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Status: Idea List, written after attending the LBF
There are many theories of aging and ideas about how to go about solving it. The following is a list of the “minimum viable experiments”, the simplest experiments I could come up with, that would give the most information informing future strategy. I believe the core questions in the field boil down to:
- Does a new body rejuvenate an old head?
- Experiment 1: Parabiotic head transplant
- Where is the true age stored?
- Experiment 2: Cell rejuvenation in a regenerated extracellular environment
- Bonus: Cryonics
- Bonus: What would the post-aging world look like?
- Coordinate
Does a new body rejuvenate an old head?
The simplest approach to solving aging is “Theseus Ship” style: just replace the parts that are broken. Given that all the parts of the body work together (they share an immune system and other interactions), the more you replace at once, the easier this becomes. The extreme of that idea is just to replace the entire lower body with a new one - performing a head or full internal organ transplant. This has never been done before, but there are good proposals to resolve some of the largest ethical and technical challenges using existing technology.
But this rests on a big assumption: what if the brain itself gets old, and a new body does not help? Then we would have to concentrate all effort on solving brain aging first, either through a similar approach (replacing parts of the brain bit by bit) or through rejuvenation.
Experiment 1: Parabiotic head transplant
- Create sheep twins (or another mammal where we have good surgery knowledge, like dogs)
- Freeze one of the blastomas
- Let one of the sheep grow up
- Wait
- Grow the other sheep
- Now transplant the head of the old sheep onto the young one (either replace it fully or just attach to the side), or transplant large parts of the internal organs from young to old
- Ideally, do a lifespan study, but given complications during the surgery that might be tricky (the longest attached head to a dog survived for only 29 days). Biomarkers of neurodegeneration could work instead.
This will give you a definite answer as to whether or not replacement is worth pursuing.
Never let your sense of morals get in the way of doing what's right.
Where is the true age stored?
If body replacement does not rejuvenate the brain, and brain replacement looks too hard, we have to fix the body “in prod” - let the body repair / replace / rejuvenate broken parts itself. This is already somewhat possible: we can restore the pattern of which parts of a chromosome are accessible (which is related to what a cell is doing) from old to young. This is called partial reprogramming and in itself a very promising technology. The big problem: if you stop the intervention, the cells tend to revert back to that old pattern. but where is that information coming from? How does a rejuvenated cell know that it should take on the pattern of an old cell?
Some possibilities (not all likely, but from first principles):
- Inside:
- It’s all adaption: the old pattern isn’t the cause of aging, but a response to damage. So if you have an old cell and you only change the epigenome without fixing the damage, it will always revert back in order to fight it
- In the DNA: maybe mutations influence the epigenome more than we think
- something, something histones
- Outside:
- Again, adoption: it’s just a response to living in a damaged body. This could be due to
- just waste products (old mice blood causes young mice to age, maybe a rejuvenated cell in an old body is affected by the same mechanism)
- chronic inflammation / an old immune system / SASP or SASP-like things produce signals that enter the local or global environment and tell the cell to become old
- a damaged extracellular matrix. The ECM has large signaling effects on cells, some of them probably causing cells to undergo aging
- or signaling: the true age is stored outside the cell and sent to it
- collective cell patterns: bioelectricity and gap junctions influence cell differentiation and general morphology - maybe old organs have an older ion gradient pattern. More generally the information could be stored decentrally: cells always want to fit in, so a rejuvenated cell will talk to its neighbors till it has assumed the pattern of the collective (which will be old, because reprogramming works only on a few percent of all cells).
- Whole body decentral “clock syncing” - maybe the information (the true system “time”) is synced by an organism-wide decision process: rejuvenated cells revert because they listen to all other cells emitting their internal time through something like exosomes
- top-down “clock syncing”: the same as the last, but the signals from the hypothalamus are taken more / only into account
There is one experiment which could give you a very definite answer to large parts of this:
Experiment 2: Cell rejuvenation in a regenerated extracellular environment
- Cut off the limb of an old organism
- Either use a naturally regenerating species or cause limb regeneration
- Wait for it to grow back
- Study the ECM of the new limb: does it have lots of crosslinks? Scar tissue?
- Study the new cells: are they rejuvenated?
If you get a young ECM and young cells you can just wait: do the cells revert back to the age of the whole organism or will there always be an age difference between limb and body, even at death? This way you can get a definite answer on whether or not aging is local or global.
If you get an organism with old cells everywhere and new ECM you can
- Partially reprogram the organism at many points, including the limb
If the cells do NOT revert back in the new ECM (assuming the ECM ages slower than the reversion of the cell epigenome) you know it’s the ECM that is the culprit of aging.
If we can somehow not create a hybrid organism with new and old ECM by relying on internal regeneration, we can just steal the limb from a clone, but that makes it harder to rule out immune system as a culprit
This experiment sounds simple, but I do think we could get a definite answer to the fundamental question of how local aging is (does it come from cells, the ECM, organs or top-down?) - and therefore rule out at least half of all aging theories.
Bonus: Cryonics
If neither of these experiments work, cryonics is a great alternative.
I’ve written down my thoughts here:
Bonus: What would the post-aging world look like?
(this is more meta, but if your not a scientist, please work on this)
Longevity science is highly underfunded. People in the field usually point to deathism as the answer: the collective ancestral learned helplessness that leads to the widespread belief that “death is good”. After all, the oldest myth we have, the Epic of Gilgamesh, is a story of a guy who wants to fight aging and gives up.
This is a fair explanation, but in practice, I don’t actually find people opposing my views after 5 minutes of conversation: the core arguments against vitalism seem to be weakly held and not thought through by anyone.
There is one question though that is unanswered: what if we succeed? The number of people who have seriously pondered this question throughout all of history seems to be less than a dozen, or at least I can’t find any writeups. Like, what would it actually entail if we stopped aging within the next few decades? How do we structure society? Life live, find love, have children? What about financial, political, educational, and spiritual institutions?
Rigorously and academically answering this question could go a long way toward taking away people’s fear of immortality. I’m thinking of creating a journal around this.
Coordinate
Now it’s time to work on any of these or suggest your own MVE. Let’s go about this strategically, so send me your ideas and give feedback, so we can create a single resource that collects all core “cruxes” of aging science.