In today’s podcast we talked with Prof. Joao Pedro De Magalhaes (@jpsenescence) about some exciting topics ranging from his current work, to philosophy and science fiction. Among other things we talked about cryonics, transhumanism, the need for a “Sputnik moment” in longevity research, fish oil and rilmenidine for longevity, inflammaging, and cellular reprogramming.
It was a pleasure to talk with Pedro because we both share very similar views about aging, longevity, transhumanism and other topics.
Short CV - Joao Pedro De Magalhaes
Prof de Magalhaes graduated in Microbiology in 1999 from the Escola Superior de Biotecnologia in his hometown of Porto, Portugal, and then obtained a PhD in 2004 from the University of Namur in Belgium. Following a postdoc with genomics pioneer Prof George Church at Harvard Medical School, in 2008 Prof de Magalhaes joined the University of Liverpool and, in 2022, he was recruited to the University of Birmingham where he leads the Genomics of Ageing and Rejuvenation Lab (http://rejuvenomicslab.com/). His lab studies the ageing process and how we can manipulate it to fend off age-related diseases and improve human health. Prof de Magalhaes has authored over 100 publications and given over 100 invited talks, including three TEDx talks. He is also CSO of YouthBio Therapeutics, a US-based biotech company developing rejuvenation gene therapies.
Pedro is the author of the widely read senescence.info https://jp.senescence.info/ webpage and of the @jpsenescence twitter account.
The reputation problem for aging research
“If you tell people that you're trying to discover a drug for Alzheimer's, everybody loves it. If you say you're discovering a drug for cancer, everybody loves it. If you say you're discovering a drug for aging, people ask why? I mean, why you want to do that? ... it generates a lot of questions and even opposition, not by everyone, but for some people.” (Joao Pedro De Magalhaes)
Many people think that lifespan extension is science fiction. However, even that is an understatement of the problem because lifespan extension is rarely portrayed at all or positively portrayed even within sci-fi literature. Pedro and I discussed possible reasons for this. One idea is that the finality of death is so ingrained and terrifying that people refuse to think about anything concerning death as a coping mechanism. This will include even positive things like lifespan extension. It is absurd to consider a future where interstellar travel is possible but not radical lifespan extension. Yet this is what is often portrayed in science fiction!
We spent the first half of the podcast digging into the psychology and philosophy of aging research and trying to figure out what will make people believe that aging research is necessary; and that we will be able to slow aging in the not-too-distant future. Even if you are not interested in aging research I think the first part is worth a listen. One of our key insights was that people who are afraid of living longer, and who are afraid of technology, now, will most likely change their opinion once the technology matures. The great majority will be keen to use longevity therapies and only a fringe minority will continue to oppose the technology:
“So, I mean, if you ask people, hey, if I have a little pill that will make you live 200 years in good health, if you ask around, there's a lot of people going to say, no, I don't want that. But trust me, if that were introduced, and people started taking that pill and being healthier, everybody would want it. That's just, you know, inevitable.“ (Joao Pedro De Magalhaes)
Transhumanism and radical lifespan extension communities
Transhumanism describes a philosophy that contends we should transcend or improve human nature using technology. The idea is that human biology is flawed and that life could be much improved if we embraced technology to improve ourselves. Such technology includes but is not limited to things like artificial intelligence, lifespan extending treatments or cryonics.
“Radical” lifespan extension tries to differentiate itself from the modest goals of regular biogerontology. Advocates for radical lifespan extension believe that we need to extend human lifespan significantly, by decades or centuries, and that we may be on the cusp of success. In the podcast we discuss that while we might not be that close to this goal, the idea of radical lifespan extension itself is worthwhile. There is no reason why we cannot have ambitious dreams.
We also discussed the recent history of the online longevity movement. Many communities, back when bulletin boards, forums and mailing lists were popular, catered to transhumanists and life extensionists of the early days, including the now renamed “Immortality Institute”.
We can consider Vitadao as a continuation and extension of these old communities. It is attractive not only to transhumanists, but also crypto enthusiasts, web3 developers, investors, scientists, the general public etc. If you want to be part of this community, here is the link to their discord:
The idea of cryopreservation is to freeze one’s body right after death, for a non-zero chance of revival in the future. The hope is that future technology might be able to reverse the damage that led to death and also reverse the damage induced by cryopreservation. Although this is a tall order the likelihood is probably not zero, even if it is very low. In that way cryonics is a modern, transhumanist Pascal’s wager.
In the meantime, while we research cryobiology with the long term goal of preserving whole organisms, every little advance we make can be used to improve the storage of donated organs, hence benefiting humanity now and not just in the future.
This is the same idea as with radical lifespan extension. One can have an ambition long term goal that is reached through reasonable intermediate steps.
Repurposing of drugs
Even though many drugs are approved for one condition they could also work for another. However, in many cases no one has tested this yet. In the process of repurposing, also called repositioning, scientists are trying to find new uses for such old drugs. If we want to cast our net wider, we can also consider drugs that passed phase II or phase III trials but were not pursued for whatever reasons. These drugs will also have a decent amount of safety data in humans and will be backed by good efficacy data.
One strategy Pedro uses to find drugs that could be repositioned is based on gene expression signatures. The idea is to find drugs that show similar gene expression to that of caloric restriction. This strategy allowed him to pinpoint allantoin as a potentially life extending drug and later rilmenidine, an approved, although rarely used, anti-hypertensive drug, that might operate via a similar mechanism (Calvert et al. 2016, Bennett et al. 2023).
Immunology of aging, inflammaging and the power of meta-analysis
In his meta-analysis of transcriptomic data Pedro found that in mammals many genes change with age (Palmers et al. 2021). Some highlights include decreased expression of mitochondrial genes, perhaps consistent with decreased mitochondrial biogenesis and function, but also increased expression of pro-inflammatory factors.
“The preponderance of inflammatory and stress response genes [over-expressed with aging] is reminiscent of the inflammageing hypothesis , which argues that ageing is caused by steadily failing responses to stress, in particular responses to the increased antigenic load that comes with age.”
In this context we also discussed new single sequencing data, suggesting age-related infiltration by immune cells and Pedro’s work in a new company focusing on reprogramming. One of the ideas that we discussed was that immune cells are generally a good target for rejuvenation because they are accessible and affect many processes in the body.
The Interventions Testing Program (ITP)
The NIA’s Interventions Testing Program is a large mouse study that seeks to rigorously test which compounds extend mouse lifespan. Anyone can propose a compound to be tested and during the podcast I suggested to Pedro he could submit rilmenidine to the ITP. If you want to learn more about this important study, we had a thorough discussion of the ITP in my podcast with Rich Miller.
Further reading – aging as a software design flaw
A controversial take we discussed during the podcast was Pedro’s idea that aging has programmatic features. I will not go too much into details here and the interested reader can check out his paper (de Magalhães 2023) and the below tweetorial, as well as our podcast discussion.
Bennett, Dominic F., et al. "Rilmenidine extends lifespan and healthspan in Caenorhabditis elegans via a nischarin I1‐imidazoline receptor." Aging Cell 22.2 (2023): e13774.
Calvert, Shaun, et al. "A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans." Aging cell 15.2 (2016): 256-266.
de Magalhães, João Pedro. "Ageing as a software design flaw." Genome Biology 24.1 (2023): 51.
The new webpage of the Immortality Institute: https://www.longecity.org/forum/
Pedro’s linkedin: https://www.linkedin.com/in/joaopedrodemagalhaes/