge in 1985 and 2000 respectively. His original field was computer science, and he did research in the private sector for six years in the area of software verification before switching to biogerontology in the mid-1990s. His research interests encompass the characterisation of all the accumulating and eventually pathogenic molecular and cellular side-effects of metabolism (“damage”) that constitute mammalian aging and the design of interventions to repair and/or obviate that damage. He has developed a possibly comprehensive plan for such repair, termed Strategies for Engineered Negligible Senescence (SENS), which breaks aging down into seven major classes of damage and identifies detailed approaches to addressing each one. A key aspect of SENS is that it can potentially extend healthy lifespan without limit, even though these repair processes will probably never be perfect, as the repair only needs to approach perfection rapidly enough to keep the overall level of damage below pathogenic levels. Dr. de Grey has termed this required rate of improvement of repair therapies “longevity escape velocity”. Dr. de Grey is a Fellow of both the Gerontological Society of America and the American Aging Association, and sits on the editorial and scientific advisory boards of numerous journals and organisations.

About Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies, Steve has provided the community with multiple educational articles, interviews, and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity Reporter, Psychology Today, and Singularity Weblog. He is a co-author of the book Aging Prevention for All – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

DNA as the Original Blockchain – Article by Alex Lightman

DNA as the Original Blockchain – Article by Alex Lightman

Alex Lightman


I think of DNA as the original Blockchain, code for 3D printing a billion years old.

Thinking of DNA as reusable software might enable us to increase our average life span by 800%.

If you think of DNA as code and don’t get distracted by phenotypes (appearances) and remember the First Rule of Engineering is “Steal, Don’t Invent”, you can find some pretty interesting code that is almost human.

Did you know that there are big mammals that can live over 200 years? And sharks that can live 400-600 years?

Mammals are all genetically over 98% the same DNA (the biological Blockchain) as Homo sapiens sapiens (humans).

One mammal able to live over 200 years is the Bowhead whale. The Greenland shark is known to live over 400 years. Sharks are not mammals, but you would be shocked at the genetic similarity. Start here to learn more.

I think we should breed vast herds of Bowhead whales and Greenland sharks and domesticate them in Seastead Communities, and maintain multi-century interspecies communication, based on the protocols developed by my old friend John Lilly, inventor of the isolation tank.

We have already identified the genetic components of longevity, which include high resistance to cancer.

Did you know this? This is why we need Transhumanist Party candidates and elected officials: we should be talking about and focused on life expectancy and cancer resistance. Half of Americans get cancer and half of those die of cancer – over 600,000 a year!

Genetic Causes of Longevity in Bowhead Whales

It was previously believed the more cells present in an organism, the greater the chances of mutations that cause age-related diseases and cancer.

Although the bowhead whale has thousands of times more cells than other mammals, the whale has a much higher resistance to cancer and aging. In 2015, scientists from the US and UK were able to successfully map the whale’s genome.

Through comparative analysis, two alleles that could be responsible for the whale’s longevity were identified.

These two specific gene mutations linked to the Bowhead whale’s ability to live longer are the ERCC1 gene and the proliferating cell nuclear antigen (PCNA) gene. ERCC1 is linked to DNA repair as well as increased cancer resistance. PCNA is also important in DNA repair.

These mutations enable bowhead whales to better repair DNA damage, allowing for greater resistance to cancer.

The whale’s genome may also reveal physiological adaptations such as having low metabolic rates compared to other mammals.

Changes in the gene UCP1, a gene involved in thermoregulation, can explain differences in the metabolic rates in cells.

Alex Lightman, Campaign Director for the California Transhumanist Party, has 25 years of management and social innovation experience and 15 years of chairman and chief executive experience. He is an award-winning inventor with multiple U.S. patents issued or pending and author of over one million published words, including the first book on 4G wireless, and over 150 articles in major publications. He chaired and organized 17 international conferences with engineers, scientists, and government officials since 2002, with the intention of achieving policy breakthroughs related to innovation. He is a world-class innovator and recipient of the first Economist magazine Readers’ Choice Award for “The Innovation that will Most Radically Change the World over the Decade 2010 to 2020” (awarded Oct. 21, 2010, out of 4,000 initial suggestions and votes over 5 months from 200 countries, and from 32 judges). He is the recipient of the 2nd Reader’s Award (the posthumous recipient announced 10/21/2011 was Steve Jobs). He is also the winner of the only SGI Internet 3D contest (both Entertainment and Grand Prize) out of 800 contestants.

Social innovation work includes repeatedly putting almost unknown technologies and innovation-accelerating policies that can leverage the abilities of humanity into the mainstream of media, business, government, foundations, and standards bodies, including virtual reality, augmented reality, Internet Protocol version 6, and 4G wireless broadband, open spectrum, technology transfer to developing countries, unified standards, crowd-sourcing, and collective intelligence, via over 40 US government agencies, over 40 national governments, and via international entities including the United Nations and the North Atlantic Treaty Organization (NATO).

Political credentials include a national innovation plan entitled “The Acceleration of American Innovation” for the White House Office of Science and Technology Policy, work for U.S. Senator Paul E. Tsongas (D-MA) and on several state campaigns and U.S. presidential campaigns for Democratic candidates (Gary Hart, Richard Gephardt), presentations to the United Nations, and advisory services to the governments of Bahrain, United Arab Emirates, New Zealand, Australia, Philippines, Japan, China, Korea, and India, as well as to the U.S. Congress, the White House (via the Office of Management and Budget), the U.S. Joint Chiefs of Staff, the Defense Information Systems Agency, and the North Atlantic Treaty Organization (NATO). Mr. Lightman is trained as an engineer at MIT and as a prospective diplomat and policy analyst at Harvard’s Kennedy School of Government.

Unique Forms of Continuity in Space – Umberto Boccioni

Unique Forms of Continuity in Space – Umberto Boccioni

Umberto Boccioni


 

The ideas of Transhumanism and post-humanist thought may seem as if they belong to the 21st century, but humans have been capturing such an imagination of the future by means of artistic expression way before they could see the state of technology today.

It was an 1909 when Italian poet F.T. Marinetti laid out the core tenets of the Futurism Movement in his manifesto. Futurism can be seen as one of the points of origin for the beautiful relationship of transhumanism and art. Born out of an era of a growing disdain for the fascist government in Italy and the state of the world at the time, Futurism called upon the prospect of bringing a future of youth, industry, and advancing technology. The Futurist Movement thus gave birth to an era of artists that aimed to capture the essence of a possible future where the lines between technology and human were completely blurred.

Unique Forms of Continuity in Space is a bronze cast sculpture that is heavily regarded as one of the core works that truly represent the aesthetic of the Futurist Movement. It’s creator was Italian artist, Umberto Boccioni. Boccioni was one of the principal figures that shaped the art of Futurism as he advocated the use of dynamic movement and the deconstruction of masses.

In Unique Forms of Continuity in Space, Boccioni presents viewers with a human figure with deconstructed masses that appear to be aerodynamic. The figure is engaged in pursuing one direction, almost as if it were its sole purpose; to move forward against the winds of demise. The deconstructed masses and lack of arms, or face for that matter, allows the viewer to perceive something that could be beyond human. It is evident that Boccioni wants us to see our body as nothing but a mere vessel that can be molded and shaped in any way imaginable, allowing us to transcend the boundaries of the physical, organic body. The lack of a discernible face implies that Boccioni believes that we should no longer identify who we are by how we perceive our current physical form. We are not bound by how we look in the mirror.

It is the creative minds like Boccioni that provoke the most profound questions concerning the state of humanity. Art is the very force that propels our human imagination forward. Now that we are nearing the end of 2017, I love looking back at how far we have come as a species despite the abundant setbacks. Art will never cease to encourage the human spirit to move forward because in the end, it is life that imitates art.

Many of the works of Umberto Boccioni and the Futurist Movement can be experienced at the New York Metropolitan Museum of Art.

~ Emanuel Iral, Director of Visual Art, U.S. Transhumanist Party, December 8, 2017

 

SENS: Progress in the Fight Against Age-Related Diseases – Article by Nicola Bagalà and Steve Hill

SENS: Progress in the Fight Against Age-Related Diseases – Article by Nicola Bagalà and Steve Hill

Nicola Bagalà

Steve Hill


Editor’s Note: In this article, Mr. Nicola Bagalà and Steve Hill discuss the progress that the SENS Research Foundation has made in tackling the aging processes. Below is a brief summary of some of the highlights of their research efforts.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, December 8, 2017

 

 

Today, there are many drugs and therapies that we take for granted. However, we should not forget that what is common and easily accessible today didn’t just magically appear out of thin air; rather, at some point, it used to be an unclear subject of study on which “more research was needed”, and even earlier, it was just a conjecture in some researcher’s head.

Hopefully, one day not too far into the future, rejuvenation biotechnologies will be as normal and widespread as aspirin is today, but right now, we’re in the R&D phase, so we should be patient and remind ourselves that the fact that we can’t rejuvenate people today doesn’t mean that nothing is being done or has been achieved to that end. On the contrary, we are witnessing exciting progress in basic research—the fundamental building blocks without which rejuvenation, or any new technology at all, would stay a conjecture.

In particular, SENS Research Foundation (SRF), a pioneering organization of the field, is sometimes unjustly accused by skeptics for failing to produce results. But produce results it has, and many at that. Skeptics either decide to ignore them or do not have access to reliable sources. For the benefit of the latter, we’ll discuss below what has been achieved by SRF over the past few years, in relation to the infamous “seven deadly things”, the seven categories of damage that aging causes as described in the SENS repair approach.

Mitochondrial mutations

In a nutshell, a mitochondrion is a cell component that is in charge of converting food nutrients into ATP (adenosine triphosphate), a chemical that powers cellular function. Your DNA is contained within the nucleus of each of your cells, but this isn’t the only DNA in your body; mitochondria have their own DNA (known as mtDNA), likely because, at the dawn of life, they were independent organisms that eventually entered a symbiotic relationship with eukaryotic cells, such as those found in our bodies.

Unfortunately, as mitochondria produce ATP, they also produce so-called free radicals as a byproduct—atoms with unpaired electrons that seek to “pair up” with other electrons, and to do so, they’ll gladly snatch them from other molecules nearby, damaging them. As free radicals are created by mitochondria, they’re very close to mtDNA, which is thus very susceptible to being damaged and undergoing mutations.

Mitochondria with damaged DNA may become unable to produce ATP or even produce large amounts of waste that cells cannot get rid of. To add insult to injury, mutant mitochondria have a tendency to outlive normal ones and take over the cells in which they reside, turning them into waste production facilities that increase oxidative stress—one of the driving factors of aging.

MitoSENS: How to solve this problem, and how far we’ve got

Cell nuclei are far less exposed to free-radical bombardment than mitochondria, which makes nuclear DNA less susceptible to mutations. For this reason, the cell nucleus would be a much better place for mitochondrial genes, and in fact, evolution has driven around 1000 of them there. Through a technique called allotopic expression, we could migrate the remaining genes to the nucleus and solve the problem of mitochondrial mutations.

Human-made allotopic expression was a mere theory until late 2016, when, thanks to the successful MitoSENS crowdfunding campaign on Lifespan.io, a proof of concept was finally completed. Dr. Matthew O’Connor and his team managed to achieve stable allotopic expression of two mitochondrial genes in cell culture, as reported in the open-access paper[1] they published in the journal Nucleic Acids Research. As Aubrey de Grey himself explains in this video, of the 13 genes SRF is focusing on, it’s now managed to migrate almost four. This had never been done before and is a huge step towards addressing this aspect of aging in humans. In the past few months, the MitoSENS team has presented its results around the world and worked on some problems encountered in the project.

A list of SRF-funded papers on the topic of mitochondrial mutations can be found here. A more detailed description of its intramural MitoSENS research can be found here.

Lysosomal dysfunction

Lysosomes are digestive organelles within cells that dispose of intracellular garbage—harmful byproducts that would otherwise harm cells. Enzymes within lysosomes can dispose of most of the waste that normally accumulates within cells, but some types of waste, collectively known as lipofuscin, turn out to be impossible to break down. As a result, this waste accumulates within the lysosomes, eventually making it harder for them to degrade even other types of waste; in a worst-case scenario, overloaded lysosomes can burst open and spread their toxic contents around.

This eventuality is especially problematic for cells that replicate little or not at all, such as heart and nerve cells—they’ve got all the time in the world to become swamped in waste, which eventually leads to age-related pathologies, such as heart disease and age-related macular degeneration.

LysoSENS: How to solve this problem, and how far we’ve got

As normal lysosomal enzymes cannot break down lipofuscin, a possible therapy could equip lysosomes with better enzymes that can do the job. The approach suggested by SRF originates with ERT—enzyme replacement therapy—for lysosomal storage diseases. This involves identifying enzymes capable of breaking down different types of intracellular junk, identifying genes that encode for these enzymes, and finally delivering the enzymes in different ways, depending on the tissues and cell types involved.

SRF funded a preliminary research project on lipofuscin clearance therapeutics at Rice University[2] and another project relating to atherosclerosis and the clearance of 7-ketocholesterol[3] (a lipofuscin subtype), which eventually spun into Human Rejuvenation Biotechnologies, an early-stage private startup funded by Jason Hope.

A LysoSENS-based approach is currently being pursued by Dr. Kelsey Moody, who used to work at SRF. Dr. Moody has been working on an ERT treatment for age-related macular degeneration. The treatment consists in providing cells of the macula (a region of the eye’s retina) with an enzyme capable of breaking down a type of intracellular waste known as A2E. The treatment, called LYSOCLEAR, is being worked on by Moody’s company Ichor Therapeutics, which earlier this year has announced a series A offering to start Phase I clinical trials of its product.

If LYSOCLEAR proves successful, it could pave the way for future LysoSENS-based therapies to treat lysosomal dysfunction in different tissues.

A list of SRF-funded papers on the topic can be found here.

Cellular senescence

As cells divide, their telomeres—the end-parts of chromosomes protecting them from damage—shorten. Once a critical length has been reached, cells stop dividing altogether and enter a state known as senescence. Senescent cells are known to secrete a cocktail of chemicals called SASP (Senescence Associated Secretory Phenotype), which promotes inflammation and is associated with several age-related conditions.

However, senescent cells are a bit of a double-edged sword; as explained by Professor Judy Campisi during RB2016, as long as they’re not too numerous, senescent cells carry out an anti-cancer function and may promote wound healing; however, too many of them have the opposite effect, and on top of that, they induce neighboring cells to undergo senescence themselves, starting a dangerous spiral.

Normally, senescent cells destroy themselves via programmed cell death, known as apoptosis, and are then disposed of by the immune system, but some of them manage to escape destruction, and as the immune system declines with age, this gets worse.

The result is that late in life, senescent cells have accumulated to unhealthy amounts and significantly contribute to the development of age-related diseases. Osteoarthritis, cardiovascular diseases, cancer, metabolic disorders such as diabetes, and obesity are all linked to the chronic age-related inflammation to which senescent cells contribute.

ApoptoSENS: How to solve this problem, and how far we’ve got

The proposed SENS solution is straightforward: if senescent cells become too numerous, then they need to be purged. Since they are useful in small amounts, the optimal solution would be periodically removing excess senescent cells without eradicating them entirely—and more importantly, leaving other cells unharmed.

This could potentially be achieved by either senolytic drugs or gene therapies that selectively target senescent cells and trigger programmed cell death. Indeed, a great deal of recent focus by researchers have been on finding ways to remove senescent cells using senolytic therapies.

Another approach that could complement senolytics is to address why the immune system stops clearing senescent cells effectively in the first place. This approach focuses on macrophages and other immune cells involved in clearing senescent cells, aiming to reduce inflammation so that these cells begin to function properly again. The irony is that as inflammation rises with age, the immune system that is supposed to clear senescent cells and keep inflammation levels down actually starts to create more inflammation and becomes part of the problem by not doing its job properly.

SRF has funded a number of studies on the subject of cellular senescence, and it’s recently begun working on a project in collaboration with the Buck Institute for Research on Aging, which is focusing on the immune system and its role in clearing senescent cells. Another extramural project, again with the Buck Institute, is focussed on SASP inhibition.

Senescent cell clearance has been all the rage for the past two years or so; Lifespan.io has hosted the MMTP project, which focused on testing senolytics in mice, and this was later followed by CellAge’s project to design synthetic biology-based senolytics.

There are other companies that have joined the race to add senescent cell clearance to the standard toolkit of doctors, such as Unity Biotechnology and Oisin Biotechnologies.

Unity’s approach uses a drug-based approach to senolytics and is scheduled to enter human clinical trials in 2018. A number of other research teams are also developing drug-based approaches to removing senescent cells, and the competition looks set to be fierce in this area in the coming years.

Oisin’s approach, which we discussed here, makes use of suicide genes and hopefully will be tested in clinical trials not too far into the future, thanks to venture funding presently being collected. If this system can be made to work, it will allow very selective targeting of senescent cells by destroying only those giving off a target gene or genes. Thus, if a unique gene expression profile for senescent cells is determined, it would mean only those cells were destroyed, with less risk of off-target effects.

Oisin owes its existence to the SENS Research Foundation and the Methuselah Foundation, which provided the necessary seed funding. Kizoo Technology Ventures has also invested in Oisin.

Extracellular crosslinks

The so-called extracellular matrix is a collection of proteins that act as scaffolding for the cells in our body. This scaffolding is rarely if ever replaced, and a really bad consequence of this is that its parts eventually end up being improperly linked to each other through a process called glycation—the reaction of (mainly) blood sugar with the proteins that make up the extracellular matrix itself.

The resulting cross-links impair the function and movement of the linked proteins, ultimately stiffening the extracellular matrix, which makes organs and blood vessels more rigid. Eventually, this leads to hypertension, high blood pressure, loss of skin elasticity, and organ damage, among other problems.

While there are different types of cross-links—known as AGEs, short for advanced glycation end-products—glucosepane is arguably the worst, being the most common and long-lasting of all, and the body is very ill-equipped to break it down.

GlycoSENS: How to solve this problem, and how far we’ve got

In order to eliminate unwanted cross-links, the SENS approach proposes to develop AGE-breaking molecules that may indeed sever the linkages and return tissues to their original flexibility. Of course, in order to do so, crosslink molecules need to be available for research to attempt to combat them with drugs, and especially in the case of glucosepane, this has been a problem for years.

Glucosepane is a very complex molecule, and very little of it can be extracted from human bodies, and not even in its pure form. This has been greatly hampering the progress of research against glucosepane, but thankfully, this problem is now solved thanks to a collaboration between the Spiegel Lab at Yale University and the SENS Research Foundation, which financially supported the study. It is now possible to fully synthesize glucosepane, allowing for researchers to create it on demand and at a cost-effective price.

The Spiegel Lab’s scientists are now developing anti-glucosepane monoclonal antibodies to cleave unwanted cross-links. The collaboration between the Spiegel Lab and SRF dates all the way back to 2011, but it was in 2015 that the Lab announced its success and published a related paper [4] in the journal Science.

Further information on glucosepane cross-link breakers can be found in this interview with Dr. David Spiegel from Yale University on Fight Aging!; a list of studies on the subject funded or otherwise supported by the SRF is available here.

SRF also worked with the Babraham Institute on a cross-link quantification project.

Let’s help SRF move forward

Readers who wish to donate to SRF to help the organization in its crusade against the ill health of old age can do so by contributing to its winter fundraiser or even becoming SRF patrons. Have a look at SRF’s donation page to find out more.

NB: Dr. Aubrey de Grey (Chief Science Officer and Co-founder of SENS Research Foundation) himself held an AMA (“ask me anything”) on Reddit on December 7, at 14:00 PST (22:00 UTC, 17:00 EST). The questions and Dr. de Grey’s responses can be found here.

Literature

[1] Boominathan, A., Vanhoozer, S., Basisty, N., Powers, K., Crampton, A. L., Wang, X., … & O’Connor, M. S. (2016). Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant. Nucleic acids research, 44(19), 9342-9357.

[2] Gaspar, J., Mathieu, J., & Alvarez, P. (2016). A rapid platform to generate lipofuscin and screen therapeutic drugs for efficacy in lipofuscin removal. Materials, Methods and Technologies, 10, 1-9.

[3] Mathieu, J. M., Wang, F., Segatori, L., & Alvarez, P. J. (2012). Increased resistance to oxysterol cytotoxicity in fibroblasts transfected with a lysosomally targeted Chromobacterium oxidase. Biotechnology and bioengineering, 109(9), 2409-2415.

[4] Draghici, C., Wang, T., & Spiegel, D. A. (2015). Concise total synthesis of glucosepane. Science, 350(6258), 294-298.

 

About Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies, Steve has provided the community with multiple educational articles, interviews, and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity Reporter, Psychology Today, and Singularity Weblog. He is a co-author of the book Aging Prevention for All – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About Nicola Bagalà

Nicola Bagalà has been an enthusiastic supporter and advocate of rejuvenation science since 2011. Although his preferred approach to treating age related diseases is Aubrey de Grey’s suggested SENS platform, he is very interested in any other potential approach as well. In 2015, he launched the blog Rejuvenaction to advocate for rejuvenation and to answer common concerns that generally come with the prospect of vastly extended healthy lifespans. Originally a mathematician graduated from Helsinki University, his scientific interests range from cosmology to AI, from drawing and writing to music, and he always complains he doesn’t have enough time to dedicate to all of them which is one of the reasons he’s into life extension. He’s also a computer programmer and web developer. All the years spent learning about the science of rejuvenation have sparked his interest in biology, in which he’s planning to get a university degree.

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

Announcement of U.S. Transhumanist Party Collaboration with the Zero State (ZS) and Participation in the ZS Alternate Reality Game

Announcement of U.S. Transhumanist Party Collaboration with the Zero State (ZS) and Participation in the ZS Alternate Reality Game

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Gennady Stolyarov II


The U.S. Transhumanist Party is pleased to announce its incipient collaboration with a Social Futurist community based in the United Kingdom – the Zero State (ZS) – described as “an organization formed in 2011 to work toward the establishment of a pro-technology, Transhumanist, distributed, virtual State. ZS’ motto is ‘Positive Social Change Through Technology’.” As one of the Zero State’s co-founders, Dirk Bruere, explains, the primary meaning of the name “Zero State” is “the lowest energy state of a system, the place to which everything returns when the energy runs out.”

Given that the U.S. Transhumanist Party strongly supports such pro-technology initiatives as advocated by the Zero State, as well as distributed systems for participation in political processes, throughout its Platform (particularly Article III, Sections V, VI, VIII, IX, XIII) and also supports various forms of political, economic, and cultural experimentation in Article III, Section XXII, our collaboration with the Zero State is a logical fit for implementing our own vision for as many polities throughout the world which open themselves to ambitious experiments in paradigm-shifting technologies.

The most recent incarnation of the Zero State is that of an Alternate Reality Game (ARG), whose premise is described on this page. The game is pursued by twelve Houses, described as follows:

The Zero State is organised into twelve Houses, and each of those Houses began with twelve Founding Members.

The first five of those are the Core members, each of whom leads their own crew of “subsid” (subsidiary/affiliated) members. The five Core members of each House together comprise a kind of meta-team, known as the House’s Core Team. That Core Team is tasked with establishing their House in the years 12017-12018, by recruiting, developing the House’s internal culture and traditions, and working on projects known as Missions.

Dr. M. Amon Twyman (Ámon Ásentir), who co-founded the Zero State, has kindly designated the use of one of the twelve Zero State Houses – House Rhadamanth – for activities that would further the goals of the U.S. Transhumanist Party. The announcement of this development is available here and reads as follows:

House Rhadamanth has now been joined by Gennady Stolyarov II, who has assumed the Core role of “Anankes Atraktos” (a Greek term from Plato‘s Republic, meaning “Spindle of Necessity“). Gennady is Chairperson of the US Transhumanist Party, Chief Executive of the Nevada Transhumanist Party, and much more besides. This connection reflects a major development in House Rhadamanth’s focus and culture, which has now expanded from drones and robotics to Transhumanism in general, and which hinges on direct support for and collaboration with the Transhumanist Party, both in the US and internationally.

House Rhadamanth is now seeking both additional Core Members and Subsidiary Members to populate it. The purpose of this arrangement will be to engage transhumanists, futurists, and life-extensionists to pursue, in a “gamified” manner, the projects that will advance the objectives of the U.S. Transhumanist Party in the real world, all the while strengthening the network of connections and beneficial interactions among future-oriented thinkers throughout the world. If you are interested in joining, please e-mail Gennady Stolyarov II here. We are interested in 10 other individuals who would be able to devote a reasonable amount of time to actively advancing ongoing projects such as the following:

  • (1) The U.S. Transhumanist Party infographic project, which it is hoped will result in detailed visual representations that would, in essence, serve as a map of the terrain of transhumanist and life-extensionist organizations, social-media pages, and key individuals.
  • (2) Participation in distributed computing projects (for instance, Folding@home) aimed at fundamental research that could help accelerate the arrival of cures to various diseases. The U.S. Transhumanist Party previously announced this activism project here.
  • (3) Campaigns for writing and advocacy on particular issues – for instance, rejuvenation biotechnology research, rights of patients of rare diseases to pursue experimental treatments, or the official recognition of biological aging as a disease.

We welcome ideas for any other projects that could be pursued in this “gamified” format as well. Much of the Alternate Reality Game remains to be developed, but the early participants will have the opportunity to shape many of its parameters and contents. The U.S. Transhumanist Party sees promise in this additional way to strengthen ties within the international transhumanist movement and explore opportunities for collaborative endeavors among transhumanists and futurists of various persuasions and backgrounds.

Gennady Stolyarov II is the Chairman of the United States Transhumanist Party. Read more about Mr. Stolyarov here.

Why Bringing Aging Under Medical Control Probably Will Not Create a Gerontocracy – Article by Nicola Bagalà

Why Bringing Aging Under Medical Control Probably Will Not Create a Gerontocracy – Article by Nicola Bagalà

Nicola Bagalà


Editor’s Note: In this article, Mr. Nicola Bagalà discusses Gerontocracy and how it is becoming less likely due to factors such as increasing wide availability of knowledge and equal opportunities.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                      ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, December 05, 2017

 

As I discussed in another article, rejuvenation biotechnology would allow older adults to continue working and producing wealth for much longer than they can today, thus benefiting society in many ways.

However, some people are concerned that this might do more harm than good; imagine all those rejuvenated old farts holding onto their jobs forever, preventing the young from getting jobs themselves! Not to mention the risk of a gerontocratic world, where powerful older people get too attached to their chairs, never allowing younger people a chance!

New is not always better

If you’re more concerned that dictators could live for centuries, then you should have a look at this article; here, I’m going to deal with another scenario: old, rejuvenated people who hold on to positions of power—not necessarily as heads of countries—or their jobs for a really long time.

Quite frankly, what’s wrong with that?

Just because someone has been in charge of the same position for long, it doesn’t mean that it’s necessarily a bad thing. If you think otherwise, you might be making the assumption I rebutted here, namely that, rejuvenated or not, older people will always tend to do things in old ways, eventually making them a worse choice than younger people. On the contrary, their long experience might make them more fit than others, especially if we’re talking about chronologically older but open-minded people who keep up to date. Younger people aren’t necessarily the default better option. Think about all those times when a great person of our time died and you found yourself thinking that the world would have been better off if he or she had lived longer.

Personally, I think what matters is that people in certain positions, whether within government or a company, are the right people for the job. If they aren’t, old or young, they should be replaced by other people who are more fit, and, generally, there are more efficient and humane ways to do so than letting them get age-related diseases—for example, voting for someone else or hiring a different person. Granted, if the person to be kicked out is really powerful, this may well be easier said than done; however, when the holder of a position of such power dies of old age, his successor is rarely a nobody with no string-pulling abilities whatsoever. It’s not really a matter of longevity; rather, it’s that power attracts power, and I doubt that creating or not creating rejuvenation will make much of a difference in this respect.

Where does power come from?

It’s easy to hypothesize that a generation of rejuvenated 200-year-olds could end up becoming a gerontocratic elite that maintains power over younger people, but how would this be accomplished, exactly?

Maybe the older generation is rich and powerful, but unless we’re talking about a totalitarian world in which the masses are intentionally kept ignorant and poor, younger generations do have fair chances to make positions for themselves. Power and wealth come from knowledge, and, these days, knowledge is more freely and widely available than ever before.

Learning new professional skills and acquiring knowledge, in general, is possible for virtually everyone, thanks to the pervasiveness of educational media and the open availability of information on the Internet, including free (or reasonably affordable) online education projects, such as Coursera and Edx. The recent European initiative to ensure that all scientific papers are open access by 2020 represents another step towards a world that shares information rather than hides it.

Truth to be told, power and wealth don’t come only from knowledge; they also come from powerful and wealthy ancestors. If we didn’t develop rejuvenation, certainly all the Scrooge McDucks of the world would die sooner than they would otherwise, but their power and wealth would go to their heirs, and so on over the generations, which wouldn’t do much to prevent the creation of an elite. So, no, old age is not an easy way out of the problem of powerful elites ruling the world, and its absence wouldn’t make the problem any worse, really. The only possible way out is giving everyone equal access to knowledge and equal opportunities.

Inevitably, some will end up being more successful and thus more powerful than others anyway; however, if this allows them to become an oppressive force on the rest of us, I think this is a problem with our socio-economic system, not with the existence of lifesaving medical technology. I don’t know about you, but I’m not very keen on waiting until the “perfect” society or “perfect” economic system are built before we decide to cure the diseases of old age.

The fortune teller’s error

We shouldn’t make the mistake of predicting a negative outcome without considering the actual odds of it happening. I think fears of a society where rejuvenated elderly make younger people’s lives more difficult are misplaced in that they assume present-day scenarios will exist in the far future.

Take the concern about jobs, for example, rejuvenated old people would stick to their jobs forever and make it harder for young people to enter the workforce. It sounds bad, but there are a few assumptions behind it that we should question.

First, would rejuvenated old people actually stick to their jobs forever? Why? You hardly hear of a professional who was in the exact same job for forty years these days. More broadly, career change is a thing already. After all, after 40 years in the same line of work, it’s conceivable you might want to try something else, thus making room for others to take your place.

Will rejuvenated old people be allowed to stick to their jobs forever? Not everyone is a manager in charge of decisions, and your boss may well decide to lay you off, rejuvenated or not, and hire someone else.

Even if old rejuvenated people did stick to the same jobs forever, would they never take a break? Even if you’re in the prime of health, after a few decades, you may well wish to “retire” for a few years before going back to work, and your employer is probably not going to wait for you that long.

Will there be so many chronologically younger people in need of jobs in the future? The world population growth rate has been hopelessly corkscrew-diving for over 50 years now, and it is projected to keep going down as larger portions of the world transition from a developing to a developed economy. (In case you’re wondering, the population growth rate is going down not because more people die, but on the contrary, because fewer are born.)

Will people’s living depend on having a job in the future? We can’t expect indefinite life extension to happen very soon; before we can have 200-year-old people in the workforce, it’ll be at least a century. Is the economy going to be the same as today’s by then? Automation already seems on its way to cause the end of work as we know it.

I’d say it’s rather silly to oppose rejuvenation today for the reason that, in a century or two, it might cause an unemployment problem due to too many people being alive. It’s simply too long a time to make any even remotely accurate predictions on what the job market will be like or if there even will be any. In all honesty, I think it makes more sense to worry about a concrete problem that we already have today—the ill health of old age—than worry about a hypothetical one that might or might not happen in a hundred years’ time—massive unemployment. As time goes by, we’ll have a better picture of potential future problems lying ahead, and we’ll be in a better position than we are in today to do something about them.

Conclusion

I’ve said this many times over: the bottom line is always the same. Yes, life extension will most likely bring challenges along with benefits, but none of these challenges are certain, insurmountable, or not more than compensated for by the expected benefits. Let’s not deny ourselves and our descendants the chance for healthier, longer lives.

About Nicola Bagalà

Nicola Bagalà has been an enthusiastic supporter and advocate of rejuvenation science since 2011. Although his preferred approach to treating age related diseases is Aubrey de Grey’s suggested SENS platform, he is very interested in any other potential approach as well. In 2015, he launched the blog Rejuvenaction to advocate for rejuvenation and to answer common concerns that generally come with the prospect of vastly extended healthy lifespans. Originally a mathematician graduated from Helsinki University, his scientific interests range from cosmology to AI, from drawing and writing to music, and he always complains he doesn’t have enough time to dedicate to all of them which is one of the reasons he’s into life extension. He’s also a computer programmer and web developer. All the years spent learning about the science of rejuvenation have sparked his interest in biology, in which he’s planning to get a university degree.

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

BGRF and SILS Scientists Analyze Viability of shRNA Therapy for Huntington’s Disease – Press Release by Biogerontology Research Foundation

BGRF and SILS Scientists Analyze Viability of shRNA Therapy for Huntington’s Disease – Press Release by Biogerontology Research Foundation

Biogerontology Research Foundation


Friday, December 1, 2017, London, UK: Researchers from the Biogerontology Research FoundationDepartment of Molecular Neuroscience at the Swammerdam Institute for Life Sciences at the University of Amsterdam, and the Department of Neurobiology, Care Sciences and Society at the Karolinska Institute announce the publication of a paper in Translational Neurodegeneration, a BioMedCentral journal, titled RNAi mechanisms in Huntington’s disease therapy: siRNA versus shRNA.

After many years of development, RNAi therapeutics are nearing the clinic. There are several variants on RNAi therapeutics, such as antisense oligonucleotides (ASOs), short-hairpin RNA (shRNA), small interfering RNA (siRNA), et cetera. The researchers’ paper aimed to answer the question of why RNAi therapeutics for nucleotide repeat disorders (specifically Huntington’s, a devastating genetic neurodegenerative disease), have lost favor in recent years. After a phenomenal amount of excitement, these therapies were hindered by problems like molecular stability, dosing, and transcriptional control of the gene therapeutic construct.

“We compared various RNAi-based therapeutic modalities available for the treatment of Huntington’s Disease and offered mechanistic proposals on how to break through current barriers to clinical development. One key problem has proven to be modulating the expression level of shRNA constructs, which would otherwise be the clear frontrunner among ASOs, siRNAs, and other methods due to duration of expression, dramatically reduced off-target effects, and ease of delivery by adeno-associated viruses that are already approved by the EMA and FDA. We also put forward novel methods of modulating construct expression and avoiding off-target effects” said Franco Cortese, co-author of the paper and Deputy Director of the Biogerontology Research Foundation.

The researchers analyzed available data on the levels of off-target effects associated with siRNA vs shRNA, surveyed emerging strategies to reduce off-target effects in shRNA therapies (such as tough decoy RNAs, or TuDs), and proposed novel methods of controlling shRNA expression, in particular through the use of negative feedback-driven oscillating promoters.

Mechanism of TFEB at the PGC1-a promoter. The PGC1a promoter contains a CLEAR-box that is known to be bound by TFEB, a transcription factor induced during autophagy and lysosomal biogenesis. A construct being the PGC1a promoter CLEAR-box would be induced by TFEB under conditions of intracellular proteotoxicity due to HTT aggregation. By this mechanism, on-demand suppression of HTT could be achieved | Credit: Translational Neuroscience

 

“We proposed two novel feedback mechanisms that 1) activate construct expression stoichiometrically with mutant Huntingtin expression, or 2) only during aggregate-induced autophagy and lysosomal biogenesis. That way, the problem of excessive construct expression may be mitigated. These ideas were inspired by feedback systems used in synthetic biology, and in ‘nonsynthetic,’ naturally occurring biological systems” said Sebastian Aguiar, lead author of the paper.

Readers can read the open-access paper here: https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-017-0101-9.

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About the Biogerontology Research Foundation

The Biogerontology Research Foundation is a UK non-profit research foundation and public policy center seeking to fill a gap within the research community, whereby the current scientific understanding of the ageing process is not yet being sufficiently exploited to produce effective medical interventions. The BGRF funds and conducts research which, building on the body of knowledge about how ageing happens, aims to develop biotechnological interventions to remediate the molecular and cellular deficits which accumulate with age and which underlie the ill-health of old age. Addressing ageing damage at this most fundamental level will provide an important opportunity to produce the effective, lasting treatments for the diseases and disabilities of ageing, required to improve quality of life in the elderly. The BGRF seeks to use the entire scope of modern biotechnology to attack the changes that take place in the course of ageing, and to address not just the symptoms of age-related diseases but also the mechanisms of those diseases.

About the Swammerdam Institute for Life Sciences

The Swammerdam Institute for Life Sciences (SILS) is the largest institute of the Faculty of Science at the University of Amsterdam. The institute comprises biological disciplines including molecular and cell biology, microbiology, plant science, physiology and neurobiology, supported by modern enabling technologies for the life sciences. The research groups of SILS also develop methods in genomics (micro-array, next-gen sequencing, proteomics), bioinformatics and advanced light microscopy technologies. Knowledge from adjacent fields of science, in particular biochemistry, biophysics, medicine, bioinformatics, statistics and information technology make SILS a multidisciplinary research institute with a systems biology approach to the life sciences. SILS’ research objective is to understand the functioning of living organisms, from the most basic aspects up to complex physiological function(s). Biological processes are studied at the level of molecules, cells, cellular networks and organisms. SILS research topics have in common that similar cellular processes and interactions are studied, likewise using similar methodologies and technologies. Therefore SILS scientists often study the same concepts in different biological systems. Within the institute, this leads to exchange of information and extension of research over the borders of different disciplines. Part of SILS research activities are directed to application-oriented research in close collaboration with industry.

Review of Philip Tetlock’s “Superforecasting” by Adam Alonzi

Review of Philip Tetlock’s “Superforecasting” by Adam Alonzi

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Adam Alonzi


Alexander Consulting the Oracle of Apollo, Louis Jean Francois Lagrenée. 1789, Oil on Canvas.

“All who drink of this treatment recover in a short time, except those whom it does not help, who all die. It is obvious, therefore, that it fails only in incurable cases.”

-Galen

Before the advent of evidence-based medicine, most physicians took an attitude like Galen’s toward their prescriptions. If their remedies did not work, surely the fault was with their patient. For centuries scores of revered doctors did not consider putting bloodletting or trepanation to the test. Randomized trials to evaluate the efficacy of a treatment were not common practice. Doctors like Archie Cochrane, who fought to make them part of standard protocol, were met with fierce resistance. Philip Tetlock, author of Superforecasting: The Art and Science of Prediction (2015), contends that the state of forecasting in the 21st century is strikingly similar to medicine in the 19th. Initiatives like the Good Judgement Project (GJP), a website that allows anyone to make predictions about world events, have shown that even a discipline that is largely at the mercy of chance can be put on a scientific footing.

More than once the author reminds us that the key to success in this endeavor is not what you think or what you know, but how you think. For Tetlock pundits like Thomas Friedman are the “exasperatingly evasive” Galens of the modern era. In the footnotes he lets the reader know he chose Friedman as target strictly because of his prominence. There are many like him. Tetlock’s academic work comparing random selections with those of professionals led media outlets to publish, and a portion of their readers to conclude, that expert opinion is no more accurate than a dart-throwing chimpanzee. What the undiscerning did not consider, however, is not all of the experts who participated failed to do better than chance.

Daniel Kahneman hypothesized that “attentive readers of the New York Times…may be only slightly worse” than these experts corporations and governments so handsomely recompense. This turned out to be a conservative guess. The participants in the Good Judgement Project outperformed all control groups, including one composed of professional intelligence analysts with access to classified information. This hodgepodge of retired bird watchers, unemployed programmers, and news junkies did 30% better than the “pros.” More importantly, at least to readers who want to gain a useful skillset as well as general knowledge, the managers of the GJP have identified qualities and ways of thinking that separate “superforecasters” from the rest of us. Fortunately they are qualities we can all cultivate.

While the merits of his macroeconomic theories can be debated, John Maynard Keynes was an extremely successful investor during one of the bleakest periods in international finance. This was no doubt due in part to his willingness to make allowance for new information and his grasp of probability. Participants in the GJP display open-mindedness, an ability and willingness to repeatedly update their forecasts, a talent to neither under- nor over-react to new information by putting it into a broader context,  and a predilection for mathematical thinking (though those interviewed admitted they rarely used an explicit equation to calculate their answer). The figures they give also tend to be more precise than their less successful peers. This “granularity” may seem ridiculous at first. I must confess that when I first saw estimates on the GJP of 34% or 59%, I would chuckle a bit. How, I asked myself, is a single percentage point meaningful? Aren’t we just dealing with rough approximations? Apparently not.

Tetlock reminds us that the GJP does not deal with nebulous questions like “Who will be president in 2027?” or “Will a level 9 earthquake hit California two years from now?” However, there are questions that are not, in the absence of unforeseeable Black Swan events, completely inscrutable. Who will win the Mongolian presidency? Will Uruguay sign a trade agreement with Laos in the next six months? These are parts of highly complex systems, but they can be broken down into tractable subproblems.

Using numbers instead of words like “possibly”, “probably”, “unlikely”, etc., seems unnatural. It gives us wiggle room and plausible deniability. They also cannot be put on any sort of record to keep score of how well we’re doing. Still, to some it may seem silly, pedantic, or presumptuous. If Joint Chiefs of Staff had given the exact figure they had in mind (3 to 1) instead of the “fair chance” given to Kennedy, the Bay of Pigs debacle may have never transpired. Because they represent ranges of values instead of single numbers, words can be retroactively stretched or shrunk to make blunders seem a little less avoidable. This is good for advisors looking to cover their hides by hedging their bets, but not so great for everyone else.

If American intelligence agencies had presented the formidable but vincible figure of 70% instead of a “slam dunk” to Congress, a disastrous invasion and costly occupation would have been prevented. At this point it is hard not to see the invasion as anything as a mistake, but even amidst these emotions we must be wary of hindsight. Still, a 70% chance of being right means there is a 30% chance of being wrong. It is hardly a “slam dunk.” No one would feel completely if an oncologist told them they are 70% sure the growth is not malignant. There are enormous consequences to sloppy communications. However, those with vested interests are more than content with this approach if it agrees with them, even if it ends up harming them.

When Nate Silver put the odds of the 2008 election in Obama’s favor, he was panned by Republicans as a pawn of the liberal media. He was quickly reviled by Democrats when he foresaw a Republican takeover of the Senate. It is hard to be a wizard when the king, his court, and all the merry peasants sweeping the stables would not know a confirmation bias from their right foot. To make matters worse, confidence is widely equated with capability. This seems to be doubly true of groups of people, particularly when they are choosing a leader. A mutual-fund manager who tells his clients they will see great returns on a company is viewed as stronger than a Poindexter prattling on about Bayesian inference and risk management.

The GJP’s approach has not spread far — yet. At this time most pundits, consultants, and self-proclaimed sages do not explicitly quantify their success rates, but this does not stop corporations, NGOs, and institutions at all levels of government from paying handsomely for the wisdom of untested soothsayers. Perhaps they have a few diplomas, but most cannot provide compelling evidence for expertise in haruspicy (sans the sheep’s liver). Given the criticality of accurate analyses to saving time and money, it would seem as though a demand for methods to improve and assess the quality of foresight would arise. Yet for the most part individuals and institutions continue to happily grope in the dark, unaware of the necessity for feedback when they misstep — afraid of having their predictions scrutinized or having to take the pains to scrutinize their predictions.

David Ferrucci is wary of the “guru model” to settling disputes. No doubt you’ve witnessed or participated in this kind of whimpering fracas: one person presents a Krugman op-ed to debunk a Niall Ferguson polemic, which is then countered with a Tommy Friedman book, which was recently excoriated  by the newest leader of the latest intellectual cult to come out of the Ivy League. In the end both sides leave frustrated. Krugman’s blunders regarding the economic prospects of the Internet, deflation, the “imminent” collapse of the euro (said repeatedly between 2010 and 2012) are legendary. Similarly, Ferguson, who strongly petitioned the Federal Reserve to reconsider quantitative easing, lest the United States suffer Weimar-like inflation, has not yet been vindicated. He and his colleagues responded in the same way as other embarrassed prophets: be patient, it has not happened, but it will! In his defense, more than one clever person has criticized the way governments calculate their inflation rates…

Paul Ehrlich, a darling of environmentalist movement, has screeched about the detonation of a “population bomb” for decades. Civilization was set to collapse between 15 and 30 years from 1970. During the interim 100 to 200 million would annually starve to death, by the year 2000 no crude oil would be left, the prices of raw materials would skyrocket, and the planet would be in the midst of a perpetual famine. Tetlock does not mention Ehrlich, but he is, particularly given his persisting influence on Greens, as or more deserving of a place in this hall of fame as anyone else. Larry Kudlow continued to assure the American people that the Bush tax breaks were producing massive economic growth. This continued well into 2008, when he repeatedly told journalists that America was not in a recession and the Bush boom was “alive and well.” For his stupendous commitment to his contention in the face of overwhelming evidence to the contrary, he was nearly awarded a seat in the Trump cabinet.

This is not to say a mistake should become the journalistic equivalent of a scarlet letter. Kudlow’s slavish adherence to his axioms is not unique. Ehrlich’s blindness to technological advances is not uncommon, even in an era dominated by technology. By failing to set a timeline or give detailed causal accounts, many believe they have predicted every crash since they learned how to say the word. This is likely because they begin each day with the same mantra: “the market will crash.”  Yet through an automatically executed routine of psychological somersaults, they do not see they were right only once and wrong dozens, hundreds, or thousands of times. This kind of person is much more deserving of scorn than a poker player who boasts about his victories, because he is (likely) also aware of how often he loses. At least he’s not fooling himself. The severity of Ehrlich’s misfires is a reminder of what happens when someone looks too far ahead while assuming all things will remain the same. Ceteris paribus exists only in laboratories and textbooks.

Axioms are fates accepted by different people as truth, but the belief in Fate (in the form of retroactive narrative construction) is a nearly ubiquitous stumbling block to clear thinking. We may be far removed from Sophocles, but the unconscious human drive to create sensible narratives is not peculiar to fifth-century B.C. Athens. A questionnaire given to students at Northwestern showed that most believed things had turned out for the best even if they had gotten into their first pick. From an outsider’s perspective this is probably not true. In our cocoons we like to think we are in the right place either through the hand of fate or through our own choices. Atheists are not immune to this Panglossian habit. Our brains are wired for stories, but the stories we tell ourselves about ourselves seldom come out without distortions. We can gain a better outside view, which allows us to see situations from perspectives other than our own, but only through regular practice with feedback. This is one of the reasons groups are valuable.

Francis Galton asked 787 villagers to guess the weight of an ox hanging in the market square. The average of their guesses (1,197 lbs) turned out to be remarkably close to its actual weight (1,198 lbs). Scott Page has said “diversity trumps ability.” This is a tad bold, since legions of very different imbeciles will never produce anything of value, but there is undoubtedly a benefit to having a group with more than one point of view. This was tested by the GJP. Teams performed better than lone wolves by a significant margin (23% to be exact). Partially as a result of encouraging one another and building a culture of excellence, and partially from the power of collective intelligence.

“No battle plan survives contact with the enemy.”

-Helmuth von Moltke

“Everyone has a plan ’till they get punched in the mouth.”

-Mike Tyson

When Archie Cochrane was told he had cancer by his surgeon, he prepared for death. Type 1 thinking grabbed hold of him and did not doubt the diagnosis. A pathologist later told him the surgeon was wrong. The best of us, under pressure, fall back on habitual modes of thinking. This is another reason why groups are useful (assuming all their members do not also panic). Organizations like the GJP and the Millennium Project are showing how well collective intelligence systems can perform. Helmuth von Moltke and Mike Tyson aside, a better motto, substantiated by a growing body of evidence, comes from Dwight  Eisenhower: “plans are useless, but planning is indispensable.”

Adam Alonzi is a writer, biotechnologist, documentary maker, futurist, inventor, programmer, and author of the novels A Plank in Reason and Praying for Death: A Zombie Apocalypse. He is an analyst for the Millennium Project, the Head Media Director for BioViva Sciences, and Editor-in-Chief of Radical Science News. Listen to his podcasts here. Read his blog here.

We are the Lifespan – Video and Commentary by the Life Extension Advocacy Foundation

We are the Lifespan – Video and Commentary by the Life Extension Advocacy Foundation

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Life Extension Advocacy Foundation


The U.S. Transhumanist Party is pleased to share this message and video from our allies at LEAF – the Life Extension Advocacy Foundation. The video includes a short clip of remarks from U.S. Transhumanist Party Chairman Gennady Stolyarov II, taken from his video for the “I am the Lifespan” campaign.


As you might remember, during the month of October (often called Longevity Month) we at LEAF were accepting videos to hear your reasons why defeating the diseases of aging is so important — and hear from you we did!

Dozens of videos poured in, and this #GivingTuesday we at LEAF are so proud to share with you all a video that shows how strong we can be when we join forces for longer, healthier lives — how together #WeAreTheLifespan.

Thank you so much for raising your voice with us in support of longevity research, and if you wish to continue to help us please feel free to join our Hero campaign or to participate in Facebook’s #GivingTuesday donation match by clicking any of the donate buttons on our Facebook page or posts. If you want to get creative, you can even make your own fundraisers easily on Facebook on posts or with a live video.

Finally, to illustrate the importance of speaking freely on what you care about, we are pleased to let you know of the developments related to the recent Open Consultation on the 13th draft programme of work of the WHO. As we wrote not long ago, the problems related to population aging and corresponding health and social issues were left out of the draft, and we invited the members of the community to step in and recommend an improvement.

90% of responses during the Open Consultation (out of around 400 responses) underlined the need to make healthy longevity one of the priorities for the 13th programme of work, and the WHO have recognized this. A joint effort of many pro-longevity organizations made that happen.

Each voice matters. Your voice matters. So please, keep being active and vocal, and let’s become the generation who can say: “I helped set all people free from age-related diseases. I helped defeat aging.”

Thank you, and happy #GivingTuesday!

Space Seascape – Painting by Ekaterinya Vladinakova

Space Seascape – Painting by Ekaterinya Vladinakova

Ekaterinya Vladinakova


 

“Space Seascape” by Ekaterinya Vladinakova

Left-click on the image for a fuller view. You can also download this painting (4846 by 7000 pixels) here.

Tranquil and contemplative, this painting of an alien moon seascape by Ekaterinya Vladinakova evokes worlds that humans could one day discover or create through terraforming. The vivid colors and stunning imagery of Vladinakova’s work inspire us to strive toward a future where the exploration of these worlds could become a reality.

Ekaterinya Vladinakova is an accomplished digital painter. See her gallery here and her DeviantArt page here.