John Wilkins – Comprehension and Compression

“In short, data is not knowledge; knowledge is not comprehension; comprehension is not wisdom”

The standard account of understanding has been, since Aristotle, knowledge of the causes of an event or effect. However, this account fails in cases where the subject understood is not causal. In this paper I offer an account of understanding as pattern recognition in large sets of data without the presumption that the patterns indicate causal chains.

All nervous systems by nature desire to process information. Consequently, entities with nervous systems tend to find information everywhere, and on the principle that if some is good a lot is better, we have come up with “Big Data”, which is often suggested as the solution to the problems of one science or another, although it is unclear exactly what counts as big data and how it is supposed to do this. In this paper I will argue (i) that understanding does not and cannot come from larger and higher dimensionality data sets, but from structure in the data that can be literally comprehended; and (ii) that big data multiplies uncertainties unless it can be summarized. In short, data is not knowledge; knowledge is not comprehension; comprehension is not wisdom.


Slides can be found here: https://www.slideshare.net/jswilkins/comprehension-as-compression

Event was held at Melbourne Uni in 2019: https://www.meetup.com/en-AU/Science-Technology-and-the-Future/events/265580084/

 

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The Age of A.I. – empowering narratives or accurate forecasts?

An interesting new series ‘The Age of A.I.’ narrated by Robert Downey Jr. – this first episode looks at how AI’s interact with humans ‘Affective Computing’ using object recognition, NLP attempting to simulate human emotion, digital avatars which work like agents for us – similar to John M. Smart’s idea of a digital twin (I kept thinking he will suddenly appear and start narrating), and robotic arms

In a lot of discussion around AI I see what seems like attempts to sooth peoples fears about AI, pandering to our need to feel relevant or unique with dichotomies that take an extreme position (like ‘Superintelligence already exists’) portraying it as a silly misconception, and then offer an attractive alternative which takes the edge off and sometimes even empowers us like ‘AI is a simulation of us’, or Gil Weinberg saying ‘AI augments us, it’s not going to replace us, AI will enhance us’ as opposed to ‘AI will overtake us or replace us’ – which dismisses nuanced alternative scenarios that look more like a combinations of the above dichotomies i.e. ‘AI simulating us’ and ‘AI innovation outside of anthropocentric design’ or ‘ai augmenting us’ as well as ‘surpassing us’… do we really need to wait see AI smashing every ball out of the park before we admit that it can outperform us and do stuff we can’t?

Another part that stuck out for me seems partly true is when Dr Ayanna Howard brings up
1) a misconception that agi / superintelligence exists (now).. I agree but I’d add ‘not yet’ – for what it’s worth, I’ve argued elsewhere that rather than think of generality in AGI as either on or off – there are degrees of generality – and it may our future selves in hind sight look back to the current trends in AI and will be able with confidence pinpoint small but apparent gradients of generality in AI in some projects.
2) and then goes onto say that AI is basically a simulation us humans… some of it attempts to be, but a lot of AI isn’t – it’s alien, it’s obvious that some projects are not trying to replicate the way humans compute intelligence. This quote seems wrong headed.

Here is episode 1: “How far is too far?”

> “Can A.I. make music? Can it feel excitement and fear? Is it alive? Will.i.am and Mark Sagar push the limits of what a machine can do. How far is too far, and how much further can we go?”

Here is the trailer:

The YouTube series so far seem like documentaries to me, and though the purpose may not be to try to be as accurate and intellectually honest as possible but instead be somewhat accurate, make people feel empowered and try not to cause a panic – I feel if we head into the future somewhat blinkered, clinging to empowering narratives, then we may be blindsided when the reality of AI kicks in – in whatever form it actually takes.

Well, maybe narratives are the easiest way for humans to process information – we aren’t unbounded rational machines ourselves, we are inherently bad at thinking about some things – but in order to avoid a narrative trap, it seems at least with some critical thinking skills to discern the world through lenses outside of narrative space we can, we are and we should continue to make headway.

— Adam Ford

 

Anders Sandberg – Freeman Dyson, Galactic Megastructures, Physical Eschatology & the Fermi Paradox

Many of you know the sad news that theoretical physicist & mathematician Freeman Dyson has passed away, so in celebration of his life and achievements, Anders Sandberg (Future of Humanity Institute) discusses Freeman Dyson’s influence on himself and others – How might advanced alien civilizations develop (and indeed perhaps our own)?

We discuss strategies for harvesting energy – star engulfing Dyson Spheres or Swarms, black hole swallowing tungsten dyson super-swarms and other galactic megastructures, we also discuss Kardashev scale civilizations (Kardashev was another great mind who we lost recently), reversible computing, birthing ideal universes to live in, Meinong’s jungle, ‘eschatological engineering’, the aestivation hypothesis, and how all this may inform strategies for thinking about the Fermi Paradox and what this might suggest about the likelihood of our civilization avoiding oblivion.  though Anders is more optimistic than some about our chances of survival..

 

 

Anders Sandberg (Future of Humanity Institute in Oxford ) is a seminal transhumanist thinker from way back who has contributed a vast amount of mind blowing material to futurology & philosophy in general. https://en.wikipedia.org/wiki/Anders_Sandberg

Happy Future Day (march 1st) : http://future-day.org

Freeman Dyson: https://en.wikipedia.org/wiki/Freeman_Dyson
Dyson Sphere: https://en.wikipedia.org/wiki/Dyson_sphere
Aestivation Hypothesis: https://en.wikipedia.org/wiki/Aestivation_hypothesis
Reversible Computing: https://en.wikipedia.org/wiki/Reversible_computing
Kardashev Scales: https://en.wikipedia.org/wiki/Kardashev_scale
Nikolai Kardashev: https://en.wikipedia.org/wiki/Nikolai_Kardashev

[Audio version] [Video here]

Conference: AI & Human Enhancement – Understanding the Future – Early 2020

Introduction

Overview

The event will address a variety of topics futurology (i.e. accelerating change & long term futures, existential risk, philosophy, transhumanism & ‘the posthuman’) in general though it will have a special focus on Machine Understanding.
How will we operate along side artificial agents that increasingly ‘understand’ us, and important aspects of the world around us?
The ultimate goal of AI is to achieve not just intelligence in the broad scene of the word, but understanding – the ability to understand content & context, comprehend causation, provide explanations and summarize material etc.  Arguably perusing machine understanding has a different focus to artificial ‘general’ intelligence – where a machine could behave with a degree of generality, without actually understanding what it is doing.

To explore the natural questions inherent within this concept the conference aims to draw on the fields of AI, AGI, philosophy, cognitive science and psychology to cover a diverse set of methods, assumptions, approaches, and systems design and thinking in the field of AI and AGI.

We will also explore important ethical questions surrounding transformative technology, how to navigate risks and take advantage of opportunities.

When/Where

Dates: Slated for March or April 2020 – definite dates TBA.

Where: Melbourne, Victoria, Australia!

Speakers

We are currently working on a list of speakers – as at writing, we have confirmed:

John S. Wilkins (philosophy of science/species taxonomy) –   Author of ‘Species: The Evolution of the Idea‘, co-author of ‘The Nature of Classification: Relationships and Kinds in the Natural Sciences‘.   Blogs at ‘Evolving Thoughts‘.

Dr. Kevin B. Korb (philosophy of science/AI)  – Co-founded Bayesian Intelligence with Prof. Ann Nicholson in 2007. He continues to engage in research on the theory and practice of causal discovery of Bayesian networks (aka data mining with BNs), machine learning, evaluation theory, the philosophy of scientific method and informal logic.   Author of ‘Bayesian Artificial Intelligence‘ and co-author of ‘Evolving Ethics

 

David Pearce (philosophy, the hedonistic imperative) – British philosopher and co-founder of the World Transhumanist Association, currently rebranded and incorporated as Humanity+, Inc., and a prominent figure within the transhumanist movement. He approaches ethical issues from a lexical negative utilitarian perspective.   Author of ‘The Hedonistic Imperative‘ and ‘The Abolitionist Project

Stelarc (performance artist) – Cyprus-born performance artist raised in the Melbourne suburb of Sunshine, whose works focus heavily on extending the capabilities of the human body. As such, most of his pieces are centered on his concept that “the human body is obsolete”.  There is a book about Stelarc and his works – ‘Stelarc: The Monograph (Electronic Culture: History, Theory, and Practice)‘ which is edited by Marquard Smith.

Jakob Hohwy (head of philosophy at Monash University) – philosopher engaged in both conceptual and experimental research. He works on problems in philosophy of mind about perception, neuroscience, and mental illness.  Author of ‘The Predictive Mind‘.

Topics

Human Enhancement, Transhumanism & ‘the Posthuman’

Human enhancement technologies are used not only to treat diseases and disabilities, but increasingly also to increase human capacities and qualities. Certain enhancement technologies are already available, for instance, coffee, mood brighteners, reproductive technologies and plastic surgery.   On the one hand, the scientific community has taken an increasing interest in innovations and allocated substantial public and private resources to them. While on the other hand, such research can have an impact, positive or negative, on individuals, the society, and future generations. Some have advocated the right to use such technologies freely, considering primarily the value of freedom and individual autonomy for those users. Others have called attention to the risks and potential harms of these technologies, not only for the individual, but also for society as a whole. Such use, it is argued, could accentuate the discrimination among persons with different abilities, thus increasing injustice and the gap between the rich and the poor. There is a dilemma regarding how to regulate and manage such practices through national and international laws, so as to safeguard the common good and protect vulnerable persons.

Long Term Value and the Future of Life in the Universe

It seems obvious that we should have a care for future generations – though how far into the future should our concern expire?    This obvious sounding idea can lead to surprising conclusions.

Since the future is big, there could be overwhelmingly far more people in the future than in there are in the present generation. If you want to have a positive impact on lives, and are agnostic as to when the impact is realised, your key concern shouldn’t be to help the present generation, but to ensure that the future goes well for life in the long-term.

This idea is often confused with the claim that we shouldn’t do anything to help people in the present generation. But the long-term value thesis is about what most matters – and what we do to have a positive impact on the future of life in the universe is an extremely important and fascinatingly complicated question.

Artificial Intelligence & Understanding

Following on from a workshop at AGI17 on ‘Understanding Understanding’ we will cover many fascinating questions, such as:

  • What is understanding?
    • How should we define understanding?
    • Is understanding an emergent property of intelligent systems? And/or a central property of intelligent systems?
    • What are the typologies or gradations of understanding?
    • Does understanding relate to consciousness?  If so how?
    • Is general intelligence necessary and/or sufficient to achieve understanding in an artificial system?
    • What differentiates systems that do and do not have understanding?
  • Why focus on developing machine understanding?
    • Isn’t human understanding enough?
    • What are the pros/cons of developing MU?
    • Is it ethical to develop it?
    • Does morality come along for the ride once MU is achieved?
    • How could MU help solve the ‘value loading’ problem in AI alignment?
  • How create machine understanding?
    • What is required in order to achieve understanding in machines?
    • How can we create systems that exhibit understanding?
    • and how can we test for understanding?
    • Can understanding be achieved through hand-crafted architectures or must it emerge through self-organizing (constructivist) principles?
    • How can mainstream techniques be used towards the development of machines which exhibit understanding?
    • Do we need radically different approaches than those in use today to build systems with understanding?
    • Does building artificially intelligent machines with versus without understanding depend on the same underlying principles, or are these orthogonal approaches?
    • Do we need special programming languages to implement understanding in intelligent systems?
    • How can current state of the art methods in AGI address the need for understanding in machines?
  • When is machine understanding likely to occur?
    • What types of research/discoveries are likely to accelerate progress towards MU?
    • What may hinder progress?

The conference will also cover aspects of futurology in general, including transhumanism, posthumanism, reducing suffering, and the long term future.

 

 

Denis Odinokov – Conquering Cross-Linking for Biomedical Longevity

In order to achieve biomedical longevity, the problem of cross-Linking of the extracellular matrix needs to be addressed. Cells are held together by special linking proteins. When too many cross-links form between cells in a tissue, the tissue can lose its elasticity and cause problems including arteriosclerosis, presbyopia and weakened skin texture. These are chemical bonds between structures that are part of the body, but not within a cell. In senescent people many of these become brittle and weak. Fixing cross-linking may prove more difficult than just removing it – as it may create a vacuum where more waste is pulled in to fill the void left behind. Though some research is being conducted, the problem deserves a lot more hands on deck – and far more funding.
Denis gives a technical explanation of why conquering cross-linking is important, and strategies for addressing this problem in this interview conducted at the Undoing Aging conference in Berlin 2019.

Introduction to Denis’ writing/research here – “The Impact of Extracellular Matrix Proteins Cross-linking on the Aging Process“.

Understanding the consequences of the formation of protein crosslinks requires more attention both from the scientific community and independent researchers who are passionate with regards to the extension of the human lifespan. By doing so, it allows us to level up the playing field where we can create and work on more serious and impactful solutions.

Also see GlycoSENSSENS proposes to further develop small-molecular drugs and enzymes to break links caused by sugar-bonding, known as advanced glycation endproducts, and other common forms of chemical linking.

 

Jim Mellon – Investing in the Age of Longevity

Interview with hugely successful investor Jim Mellon at the Undoing Aging conference in Berlin 2019!
We cover reasons why it’s a good time to invest in Anti-Aging and rejuvenation biotechnology today, the ethical reasons why we should, and effective advocacy: i.e. what one would say to a billionaire to convince them that investing in longevity medicine is a good thing to do now.
Jim raised over $150 Million for his venture Juvenescence recently!

Transcript

My name is Jim Mellon, and I’m the chairman of Juvenescence, which is a company involved in the science of longevity. It is relatively recently formed; it is about a year and a bit old, but we’ve raised a significant amount of funding – nearly $160 million now – in the last year to advance the cause of longevity science. By the end of this year, we’ll have made 18 investments. Most of them are subsidiary companies of ours, so we control those companies. We give both development and financial backing to the scientist-entrepreneurs and institutions that we collaborate with.

I am fortunate to have two partners who have broad experience in the biotech and healthcare area, in particular, Declan Doogan, who was the head of drug development at Pfizer for a long period, and then he became the CEO of Amarin, which, as you know, is a very successful biotech company with a nearly $10 billion market valuation today. About four years ago, the three of us started a company called Biohaven, which is now listed on the New York Stock Exchange and has a valuation of about $2.5 billion. The company has approval for a drug for migraine, which will be on the market in the US next year. There is a good team of veteran drug developers and business entrepreneurs who have come together to create this Juvenescence company, and we’re very, very excited about it. We’re the biggest investors in the company ourselves, on the same terms as other investors. We will take the company public in the first quarter of next year, barring market disasters, and probably on the US stock exchanges.

We’re interested in this field of longevity science and able to raise significant funding because we’ve been in biotech for quite a long period of time, together, and created a number of companies. It seemed to be a natural outgrowth of the great developments that have occurred in the last few years. The unveiling of the human genome identified aging pathways that can now be manipulated. For the first time ever, you and I are in the cohort that is able to be bioengineered to live a healthier and longer life. It is still in a very primitive stage; we’re in the internet dial-up era equivalent, but the science is advancing very quickly.

I always say that I wrote my first book on biotech seven years ago, it was called Cracking the Code, and since then, we’ve had CRISPR/Cas9, which didn’t exist seven years ago, we’ve had the cure for Hepatitis C, we’ve had artificial intelligence for the development of novel compounds. The latter of which is a key part of our strategy, as investors in In Silico Medicine, which I think you are familiar with. Then, of course, you have cancer immunotherapy, which didn’t exist seven years ago, and is now a $100 billion / year industry. So, what’s going to happen in the next seven years? We don’t know, but it’s going to be very, very good. If you want to regard it as a casino table, we’re covering all the markers that we can with the funds that we’ve raised. We hope to raise a substantial further amount on the initial public offering of the company in the first quarter of next year, and that will give us enough firepower to do five Phase 2 trials without partners so that we can get the maximum leverage on the products that we’re developing.

So far, we’ve invested in small molecules, which is the specialization of our team. For instance, we have a senolytic drug in development in that area. We’ve also invested in stem cells; we’re the largest investor in Mike West’s company, AgeX Therapeutics, which is now a public company in the US. We own about 46% of that company. Then, via Lygenesis, we’ve also got our first product going into patients in the first quarter of next year, sick patients in a phase II trial, for organ regeneration, regenerating the liver, using hepatocytes to seed lymph nodes to act as ectopic bioreactors to grow fully functioning liver tissue. The FDA has agreed to the protocol for doing that in sick patients, which is a remarkably fast path to demonstrating successful outcomes in that area. If that is successful, then we will look to regenerate other organs, in particular the thymus, which as you know is related to aging in a big way.

We’re moving very, very quickly. We’ve got great colleagues; Margaret Jackson from Pfizer is on our team. Howard Federoff, ex-Pfizer, is on our team. Annalisa Jenkins, who was head of drug development and research and development at Merck Serono, a very big drug company, is on our team. We’ve put it all together remarkably quickly, but we have experience in doing that, and so we’re full of confidence. This is a remarkable time to be alive, and I want to be alive for at least another 20 or 30 years beyond what would be considered to be my allotted life span. The same is the motivating factor for my cofounders, Declan Doogan and Greg Bailey.

Working to extend life is an ethical cause. No one can argue, successfully at least, that this isn’t a good thing to do. There are some people who say “well, it is for the haves and not for the have-nots” but that is rubbish, because, ultimately, all these drugs will become generally available, and some of them already are. Metformin, which, as you are aware, is a drug that has some anti-aging properties, costs essentially nothing. It is a generic drug. As antibiotics, ulcer drugs, and so forth were once expensive and are now very cheap, the same thing will happen to drugs for longevity. Gene therapy and stem cells are another matter, though, and they will probably be expensive things for some time to come. But, undoubtedly, the cost will come down for those as well.

The other people who argue against work on aging talk about overpopulation; if there are all these old people, will there be enough room on the planet. Well, the answer is, we’re already alive, so we’re not going to be adding to the population. You and I are already here. The big issue on population is how many children does each woman have around the world, and that figure is falling dramatically, to the point where we can see populations actually shrinking. Just as an example, if Japan doesn’t allow immigration, or doesn’t have a baby boom, its population will fall from 126 million today to 50 million by the year 2100. So both those arguments, the haves versus the have-nots, and the overpopulation concern, are nonsensical arguments. In my view, there is absolutely no reason why governments, institutions, the general population, and the voting population shouldn’t be pushing really hard to make this happen.

Regarding the aging of the existing population and how to cope with it, the main point made by Aubrey de Grey, and other eminent scientists as well, is that if you treat the top of the cascade of damage in aging, then you are going to treat the underlying diseases of aging that pharmaceutical companies are trying to address. But for those pharmaceutical companies, it is a whack-a-mole exercise, so if you get one disease and that is cured, then you’ll get another one, and they’ll have to cure that one. Ultimately, we become destabilized and we die, all of us. So, let’s try and treat aging as the central disease, and from that as the unitary disease, we’ll be treating the cascade that follows from that.

Some people say it is hubris to target aging, but I think that this is because until relatively recently, nothing worked. It has been an aspiration of human beings for millennia to find the fountain or elixir of youth, and nothing has worked. So, people are skeptical about the fact that it might be working now: why now rather than 20 years ago or 20 years in the future? But the fact is that it is now, and we need to seize the moment and rise to the challenge. We need much more funding to come into this area, and that funding will drive the science. We need many more advocates for this cause to come to the fore and tp spread the word, that this is going to be monumentally great for human beings.

In my own case, I’ve set up a charity with Andrew Scott, who wrote The 100 Year Life, and we do a Longevity Week in London. We did the first one last year, and we’re doing the next one in November of this year, to spread the word. This will have a big societal impact, on consumption, on the way in which we look at the trajectory of life, but it is also going to have a major impact on us as human beings. In the past, you’d have expected to live to about 85 or 90, the same with me, and now we’re very likely to live to 110 or 120, so let’s do it. Let’s make it happen. I think that all of us, yourself, myself, have relatives, dear friends, and acquaintances who are suffering the indignities of aging as it currently exists. We’d like to relieve that burden of suffering by extending the healthy span of life. The personal motivation is a very big factor. Here in Berlin, there are 300 or 400 people at this conference, and I imagine that all of them, beyond just the business or scientific side of things, have an altruistic motivation for this as well. More people need to do it, so get on to it!

The elevator pitch for high net worth people thinking about investing in this space is that, first of all, we’re at the front end of a huge upward curve. I said earlier on that this was like the internet dial-up phase of longevity biotech. If you’d invested in the internet in the very early days, you’d be more than a billionaire now; you’d be one of the richest people on the planet. We’re at that stage now, so the opportunity for investors is huge, but you could do both. You could invest in something like the SENS Research Foundation or the Buck Institute or one of those wonderful organizations that is trying to advance the cause, and at the same time invest in some of the companies that come out of those institutions. We’ve undertaken two joint ventures with the Buck Institute, and we’ve made a couple of investments as a result of introductions by the SENS Research Foundation, including the organ regeneration program. If you’re a sensible billionaire, you will be putting some of your funds to work in a combination of a charitable enterprise that drives the science and the businesses themselves that come out of those enterprises.

Many thanks to Leaf Science for doing the transcript!

Perhaps one of the most interesting companies in which Juvenescence has invested is Lygenesis, which is developing an approach to address liver failure by creating miniature livers to pick up the slack. Lygenesis is using a technique in which liver cells are delivered to lymph nodes, where they develop and grow into fully working liver tissue, albeit smaller than the organ they replace. If these organs are shown to perform all the functions of a working liver, they could potentially remove the need to replace damaged livers through transplants. Initial work in mice and pigs has been promising, and Lygenesis plans to move to phase 2 clinical trials in early 2020.

Judith Campisi – Senolytics for Healthy Longevity

I had the absolute privilege of interviewing Judith Campisi at the Undoing Aging conference in Berlin.  She was so sweet and kind – it was really a pleasure to spend time with her discussing senolytics, regenerative medicine, and the anti-aging movement.

 

 

 

Judith Campisi was humble, open minded, and careful not to overstate the importance of senolytics, and rejuvenation therapy in general.  Though she really is someone who has made an absolutely huge impact in anti-aging research.  I couldn’t have said it better than Reason at Fight Aging!

As one of the authors of the initial SENS position paper, published many years ago now, Judith Campisi is one of the small number of people who is able to say that she was right all along about the value of targeted removal of senescent cells, and that it would prove to be a viable approach to the treatment of aging as a medical condition. Now that the rest of the research community has been convinced of this point – the evidence from animal studies really is robust and overwhelming – the senescent cell clearance therapies known as senolytics are shaping up to be the first legitimate, real, working, widely available form of rejuvenation therapy.

“Biomimicry”, a Documentary

Biomimicry is a 20 minute long documentary film, produced by Leonardo DiCaprio (film producer, and environmentalist), on the topic of how life and biology can be the mentors for our own innovation in the world.

Janine Benyus, the founder of the Biomimicry Institute, describes how biomimicry has been applied to different problems successfully, from designing forms that capture carbon to replacing toxic solvents we use.

Benyus believes that there is much to be learned in terms of sustainability and success in innovation from the organisms that compose the history of life in our planet. Biomimicry is brought to us by Leonardo DiCaprio, Executive Producer Oliver Stanton, and directed by Leila Conners, produced by Mathew Schmid and Bryony Schwan, with Executive Producers Roee Sharon Peled and George DiCaprio.

Biomimicry, the practice of looking deeply into nature for solutions to engineering, design and other challenges, has inspired a film about it’s ground-breaking vision for creating a long-term, sustainable world. This film covers how mimicking nature solves some of our most pressing problems, from reducing carbon emissions to saving water. The film, titled “Biomimicry” features Janine Benyus, is brought to you by Leonardo DiCaprio, Executive Producers Oliver Stanton, directed by Leila Conners, produced by Mathew Schmid and Bryony Schwan, created by Tree Media with Executive Producers Roee Sharon Peled and George DiCaprio.

For more on the film: http://www.treemedia.com

Reason – Philosophy Of Anti Aging: Ethics, Research & Advocacy

Reason was interviewed at the Undoing Aging conference in Berlin 2019 by Adam Ford – focusing on philosophy of anti-aging, ethics, research & advocacy. Here is the audio!

And the video:

Topics include philosophical reasons to support anti-aging, high impact research (senolytics etc), convincing existence proofs that further research is worth doing, how AI can help and how human research (bench-work) isn’t being replaced by AI atm or in the foreseeable future, suffering mitigation and cause prioritization in Effective Altruism – how the EA movement sees anti-aging and why it should advocate for it, population effects (financial & public health) of an aging population and the ethics of solving aging as a problem…and more.

Reason is the founder and primary blogger at FightAging.org

Jerry Shay – The Telomere Theory of Ageing – Interview At Undoing Ageing, Berlin, 2019

“When telomeres get really short that could lead to a dna damage signal and cause cells to undergo a phenomenon called ‘replicative senescence’…where cells can secrete things that are not necessarily very good for you..”

Why is it that immune cells don’t work as well in older age?

Listen to the interview here

Jerry and his team compared a homogeneous group of centenarians in northern Italy to 80 year olds and 30 year olds – and tested their immune cells (T-Cells) for function (through RNA sequencing) – what was observed was all the young people clustered apart from most of the old people clustered.. but the centenarians didn’t cluster in any one spot.  It was found that the centenarians clustered along side the younger cohorts had better telomere length.

Out of 7 billion people on earth, there is only about ~ half a million centenarians – most of them are frail – though the ones with longer telomeres and more robust T-Cell physiology seem to be quite different to the frail centenarians.   What usually happens is when telomeres wear down the DNA in the cell gets damaged, triggering a DNA damage response. From this, Jerry and his team made a jump in logic – maybe there are genes (i.e. telomere [telomere expression genes?]) that when the telomeres are long these genes are repressed, and when the telomeres short the genes get activated – circumventing the need for a DNA damage response.  What is interesting is that they found genes that are really close to the telomere genes (cytokines – inflammatory gene responses – TNF Alpha, Ennalucan 1 etc) – are being activated in humans – a process called ‘Telomere Looping’. As we grow and develop our telomeres get longer, and at a certain length they start silencing certain inflammation genes, then as we age some of these genes get activated – this is sometimes referred to as the ‘Telomere Clock’.  Centenarians who are healthy maintain longer telomeres and don’t have these inflammation genes activated.

 

During early fetal development (12-18 weeks) telomerase gets silenced – it’s always been thought that this was to stop early onset of cancer – but Dr Shay asked, ‘why is it that all newborns have about the same length of telomeres?’ – and it’s not just in humans, it’s in other animals like whales, elephants, and many large long-lived mammal – this doesn’t occur in smaller mammals like mice, rats or rabbits.   The concept is that when the telomere is long enough, it loops over and silences its own gene, which stays silent until we are older (and in need of it again to help prevent cancer).

This Telomere Looping probably evolved as part of Antagonistic Pleiotropy – where things that may have a protection or advantage early in life may have unpredicted negative consequences later in life. This is what telomerase is for – we as humans need it in very early development, as do large long-lived mammals, and  a mechanism to shut it off – then at a later older age it can be activated again to fight against cancer.

 

There is a fair amount of evidence for accumulated damage as hallmarks for ageing – can we take a damage repair approach to rejuvenation medicine?

Telomere spectrum disorders or telomeropathies – human diseases of telomere disfunction – diseases like idiopathic pulmonary fibrosis in adults and dyskeratosis congenita in young children who are born with reduced amounts of telomeres and telomerase – they get age related diseases very early in life.  Can they be treated? Perhaps through gene therapy or by transiently elongating their telomeres. But can this be applied for the general population too?  People don’t lose their telomeres at the same rate – we know it’s possible for people to keep their telomeres long for 100 years or more – it’s just not yet known how.  It could be luck, likely it has a lot to do with genetics.

 

Ageing is complex – no one theory is going to explain everything about ageing – the telomere hypothesis of ageing perhaps makes up for about on average 5% or 10% of aging – though understanding it enough might give people an extra 10% of healthy life.   Eventually it will be all about personalised medicine – with genotyping we will be able to say you have about a 50% chance of bone marrow failure when you’re 80 years old – then if so you may be a candidate for bone marrow rejuvenation.

What is possible in the next 10 years?

 

Inflammation is highly central to causing age related disease.  Chronic inflammation can lead to a whole spectrum of diseases. The big difference between the subtle low grade inflammation that we have drugs for – like TNF blockers (like Humira and Enbrel) which subtly reduce inflammation – people can go into remission from many diseases after taking this.

There are about 40 million people on Metformin in the USA – which may help reduce the consequences of ageing – this and other drugs like it are safe drugs – if we can find further safe drugs to reduce inflammation etc this could go a long way – Aspirin perhaps (it’s complicated) – but it doesn’t take much to get a big bang out of a little intervention – the key to all this is safety – we don’t want to do any harm – so metformin and Asprin have been proven to be safe over time – now we need to learn how to repurpose those to specifically address the ageing problem.

 

Historically we have more or less ignored the fundamental problem of ageing and targeted specific diseases – but by the time you are diagnosed, it’s difficult to treat the disease – by the time you have been diagnosed with cancer, it’s likely so far advanced that it’s difficult to stop the eventual outcomes.   The concept of intervening in the ticking clock of ageing is becoming more popular now. If we can intervene early in the process we may be able to mitigate downstream diseases.

Jerry has been working on what they call a ‘Telomerase Mediated Inhibitor’ (see more about telomerase meditation here) – “it shows amazing efficacy in reducing tumor burden and improving immune cell function at the same time – it gets rid of the bad immune cells in the micro environment, and guess what?  the tumors disappear – so I think there’s ways to take advantage of the new knowledge of ageing research and apply it to diseases – but I think it’s going to be a while before we think about prevention.”

Unfortunately in the USA, and really globally “people want to have their problems their lifestyles the way they want them, and when something goes wrong, they want the doctor to come and and give them a pill to fix the problem instead of taking personal responsibility and saying that what we should be doing is preventing it in the first place.”  We all know that prevention is important, though most don’t want to practise prevention over the long haul.

 

The goal of all this not necessarily to live longer, but to live healthier – we now know that the costs associated with intervening with the pathologies associated with ageing is enormous.  Someone said that the 25% of medicare costs in the USA is in treating people that are on dialysis – that’s huge. If we could compress the number of years of end of life morbidities into a smaller window, it would pay for itself over and over again.   So the goal is to increase healthspan and reduce the long period of chronic diseases associated with ageing. We don’t want this to be a selected subgroup who have access to future regenerative medicine – there are many people in the world without resources or access at this time – we hope that will change.

Jerry’s goal is to take some of the discovered bio-markers of both healthy and less healthy older people – and test them out on larger population numbers – though it’s very difficult to get the funding one needs to conduct large population studies.