In this week’s newsletter

✅ Introduction to Episode 18 with Dr. Aubrey de Grey. ✅ Detailed show notes. ✅ Getting to Robust Mouse Rejuvenation in three years.  ✅ ”I believe that things are going to move extremely fast from that point.” ✅ COVID provides a precedent for accelerating approvals.

I'll keep the introduction brief this time. First of all Aubrey de Grey hardly needs one.

But I also want to draw your attention to our show notes below. I always aim to make them as detailed as possible, and for this episode, they serve as a gateway to much of the recent past in longevity and geroscience.

Alright, without further ado - here’s a quick overview of our interview with Aubrey.

The longevity revolution is coming

🚀 We could be three years from a global war on aging. In this in-depth interview on the LEVITY podcast Aubrey de Grey explains how the experiments his LEV Foundation is conducting now could trigger a revolution in longevity research.

⌛ During our two hour conversation we also cover:

✅ His predictions for reaching longevity escape velocity by the late 2030s.

✅ What he would change about Bryan Johnson's longevity algorithm.

✅ Why AI won't solve aging without proper experimental data.

✅ How Demis Hassabis is the smartest person Aubrey's ever met.

✅ His involvement in designing the XPRIZE Healthspan competition.

✅ His rebuttal to the ”replacement strategy” approach.

You can watch the episode below or listen to it on Spotify, Apple Podcasts or other places, like PocketCasts. Please follow, like and subscribe! 🙏🏼 This will boost our chances of reaching a bigger audience.

A detailed overview of the episode

Introduction and background

• Dr. Aubrey de Grey is introduced as an internationally recognized biomedical gerontologist who devised strategies for engineered negligible senescence - a comprehensive set of methods to rejuvenate the human body.

• He co-founded multiple influential organizations including Methuselah Foundation, SENS Research Foundation, and most recently the LEV Foundation.

• Peter Ottsjö (host, and author of Evigt Ung) compares Aubrey to Jürgen Klopp (former Liverpool football manager) who turned ”doubters into believers”.

• Aubrey responds: ”I see it more as I've turned people who are despairing into people who are not despairing... people who already have no doubts that aging is a bad thing and it would be rather good if we could fix it into people who no longer believe that actually we can't fix it, and now believe that we have a chance.”

• Aubrey shares that he's proud of both inspiring people and his scientific contributions.

The LEV Foundation and Robust Mouse Rejuvenation

• Aubrey explains his key scientific contribution from 25 years ago: realizing that repairing aging (taking people back to a younger biological age) would be easier to achieve medically than slowing aging down.

• He explains the ”divide and conquer” strategy with two phases:

  1. Developing different damage repair approaches for different types of damage.

  2. Putting those approaches together in the same individual simultaneously.

• Aubrey notes that unlike engineering with man-made machines, the human body has unknown complexities that make combining therapies challenging.

• His first two organizations (Methuselah Foundation and SENS Research Foundation) focused on developing individual interventions, particularly the most difficult ones that were being neglected by others due to ”short-termism constraints”.

• The LEV Foundation was established to focus on combining multiple therapies in mice to achieve synergistic effects.

• The foundation's first study began in February 2023, costing approximately $3.5 million.

• The study uses 1,000 mice (500 males, 500 females) divided into 10 treatment groups.

• The interventions being tested include:

  1. Rapamycin (a calorie restriction mimetic, given continuously).

  2. Telomerase gene therapy (one-time treatment).

  3. Senolytic therapy (targeting senescent cells).

  4. Young blood stem cells (bone marrow transplant from young mice).

Current results of the mouse rejuvenation studies

• Aubrey shares the results so far: ”We haven't completely knocked it out of the park, but we've definitely shown that these things do have additive effects.”

• The combined effect is about 4 months of postponement of health problems and death, similar to what calorie restriction achieves starting at the same age.

• Results differ between males and females, with females showing clearer additive effects.

• Males showed more complex responses with some treatment groups initially doing worse than controls, but eventually catching up.

• The group receiving all four interventions is doing better than or at least as well as any other group.

• Aubrey explains they worked with Ichor Life Sciences (one of their spin-out companies led by Kelsey Moody) to conduct the experiments.

Path to Robust Mouse Rejuvenation (RMR)

• Aubrey defines Robust Mouse Rejuvenation (RMR) as achieving 12 months of delay in health decline and death in mice (vs. the current record of 4 months).

• He believes there's a 50-50 chance of achieving RMR in about three years with sufficient funding.

• Future studies will include more interventions (7-8 damage repair interventions), including partial reprogramming.

• Aubrey states that achieving RMR will trigger rapid changes in expert opinion, influencer messaging, and public attitudes toward aging.

• ”I believe that things are going to move extremely fast from that point. First thing that's going to happen is experts are going to come out and start saying, 'Yeah, you know what, we're in a new world'.”

• He predicts influencers will advocate for ”a proper war on aging” (like ”the response to COVID but on steroids”).

• This will lead to public awakening from the ”pro-aging trance” and government action.

Longevity Escape Velocity predictions

• Aubrey maintains his prediction of a 50-50 chance of reaching Longevity Escape Velocity (LEV) in 12-15 years (by the late 2030s).

• He notes this timeline hasn't slipped in the past 10 years, unlike the previous decade, due to greater acceptance of his damage repair approach and increased funding.

• Regarding regulatory hurdles, he believes COVID provides a precedent for accelerating approvals during a major health crisis.

• "We know that there was a full order of magnitude reduction in the time it took from discovery to dissemination of a vaccine, relative to what had ever been done before. I think we'll probably see more than an order of magnitude in this case."

The Replacement strategy debate

• Peter brings up Mark Hamalainen and the Longevity Biotech Fellowship's focus on the ”replacement strategy” rather than Aubrey's SENS approach.

• Aubrey acknowledges his friendship with Mark (whom he seed funded) and explains his position on replacement approaches:

On organ and body replacement:

• Aubrey believes organ replacement will be necessary initially as a version 1.0 of LEV where some rejuvenation methods don't work well.

• He discusses whole body replacement approaches:

  1. Using bodies from deceased donors (mentioned work by Sergio Canavero).

  2. Growing brainless bodies (similar to anencephalic development)

• Technically challenging aspects include:

  • Growing bodies outside the womb.

  • Natural growth timeframes that can't be accelerated.

  • Astronomical costs to grow replacement bodies.

  • Questions about brain rejuvenation effects.

On brain replacement and Jean Hebert's work:

• Jean Hebert (author of Replacing Aging and neurologist at ARPA-H who Mark works for) is skeptical about brain rejuvenation through molecular/cellular means.

• Hebert's approach to brain replacement focuses on relocating information within the brain.

• Aubrey explains the challenges: "Only information that's actually retrieved into consciousness is actually relocated by effectively being rewritten in the new place."

• Aubrey believes the molecular/cellular approach can work for the brain with proper development.

Summary of disagreement with replacement strategy:

• Aubrey thinks Mark is "too optimistic about how you do replacement, especially of the brain, and also unreasonably pessimistic about the molecular and cellular approach."

• Mark's concern about having ”zero aging interventions” is addressed by Aubrey: "We know that it's a divide and conquer strategy. Of course, we don't have them yet! Because there are some bits that we don't yet and we haven't yet developed. But there are some bits that we have."

Advanced bioengineering discussion

• Peter asks about ”advanced bioengineering” mentioned by Mark's group.

• Aubrey explains this relates to the need for more granular understanding of aging and better tools.

• He notes it's not a fundamental difference in approach but a question of degree - how much understanding is necessary before interventions can work.

• "They're certainly not saying that it's impossible because you would have to understand the system completely. They accept, they agree with me that there's a certain amount of understanding that would be enough. It's just that they currently feel that that amount is greater than I think it is."

Debate with Peter Fedichev on epigenetic noise

• Peter brings up the debate between Aubrey and Peter Fedichev.

• Aubrey explains Fedichev's position is not a different theory of aging but rather about the importance of epigenetic noise.

• This concept relates to the randomization of epigenetic information that determines which genes are turned on/off.

• Fedichev argues epigenetic noise plays a much bigger role in human aging than in laboratory mice.

• The controversial claim is that we can't fix this epigenetic noise because we would need an ”oracle” to know what the correct state should be.

• Aubrey's counterargument centers on partial reprogramming:

  • Partial reprogramming with Yamanaka factors can reverse the developmental clock without needing to know the ”correct” state.

  • He explains his concept of ”unaccessed informatic redundancy”.

  • Using a metaphor of liver cells, Aubrey explains how partial reprogramming could restore functionality without needing perfect information:

    • "This is bang up rejuvenation. This is what I believe is happening with partial reprogramming and it totally nullifies Peter's pessimism."

• Aubrey notes they've ”agreed to disagree” until more experiments provide definitive answers.

Evolutionary perspective on aging

• Patrick asks about aging as an evolved trait versus something evolution missed.

• Aubrey explains that even if aging existed because evolution ”wanted” it, that doesn't mean we shouldn't fight it.

• He supports the mainstream view that aging is a product of ”evolutionary neglect” (term from Leonard Hayflick) rather than evolutionary intent.

• Aging exists because some types of damage occur so slowly they don't harm us until after reproduction, so evolution didn't select for repair mechanisms.

• He explains antagonistic pleiotropy as a special case of evolutionary neglect - genes beneficial in early life and detrimental later weren't turned off because evolution ”couldn't be bothered”.

Artificial intelligence and longevity research

• Peter brings up Demis Hassabis (Nobel Prize winner, DeepMind founder) who predicted solving all diseases in 10-20 years.

• Aubrey's background was in AI research before biology.

• He's known Demis since his undergraduate days at Cambridge and calls him "the single smartest person I've ever met".

• Aubrey discusses AlphaGo's evolution from being trained on expert games to AlphaGo Zero which started only with rules.

• He explains the challenge with AI in aging research is different types of data:

  • We have abundant omics data (genomes, epigenomes, transcriptomes).

  • We lack data on the effect of interventions on longevity, especially combination interventions.

  • ”In the case of aging, you've got lots of different types of data you might lean on... but one type of data... that we care about, which is longevity... we just don't have a fraction of the data we need.”

• Regarding Sam Altman's view that AI will tell us what experiments to do:

  • ”Sam says, 'Yeah, what's going to happen is the AI is going to tell us what experiments to do, and we'll do them, and we'll feed the data back and so on.' And he's right. That is what's going to happen. But the AI has to start somewhere.”

• Aubrey argues we need to do experiments now to give AI a starting point, not wait for AI to solve everything.

• He mentions that some wealthy longevity proponents are resting on their laurels, believing AI will solve everything:

  • "Sam appears to be one of those people right now. Not, as I understand it, giving any more money to Retro [Bio]."

  • Similar situation with Eric Verdin, whose funding for experiments similar to LEV Foundation's was withdrawn because the funder decided ”AI would do it all for us”.

XPRIZE Healthspan competition

• Aubrey reveals how he has his ”fingerprints all over” the XPRIZE Healthspan.

• He explains the term ”healthspan” is used for marketing purposes, but it's actually a rejuvenation prize.

• The prize criteria: achieve a 10-20 year reduction in biological age of a reasonably sized cohort of people with interventions administered for maximum one year.

• Aubrey and Peter Diamandis (XPRIZE founder) had been discussing a longevity prize for 15+ years.

• Sergey Young (investor) provided initial funding ($500,000) for the design phase.

• Aubrey was heavily involved in the early stages and scientific design, though he's taken a backseat as the prize moved to funding and marketing stages.

• He supports the focus on measuring functional outcomes (cognitive, muscle, and immune function) rather than relying solely on biomarkers:

  • "We should be focusing entirely on function... the acid test has to be on people who are already going downhill... and who therefore can be measurably rejuvenated at the level of what they can do."

Special Economic Zones and regulatory innovation

• Aubrey discusses Special Economic Zones as one approach to faster progress:

  • Mentions Próspera on Roatan island (Honduras) which focuses on biomedical innovations.

  • Notes these zones tend to exist in politically unstable areas (Prospera is under threat from the current Honduran government).

• He highlights legislative progress in Montana, which passed a law allowing access to drugs that have passed Phase 1 safety trials (not just for terminally ill patients).

• This effort was spearheaded by the Alliance for Longevity Initiatives (A4LI), which Aubrey seed funded.

• Several US senators and representatives have formed a longevity caucus.

Views on Bryan Johnson's approach

• Asked what algorithm he would write for Bryan Johnson (who spends $2M/year on personal longevity interventions), Aubrey says:

  • ”I would put three quarters of my $2 million a year that he's spending into research.”

  • He believes individual efforts can only modestly extend lifespan, while research funding could push back the ”glass ceiling”.

  • ”I would recognize that however much I do with what can be done today, even if I have an MRI machine in my house and things like that, I'm only going to extend my own healthy lifespan or total lifespan by a very modest amount. And the only way I'm going to transcend that glass ceiling is by taking advantage of advances that happen in the meantime.”

• Aubrey considers Johnson a ”net positive for the movement” because he's ”utterly fearless” about sharing what he's doing.

• But he suggests Johnson knows his approach isn't maximally rational but ”can't help himself”.

Future outlook and book recommendations

• When asked what excites him most, Aubrey focuses on RMR:

  • ”I'm excited about getting to RMR. I think that we are genuinely within close striking distance of achieving this threshold of a year of postponement of mouse lifespan. I'm absolutely certain that once that is achieved, my job is done.”

• Book recommendations:

  1. Ending Aging (his own book) - still relevant though technology options have expanded

  2. Lifespan: Why We Age – and Why We Don't Have To by David Sinclair.

  3. Methuselah's Zoo by Steven Austad - provides excellent perspective from a zoologist with deep understanding of aging across species.

  4. Replacing Aging by Jean Hebert - highlights alternative approaches to rejuvenation not covered elsewhere.

Additional mentions throughout the conversation

• David Sinclair - Harvard professor, author of Lifespan (mentioned regarding the ”information theory of aging” and how he had to wait longer to publish due to academic constraints).

• Michael and Irina Conboy - Researchers who demonstrated rejuvenation through parabiosis.

• Tom Rando - Associated with parabiosis research.

• María Blasco - Researcher who demonstrated benefits of telomerase overexpression.

• Yuri Deigin - CEO of YouthBio, commented on Aubrey's results, advocates for partial reprogramming.

• Brian Kennedy, Matt Kaeberlein, Eric Verdin, Nir Barzilai - Leading aging researchers mentioned regarding expert consensus.

• Richard Cutler - Pioneering gerontologist who proposed the "dysdifferentiation theory of aging" over 40 years ago.

• Robin Holliday - Researcher who coined the term ”epimutation” for epigenetic noise.

• Josh Mitteldorf - Proponent of the view that aging is a product of evolutionary intent.

• Chip Wilson - Founder of Lululemon, FSHD patient, and funder of XPRIZE Healthspan.

• Geoffrey Hinton - AI pioneer and Nobel laureate mentioned in the context of neural network revival.

• John Jumper - Nobel Prize winner for AlphaFold.

• Andrew Brack - Works at ARPA-H, oversees the PROSPR program.