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João Pedro de Magalhães’ Path to Ending Aging


The quest to end aging and prolong human life indefinitely has stepped outside the worlds of religion and science fiction, and is now the stuff of serious science. The number of research biologists consciously and intently working toward this once-outrageous-sounding goal increases year after year. Exactly when we’ll get to the end goal remains quite unclear – but the steady march of progress in that direction has become unmistakeable.

In many cases, the work of life-extension-oriented scientists may be mostly funded by research grants or commercial projects aimed at curing specific age-associated diseases or other relatively down-to-earth goals. But even research approaching the matter of ending aging via this slightly indirect route can have dramatic impact on the core problem. And in some cases, it’s hard to distinguish work on specific age-associated conditions from work aimed at ending the condition of aging itself.

As we peer closer and closer to the essence of aging, some researchers feel it looks less like a unified entity, and more like a combination of multiple complex phenomena in complex biological networks. Others feel there may be one or a handful of critical underlying biological processes driving the panoply of aging-associated phenomena. Either way, year by year we are gathering more and more data – and deeper and deeper ideas – pertinent to cracking the puzzle.

Since I started following the longevity research literature carefully back in 2002, one of my favorite researchers in the area has been João Pedro de Magalhães, a Portuguese biologist currently leading the Integrative Genomics of Aging group at the University of Liverpool. His work combines an evolutionary focus, a mastery of complex bioinformatics tools, an appreciation for complex biological networks, and a futurist mind-set. And his website senescence.info has for many years been a valuable resource for both the novice and the experience longevity researcher.

João Pedro’s personal web page makes no secret of his ambitious perspective. “I’m a scientist and philosopher, a dreamer, and a transhumanist,” he writes. And in keeping with the transhumanist ethos, he avers that “the human condition is only the beginning of the extraordinary journey of the mind through the universe. I defend humankind stands a better chance of success if we understand technology rather than try to ban it. Technologies like genetic engineering, cloning, cybernetics, and nanotechnology will allow us to escape our human limitations and evolve beyond our dreams. May the dreams of today become the future.”

João Pedro also plays guitar, composes music and does stand-up comedy. But when I decided to interview him for H+ Magazine, I promised myself to resist the urge to ask him to participate in an online metal-fusion jam session, and instead resolved to probe into his views on the particulars of longevity research. I was especially interested to get his latest ideas about the relationship between development and aging, since this pertains to some of my own current work with Genescient, studying aging in long-lived fruit flies with a view toward discovering therapies for age-associated diseases in humans. I also wanted to get his take on some arguments between aging researchers Aubrey de Grey and Michael Rose that I’ve been poking my nose into recently. I thought João Pedro would have some interesting comments, and I wasn’t disappointed….

Ben:
I’ll start off with some general questions, and then we’ll plunge into some nitty-gritty longevity biology a little later.

First of all I’m curious for your impressions of the overall trend of the life extension research field. You’ve been working on life-extension related biology for a number of years now, and I’m wondering if you’ve noticed any shift in peoples’ attitudes toward this sort of work, during the course of your career? Do you think people are getting significantly more comfortable with the notion of radical life extension, or have we not reached that phase yet?

João Pedro:
Clearly the biggest shift in attitudes has come from Aubrey de Grey’s SENS (Strategies for Engineering Negligible Senescence) program, which introduced a large fraction of the general public to radical life extension and I guess it also led to some soul searching in the research community. My impression is that most researchers working in the field are still skeptical and some even opposed to radical life extension. But SENS also forced many to discuss and even some to openly accept radical life extension as a long-term goal of the field.

Ben:
Speaking of Aubrey — you’re of course familiar with his notion of “Longevity Escape Velocity”, aka “the Methuselarity.” That is, to put it roughly: the point in time at which, if you’re alive then, your odds of dying due to age-associated medical problems become very low, due to ongoing and ever-improving biomedical advances. What’s your take on the Methuselarity?

João Pedro:
Methuselarity makes sense, though if you look at the history of science what often happens is that, rather than small incremental improvements in a given field, there’s usually one amazing breakthrough. I see aging being cured by one amazing discovery — or triggered by a single breakthrough — rather than a continuous progress towards a cure.

Ben:
And do you have any intuitive sense of when that breakthrough might occur? Tomorrow? 500 years from now? 15 years? 40?

João Pedro:
Predicting when we will reach Methuselarity or the point of being able to cure aging is obviously incredibly hard. I used to be optimistic that it would happen around the midpoint of this century but have become more doubtful of it lately, in part because of funding difficulties (it’s relatively difficult to get funding for directly life extension oriented work, compared to many other sorts of human biomedical research). I think it’s clear that the more funding being directed at aging research, the more people working on it, the faster the progress, the higher the chances of a breakthrough.

The other critical issue is whether the technology to develop a cure for aging exists nowadays or whether progress in many adjacent fields, like nanotechnology, synthetic biology and stem cells, are a pre-requisite. I guess what we need to do to maximize our chances of curing aging is to invest more not only in basic aging research and biomedical sciences but also in several other key scientific areas.

Ben:
Yes, that certainly makes sense to me. And I’d add AI – my own main research field, though I’ve also done a lot of other stuff including longevity-related bioinformatics as you know – to your list….

So let me ask a question about that — about the hypothesis of advanced Artificial General Intelligences (AGIs) doing longevity biology themselves. I wonder how much do you think progressvtoward ending aging would be accelerated if we had an AGI system that was, let’s say, roughly as generally intelligent as a great human scientist, but also had the capability to ingest the totality of biological datasets into its working memory and analyze them using a combination of humanlike creative thought and statistical and machine learning algorithms? Do you think with this sort of mind working on the problem, we could reach the Methuselarity in 5 or 10 years? Or do you think we’re held back by factors that this amazing (but not godlike) level of intelligence couldn’t dramatically ameliorate?

João Pedro:
Based on your definition of AGI, I think this would truly advance progress in aging research (as well as in many other fields). As an observer of the AI field (but in no way an expert) my doubt, however, is whether an AGI system can be devised in a near future with such a combination of skills in terms of memory, creativity, intelligence, etc.

Answering your questions about the pace of progress, there are factors that not even a godlike intelligence could overcome, like the time it takes to do experiments on aging and government regulations on clinical testing. But if the progress becomes exponential due to AGI systems then I can see a cure for aging being developed.

Ben:
OK … well, it would be fun to debate the plausibility of achieving advanced AGI in the near term with you, but I guess that would take us too far afield! So now let’s plunge into some of the biology of aging….

At the last Humanity+ conference (at Caltech) we had some great give-and-take between Michael Rose and Aubrey de Grey, and one of the issues they disagree on is the main cause of the aging phenomenon. To simplify a little, Michael Rose believes that antagonistic pleiotropy is the major cause of aging. Aubrey de Grey thinks it’s accumulated damage. Which side do you come down on?

Antagonistic pleiotropy is a technical genetics concept that may be understood roughly as follows. Organisms evolve different genetic mutations arise to adapt the organism’s functionality at different stages of its life. But each gene may carry out multiple functions, and in each of these functions, it’s subtly interlinked with other genes. So various adaptations, focused on different stages of life, may interfere with each other in complex ways — an instance of the phenomenon known in genetics lingo as “antagonistic pleiotropy.” According to this explanation of aging: the more different life-stages worth of adaptations get piled on top of each other, the more confusion occurs in the body’s various interlocking systems, causing the problems we all experience as we age. When an organism gets old enough, it reaches an age for which there hasn’t yet been much evolutionary adaptation in its history. Few organisms in its species have lived that long, so the genes of the species haven’t adapted much to the requirements of life at that age.

João Pedro:
I think both perspectives are partly correct, though at different levels.

The antagonistic pleiotropy theory, the idea that genes with beneficial functions early in life may have detrimental actions late in life, explains aging from an evolutionary perspective. However, it doesn’t explain the causes of aging at the mechanistic, molecular level, which I think is what people generally mean by “causes of aging”.

Accumulated damage can be considered a major cause of aging, yet “damage” is such a broadly defined term that I’m not satisfied with this concept. Almost any detrimental molecular or cellular event in the body can be defined as “damage”, and many (perhaps most) forms of “damage” in the body do not cause aging. So what we need to find out is what are the specific molecular and cellular processes that drive aging, and unfortunately we don’t know yet what these are. I believe that DNA damage accumulation, and its effects on cells and on the depletion of stem cell pools, could be a key cause of aging but this is only a guess.

Also, I’m also keen on the idea — underrated by most experts — that developmental mechanisms contribute to aging .

Ben:
Yes, I want to ask you about your work on the developmental approach to aging — we’ll get to that shortly! But first I want to ask another “Michael versus Aubrey question”! A large part of the debate between Michael and Aubrey at the Humanity+ conference centered around “biological immortality” and the late-life phase. As you know, in some of his recent scientific works, Michael Rose has presented data and arguments in favor of a “late life” phase in fruit flies and other animals including humans. Basically, as I understand it, he’s argued that during “late life” the odds of the organism dying during any given day (or year) becomes essentially constant. Others have argued this isn’t a real phenomenon and it’s an illusion caused by heterogenous aging patterns among different populations. And Aubrey tends to agree with this. What’s your view?

João Pedro:
Late life mortality plateaus have been observed in several populations of different species, including humans. My view is that this is due to heterogeneity intrinsic to any population. Even genetically identical organisms show phenotypic variation due to interactions with the environment and to sheer chance. It’s much more likely that this heterogeneity causes mortality plateaus — and this is predicted by mathematical models — than some unknown biological phenomenon.

Ben:
I see, so on that particular point you basically agree with Aubrey, it seems….

On the other hand, I have to admit Michael has pretty much convinced me that heterogeneity is not the sole explanation for the observed late-life plateau…. He has a new book coming out soon, that will present his mathematical arguments for this point in a lot of detail, so I’ll be curious to get your reaction once his book comes out and you take a look at it! …

João Pedro:
I look forward to seeing what new arguments Michael has on the mortality plateaus debate.

Ben:
OK, so let’s get back to development. You’ve just mentioned that in your view, developmental processes are critical for understanding aging. Can you briefly elaborate on why? Is this basically an instance of antagonistic pleiotropy, or is there more to it?

João Pedro:
The developmental theory of aging can indeed be seen as a form of antagonistic pleiotropy, of genes or mechanisms beneficial early in life (in this case for growth and development) being detrimental late in life and contributing to aging. The idea is very simple: some of the same genetically-regulated processes that are crucial in development continue throughout adulthood and become harmful. For example, far-sightedness is thought to derive from the continual growth of eye lenses. During development the eye lenses must grow but it seems that the genetic program determining their growth continues in adulthood and this contributes to a specific age-related disease. My hypothesis is that several processes programmed in the genome for important roles during development become harmful late in life and contribute to aging. In an indirect sense, it’s a form of programmed aging processes.

Ben:
Yes, I see…. But could you briefly list what some of these processes are, and how/why you hypothesize they become harmful?

João Pedro:
The general concept is that changes occurring during early stages of life as part of programmed developmental processes then become detrimental late in life. More work is necessary to establish exactly which processes fall into this category but there are already several examples.

For instance, a few years ago, Anders Sandberg and myself developed a model of brain aging which briefly argues that the continuation of the genetic programs that are essential for brain development early life contribute to cognitive aging and neurodegeneration. One example of a specific process is brain plasticity which necessarily decreases prior to adulthood, but as it continues to decrease in adulthood it will eventually becomes detrimental. There’s also recent evidence that changes in gene expression during aging follow trajectories that are set during development and this is due to regulated processes, perhaps involving micro RNAs. One recent study found that the genetic program that coordinates growth deceleration during development persists into adulthood. In other words, most animals like humans are genetically programmed to stop growing and this involves molecular and cellular changes. But as the same molecular and cellular changes involved in growth deceleration persist into late life then these will be harmful.

Ben:

Yes, that paper by you and Anders is very fascinating, and I think in the future it may be broadly viewed as a milestone toward the understanding of age-associated neurodegeneration. But of course it’s a 2005 paper … I wonder if any particularly exciting pieces of evidence in favor of that theory have arisen since then?

Some choice extracts from Cognitive aging as an extension of brain development by João Pedro de Magalhães and Anders Sandberg:

After puberty, the priority is no longer adaptation or intellectual developmental. The brain must be more stable because the emphasis has shifted to reproduction and childbearing…. Thus, synaptic plasticity, the activity- dependent modification of synapses, decreases with age, as does synaptic density….

Brain plasticity and neuromodulation continue to decrease even in aged individuals. ‘‘You can’t teach an old dog new tricks’’, or so the proverb goes and, in fact, a decline in learning rate has been observed in elderly people as well as in numerous animal models. Brain plasticity in adulthood has also been shown to be decline. Therefore, our hypothesis is that, in later stages, this developmentally linked process continues – because there is no evolutionary pressure for it not to – and causes cognitive dysfunction. Our proposal is that the brain plasticity changes aimed at increasing the robustness of the human mind in childhood and adolescence later contribute to cognitive aging and eventually dementia.

The figure from the paper , reproduced here to the right, shows the number of neurons (black line) and synapses (gray line) during the lifespan:

And, about the relation between calorie restriction, development and neurodegeneration:

In line with the delay of cognitive aging in CR mice, CR in rodents attenuates the age-related decline in neurotransmitters during aging as well as some neuronal receptors, and induces the expression of genes involved in brain plasticity. In fact, CR induces the expression of developmentally regulated genes in the mouse brain when compared to age-matched controls. The next step is linking these players, such as neurotransmitters, neurotrophic factors, and hormones, to the developmental program in order to understand the complex transcriptional control involved.

And about oxidative stress (ROS, Reactive Oxygen Species) and neurodegeneration and the complex networks involved therein:

Considerable evidence exists that ROS generation increases with age and oxidative stress is associated with learning impairments. Yet our proposal is that this increase in ROS with age is a consequence of the lack of responsiveness in the brain to ROS. ROS may then indirectly cause damage and so a feedback loop is formed between ROS trying to stimulate synaptic plasticity and oxidative stress. Therefore, our argument is that ROS do not trigger cognitive aging, but rather are under control by developmental mechanisms and thus form part of its signaling cascade. Like many other factors, ROS are deregulated with age due to the actions of the developmental program and thus cause damage.

João Pedro:
There’ve been a few papers along these lines, but not that many. Arguably the best I’ve seen recently is one by some researchers from Shanghai, on “MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain

Here is the abstract of “MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain,” by Mehmet Somel and his colleagues at the Partner Institute for Computational Biology, at the Chinese Academy of Sciences in Shanghai:

Changes in gene expression levels determine differentiation of tissues involved in development and are associated with functional decline in aging. Although development is tightly regulated, the transition between development and aging, as well as regulation of post-developmental changes, are not well understood. Here, we measured messenger RNA (mRNA), microRNA (miRNA), and protein expression in the prefrontal cortex of humans and rhesus macaques over the species’ life spans. We find that few gene expression changes are unique to aging. Instead, the vast majority of miRNA and gene expression changes that occur in aging represent reversals or extensions of developmental patterns. Surprisingly, many gene expression changes previously attributed to aging, such as down-regulation of neural genes, initiate in early childhood. Our results indicate that miRNA and transcription factors regulate not only developmental but also post-developmental expression changes, with a number of regulatory processes continuing throughout the entire life span. Differential evolutionary conservation of the corresponding genomic regions implies that these regulatory processes, although beneficial in development, might be detrimental in aging. These results suggest a direct link between developmental regulation and expression changes taking place in aging.

Ben:
Yes, that’s outstanding stuff; and I confess I missed that paper when it came out, though Google reveals it was written up in Science Daily not long ago! Thanks for bringing me up to speed…. There’s so much good biology published these days, it’s hard to keep up with it all.

We’ll be doing a Humanity+ conference in Hong Kong in November, and I’ll be trying to pull in some Chinese researchers doing life extension work, as well as cognitive neuroscience and other areas. I’ll definitely try to get someone from that lab to come talk about their work.

Also I’m thinking about the connections between these ideas and my own work applying AI bioinformatics to genetics data from Genescient’s super-long-lived “Methuselah” fruit flies (that have been selectively bred to live 4x as long as regular flies of the same species). It will be interesting to look for corroboration for the neurodevelopment/neurodegeneration connection in the Methuselah fly gene sequence data when we obtain it in a month or two.

Although, I suppose that to really explore that theory it would also be nice to have time-series gene expression data from Methuselah versus control flies over their whole lifespan, to see the perturbations in both the neurodevelopment and neurodegenerative phases…

João Pedro:
Yes, I think you’d need data across the lifespan to study development-aging links.

Ben:
Well, I’m sure Genescient will get that sort of data before too long. One of the wonderful things about doing biology in the era of accelerating change is that experimental data collection gets cheaper year upon year, at an amazing rate. This of course is one of the things driving the outstanding recent progress in biology.

So much data is gathered these days, that even using the best AI tools we have available, we struggle to deal with it. Thought it’s a fun struggle! But of course, if we have a good theory of what kinds of patterns we’re likely to see in the data, that makes the analysis process a bit easier…. Which is part of why your own theories on aging interest me so much.

João Pedro:
Well, I should emphasize that this developmental theory of aging (or DevAge as I like to call it) is in contrast with most other theories of aging which tend to focus on random damage accumulation, often from by-products of metabolism.

Ben:
Yes … in that respect your views seem closer to those of Michael than of Aubrey…. But you focus on some fairly specific aspects of antagonistic pleiotropy, related to the development process.

João Pedro:
Well, what DevAge suggests is that some aspects of aging follow pre-determined patterns encoded in the genome as part of developmental processes. In other words, the genome does indeed contain instructions that drive aging. For anti-aging interventions this has profound implications because it means that if we can unravel the regulatory elements of these processes via genomics and bioinformatics then we may be able to manipulate them and therefore develop new anti-aging interventions.

Ben:
So, given this perspective, what research are you focusing on recently? And how does it fit into the big picture of combating aging and increasing human healthspan?

João Pedro:
My strategy for fighting aging has always been to first learn more about the precise molecular, cellular and genetic causes of aging and then, with more specific targets in mind, develop interventions.

Ben:
Yes, I see: understand first, cure after. It’s an appealing approach to me, as a scientist. On the other hand, we have to recall that none of the broadly successful vaccines were developed based on deep understanding – they all basically came out of educated guesswork and trial and error. One of Aubrey’s ideas is that we may be able to extend life significantly via this sort of educated guesswork and tinkering, even without a full fundamental understanding of the underlying biological networks.

João Pedro:
Breakthroughs based on fairly limited understanding are of course possible. But I think we stand a better chance of retarding and ultimately curing aging if we better understand its basic mechanisms. As such, we’ve been doing a lot of work at the genetic level and trying to identify genes that are important for longevity. This involves experimental work (including with next-generation sequencing technologies) and bioinformatics to predict from large datasets which genes are the important ones and even whether they could be suitable drug targets.

Another approach I’ve always been keen on is comparative biology or trying to identify the genes and processes determining species differences in aging (e.g., why humans live over 100 years while mice live only 4 years?). Among other studies, we’ve been doing a lot of work on the naked mole-rat, a long-lived and cancer-resistant mammal, with the goal of identifying genes that protect against aging and cancer.

Ben:
Hmmmm… yes, that’s a different approach from the ones most scientists are taking. Are there any specific, interesting conclusions that have come out of this comparative approach so far?

João Pedro:
I have to say there’s still a lot of work to be done before we have a coherent picture of why some species live longer than others. One thing we did show a few years back was that, contrary to many predictions, long-lived species do not have lower metabolic rates, so something else must be underlying their long lifespans. There’s some results hinting that some repair pathways, like DNA repair, may be optimized in long-lived mammals but no conclusive results yet. The problem is that it’s not easy from a practical perspective to study multiple species, including the long-lived ones like whales. This is one of the reasons why the genomics revolution is so important to comparative approaches to aging. The availability of a large number of genome sequences allows us to identify potential genes and mechanisms involved in the evolution of long lifespans using bioinformatics. Our lab is already working on this and as more genomes are sequenced our capacity and statistical power will increase exponentially and I suspect we’ll start to have some good answers soon.

Ben:
You’ve done some work related to caloric restriction too, is that right?

João Pedro:
Yes, we’ve also been working on dietary manipulations of aging, such as caloric restriction, again to predict key genes that modulate the life-extending effects of CR and may be suitable targets for drug development.

Ben:
I did some work like that myself, together with Lucio Coelho at Biomind. We used our AI tools to cross-analyze four gene expression datasets from mice under calorie restriction, and look for the genes that seemed most important across all the experiments. We came up with a lot of cool stuff that wasn’t in any of the published literature. I know the sirtuins got a lot of attention as genes related to CR – and they did come out of our analysis, but they weren’t at the top of the list. For instance, we got a lot of information pointing to a significant role for Mrpl12 – a nuclear gene coding for mitochondrial ribosomal proteins. I still don’t know how Mrpl12 plays into the CR story. There’s a lot unknown about the mechanisms of CR, and a lot that can be learned from them I’m sure.

João Pedro:
For transhumanists, I guess CR may be of limited value as it only retards aging to some degree; but I think we need to take one step at a time. If we could retard aging using drugs that mimic effects of CR then this would bring enormous impetus to the field and allow us to then explore more ambitious avenues.

Ben:
Seems we’ll need to wrap up soon – we’ve covered a lot of ground! — but I want to ask one more thing. Looking beyond your own work, of all the work currently going on in the anti-aging research field, what excites you most? What do you think has the most promise?

João Pedro:
The finding that rapamycin can extend lifespan in middle-aged mice was exciting and arguably the most important in anti-aging research of the past 2-3 years. Because rapamycin has serious side-effects, however, it’s not suitable as an anti-aging treatment, but this discovery could open the door for development of other less harmful drugs targeting the same pathway. There’s also very exciting progress being done in areas that could have a great impact on anti-aging research, like regenerative medicine, synthetic biology and genomics. The recent progress in genomics has been amazing and the fact we’ll soon be able to sequence virtually everyone’s genome is tantalizing. The work on reprogramming of adult cells to become pluripotent stem cells has also been remarkable.

Ben:
It’s certainly an exciting time to be working in biology. So much amazing scientific progress, year after year – and then, such an ongoing stream of reminders as to how the (even more amazing) subtlety and complexity of biological networks repeatedly eludes our attempts at simplified understanding.

For instance, the fact that CR extends maximum lifespan is amazing, and it’s great that we have the technology to isolate some of the underlying genetic factors like the sirtuins, Mrpl12, and so forth. But then Sirtris’s attempts to commercially exploit our understanding of the sirtuin pathway for life extension pharmaceuticals, have been fairly problematic so far. And like you say, the rapamycin discovery was incredible, but side-effects due to various complex biological networks mean it’s not practically usable in humans, though it gives some interesting directions for research.

On the one hand the complexity of living systems is incredibly intellectually interesting; and the other hand, it means that we (or our AI systems) may have to become pretty damn good at understanding complex self-organizing systems to have that Methuselarity. And yet, in spite of all this complexity (and of course powered by the complex biological networks in our brains and our society, and the complex digital information networks we’ve created), we are making progress, year on year…

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    bengoertzel
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    The quest to end aging and prolong human life indefinitely has stepped outside the worlds of religion and science fiction, and is now the stuff of serious science. The number of research biologists consciously and intently working toward this once-outrageous-sounding goal increases year after year. Exactly when we’ll get to the end goal remains quite unclear – but the steady march of progress in that direction has become unmistakeable.

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