✅ The LEVITY podcast. ✅ The very ambitious roadmap to solve aging. ✅ A foundation model for biology. ✅ Beating Bryan Johnson on a budget. ✅ Nick Bostrom’s new book. ✅ Longevity escape velocity in 2029 says Ray Kurzweil.

Before we begin: it’s been two months since my last newsletter. I am sorry about that. And also not sorry about that! Why? Well, the reason behind the delay is that LEVITY is evolving.

In addition to being a newsletter it will soon also be a podcast. The LEVITY podcast is a joint effort between me and philosopher Patrick Linden, the author of the extraordinary book The Case Against Death.

We are both extremely excited about this and our aim is to launch the podcast this spring. We’ve recorded the first few episodes and already have an amazing line-up of guests.

This means, however, that much of what I’d planned to feature in this newsletter now will migrate to the podcast. Meanwhile the newsletter will continue - but probably in a somewhat different costume. To be completely honest I’m still in the process of figuring all of this out.

As a result, there may be an even longer pause before the next newsletter arrives. Patrick and I are juggling research, recording, editing, and publishing single-handedly, a demanding but rewarding endeavor that must take precedence for now.

In the meantime, here’s a short teaser!

Why should you follow LEVITY? Well, to learn about the desirability and coming possibility of extending human lifespan - not just incrementally as we have already achieved in recent history, but indefinitely.

I might write about wearables, biomarkers, drugs, aging as a disease, dementia, weight lifting, fasting-mimicking diets, weight loss medication, alchemy*, death apologism (and the remedies for that particular affliction), supplements, partial reprogramming and on and on.

All of those are interesting, but it’s important not to lose track of the north star - solving aging entirely.

* Alchemy is not science of course, but very much part of longevity history.

Can we reach that elusive faint spot in the sky? Can we engineer our own biology to escape from death? What is the plan?

These are questions Nathan Cheng and Mark Hamalainen - cofounders of the Longevity Biotech Fellowship - have spent a lot of time thinking about recently. First they discovered that there was no answer. There is no plan. At least no concrete one, with clear steps and well defined and specific technological objectives.

It's commonly noted that significant barriers exist between different fields of medical research, such as cancer and dementia. Despite the underlying causes of these diseases sharing many similarities, specialized researchers are incentivized to remain within their specific fields, following well defined paths established by academic, government, publication and funding institutions. They are reluctant to venture beyond their established domains.

The field of longevity, geroscience, biogerontology or whatever you want to call it, is much the same. Everyone has their own little island, working on their own little problem, with little regard for the bigger picture. And many of those associated with the longevity field is not even interested in the grand challenge of solving aging, but focus only on healthspan (which is, sadly, more socially acceptable even in the scientific community).

I must admit that when I wrote my book I relied heavily on the famous Hallmarks of Aging paper that came out in 2013 (which itself was derivative of Aubrey de Grey’s strategies for negligible senescence, SENS).

There were several reasons for this; it’s a nice categorization system for the existing aging biology literature; there are efforts being made to adress each hallmark; both the Hallmarks paper and SENS have been longstanding guiding frameworks for the field.

Aubrey de Grey often says that what is needed is a divide and conquer approach: to combat each and everyone hallmark in order to defeat aging. There’s also this idea of a domino effect whereby if you manage to take care of one hallmark others will fall as well.

But to Nathan Cheng and Mark Hamalainen this strategy is, as Mark tells me, ”myopic, scattershot, and generally deficient in strategic planning”. Which of the hallmarks is most important to work on? Why do we think they are comprehensive? Which intervention modalities holds the most promise? Are resources being allocated in an optimal way? If there are answers to these questions they’re not always very convincing. Not to mention that while the hallmarks provides an overview, they’re light on details.

So Nathan and Mark set out to develop the Longevity Acceleration Roadmap - A technical plan to solve aging. It’s different to anything I’ve seen in this space before.

It is, to quote directly from the roadmap, ”direct, specific and actionable”. It has ”well defined objectives with key technical milestones” and ”projects with time and cost estimates + how to join / support them”.

The lack of such a plan has made it hard to attract talent to the field, to get investors to pay attention and to allocate resources where they’re most needed.

The technology paths advocated in the Longevity Acceleration Roadmap to reach the ageless era are nothing if not groundbreaking. Or, to quote Mark, ”contrarian to the status quo in biotechnology and pharmaceutical research”.

I’ll briefly mention them here, but just know that I’ll spend a lot more time this year to talk about them in more detail. We’ll actually have Mark and Nathan on the LEVITY podcast in a few months time.

The Longevity Acceleration Roadmap has three primary pillars, but I’ll add a fourth (and, to make it very confusing, place it first) that is actually not in the roadmap.

1. The boring buy time pillar.

2. The very very exciting buy time pillar.

3. The solve aging without actually knowing much about aging pillar.

4. The solve aging by total understanding and gaining full engineering control of biology pillar.

Let’s go through them, one by one.

The boring buy time pillar. This is what most of geroscience and the longevity movement is preoccupied with at the moment. The idea is to develop drugs or other interventions that modulate biological processes to slow aging.

Labeling this pursuit as boring is a bit harsh and misguided (but fun). Yet it's important to acknowledge that, so far, these efforts haven't extended human lifespans. Currently, there are no anti-aging drugs on the market, and it's debatable whether this strategy alone can fully address the complexities of aging. ”They are in fact based on reductionist theories of aging that have repeatedly failed to be validated”, Mark says.

Nathan and Mark suggest that these ”low hanging fruits” of ”traditional pharma” might extend human lives by about ten years at best* - perhaps an extraordinary achievement, yet trivial in the broader context of our aspirations for longevity.

* From my perspective, it's far too early to quantify the potential lifespan extension this approach may offer. I remain more optimistic, despite acknowledging that there are types of aging-related damage we have yet to understand how to counteract.

But this strategy also presents a paradox. While it promises additional years of life, it currently dominates allocation of resources - time, money, and expertise - to the detriment of alternative methods that could offer much greater potential impact towards solving aging.

2. The very very exciting buy time pillar. To keep it short: put life on pause until we figure out to how to commandeer biology well enough to both solve aging and how to push play on life again. This is called biostasis and one of the most known methods is cryopreservation.

Biostasis remains an area of research that's both woefully underfunded and widely misunderstood. However, Emil Kendziorra, CEO of the cryonics company Tomorrow, likes to point out that biostasis represents a tangible action you and I can take against aging today. Indeed, it's currently the only option available. I've taken the leap myself and signed up for cryopreservation.

I'll delve into the details of the cryopreservation process, explore my decision to halt my 'cryocrastination' (the notion that signing up for cryonics can always wait), and address the profound questions this field raises about the boundaries between life and death in a later newsletter. We’ll also try to have Emil on the LEVITY podcast soon.

3. The solve aging without actually knowing much about aging pillar. We already transplant organs, let’s replace the whole goddamn thing (by ”goddamn thing” I mean your whole aged body with a cloned young one). We don’t really need to know much about aging biology to do this. It’s called the replacement strategy.

I’ll just mention this matter of factly now and do a deep dive at a later date.

Step 1: Grow a non sentient (no functioning brain) clone genetically identical to the recipient.

Step 2: Replace your body with the young cloned transplant.

Step 3: Gradually replace the recipient’s brain (to keep identity, personality, memory and all of the subjective stuff that makes you feel like you intact).

Before you say that this sounds completely preposterous you should grab a copy of Jean Hebert’s book, Replacing Aging. Or wait for LEVITY to explain it to you in way more detail.

4. The solve aging by total understanding and gaining full engineering control of biology pillar. If we understand biology and develop tools to engineer it the only theoretical limits are, really, the laws of physics. And they do not imply any upper limit. Evolution has already produced species that live for thousands of years.

In a very first principles way of thinking Nathan and Mark notes: ”Entropy can be kept at bay while free energy is available, curing aging doesn’t break the laws of physics”. In this statement, they echo the sentiments of Richard Feynman. Long ago, he told us that:

”It is one of the most remarkable things that in all of the biological sciences there is no clue as to the necessity of death. If you say we want to make perpetual motion, we have discovered enough laws as we studied physics to see that it is either absolutely impossible or else the laws are wrong. But there is nothing in biology yet found that indicates the inevitability of death. This suggests to me that it is not at all inevitable, and that it is only a matter of time before the biologists discover what it is that is causing us the trouble and that that terrible universal disease or temporariness of the human’s body will be cured.”

With regards to engineering there is rapid progress being made in computational biology, synthetic biology, artificial intelligence and - maybe to a lesser degree - nanotechnology. But we are still talking about a granular understanding of one of the most complex processes we know of. I mean, have you seen this?

Sure, we can peek into a cell and make a (partial) list of the stuff in it. We have some understanding of the ”what” and ”where”. But we are a little clueless about the ”how” and ”when”.

A useful analogy might be photography. We've become adept at capturing and analyzing biological snapshots. But just as a single frame can hint at a film's storyline without revealing its full narrative, our static images of biology fall short of conveying the dynamic intricacy at play.

The challenge of recording the entire ”film” of biological processes and understanding each minute detail is significantly more daunting. Biological systems operate at a staggering pace, with components interacting in complex ways and evolving over time. A single cell alone can house thousands of molecular varieties - DNA, RNA, proteins, lipids, metabolites - all participating in a myriad of biochemical reactions and signaling pathways. The multiplicity of states and interactions among these components causes complexity to skyrocket exponentially.

Yet, if we aim to engineer a solution to aging, a comprehensive understanding becomes indispensable. And beyond grasping the full spectrum of biological dynamics, we'll also need to master the means of precise intervention.

I’ll use a few example technical objectives from the roadmap just to give you a sense of what is being proposed:

”Full Aging Characterization

The ‘Hallmarks of Aging’ is a categorization of the gerontology literature, not an empirical analysis or even a theory of aging. We need a Human Genome Project (times 100-1000X) level effort to fully characterize aging, not more piecemeal small studies.

Full Cell State Capture

Just as the shift from bulk to single cell samples in transcriptomics revolutionized biology - we need multiomic analysis of single cells to deepen our understanding and train models of biology.

Full Cell Simulation

The iteration time of wet lab experimentation, particularly lifespan studies, is too slow. We need to aggressively develop and validate more computational models and design tools at every layer of abstraction.

Cell State Mapping

AKA cellular reprogramming, this technology attempts to reproduce the aging reset that happens between generations during reproduction, but for somatic cells. While unlikely to be a full solution to aging, it is a promising tool.

Full Body Gene Delivery

Huge outstanding technical challenges in gene delivery including immunogenicity, biodistribution, payload size and genotoxicity need solutions - or creative alternative approaches to bypass them.

Exhaustive Comparative Bio

Nature has produced mechanisms for extreme longevity in multiple branches of the evolutionary tree - and in multiple cases these have been demonstrated to be transferable between species. Yet little of this diversity has been studied.

Damage Repair

While cells can repair, recycle, dilute or excrete most day-to-day ’damage’ - long lived structures such as the ECM have slow or no turnover mechanisms. Some damage accumulates slowly enough that natural selection didn’t bother to produce a repair mechanism for it. We need new and synthetic biological solutions to repair or replace these.

Engineered Cells

To solve many complex aspects of aging such as cancer or ECM damage, we’ll need to program cells with precise logic. CAR-T offers an early example of the promise of this technique, but more complex engineering will be necessary.”

While Nathan and Mark concede that there are ”too many unknown unknowns” to calculate the cost of this endeavor the ”optimistic napkin math by experts” is $1 Trillion per year over 25 years. It would be like, as they put it, multiple parallel Apollo level projects.

All the more reason, then, to also pursue biostasis and replacement - both of which could be thoroughly examined and developed for a fraction of the cost of the advanced bioengineering path.

These are, as noted, bold ideas and something we will soon explore in more detail. Later this year we will have both Mark and Nathan on the LEVITY podcast for a roadmap deep dive.

News from around the longevity and health space.

Insilico is one of the most interesting companies in the world right now.

I mentioned Rubedo (with its name taken from alchemy - rubedo was considered the fourth and final major stage in alchemist’s magnum opus) in my book. Two years later, they’ve taken some major steps.

While very difficult to reach a comprehensive understanding of aging, recent breakthroughs in artificial intelligence might speed things up. French startup Bioptimus are working on what seems like a very ambitious project: a foundation model for biology.

I have serious reservations about the value of so-called commercial biological age tests. Similarly, I'm skeptical that Bryan Johnson's costly regimen offers any significant benefits over well-established health practices, such as, you know, not eating crap and exercising regularly. Although I generally don't pay much attention to reports like the one below, I do find them somewhat entertaining.

Worth your time

Last year I began developing some ideas for a novel. It would take place in a not that far off future where artificial intelligence have solved most of our problems except, maybe, for the lack of a sense of purpose many of us might feel in such a world.

Nick Bostrom was of course way ahead of me (but then again he’s way ahead of most people). His latest book is called Deep Utopia: Life and Meaning in a Solved World. Am I reading it? You bet I am. Is it any good? Of course it is. And one is also reminded of how funny Bostrom can be.

What I’ve been up to lately.

I recently attended the release party for Sigrid Therapeutics’ supplement at the Royal Swedish Academy of Engineering Sciences in Stockholm.

Sigrid is a Swedish healthtech startup that has developed an ”enzyme trap” for digestive enzymes such as α-amylase (breaks down complex carbohydrates) and lipase (breaks down dietary fats).

This ”trap” is actually a micron-sized silica particle with ”tailored porosity”. These nanometre sized pores in the particle traps the digestive enzymes which, according to Sigrid, helps stabilize blood sugar, promotes a sense of fullness after meals and may also assist with weight management.

In addition to that co-founder and CEO Sana Alajmovic has quite the backstory, which I wrote about in a big feature for Ny Teknik.

I purchased a bottle of their supplement, Gluco Stabilizer, at the event (I may share my experiences with it in a future update). With the current surge in interest for weight loss solutions, Sigrid, though not producing a traditional drug (their approach is mechanical rather than chemical), is tapping into an expansive market.

Ray Kurzweil says to Joe Rogan we’ll reach longevity escape velocity in 2029. That’s quite a tall order (for the reasons mentioned above). But then again it’s sometimes unwise to bet against the predictions of this man.

Hey, you’ve made it all the way here! Thank you so much for reading! 🫶🏼